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1afa39f1ecc2f5f5b96267e2f6f53fa7465244b9	nice	New generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) for cardiac imaging in people with suspected or known coronary artery disease in whom imaging is difficult with earlier generation CT scanners	New generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) for cardiac imaging in people with suspected or known coronary artery disease in whom imaging is difficult with earlier generation CT scanners Evidence-based recommendations on new generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) for cardiac imaging in people with suspected or known coronary artery disease in whom imaging is difficult with earlier generation CT scanners. # Recommendations New generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) are recommended as an option for first-line imaging of the coronary arteries in people with suspected stable coronary artery disease (with an estimated likelihood of coronary artery disease of 10 to 29%) in whom imaging with earlier generation CT scanners is difficult. New generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) are recommended as an option for first-line evaluation of disease progression, to establish the need for revascularisation, in people with known coronary artery disease in whom imaging with earlier generation CT scanners is difficult. CT scanning might not be necessary in situations in which immediate revascularisation is being considered. Service providers, working with commissioners and cardiac networks, should take into account the benefits of access to new generation cardiac CT scanners for use in the circumstances described in 1.1 and 1.2. They should do this when selecting CT scanners as part of medium term asset planning.# The technologies Aquilion ONE (Toshiba Medical Systems), Brilliance iCT (Philips Healthcare), Discovery CT750 HD (GE Healthcare) and Somatom Definition Flash (Siemens AG Healthcare) are new generation computed tomography (CT) scanners that have a variety of enhancements compared with earlier generation CT scanners. These enhancements, which vary among the four scanners, may include better temporal resolution, better spatial resolution and shorter acquisition times. It is claimed that the new generation CT scanners can better detect coronary artery stenosis in people with suspected or known coronary artery disease in whom imaging is difficult with earlier generation CT scanners. The scope of the evaluation was limited to these four new generation scanners that, although technically different, were viewed as being broadly comparable for cardiac imaging. The acquisition cost of these scanners varies depending on local discounts but estimates range from £900,000 to £1.1 million.# Clinical need and practice # The problem addressed The primary focus of this evaluation is to assess the diagnostic accuracy, effect on patient outcomes and cost effectiveness of specific new generation cardiac CT scanners in: Adults (18 years or older) with suspected coronary artery disease in whom imaging with earlier generation CT is difficult (see section 3.4) and with a 10 to 29% pre-test likelihood of coronary artery disease Adults (18 years or older) with known coronary artery disease in whom imaging with earlier generation CT is difficult (see section 3.4) and in whom revascularisation is being considered. # The condition Coronary artery disease is characterised by narrowing of the coronary artery. It is most commonly caused by atherosclerotic deposits of fibrous and fatty tissue, leading to a reduction in blood flow to the heart, and angina. The NICE guideline on recent-onset chest pain of cardiac origin defines significant coronary artery disease as 70% or greater diameter stenosis of at least one major epicardial artery segment or 50% or greater diameter stenosis in the left main coronary artery. The NICE guideline on recent-onset chest pain, before the 2016 update, recommended CT coronary angiography and invasive coronary angiography to assess arteries and identify significant stenosis. The guideline recommended using a 64-slice (or above) CT scanner in people with an estimated likelihood of coronary artery disease of 10 to 29% and a calcium score of 1 to 400. Conditions that make CT imaging difficult are: -besity high levels of coronary calcium (calcium score above 400) arrhythmias high heart rates that cannot be lowered pharmacologically (after consultation with clinical experts, the definition of high heart rate was broadened from over 70 beats per minute as stated in the scope, to over 65 beats per minute, in order to avoid loss of potential data) stents previous bypass grafts. # Prevalence and risk In the UK an estimated 2.6 million people have coronary artery disease, with 2 million having symptoms of angina. In 2007, coronary artery disease was estimated to have caused 91,000 deaths in the UK (approximately 19% of deaths in men and 13% in women). It was not possible to estimate the number of people with cardiac disease in whom imaging would be difficult. However, a range of data sources can be used to give an estimate of this population in whom coronary imaging would be difficult. According to the Health Survey for England (2009), 22% of men and 24% of women are obese. Hospital Episode Statistics show that there were a total of 313,765 unique patients with arrhythmias, stent implantations and bypass grafts in England in the last 3 years. If the estimated number of people with a heart rate of over 65 beats per minute and intolerance to beta blockers is included, the number of people in England in whom imaging with earlier generation CT scanners is difficult can be estimated to range from 10 million to 18 million. # The diagnostic and care pathways The care pathway for this evaluation was taken from the NICE guideline on recent-onset chest pain, before the 2016 update. The key elements (for the imaging strategy) from the guideline's care pathway are as follows: People with chest pain who have an estimated likelihood of coronary artery disease of 10 to 29% should be offered calcium scoring, followed by CT coronary angiography if the calcium score is between 1 and 400. A calcium score above 400 indicates that imaging using earlier generation CT scanners would be difficult, and the guideline recommends invasive coronary angiography if this is considered clinically appropriate. People with chest pain who have an estimated likelihood of coronary artery disease of 30 to 60% should be offered non-invasive functional imaging for myocardial ischaemia. People with chest pain who have an estimated likelihood of coronary artery disease of 61 to 90% should be offered invasive coronary angiography if clinically appropriate and if coronary revascularisation is being considered. The key options for non-invasive functional imaging are: myocardial perfusion scintigraphy with single photon emission computed tomography or stress echocardiography or first-pass contrast-enhanced magnetic resonance perfusion or magnetic resonance imaging for stress-induced wall motion abnormalities. People diagnosed as having significant coronary artery disease should be initially managed as having stable angina. Management of these people was assumed to follow the recommendations from the NICE guideline on managing stable angina when modelling patient outcomes and cost effectiveness.# The diagnostic tests # The individual tests: Aquilion One, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash New generation cardiac CT scanners identified and included in this evaluation have advanced technical features that address drawbacks associated with earlier generation CT scanners. These drawbacks include spatial resolution, low contrast detection, noise artefacts and higher levels of radiation. The scanners included in this evaluation are Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash. ## Aquilion ONE The Aquilion ONE is a CT scanner with 320 × 0.5 mm detector rows giving z-axis coverage of 160 mm. This specification allows the imaging of whole organs in a single non-helical rotation, for example, an image of the heart can be captured within a single heartbeat. As well as reducing the examination time, the radiation and the contrast dose are also reduced. ## Brilliance iCT The Brilliance iCT is a CT scanner with 128 × 0.625 mm detector rows providing total z-axis coverage of 80 mm. Each detector row is double sampled to increase spatial resolution. It is claimed that it can capture an image of the heart in two heart beats. ## Discovery CT750 HD The Discovery CT750 HD is a 64 × 0.625 mm detector dual-energy CT scanner. It has a single X-ray source that switches between two energy levels, allowing two data sets – high energy and low energy – to be acquired simultaneously. It uses a Gemstone detector that contributes to high image quality, and a prospectively gated axial scanning technique called SnapShot Pulse, which allows a complete picture of the heart to be captured in three or four 'snapshots' taken at precise table positions and timed to correspond to a specific phase of the cardiac cycle. ## Somatom Definition Flash The Somatom Definition Flash is a second-generation 64 × 0.6 mm detector dual-source CT scanner designed to provide high resolution images at a fast scanning speed with low-dose radiation. It has two X-ray tubes and two detector arrays mounted at 95° to each other. It has a maximum scan speed of 458 mm/s. Fast acquisition times may be of benefit for use with people who cannot remain still or who have difficulty holding their breath. The scanner also uses different strategies to reduce the radiation dose associated with imaging. # The comparator: invasive coronary angiography Because earlier generation CT scanners are not considered viable for imaging some people (see section 3.4), and it is this population that is of interest, the comparator is invasive coronary angiography. Invasive coronary angiography uses a contrast dye and X-rays to provide anatomical information about the degree of stenosis in the coronary arteries. A catheter is generally inserted into an artery in the groin or wrist and is moved up the aorta and into the coronary arteries. Once in place, the dye is injected through the catheter, and a rapid series of X-ray images is taken to show how the dye moves through the branches of the coronary arteries. Narrowing of the arteries will show up on the X-ray images. Invasive coronary angiography is considered the reference standard for providing anatomical information and defining the site and severity of coronary artery lesions. Some rare but serious complications include death, myocardial infarction, cerebrovascular accident, arrhythmia, vascular complications, allergic reaction to contrast media, haemodynamic complications and perforation of the heart chamber.# Outcomes The Diagnostics Advisory Committee (section 9) considered evidence from a number of sources (section 10). # How outcomes were assessed The assessment consisted of a systematic review of the evidence on clinical effectiveness for new generation cardiac CT scanners in people with known and suspected coronary artery disease in whom imaging is difficult. All studies included in the systematic review reported test accuracy data for people in whom imaging is difficult. Results were summarised by patient group (obese, high heart rate, high coronary calcium score and so on) and further stratified by unit of analysis (patient, artery, or arterial segment). For all included studies, the absolute numbers of true positive, false negative, false positive and true negative test results, as well as sensitivity and specificity values, with 95% confidence intervals (CIs), were presented. Modelling was undertaken to assess final patient outcomes and cost effectiveness. Diagnostic strategies themselves do not have direct implications for health-related quality of life. Therefore, a linked evidence approach to modelling was used to link intermediate outcomes (diagnostic accuracy of the tests) to treatment outcomes and hence quality-adjusted life year (QALY) gains. # Assessment of test accuracy Based on the data from the included studies, the External Assessment Group was able to deduce true positive, true negative, false positive and false negative rates for new generation cardiac CT scanners compared with invasive coronary angiography. Sensitivities and specificities were computed from meta-analysis (a bivariate summary receiver operating curve model). When the bivariate model could not be fitted because of the small number of relatively homogenous studies involved, the DerSimonian and Laird method for meta-analysis was used. Per-patient summary estimates were also used when possible. A summary of the data on the test performance of the scanners among the patient groups in whom imaging is difficult is given below. In all cases the studies were quite consistent and inter-study heterogeneity was low to moderate. ## People with obesity One study involving 125 participants reported 543 per segment data on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with obesity. Obesity was defined as having a body mass index (BMI) of 30 kg/m2 or above. The index test was Somatom Definition (a model predating the Somatom Definition Flash) and the reference test was invasive coronary angiography. The sensitivity was 90.4% (95% CI 83.8 to 94.9) and the specificity was found to be 92.1% (95% CI 89.1 to 94.5). ## People with high levels of coronary calcium Four studies reported on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with high levels of coronary calcium. The high calcium score threshold was set to above 400. Data were derived from 1,304 segments in 91 participants. The index test was Somatom Definition and the reference test was invasive coronary angiography. The sensitivity was 92.7% (95% CI 88.3 to 95.6) and the specificity was 90.6% (95% CI 80.6 to 95.8%). ## People with arrhythmia Five studies reported on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with arrhythmia. Data for 126 patients and 1,526 segments were obtained from the studies. For the patient data, sensitivity was 97.7% (95% CI 88.0 to 99.9) and specificity was 81.7% (95% CI 71.6 to 89.4). For the segment data, sensitivity was 87.4% (95% CI 68.3 to 95.7) and specificity was 96.0% (95% CI 91.2 to 98.2). ## People with a high heart rate Eight studies in total reported 24 data sets on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with a high heart rate. Five studies with 462 participants reported per-patient data. The pooled estimates of sensitivity and specificity, derived from these data using a bivariate model, were 97.7% (95% CI 93.2 to 99.3) and 86.3% (95% CI 80.2 to 90.7) respectively. Four studies reported data for 664 arteries. The pooled estimates of sensitivity and specificity, derived from these data using a bivariate model, were 93.7% (95% CI 87.8 to 96.9) and 92.4% (95% CI 83.3 to 96.8) respectively. All eight studies reported accuracy data by arterial segment (8,133 segments). The pooled estimates of sensitivity and specificity, derived from these data using a bivariate model, were 92.7% (95% CI 89.3 to 95.1) and 95.7% (95% CI 92.8 to 97.4) respectively. All eight studies used a threshold of vessel narrowing of at least 50% to define significant stenosis. Beta-blockers are normally prescribed to slow the heart rate for people with heart rates too high for scanning. Some people with high heart rates are intolerant to beta-blockers, which makes it difficult to image them with earlier generation CT scanners. However, no studies were identified on the accuracy of new generation cardiac CT scanners for the detection of coronary artery disease in people who are intolerant to beta-blockers. ## People with previous stent implants Seven studies reported ten data sets describing the accuracy of new generation cardiac CT scanners for the detection of coronary artery disease in people with previous stent implantation. Four studies reported per-patient data for 233 participants. The pooled estimates of sensitivity and specificity were 96.0% (95% CI 88.8 to 99.2) and 81.6% (95% CI 74.7 to 87.3) respectively. Six studies reported accuracy data by stent or stented lesion (n = 582). The pooled estimates of sensitivity and specificity were 93.6% (95% CI 86.1 to 97.2) and 91.0% (95% CI 87.3 to 93.7) respectively. # Clinical outcomes The modelling comprised five sub-models based on existing models to estimate the clinical outcomes of using new generation cardiac CT scanners. QALYs and costs in all five models were calculated and discounted at a rate of 3.5% for benefits and costs. These models are described below. ## Diagnostic model A diagnostic model was used to estimate the initial outcomes of treatment and initial diagnosis. This model was created through extending and linking the five sub-models. The primary measures of benefit used in this analysis were: the complication rate for invasive coronary angiography and revascularisation (myocardial infarction and stroke) the benefits associated with reduction in the incidence of cancer as a result of reduction in radiation dose morbidity and mortality from coronary artery disease. Using invasive coronary angiography as a comparator, three diagnostic strategies were evaluated. These strategies were: Invasive coronary angiography only: people in whom imaging is difficult had invasive coronary angiography only, which was assumed to be perfectly accurate. New generation cardiac CT scanner only: people in whom imaging is difficult had a new generation cardiac CT scan only; the accuracy of the scan was based on invasive coronary angiography as the reference standard. New generation cardiac CT scan plus invasive coronary angiography: cardiac CT was performed on everyone in whom imaging is difficult, and those with a positive scan then had invasive coronary angiography. No false positives could occur with this strategy because invasive coronary angiography was assumed to have perfect specificity. The clinical outcomes assessed for people with coronary artery disease were mortality, morbidity and the percentage of correct diagnostic classifications (true positives, false positives, true negatives, false negatives) associated with each of the three strategies. ## Healthy population model Using life tables, a healthy population model that only applied to people without coronary artery disease (true negatives and false positives) was used to predict mortality on the assumption that people with true negative and false positive test results do not differ from the average UK population. ## EUROPA model The EUROPA model modelled the progression of stable coronary artery disease by predicting cardiovascular events and mortality. Health-related quality of life estimates were assigned to each Markov state based on age, gender, baseline Canadian Cardiovascular Society classification and whether the person had undergone treatment. ## Stroke model The costs and outcomes of people who experienced a stroke because of initial invasive coronary angiography or revascularisation were modelled with a mortality model. Mortality rates were based on UK life tables and a relative risk of 2.5 to reflect the increased risk of mortality after a stroke. ## York radiation model The York Radiation Model estimated the impact of imaging in terms of radiation dose on cancer morbidity and mortality. This model was used as there is no direct evidence on radiation dose effects in the populations included in the scope. # Cost and cost effectiveness The models described above were also used to estimate the costs of the diagnostic tests and treatments people received for their initial conditions, and any subsequent related conditions that developed. Although there is some variation in the costs of the new generation cardiac CT scanners, the models assumed that each scanner cost £1 million. The comparator, invasive coronary angiography, was presumed to be perfectly accurate (a gold standard) and, despite a known increase in complication rate compared with CT, generated more QALY gains than CT. It was also more expensive than imaging with a new generation cardiac CT scanner. The incremental cost-effectiveness ratio (ICER) of invasive angiography when compared with new generation cardiac CT is significantly greater than the NICE cost-effectiveness threshold. In people with suspected coronary artery disease in whom imaging is difficult, the health economic analysis showed that, given a threshold of £20,000 per QALY gained, using new generation cardiac CT scanners instead of invasive coronary angiography is cost effective. The 'new generation CT scanner only' strategy was the most cost-effective strategy. The 'new generation CT scan plus invasive coronary angiography for those with positive CT scans' strategy delivered very small additional QALYS per patient (0.002) at a cost of £142. The ICER was £71,000 per QALY gained compared to the 'new generation CT scanner only' strategy. Similarly, relative to the 'new generation CT scanner only' strategy, 'invasive coronary angiography alone' also delivered a very small number of additional QALYS per patient (0.009) at a cost of £726 (ICER of £80,667 per QALY gained). In people with known coronary artery disease who are difficult to image, the most cost-effective strategy was 'new generation cardiac CT scan plus invasive coronary angiography' for those with positive CT scans. This strategy dominated (more effective and less costly) the 'invasive coronary angiography only' strategy, generating more QALYs per patient (0.022) at reduced cost. The 'new generation cardiac CT scan plus invasive coronary angiography' strategy was the most preferred strategy for this cohort. Although it generated a very small reduction in QALYs per patient (0.001), it yielded a relatively large reduction in cost (£443) (ICER £726,230 per QALY) relative to the 'new generation cardiac CT scan only'.# Considerations The scope assumed that Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash provided broadly similar benefits for people in whom imaging is difficult. The assessment was carried out on this basis. The Committee considered comments on the diagnostics assessment report from stakeholders about the equivalence of the four scanners. The Committee heard that the scanners use different technologies to gain image improvement and dose reduction, and that the different approaches may provide differential benefits depending on the reasons for imaging being difficult. For the purposes of this assessment, the Committee considered that it was reasonable to assume that each of the devices was capable of providing adequate imaging for all groups of people in whom imaging is difficult. Moreover, the Committee concluded that many people have combinations of conditions that lead to imaging difficulties and, therefore, it would not be optimal to specify use of any one particular device. Of the 24 test accuracy studies included in the diagnostics assessment report, 3 studies did not specify the model of the scanner used, 1 study used Somatom Definition Flash, 1 used Aquilion ONE and 19 used Somatom Definition (a model predating the Somatom Definition Flash). The manufacturer of the Discovery CT750 HD confirmed the CT750 HD had been used in a study in which the details of the scanner were not provided. Although test accuracy data exist for all of the systems considered, most studies did not stratify outcome reporting for the difficult-to-image subsets and thus the data could not be used in the assessment. The assessment was based on the 24 studies with stratified data. The Committee concluded that the evidence base for these technologies provided it with sufficient certainty for it to formulate recommendations. However, the Committee considered it important that manufacturers make available specific test accuracy data stratified by important patient subgroups, and noted that the current lack of such data made it difficult to make recommendations. The Committee noted that it would only make recommendations on the scanners included in the scope, although evidence from scanners other than the four being evaluated was included in the assessment. The Committee discussed the extent to which the usable test accuracy studies, particularly the studies of the older Somatom model, could be generalised across scanners. The Committee heard from the External Assessment Group that statistical tests of the test accuracy results of the different scanners showed the results were not heterogeneous and thus could be combined, and the Committee accepted this explanation. The Committee concluded that even though no usable data were available for Brilliance iCT, and one study each was available for Aquilion ONE, Discovery CT750 HD and Somatom Definition Flash, nevertheless it was reasonable for the Committee to make recommendations that applied to all four of the assessed scanners. The Committee considered whether all relevant studies had been included in the assessment. In response to comments from representatives of manufacturers about the inclusion of relevant studies, the External Assessment Group confirmed that the literature search was designed to be very sensitive and to maximise identification of papers containing test accuracy data for the groups of patients included in the scope. In addition, all manufacturers had been asked to provide relevant data. Unfortunately, most of the data provided by manufacturers could not be included because it did not contain test accuracy results stratified for the relevant populations for the assessment. The Committee acknowledged that the reference standard, invasive coronary angiography, although not 100% accurate in clinical practice, is an accepted reference standard for assessment of anatomic coronary disease. The high accuracy of CT when compared with angiography, coupled with the known inaccuracies of angiography, imply that CT may be even more effective and cost effective than the assessment indicated because it may be more accurate, and angiography less accurate, than modelled. The Committee acknowledged that from a patient perspective, a non-invasive cardiac diagnostic test is more appealing than invasive coronary angiography because of the greater morbidity and mortality risks associated with angiography. The External Assessment Group informed the Committee that the modelling had reflected this preference to some extent, because it included the increased morbidity and mortality resulting from invasive procedures as well as their associated costs. CT was found to be more cost effective than angiography because of the lower risk of these outcomes and the reduced costs associated with CT (reduced imaging costs and reduced downstream healthcare costs from dealing with complications), even though angiography had been assumed to be the more accurate test. The Committee considered how using new generation cardiac CT scanners for evaluating people with suspected coronary artery disease would fit in the context of the NICE guideline on recent-onset chest pain. The Committee concluded that the evidence presented indicated that new generation cardiac CT was more cost effective for people in whom imaging is difficult than proceeding directly to invasive angiography. The Committee noted that earlier generation CT scanners used for people in whom imaging is not difficult are even less expensive and have similar risks and benefits than the new generation scanners. CT could be more cost effective than angiography for all people presenting with chest pain and a pre-test likelihood of 10 to 29% of coronary artery disease. The NICE guideline on recent-onset chest pain, before the 2016 update, recommended calcium scoring to assess patients with an estimated likelihood of coronary artery disease of 10 to 29%, and varied its further imaging recommendations based on the calcium level. The value of calcium scoring was outside the scope of this evaluation and, thus, not explored further by the Committee. The Committee considered whether angiography after CT was needed for people with positive CT scans. The analysis showed that CT alone was more cost effective than CT with angiography for people with suspected coronary artery disease, but CT alone was not more cost effective for people with known coronary artery disease. For both groups, CT followed by invasive coronary angiography for those with positive CT scans was more cost effective than invasive coronary angiography alone. The Committee was informed that, in current practice, people who are expected to have revascularisation would usually have angiography either before or as a part of treatment, but that the rate of elective angiography was dropping. The Committee also heard that with time and additional clinician experience with CT angiography, it was likely that follow-up angiography solely for diagnostic purposes would become less frequent. A negative CT scan result would be sufficient to avoid angiography and often low-risk patients with a negative scan could be discharged from specialty care immediately. The Committee heard that if a CT scan result shows moderate stenosis (40 to 60%), then the patient usually proceeds to functional imaging, whereas for severe stenosis (80%), the patient would be offered invasive coronary angiography. The Committee was advised that having the option to diagnose with CT before proceeding to functional imaging and/or invasive coronary angiography would not affect the throughput of a cardiology department. The Committee considered whether it was appropriate to recommend CT scanning for people with known coronary artery disease in whom imaging was not difficult. However, evidence for this population had not been examined and no analysis had been undertaken. The Committee also considered whether it was appropriate to recommend CT scanning for people with suspected coronary artery disease who had prior likelihoods of coronary artery disease higher than 10 to 29%. The sensitivity analysis had shown that the use of new generation CT scanning is within NICE's standard levels of cost effectiveness compared with angiography for people in whom imaging is difficult and who have moderately higher than 29% pre-test probabilities of coronary artery disease. The Committee heard that immediate revascularisation was no longer considered the preferred practice in this population. However, because data for this population had not been examined, it was not possible to make a recommendation. The Committee concluded that, based on the results of the assessment carried out by the External Assessment Group, new generation cardiac CT scanners should be recommended for: first-line imaging of coronary arteries in people with suspected stable coronary artery disease whose estimated likelihood of coronary artery disease is 10 to 29%, and first-line evaluation of disease progression in people with known coronary artery disease in whom imaging is difficult. The Committee was informed that there are currently up to 40 new generation cardiac CT scanners being used in the NHS in England. The Committee considered that its recommendations would help optimise the use of the scanners that are currently in operation. The Committee acknowledged that the impact of its recommendations would support the further introduction of new generation cardiac CT scanners in the NHS over the next few years. The Committee considered if there were any specific equalities issues that would be relevant to this assessment, but none were raised.# Recommendations for further research The Diagnostics Advisory Committee has not made specific recommendations for further research. Nevertheless, the Committee recognised that there is uncertainty about a number of issues relating to the new generation cardiac CT scanners for the assessed population (for example, test accuracy in people with obesity and people with very high calcium scores) and that there is concern that angiography was not an accurate gold standard.# Review NICE has not set a specific time for review, but will monitor developments in the evidence base for the technologies to determine when a review would be appropriate. Andrew DillonChief ExecutiveJanuary 2012	{'Recommendations': 'New generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) are recommended as an option for first-line imaging of the coronary arteries in people with suspected stable coronary artery disease (with an estimated likelihood of coronary artery disease of 10\xa0to\xa029%) in whom imaging with earlier generation CT scanners is difficult.\n\nNew generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) are recommended as an option for first-line evaluation of disease progression, to establish the need for revascularisation, in people with known coronary artery disease in whom imaging with earlier generation CT scanners is difficult. CT scanning might not be necessary in situations in which immediate revascularisation is being considered.\n\nService providers, working with commissioners and cardiac networks, should take into account the benefits of access to new generation cardiac CT scanners for use in the circumstances described in 1.1 and 1.2. They should do this when selecting CT scanners as part of medium term asset planning.', 'The technologies': 'Aquilion ONE (Toshiba Medical Systems), Brilliance iCT (Philips Healthcare), Discovery CT750 HD (GE Healthcare) and Somatom Definition Flash (Siemens AG Healthcare) are new generation computed tomography (CT) scanners that have a variety of enhancements compared with earlier generation CT scanners. These enhancements, which vary among the four scanners, may include better temporal resolution, better spatial resolution and shorter acquisition times. It is claimed that the new generation CT scanners can better detect coronary artery stenosis in people with suspected or known coronary artery disease in whom imaging is difficult with earlier generation CT scanners. The scope of the evaluation was limited to these four new generation scanners that, although technically different, were viewed as being broadly comparable for cardiac imaging. The acquisition cost of these scanners varies depending on local discounts but estimates range from £900,000 to £1.1 million.', 'Clinical need and practice': "# The problem addressed\n\nThe primary focus of this evaluation is to assess the diagnostic accuracy, effect on patient outcomes and cost effectiveness of specific new generation cardiac CT scanners in:\n\nAdults (18 years or older) with suspected coronary artery disease in whom imaging with earlier generation CT is difficult (see section 3.4) and with a 10\xa0to\xa029% pre-test likelihood of coronary artery disease\n\nAdults (18 years or older) with known coronary artery disease in whom imaging with earlier generation CT is difficult (see section 3.4) and in whom revascularisation is being considered.\n\n# The condition\n\nCoronary artery disease is characterised by narrowing of the coronary artery. It is most commonly caused by atherosclerotic deposits of fibrous and fatty tissue, leading to a reduction in blood flow to the heart, and angina. The NICE guideline on recent-onset chest pain of cardiac origin defines significant coronary artery disease as 70% or greater diameter stenosis of at least one major epicardial artery segment or 50% or greater diameter stenosis in the left main coronary artery.\n\nThe NICE guideline on recent-onset chest pain, before the 2016 update, recommended CT coronary angiography and invasive coronary angiography to assess arteries and identify significant stenosis. The guideline recommended using a 64-slice (or above) CT scanner in people with an estimated likelihood of coronary artery disease of 10\xa0to\xa029% and a calcium score of 1\xa0to\xa0400.\n\nConditions that make CT imaging difficult are:\n\nobesity\n\nhigh levels of coronary calcium (calcium score above 400)\n\narrhythmias\n\nhigh heart rates that cannot be lowered pharmacologically (after consultation with clinical experts, the definition of high heart rate was broadened from over 70 beats per minute as stated in the scope, to over 65 beats per minute, in order to avoid loss of potential data)\n\nstents\n\nprevious bypass grafts.\n\n# Prevalence and risk\n\nIn the UK an estimated 2.6 million people have coronary artery disease, with 2 million having symptoms of angina. In 2007, coronary artery disease was estimated to have caused 91,000 deaths in the UK (approximately 19% of deaths in men and 13% in women).\n\nIt was not possible to estimate the number of people with cardiac disease in whom imaging would be difficult. However, a range of data sources can be used to give an estimate of this population in whom coronary imaging would be difficult. According to the Health Survey for England (2009), 22% of men and 24% of women are obese. Hospital Episode Statistics show that there were a total of 313,765 unique patients with arrhythmias, stent implantations and bypass grafts in England in the last 3 years. If the estimated number of people with a heart rate of over 65 beats per minute and intolerance to beta blockers is included, the number of people in England in whom imaging with earlier generation CT scanners is difficult can be estimated to range from 10 million to 18 million.\n\n# The diagnostic and care pathways\n\nThe care pathway for this evaluation was taken from the NICE guideline on recent-onset chest pain, before the 2016 update. The key elements (for the imaging strategy) from the guideline's care pathway are as follows:\n\nPeople with chest pain who have an estimated likelihood of coronary artery disease of 10\xa0to\xa029% should be offered calcium scoring, followed by CT coronary angiography if the calcium score is between 1 and 400. A calcium score above 400 indicates that imaging using earlier generation CT scanners would be difficult, and the guideline recommends invasive coronary angiography if this is considered clinically appropriate.\n\nPeople with chest pain who have an estimated likelihood of coronary artery disease of 30\xa0to\xa060% should be offered non-invasive functional imaging for myocardial ischaemia.\n\nPeople with chest pain who have an estimated likelihood of coronary artery disease of 61\xa0to\xa090% should be offered invasive coronary angiography if clinically appropriate and if coronary revascularisation is being considered.\n\nThe key options for non-invasive functional imaging are:\n\nmyocardial perfusion scintigraphy with single photon emission computed tomography or\n\nstress echocardiography or\n\nfirst-pass contrast-enhanced magnetic resonance perfusion or\n\nmagnetic resonance imaging for stress-induced wall motion abnormalities.\n\nPeople diagnosed as having significant coronary artery disease should be initially managed as having stable angina. Management of these people was assumed to follow the recommendations from the NICE guideline on managing stable angina when modelling patient outcomes and cost effectiveness.", 'The diagnostic tests': "# The individual tests: Aquilion One, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash\n\nNew generation cardiac CT scanners identified and included in this evaluation have advanced technical features that address drawbacks associated with earlier generation CT scanners. These drawbacks include spatial resolution, low contrast detection, noise artefacts and higher levels of radiation. The scanners included in this evaluation are Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash.\n\n## Aquilion ONE\n\nThe Aquilion ONE is a CT scanner with 320\xa0×\xa00.5\xa0mm detector rows giving z-axis coverage of 160\xa0mm. This specification allows the imaging of whole organs in a single non-helical rotation, for example, an image of the heart can be captured within a single heartbeat. As well as reducing the examination time, the radiation and the contrast dose are also reduced.\n\n## Brilliance iCT\n\nThe Brilliance iCT is a CT scanner with 128\xa0×\xa00.625\xa0mm detector rows providing total z-axis coverage of 80\xa0mm. Each detector row is double sampled to increase spatial resolution. It is claimed that it can capture an image of the heart in two heart beats.\n\n## Discovery CT750 HD\n\nThe Discovery CT750 HD is a 64\xa0×\xa00.625\xa0mm detector dual-energy CT scanner. It has a single X-ray source that switches between two energy levels, allowing two data sets – high energy and low energy – to be acquired simultaneously. It uses a Gemstone detector that contributes to high image quality, and a prospectively gated axial scanning technique called SnapShot Pulse, which allows a complete picture of the heart to be captured in three or four 'snapshots' taken at precise table positions and timed to correspond to a specific phase of the cardiac cycle.\n\n## Somatom Definition Flash\n\nThe Somatom Definition Flash is a second-generation 64\xa0×\xa00.6 mm detector dual-source CT scanner designed to provide high resolution images at a fast scanning speed with low-dose radiation. It has two X-ray tubes and two detector arrays mounted at 95° to each other. It has a maximum scan speed of 458\xa0mm/s. Fast acquisition times may be of benefit for use with people who cannot remain still or who have difficulty holding their breath. The scanner also uses different strategies to reduce the radiation dose associated with imaging.\n\n# The comparator: invasive coronary angiography\n\nBecause earlier generation CT scanners are not considered viable for imaging some people (see section 3.4), and it is this population that is of interest, the comparator is invasive coronary angiography. Invasive coronary angiography uses a contrast dye and X-rays to provide anatomical information about the degree of stenosis in the coronary arteries. A catheter is generally inserted into an artery in the groin or wrist and is moved up the aorta and into the coronary arteries. Once in place, the dye is injected through the catheter, and a rapid series of X-ray images is taken to show how the dye moves through the branches of the coronary arteries. Narrowing of the arteries will show up on the X-ray images.\n\nInvasive coronary angiography is considered the reference standard for providing anatomical information and defining the site and severity of coronary artery lesions. Some rare but serious complications include death, myocardial infarction, cerebrovascular accident, arrhythmia, vascular complications, allergic reaction to contrast media, haemodynamic complications and perforation of the heart chamber.", 'Outcomes': "The Diagnostics Advisory Committee (section 9) considered evidence from a number of sources (section 10).\n\n# How outcomes were assessed\n\nThe assessment consisted of a systematic review of the evidence on clinical effectiveness for new generation cardiac CT scanners in people with known and suspected coronary artery disease in whom imaging is difficult.\n\nAll studies included in the systematic review reported test accuracy data for people in whom imaging is difficult. Results were summarised by patient group (obese, high heart rate, high coronary calcium score and so on) and further stratified by unit of analysis (patient, artery, or arterial segment). For all included studies, the absolute numbers of true positive, false negative, false positive and true negative test results, as well as sensitivity and specificity values, with 95% confidence intervals (CIs), were presented.\n\nModelling was undertaken to assess final patient outcomes and cost effectiveness. Diagnostic strategies themselves do not have direct implications for health-related quality of life. Therefore, a linked evidence approach to modelling was used to link intermediate outcomes (diagnostic accuracy of the tests) to treatment outcomes and hence quality-adjusted life year (QALY) gains.\n\n# Assessment of test accuracy\n\nBased on the data from the included studies, the External Assessment Group was able to deduce true positive, true negative, false positive and false negative rates for new generation cardiac CT scanners compared with invasive coronary angiography. Sensitivities and specificities were computed from meta-analysis (a bivariate summary receiver operating curve [SROC] model). When the bivariate model could not be fitted because of the small number of relatively homogenous studies involved, the DerSimonian and Laird method for meta-analysis was used. Per-patient summary estimates were also used when possible. A summary of the data on the test performance of the scanners among the patient groups in whom imaging is difficult is given below. In all cases the studies were quite consistent and inter-study heterogeneity was low to moderate.\n\n## People with obesity\n\nOne study involving 125 participants reported 543 per segment data on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with obesity. Obesity was defined as having a body mass index (BMI) of 30\xa0kg/m2 or above. The index test was Somatom Definition (a model predating the Somatom Definition Flash) and the reference test was invasive coronary angiography. The sensitivity was 90.4% (95% CI 83.8 to 94.9) and the specificity was found to be 92.1% (95% CI 89.1 to 94.5).\n\n## People with high levels of coronary calcium\n\nFour studies reported on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with high levels of coronary calcium. The high calcium score threshold was set to above 400. Data were derived from 1,304 segments in 91 participants. The index test was Somatom Definition and the reference test was invasive coronary angiography. The sensitivity was 92.7% (95% CI 88.3 to 95.6) and the specificity was 90.6% (95% CI 80.6 to 95.8%).\n\n## People with arrhythmia\n\nFive studies reported on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with arrhythmia. Data for 126 patients and 1,526 segments were obtained from the studies. For the patient data, sensitivity was 97.7% (95% CI 88.0 to 99.9) and specificity was 81.7% (95% CI 71.6 to 89.4). For the segment data, sensitivity was 87.4% (95% CI 68.3 to 95.7) and specificity was 96.0% (95% CI 91.2 to 98.2).\n\n## People with a high heart rate\n\nEight studies in total reported 24 data sets on the performance of new generation cardiac CT scanners in detecting coronary artery disease in people with a high heart rate. Five studies with 462 participants reported per-patient data. The pooled estimates of sensitivity and specificity, derived from these data using a bivariate model, were 97.7% (95% CI 93.2 to 99.3) and 86.3% (95% CI 80.2 to 90.7) respectively. Four studies reported data for 664 arteries. The pooled estimates of sensitivity and specificity, derived from these data using a bivariate model, were 93.7% (95% CI 87.8 to 96.9) and 92.4% (95% CI 83.3 to 96.8) respectively. All eight studies reported accuracy data by arterial segment (8,133 segments). The pooled estimates of sensitivity and specificity, derived from these data using a bivariate model, were 92.7% (95% CI 89.3 to 95.1) and 95.7% (95% CI 92.8 to 97.4) respectively. All eight studies used a threshold of vessel narrowing of at least 50% to define significant stenosis.\n\nBeta-blockers are normally prescribed to slow the heart rate for people with heart rates too high for scanning. Some people with high heart rates are intolerant to beta-blockers, which makes it difficult to image them with earlier generation CT scanners. However, no studies were identified on the accuracy of new generation cardiac CT scanners for the detection of coronary artery disease in people who are intolerant to beta-blockers.\n\n## People with previous stent implants\n\nSeven studies reported ten data sets describing the accuracy of new generation cardiac CT scanners for the detection of coronary artery disease in people with previous stent implantation. Four studies reported per-patient data for 233 participants. The pooled estimates of sensitivity and specificity were 96.0% (95% CI 88.8 to 99.2) and 81.6% (95% CI 74.7 to 87.3) respectively. Six studies reported accuracy data by stent or stented lesion (n = 582). The pooled estimates of sensitivity and specificity were 93.6% (95% CI 86.1 to 97.2) and 91.0% (95% CI 87.3 to 93.7) respectively.\n\n# Clinical outcomes\n\nThe modelling comprised five sub-models based on existing models to estimate the clinical outcomes of using new generation cardiac CT scanners. QALYs and costs in all five models were calculated and discounted at a rate of 3.5% for benefits and costs. These models are described below.\n\n## Diagnostic model\n\nA diagnostic model was used to estimate the initial outcomes of treatment and initial diagnosis. This model was created through extending and linking the five sub-models. The primary measures of benefit used in this analysis were:\n\nthe complication rate for invasive coronary angiography and revascularisation (myocardial infarction and stroke)\n\nthe benefits associated with reduction in the incidence of cancer as a result of reduction in radiation dose\n\nmorbidity and mortality from coronary artery disease.\n\nUsing invasive coronary angiography as a comparator, three diagnostic strategies were evaluated. These strategies were:\n\nInvasive coronary angiography only: people in whom imaging is difficult had invasive coronary angiography only, which was assumed to be perfectly accurate.\n\nNew generation cardiac CT scanner only: people in whom imaging is difficult had a new generation cardiac CT scan only; the accuracy of the scan was based on invasive coronary angiography as the reference standard.\n\nNew generation cardiac CT scan plus invasive coronary angiography: cardiac CT was performed on everyone in whom imaging is difficult, and those with a positive scan then had invasive coronary angiography. No false positives could occur with this strategy because invasive coronary angiography was assumed to have perfect specificity.\n\nThe clinical outcomes assessed for people with coronary artery disease were mortality, morbidity and the percentage of correct diagnostic classifications (true positives, false positives, true negatives, false negatives) associated with each of the three strategies.\n\n## Healthy population model\n\nUsing life tables, a healthy population model that only applied to people without coronary artery disease (true negatives and false positives) was used to predict mortality on the assumption that people with true negative and false positive test results do not differ from the average UK population.\n\n## EUROPA model\n\nThe EUROPA model modelled the progression of stable coronary artery disease by predicting cardiovascular events and mortality. Health-related quality of life estimates were assigned to each Markov state based on age, gender, baseline Canadian Cardiovascular Society classification and whether the person had undergone treatment.\n\n## Stroke model\n\nThe costs and outcomes of people who experienced a stroke because of initial invasive coronary angiography or revascularisation were modelled with a mortality model. Mortality rates were based on UK life tables and a relative risk of 2.5 to reflect the increased risk of mortality after a stroke.\n\n## York radiation model\n\nThe York Radiation Model estimated the impact of imaging in terms of radiation dose on cancer morbidity and mortality. This model was used as there is no direct evidence on radiation dose effects in the populations included in the scope.\n\n# Cost and cost effectiveness\n\nThe models described above were also used to estimate the costs of the diagnostic tests and treatments people received for their initial conditions, and any subsequent related conditions that developed. Although there is some variation in the costs of the new generation cardiac CT scanners, the models assumed that each scanner cost £1\xa0million.\n\nThe comparator, invasive coronary angiography, was presumed to be perfectly accurate (a gold standard) and, despite a known increase in complication rate compared with CT, generated more QALY gains than CT. It was also more expensive than imaging with a new generation cardiac CT scanner. The incremental cost-effectiveness ratio (ICER) of invasive angiography when compared with new generation cardiac CT is significantly greater than the NICE cost-effectiveness threshold.\n\nIn people with suspected coronary artery disease in whom imaging is difficult, the health economic analysis showed that, given a threshold of £20,000 per QALY gained, using new generation cardiac CT scanners instead of invasive coronary angiography is cost effective. The 'new generation CT scanner only' strategy was the most cost-effective strategy. The 'new generation CT scan plus invasive coronary angiography for those with positive CT scans' strategy delivered very small additional QALYS per patient (0.002) at a cost of £142. The ICER was £71,000 per QALY gained compared to the 'new generation CT scanner only' strategy. Similarly, relative to the 'new generation CT scanner only' strategy, 'invasive coronary angiography alone' also delivered a very small number of additional QALYS per patient (0.009) at a cost of £726 (ICER of £80,667 per QALY gained).\n\nIn people with known coronary artery disease who are difficult to image, the most cost-effective strategy was 'new generation cardiac CT scan plus invasive coronary angiography' for those with positive CT scans. This strategy dominated (more effective and less costly) the 'invasive coronary angiography only' strategy, generating more QALYs per patient (0.022) at reduced cost. The 'new generation cardiac CT scan plus invasive coronary angiography' strategy was the most preferred strategy for this cohort. Although it generated a very small reduction in QALYs per patient (0.001), it yielded a relatively large reduction in cost (£443) (ICER £726,230 per QALY) relative to the 'new generation cardiac CT scan only'.", 'Considerations': "The scope assumed that Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash provided broadly similar benefits for people in whom imaging is difficult. The assessment was carried out on this basis. The Committee considered comments on the diagnostics assessment report from stakeholders about the equivalence of the four scanners. The Committee heard that the scanners use different technologies to gain image improvement and dose reduction, and that the different approaches may provide differential benefits depending on the reasons for imaging being difficult. For the purposes of this assessment, the Committee considered that it was reasonable to assume that each of the devices was capable of providing adequate imaging for all groups of people in whom imaging is difficult. Moreover, the Committee concluded that many people have combinations of conditions that lead to imaging difficulties and, therefore, it would not be optimal to specify use of any one particular device.\n\nOf the 24 test accuracy studies included in the diagnostics assessment report, 3 studies did not specify the model of the scanner used, 1 study used Somatom Definition Flash, 1 used Aquilion ONE and 19 used Somatom Definition (a model predating the Somatom Definition Flash). The manufacturer of the Discovery CT750 HD confirmed the CT750 HD had been used in a study in which the details of the scanner were not provided. Although test accuracy data exist for all of the systems considered, most studies did not stratify outcome reporting for the difficult-to-image subsets and thus the data could not be used in the assessment. The assessment was based on the 24 studies with stratified data. The Committee concluded that the evidence base for these technologies provided it with sufficient certainty for it to formulate recommendations. However, the Committee considered it important that manufacturers make available specific test accuracy data stratified by important patient subgroups, and noted that the current lack of such data made it difficult to make recommendations. The Committee noted that it would only make recommendations on the scanners included in the scope, although evidence from scanners other than the four being evaluated was included in the assessment.\n\nThe Committee discussed the extent to which the usable test accuracy studies, particularly the studies of the older Somatom model, could be generalised across scanners. The Committee heard from the External Assessment Group that statistical tests of the test accuracy results of the different scanners showed the results were not heterogeneous and thus could be combined, and the Committee accepted this explanation.\n\nThe Committee concluded that even though no usable data were available for Brilliance iCT, and one study each was available for Aquilion ONE, Discovery CT750 HD and Somatom Definition Flash, nevertheless it was reasonable for the Committee to make recommendations that applied to all four of the assessed scanners.\n\nThe Committee considered whether all relevant studies had been included in the assessment. In response to comments from representatives of manufacturers about the inclusion of relevant studies, the External Assessment Group confirmed that the literature search was designed to be very sensitive and to maximise identification of papers containing test accuracy data for the groups of patients included in the scope. In addition, all manufacturers had been asked to provide relevant data. Unfortunately, most of the data provided by manufacturers could not be included because it did not contain test accuracy results stratified for the relevant populations for the assessment.\n\nThe Committee acknowledged that the reference standard, invasive coronary angiography, although not 100% accurate in clinical practice, is an accepted reference standard for assessment of anatomic coronary disease. The high accuracy of CT when compared with angiography, coupled with the known inaccuracies of angiography, imply that CT may be even more effective and cost effective than the assessment indicated because it may be more accurate, and angiography less accurate, than modelled.\n\nThe Committee acknowledged that from a patient perspective, a non-invasive cardiac diagnostic test is more appealing than invasive coronary angiography because of the greater morbidity and mortality risks associated with angiography. The External Assessment Group informed the Committee that the modelling had reflected this preference to some extent, because it included the increased morbidity and mortality resulting from invasive procedures as well as their associated costs. CT was found to be more cost effective than angiography because of the lower risk of these outcomes and the reduced costs associated with CT (reduced imaging costs and reduced downstream healthcare costs from dealing with complications), even though angiography had been assumed to be the more accurate test.\n\nThe Committee considered how using new generation cardiac CT scanners for evaluating people with suspected coronary artery disease would fit in the context of the NICE guideline on recent-onset chest pain. The Committee concluded that the evidence presented indicated that new generation cardiac CT was more cost effective for people in whom imaging is difficult than proceeding directly to invasive angiography. The Committee noted that earlier generation CT scanners used for people in whom imaging is not difficult are even less expensive and have similar risks and benefits than the new generation scanners. CT could be more cost effective than angiography for all people presenting with chest pain and a pre-test likelihood of 10\xa0to\xa029% of coronary artery disease.\n\nThe NICE guideline on recent-onset chest pain, before the 2016 update, recommended calcium scoring to assess patients with an estimated likelihood of coronary artery disease of 10\xa0to\xa029%, and varied its further imaging recommendations based on the calcium level. The value of calcium scoring was outside the scope of this evaluation and, thus, not explored further by the Committee.\n\nThe Committee considered whether angiography after CT was needed for people with positive CT scans. The analysis showed that CT alone was more cost effective than CT with angiography for people with suspected coronary artery disease, but CT alone was not more cost effective for people with known coronary artery disease. For both groups, CT followed by invasive coronary angiography for those with positive CT scans was more cost effective than invasive coronary angiography alone.\n\nThe Committee was informed that, in current practice, people who are expected to have revascularisation would usually have angiography either before or as a part of treatment, but that the rate of elective angiography was dropping. The Committee also heard that with time and additional clinician experience with CT angiography, it was likely that follow-up angiography solely for diagnostic purposes would become less frequent. A negative CT scan result would be sufficient to avoid angiography and often low-risk patients with a negative scan could be discharged from specialty care immediately. The Committee heard that if a CT scan result shows moderate stenosis (40\xa0to\xa060%), then the patient usually proceeds to functional imaging, whereas for severe stenosis (80%), the patient would be offered invasive coronary angiography. The Committee was advised that having the option to diagnose with CT before proceeding to functional imaging and/or invasive coronary angiography would not affect the throughput of a cardiology department.\n\nThe Committee considered whether it was appropriate to recommend CT scanning for people with known coronary artery disease in whom imaging was not difficult. However, evidence for this population had not been examined and no analysis had been undertaken.\n\nThe Committee also considered whether it was appropriate to recommend CT scanning for people with suspected coronary artery disease who had prior likelihoods of coronary artery disease higher than 10\xa0to\xa029%. The sensitivity analysis had shown that the use of new generation CT scanning is within NICE's standard levels of cost effectiveness compared with angiography for people in whom imaging is difficult and who have moderately higher than 29% pre-test probabilities of coronary artery disease. The Committee heard that immediate revascularisation was no longer considered the preferred practice in this population. However, because data for this population had not been examined, it was not possible to make a recommendation.\n\nThe Committee concluded that, based on the results of the assessment carried out by the External Assessment Group, new generation cardiac CT scanners should be recommended for:\n\nfirst-line imaging of coronary arteries in people with suspected stable coronary artery disease whose estimated likelihood of coronary artery disease is 10\xa0to\xa029%, and\n\nfirst-line evaluation of disease progression in people with known coronary artery disease in whom imaging is difficult.\n\nThe Committee was informed that there are currently up to 40 new generation cardiac CT scanners being used in the NHS in England. The Committee considered that its recommendations would help optimise the use of the scanners that are currently in operation. The Committee acknowledged that the impact of its recommendations would support the further introduction of new generation cardiac CT scanners in the NHS over the next few years.\n\nThe Committee considered if there were any specific equalities issues that would be relevant to this assessment, but none were raised.", 'Recommendations for further research': 'The Diagnostics Advisory Committee has not made specific recommendations for further research. Nevertheless, the Committee recognised that there is uncertainty about a number of issues relating to the new generation cardiac CT scanners for the assessed population (for example, test accuracy in people with obesity and people with very high calcium scores) and that there is concern that angiography was not an accurate gold standard.', 'Review': 'NICE has not set a specific time for review, but will monitor developments in the evidence base for the technologies to determine when a review would be appropriate.\n\nAndrew DillonChief ExecutiveJanuary 2012'}	https://www.nice.org.uk/guidance/dg3	Evidence-based recommendations on new generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) for cardiac imaging in people with suspected or known coronary artery disease in whom imaging is difficult with earlier generation CT scanners.
272c95100a9e9b8c99957a81d8c8e03258d8159f	nice	Air pollution: outdoor air quality and health	Air pollution: outdoor air quality and health This guideline covers road-traffic-related air pollution and its links to ill health. It aims to improve air quality and so prevent a range of health conditions and deaths. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Planning Include air pollution in 'plan making' by all tiers of local government, in line with the Department for Communities and Local Government's National Planning Policy Framework. This includes county, district and unitary authorities, as well as regional bodies and transport authorities. The Local Plan and other strategic planning processes (such as the core strategy, local transport plan, environment and health and wellbeing strategies) should include zero- and low-emission travel, for example cycling and walking (see the section on walking and cycling and NICE's guideline on physical activity: walking and cycling). Other strategies for zero- and low-emission travel could include: Providing charge points for electric vehicles in workplaces, commercial developments and residential areas. Supporting car sharing schemes or car clubs. When 'plan making' consider: siting and designing new buildings, facilities and estates to reduce the need for motorised travel minimising the exposure of vulnerable groups to air pollution by not siting buildings (such as schools, nurseries and care homes) in areas where pollution levels will be high siting living accommodation away from roadsides avoiding the creation of street and building configurations (such as deep street canyons) that encourage pollution to build up where people spend time including landscape features such as trees and vegetation in open spaces or as 'green' walls or roofs where this does not restrict ventilation including information in the plan about how structures such as buildings and other physical barriers will affect the distribution of air pollutants. If the local plan does not address air pollution, consider developing local guidance (such as supplementary planning documents, see the Department for Communities and Local Government information on local plans) on how to design buildings and spaces to improve local air quality until the local plan is amended. See how the committee made recommendations 1.1.1 to 1.1.3. # Development management Consider ways to mitigate road-traffic-related air pollution. This could include: Taking action to reduce the number of motorised trips. For instance, by: incorporating air quality outcomes in travel plans developing local parking plans supporting car clubs supporting active travel (see NICE's guideline on physical activity: walking and cycling). Supporting the use of zero- and low-emission vehicles for instance, by providing charging facilities for electric vehicles. Managing street trees and vegetation to reduce the risk of restricting street ventilation, where this may contribute to poor air quality (for instance, by the choice of species, siting and pruning regimes). In consultation with local communities, consider including air quality monitoring and measures to reduce road-traffic-related emissions in the Regulation 123 list of funding options for using the Community Infrastructure Levy (see the Planning Portal information on the Community Infrastructure Levy). See how the committee made recommendations 1.2.1 and 1.2.2. # Clean air zones Consider introducing a clean air zone that: includes restrictions or charges on certain classes of vehicle supports zero- and low-emission travel (including active travel) includes targets to progressively reduce pollutant levels below EU limits and aim to meet World Health Organization air quality guidelines aims to reduce exposure to air pollution across the whole zone rather than focusing on air pollution hotspots. Identify which classes of vehicles to restrict or charge in a clean air zone (see recommendation 1.3.1) based on an understanding of local conditions (such as local sources of road-traffic-related pollution and factors influencing dispersion). Use nationally recognised vehicle types (such as the Euro classification for diesel and petrol vehicles). Work across local authority boundaries to address regional air pollution and prevent migration of traffic and emissions to other communities, resulting in areas of poor air quality. Consider support for zero- and low-emission travel. This could include: Encouraging walking and cycling (see NICE's guideline on physical activity: walking and cycling). Encouraging uptake of zero- and low-emission vehicles, for instance: Providing electric charging points. Encouraging public and private sector organisations to use zero- or low-emission vehicles for deliveries to retail, office, residential or other sites in the zone, particularly for the last mile of deliveries in city centres. Developing integrated public transport networks (including park and ride schemes) based on low-emission vehicles. Consider taking action to reduce emissions within the clean air zone. For instance: Introducing fuel-efficient driving initiatives including: Bylaws and other action to support 'no vehicle idling' areas, particularly where vulnerable groups congregate (such as outside schools, hospitals and care homes) and in areas where exposure to road-traffic-related air pollution is high. Driver training to reduce emissions (see the section on reducing emissions from public sector transport services and vehicle fleets). Actions to smooth traffic flow (see the section on smooth driving and speed reduction). Action to minimise congestion caused by delivery schedules. Using a fleet recognition scheme (such schemes help fleet operators improve efficiency by reducing fuel consumption and emissions: the system recognises operators who meet best operational standards). Addressing emissions from public sector transport activities (see the section on reducing emissions from public sector transport services and vehicle fleets). Specifying emission standards for private hire and other licensed vehicles. Where traffic congestion is contributing to poor air quality, consider incorporating a congestion charging zone within the clean air zone. Consider monitoring outside the zone to identify whether its implementation is causing problems in terms of traffic composition and flow. If so, address any issues identified. For instance, by changing the boundaries to address increased pollution at the margins of the zone or problems caused by diversion of traffic. Assess the impact of any proposed charges (including exemptions for zero- and low-emission vehicles) on vulnerable groups. See how the committee made recommendations 1.3.1 to 1.3.8. # Reducing emissions from public sector transport services and vehicle fleets ## Driver training Consider introducing fuel-efficient driving as part of any test carried out when appointing or re-appraising staff who drive as part of their work. Consider training staff drivers to reduce their vehicle emissions. This could include: reducing rapid accelerations and decelerations, and correct gear selection to improve fuel consumption switching off engines, if practical and safe, when parked by the roadside and when dropping off people or deliveries vehicle maintenance, including pumping up tyres to the recommended pressure emphasising that lower vehicle emissions will reduce both fuel costs and air pollution. Consider using: 'in-vehicle' elements, for instance to ensure vehicles display real-time information about current fuel efficiency, appropriate gear selection and speed telematics technology to provide next-day information about driving style. Consider monitoring fuel efficiency and providing feedback to drivers after training. This could include providing support from colleagues or 'buddies' to improve their driving style and rewards for those who drive efficiently (see NICE's guideline on behaviour change: individual approaches). Consider monitoring the fleet's fuel consumption and evaluating the local effect on air pollutant emissions to demonstrate the benefits of training on fuel use and air quality. ## Procuring public sector vehicles Consider making low vehicle emissions (nitrogen oxides and particles) one of the criteria when making routine procurement decisions. This could include selecting low-emission vehicles, including electric vehicles. See how the committee made recommendations 1.4.1 to 1.4.6. # Smooth driving and speed reduction Consider promoting a smooth driving style by using: speed limits and average speed technology on the roadside real-time information to tell drivers what the current optimum driving speed is mph limits without physical measures to reduce speeds in urban areas where average speeds are already low (below around 24 mph) to avoid unnecessary accelerations and decelerations signs that display a driver's current speed to reduce unnecessary accelerations. See also recommendations 1.4.1 and 1.4.2. Where physical speed reduction measures are used to reduce road danger and injuries (20 mph zones – see NICE's guideline on unintentional injuries on the road), consider using them to encourage drivers to maintain a reduced, steady pace along the whole stretch of road, rather than road humps that may increase acceleration- and braking-related emissions. See how the committee made recommendations 1.5.1 to 1.5.2. # Walking and cycling Provide support for active travel (see NICE's guidelines on physical activity: walking and cycling and physical activity and the environment). Provide a choice of cycle routes, including routes that avoid highly polluted roads. Ideally use quiet streets or segregated routes. Where busy roads are used consider: Providing as much space as possible between the cyclist and motorised vehicles. Using dense foliage to screen cyclists from motor vehicles, without stopping air pollution from dispersing or reducing the visibility or safety of cyclists near junctions. Also take into account concerns about personal safety. Reducing the time cyclists spend at highly polluted sites, including some junctions, where this can be done without increasing the time that other groups spend exposed to poor air quality. See how the committee made recommendations 1.6.1 to 1.6.3. # Awareness raising Base actions to raise awareness of road-traffic-related air pollution (and so change people's behaviour) on NICE's guidelines on: behaviour change (general approaches) behaviour change (individual approaches) community engagement (in particular, the section on a local approach to making community engagement an integral part of health and wellbeing initiatives). Ensure healthcare professionals are aware that information on air quality is available, what it means for patients and what actions are recommended. Consider providing information on air quality (using the Department for Environment, Food and Rural Affairs' Daily Air Quality Index) with weather forecasts and the pollen index. This could be provided through local, national and social media. Consider providing information on: How health is affected by exposure to air pollutants in the long term as well as during specific periods of poor air quality. The impact of local pollution on air quality inside, as well as outside, a vehicle (levels of pollution are not always lower inside). How to reduce air pollutants and people's exposure, including the need to: Reduce the number of motor vehicle journeys, if possible. Drive in a style that minimises emissions by: avoiding rapid accelerations and decelerations, restricting the time spent with an engine 'idling' and ensuring the vehicle is correctly maintained (see the Energy Saving Trust's driving advice). Change routes to avoid highly polluted areas and adding to traffic congestion. Consider public awareness initiatives such as car-free days or National Clean Air Day to raise awareness of air pollution. Consider giving businesses information on how they can reduce road-traffic-related air pollution and improve fuel efficiency. For example, they could: help their drivers develop an energy-efficient driving style (see the section on reducing emissions from public sector transport services and vehicle fleets) schedule deliveries to minimise congestion encourage employees to cycle to work (see NICE's guideline on physical activity: walking and cycling). ## Vulnerable groups Healthcare professionals should be aware of vulnerable groups who are particularly affected by poor outdoor air quality. When notified of poor outdoor air quality, during any contact with vulnerable groups healthcare professionals should give general advice on how to avoid contributing to levels of air pollution and raise awareness of how to minimise exposure. This could include advice to: Avoid or reduce strenuous activity outside, especially in highly polluted locations such as busy streets, and particularly if experiencing symptoms such as sore eyes, a cough or sore throat. Use an asthma reliever inhaler more often, as necessary. Close external doors and windows facing a busy street at times when traffic is heavy or congested to help stop highly polluted air getting in. (See also the Department for Environment, Food and Rural Affairs' information about the Daily Air Quality Index.) See how the committee made recommendations 1.7.1 to 1.7.7. # Terms used in this guideline This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary. ## Electric vehicles Any vehicle that uses 1 or more electric motors for propulsion. It includes electric bikes and electrically assisted pedal cycles (see the Highway Code information on electric bikes: licensing, tax and insurance). ## Smooth driving Driving in a way that assesses the road ahead to avoid unnecessary braking and acceleration, which increase the amount of fuel used and emissions. ## Street canyons Streets flanked by buildings on both sides. They can be categorised using the ratio of the height of the buildings to the width of the road, with a deep canyon having taller buildings relative to the width. The geometry of the canyon and its orientation to the prevailing wind influence the flow of air. This can lead to the formation of vortices and the recirculation of air that trap pollutants emitted within the canyon. It can also restrict dispersion, potentially leading to areas of high air pollution. ## Vulnerable groups Children, older people and people with chronic health problems are among the most vulnerable to air pollution. Short-term (for example day-to-day) peaks of elevated air pollution are linked with increased hospital admissions for people with respiratory and cardiovascular conditions. The Royal College of Physician's report on air pollution (Every breath we take: the lifelong impact of air pollution) noted that it can affect the growth of an unborn baby and may be linked to premature birth.# Context The major human sources of air pollution are the combustion of fuels for heat, electricity and transport. Road transport accounts for 31% of nitrogen oxides (NOx), 19.5% of PM2.5 and 18% of PM10 UK emissions. It frequently accounts for more than 64% of air pollution at urban monitoring sites (European Topic Centre on Air Pollution and Climate Change Mitigation's technical paper on road traffic's contribution to air quality in European cities). This comes from exhausts and other sources such as the wear of tyres, brakes and the road. Non-exhaust sources account for around 21% of PM2.5 from vehicles. As exhaust emissions are reduced, the relative contribution from other sources becomes more significant. In 2008, the effect of human-produced (anthropogenic) particulate air pollution on mortality in the UK was estimated as equivalent to nearly 29,000 deaths at typical ages, and an associated loss of total life of 340,000 life years (Public Health England's report COMEAP: mortality effects of long-term exposure to particulate air pollution in the UK). In 2010, the total mortality burden of anthropogenic PM2.5 in London was 52,630 life years lost and of long-term exposure to NO2 was up to 88,113 life years lost (King's College London's Understanding the health impacts of air pollution in London). This figure assumes the World Health Organization value of up to a 30% overlap between the effects of PM2.5 and NO2. The authors note that the figure for NO2 is much less certain than that for PM2.5. The health impact of PM2.5 pollution from human activities in the UK is estimated to cost between £8.5 billion and £18.6 billion a year (UK Parliament's Ambient air quality). Over recent decades air pollutant emissions have reduced. But in 2013, UK levels of nitrogen dioxide (NO2) exceeded the EU directive limit in 38 of 43 geographical zones. The UK is divided into 43 zones for assessing air quality and reporting compliance with EU targets. These zones generally include more than 1 local authority (UK Government's Air quality plan for NO2 in the UK; European Parliament and Councils Directive 2008/50/EC). The way air pollution is distributed is not straightforward. Pollutant concentrations vary: The most deprived areas tend to have higher concentrations of NO2 and PM10. Regardless of socioeconomic status, urban areas tend to have higher pollutant levels than rural areas, which often have larger populations in the mid-range of deprivation. The national trend shows high average concentrations in both the most and least deprived areas, and lower concentrations in the (predominantly rural) mid-decile areas. Children (14 and under) and older people (65 and older) are more susceptible to the effects of air pollution (Department of Environment, Food and Rural Affairs' Air quality and social deprivation in the UK: an environmental inequalities analysis). Addressing air pollution by encouraging people to walk and cycle rather than drive, can help people to become fitter and healthier. Changing the way we travel can also help reduce emissions of greenhouse gases that contribute to climate change. Climate change is linked to increased risk of extreme weather and other events that have an adverse effect on health, such as floods, heatwaves and the spread of some infectious diseases (Intergovernmental Panel on Climate Change's Working Group 1's Climate change 2013: the physical science basis).# Committee discussion Evidence statement numbers are given in square brackets. See 'The evidence' at the end of each section for details. # Overview The committee discussions below relate to all the recommendations. ## Key pollutants Various air pollutants are related to road transport including carbon monoxide, benzene and volatile organic compounds (VOC). This guideline focuses on particulate matter and NO2 because these have the greatest impact on health at levels currently seen in the UK. The committee heard evidence that both long- and short-term exposure to air pollution adversely affects health and that fine particles and NO2 are both important contributors . Members noted that various metrics are used for particulate pollution including size (such as PM2.5, PM10 and ultra-fine particles), particle numbers and particle composition (such as black carbon and elemental carbon). They also noted a possible causal relationship between road-traffic-related air pollution and negative health outcomes, and that black carbon is an indicator for such pollution. Short-term exposure (over hours or days) to elevated levels of air pollution can lead to: effects on lung function exacerbation of conditions such as asthma increases in hospital admissions and mortality. Epidemiological studies have shown that long-term exposure (over several years) reduces life-expectancy, mainly because of increased risk of mortality from cardiovascular and respiratory causes and from lung cancer . The committee agreed that studies of interventions related to air pollutants are important but often carried out by disciplines other than public health and focus on environmental or road-traffic-related effects rather than health outcomes. The committee agreed that measures of particles and nitrogen oxides (NOx) were a key indicator of road-traffic-related air pollution so members focused on these as a proxy for health outcomes. The connection between fuel efficiency and emission of air pollutants is well known, so proxy measures such as fuel efficiency are also useful if other metrics are not available. ## Limits, guidelines and indicator values Maximum levels of outdoor air pollutants that affect health, such as particles (PM10 and PM2.5) and NO2, are set out in the 2008 Ambient Air Quality Directive (2008/50/EC) . This was made law in England through the Air Quality Standards Regulations 2010, which sets targets and mandatory limits for levels of outdoor air pollutants. Equivalent regulations exist in Scotland, Wales and Northern Ireland. There is also a public health outcomes framework indicator on air pollution. The June 2017 indicator is: 'fraction of all-cause adult mortality attributable to anthropogenic particulate air pollution (measured as fine particulate matter, PM2.5)'. In addition, the committee was aware of guideline values, including for PM2.5, PM10 and NO2, in the World Health Organization's Ambient (outdoor) air quality and health. Members noted that there is little evidence to suggest a threshold below which no adverse health effects would be anticipated. So reducing pollution below the EU limits will provide even more health benefits. ## Additional impacts The committee agreed that interventions to address air pollution are also likely to help reduce climate change from emissions of CO2. Interventions that support a shift to active transport, like walking or cycling, will also lead to potentially substantial health benefits, mainly associated with increased physical activity levels. The committee noted that a number of recommendations, principally those on planning, might have other impacts on health as a result of changes to, and use of, the built and natural environment. For instance, physical changes (such as changes that alter temperature or provide shade) might help prevent both overexposure to heat and skin cancer. In addition, changes in the way the environment is viewed and used could mean more people socialise in that environment. Planning changes can also influence economic activity (and so, in turn, the health) of an area. But these issues were out of scope of the current guideline. The committee noted that it was important to link information about air pollution to other health advice, such as the benefits of physical activity and the importance of social contact (see NICE's guideline on older people: independence and mental wellbeing). ## Multiple interventions Generally, the evidence gathered for this guideline examined single interventions. The committee felt that single, small scale actions were unlikely to lead to the significant reduction in air pollution needed to protect health. Although there was no evidence to demonstrate the effect, members agreed that multiple interventions, each producing a small benefit, would be likely to act cumulatively to produce significant change. ## Monitoring The committee agreed that although evidence suggests an intervention may produce a particular effect, local factors such as the type of vehicles involved, topography and weather conditions can all have an impact. It also agreed with evidence that air quality monitoring will be an important part of most large-scale changes – before and after implementation . The committee noted that traffic data for most roads is currently ad-hoc and of low quality. Measurements of traffic will provide the high quality information needed for planning changes. The committee noted that there was a risk that intended changes would erode over time as drivers became used to the change and readjust their behaviours. Continual monitoring of the effect of schemes and adjustments to them will probably be needed to ensure that positive, progressive effects are achieved. ## Euro standards A recognised approach to tackling air pollution has been to develop plans and initiatives to encourage cleaner vehicles and to work with transport authorities to discourage high polluting vehicles from entering certain geographical areas. This is based on the assumption that newer vehicles will produce lower emissions. The committee heard that tail-pipe emissions from vehicles are regulated under a series of European Directives (commonly referred to as Euro standards) for all types of vehicles . The standards currently extend from Euro 1 to Euro 6 for cars and vans, and from Euro I to Euro VI for heavy goods vehicles (HGVs), buses and coaches. The Euro standards have introduced progressively tighter emission limits for various air pollutants, but they have not led to a corresponding reduction in concentrations of NO2. The committee heard that this is because of a difference in emissions during test procedures compared with 'real world' driving, combined with an increase in the number of diesel vehicles on the road. The committee heard that the latest Euro standard (6/VI) requires manufacturers to adhere to tighter standards of emissions. Although NOx emissions from Euro 6/VI diesel vehicles in normal use may be higher than the standard might suggest, they will be substantially lower than Euro 5/V vehicles. From September 2017, emissions tests for cars will include on-road tests as opposed to the laboratory tests that have been used to date. This is already a requirement for heavy duty vehicles. ## Equality issues The committee heard that children, older people and those with chronic health problems are among the most vulnerable to air pollution . In addition, more deprived urban neighbourhoods often experience higher levels than more affluent areas. So any reduction in air pollution is likely to help tackle health inequalities. But at the same time, these vulnerable groups are less likely to be able to afford a new vehicle with low emissions and could be disadvantaged by any changes to restrict older, more polluting vehicles. Overall, the committee agreed that removing older vehicles from the road would reduce health inequalities, provided these groups could get to the places and services they need. ## Cost effectiveness The economic modelling was based on assessments of specific interventions that had demonstrated effectiveness. It suggests those interventions could be highly cost effective in some settings. But both the effect and cost of any intervention will be highly dependent on factors specific to the local setting, so this may vary considerably from the case studies. A key limitation is that there were no data on pollution dispersal in relation to population for any of the case studies modelled. Some identified benefits could not be quantified, suggesting that the overall benefits might be greater than the figure given. So the committee concluded that interventions could offer good value for money. ## The evidence The committee looked at evidence in: expert paper 1 (EP1): expert testimony on key issues in the epidemiology of air pollution and health expert paper 2 (EP2): expert testimony on national and local frameworks for action expert paper 3 (EP3): expert testimony on the use of Euro Standards to control vehicle emissions. # Planning The discussion below explains how the committee made recommendations 1.1.1 to 1.1.3. ## Rationale and impact Some evidence suggests that strategic plans can have an important influence on air pollution. Based on the epidemiological evidence on the health impacts of air pollution, particularly for vulnerable groups, and committee consensus, the committee recommended several approaches. This includes action to encourage a move to zero- and low-emission travel (including active travel) by linking to the existing NICE guideline on walking and cycling. Some expert testimony, supported by the committee's own expertise, suggests that the layout of new developments will affect motorised travel. The committee agreed that it is important to take account of how air pollution disperses and where people spend time because these factors will influence their exposure. Some evidence showed that street trees and green walls or roofs have a mixed effect on street air quality – in some cases they restrict street ventilation causing poorer air quality, in others, they improve it. Because the evidence was uncertain, the committee recommended this as an action to consider. The committee agreed by consensus that if air pollution is not included in the current local plan, other local policies should be developed until it is updated. Because the evidence was uncertain they recommended this as an action to consider. Our built environment can affect the emission of road-traffic-related air pollutants by influencing how, and how much, we travel. It can also affect the way air pollutants are dispersed (through street design and the resulting impact on air flow). Some areas experience poor air quality from motor vehicles passing through (rather than travel within) an area. Air pollution issues are not always incorporated into local plans, making it difficult to reject a proposal that would have adverse effects. Physical features (such as buildings, barriers, vegetation and landscape) influence the way air pollution moves and disperses and can sometimes create high pollution levels where people spend time. For instance, trees don't always reduce air pollution: it depends on the street design, species, number and siting of trees, canopy density, time of year and wind direction relative to the street. Only a limited amount of new building occurs at a time, but it will have an impact on road-traffic-related air pollution for decades. In addition, relatively small changes in the layout of buildings (such as the siting of air vents away from the roadside or small increases in distance from sources of pollution) might have an important impact on residents' exposure to air pollutants. Addressing these and other issues at the planning stage may reduce the need for more expensive (and probably less effective) remedial action at a later date. ## Evidence discussion The committee agreed that the most important outcomes are health outcomes (for instance, mortality or exacerbations of respiratory conditions). But these are not usually measured directly in studies of air pollution, which rely instead on examining air pollutants. The most important of these are: ambient levels of particles, in particular PM2.5 ambient levels of NO2. Other outcomes relating to the need to travel and choice of vehicles are also likely to be relevant to planning interventions. The committee considered evidence on the impact of air pollution on health, particularly for vulnerable groups. This was from expert paper 1 but was based on the work of the Committee on the Medical Effects of Air Pollutants (COMEAP). Members also considered evidence on the impact of planning on air pollution. This was from expert paper 6 but was based on guidance produced by Environmental Protection UK and the Institute of Air Quality Management. Members agreed that both of these represented good quality evidence that could be used to support recommendations. The committee considered the evidence of effectiveness of natural and artificial barriers in terms of impact on air pollutants. Five studies (4 from the USA, 1 from the UK) looked at barriers alongside major roads. All were rated as poor quality and so at high risk of bias . Two of these studies examined solid noise barriers. They found that although barriers reduced air pollution in the immediate lee of the barrier, levels at some distance away were higher than without the barrier . The committee considered 3 modelling studies (2 from Belgium, 1 from the UK) that examined the impact of street trees and vegetation on air pollution . One study was rated as moderate quality and 2 were rated as poor quality. They found that: Vegetation that does not interfere with air flow in a street canyon (such as green roofs or walls, or vegetation not situated within a street canyon) may reduce air pollution. Street trees were unlikely to reduce air pollution in most street designs and could worsen it in some cases. The committee felt that the studies were plausible. No effectiveness studies were found. Another 3 studies (1 from the UK, 1 from France, 1 from the US), rated as poor quality, agreed with what the committee knew about placing and maintaining trees but did not reduce the uncertainty in the evidence about their effects in any particular direction . This further supports the need for additional research and the research recommendation developed by the committee. Members agreed that specific factors in the individual settings were highly important in determining the outcome. However, they felt it was appropriate to recommend caution when using street trees and not to consider them as always being beneficial, because if they are poorly placed or maintained this may affect ventilation at street level and inadvertently create a canopy that traps air pollutants. The committee agreed that the limited number of effectiveness studies (and the absence of corroboration of the findings of modelling studies around the effects of street trees) represented a gap in the available evidence base. Benefits include: New developments that do not exacerbate poor air quality or expose people to high levels of air pollution and that encourage zero- and low-emission travel (including active travel). Reduced risk of inadvertent exposure of people to poor air quality from the redistribution of pollution. Use of trees to encourage deposition of air pollutants, to reduce heat stress, provide shade and create a more attractive environment – all of which benefit health without inadvertently creating areas of poor air pollution. Potential harms include: Using trees in areas where they do reduce ventilation. Using barriers in a way that creates poorer air quality (see also the section on additional impacts in the overview at the start of the committee discussion). The evidence reviewed did not focus on the unintended consequence of interventions that may increase allergen levels. Taking air pollution issues into account at the plan making stage involves additional cost for training in relevant issues and could have an impact on public consultation. However, this is likely to be relatively small. There will be a cost impact for developers. This may extend beyond the initial site if changes to infrastructure are needed. The committee did not recommend widespread use of green walls and roofs. The evidence from the reviews (based on modelling studies) suggests that these may improve air quality in some circumstances (where it does not reduce ventilation in the street). However, the committee felt that the very high resource impact for retrofitting green walls and roofs to existing buildings was not likely to be cost effective in terms of air pollution reduction alone. But they may be appropriate for new buildings. The committee agreed that urban trees and greenery play an important part in the urban landscape. They provide a number of positive benefits, including health benefits. Leaves and branches slow air currents, causing pollutants to settle out. They may also act as 'sinks' for particles and chemicals that may have direct or indirect effects on air quality (in particular, VOCs). The extent to which this is the case depends on factors such as species, time of year and growing conditions. The impact of trees on ventilation in a street canyon will influence their impact on air quality. Ventilation will vary according to the size, distribution and species of tree and their position within the canyon. For instance, air quality might deteriorate at street level near vehicle sources if ventilation were restricted, while improving near first floor windows above the canopy. Although it is important to avoid the possible negative effects, it is also important to recognise the positive benefits of properly selected, sited and managed trees. The committee discussed the dispersion of air pollutants by solid barriers. They agreed this is complex and depends on a range of local factors. There is some evidence to suggest that barriers may result in improved air quality near to the barrier but poorer air quality at a distance. As a result, air quality may be affected downwind from a roadside barrier. The impact on health will depend on the details of this dispersion and on where people live or spend time in relation to the barrier. The committee noted that there was a concern that some local authorities might adopt the recommendations but others may not. This could mean that developers focus on areas with fewer controls, resulting in a loss of investment for those aiming for better air quality. It noted that recommendations to all local authorities might lead to a more consistent approach, to the benefit of all. It also noted members' experience of the benefits of a good quality environment in attracting developers. ## The evidence The committee looked at evidence in: evidence review 1: environmental change and development planning: ES4.1a, ES4.1b, ES4.4 expert paper 1 (EP1): expert testimony on key issues in the epidemiology of air pollution and health expert paper 6 (EP6): expert testimony on the role of the local authority planning regime in delivering improvements to ambient air quality and in reducing public exposure to pollution. # Development management The discussion below explains how the committee made recommendations 1.2.1 and 1.2.2. ## Rationale and impact Evidence on actions to address road-traffic-related air pollution suggested that travel plans could offer an opportunity to re-evaluate journeys to work and help a more general move away from car travel. Committee members also noted from their experience that these plans could support zero- and low-emission travel and could be implemented as part of the planning approval process. Evidence indicated that the species, siting and management of trees and vegetation is important in reducing the risk of adversely affecting air quality. Because the evidence was uncertain the committee recommended this as an action to consider. Based on their expertise, the committee agreed that it is appropriate to use funds from developers, via the Community Infrastructure Levy, to pay for work to address air pollution issues. They also agreed that this is best carried out in consultation with local communities. Because the evidence was uncertain the committee recommended this as an action to consider. Local development plans do not always address traffic-related air pollution. If action to reduce traffic-related air pollution is incorporated in the development plans for new buildings and estates, this will help maintain people's health and wellbeing, both in terms of reducing pollution levels and encouraging physical activity. In turn, this may help reduce the need for NHS treatment and other support in the future. ## Evidence discussion The committee agreed that the most important outcomes are health outcomes (for instance, mortality or exacerbations of respiratory conditions). But these are not usually measured directly in studies of air pollution, which rely instead on measuring air pollutant levels. The most important of these are: ambient levels of particles, in particular PM2.5 ambient levels of NO2. Other outcomes relating to the need to travel and choice of vehicles are also likely to be relevant. The committee considered evidence on the impact of air pollution on health, including for vulnerable groups. This was from expert paper 1 but was based on the work of the Committee on the Medical Effects of Air Pollutants (COMEAP). Members also considered evidence on the impact of planning on air pollution. This was from expert paper 6 but was based on guidance produced by Environmental Protection UK and the Institute of Air Quality Management. Members agreed that both of these represented good quality evidence that could be used to support recommendations. Evidence relating to travel plans consisted of 2 poor-quality studies . Both were carried out in the UK so the evidence is directly applicable. Both looked at changes in mode of travel, rather than air pollutant emission or air quality data. They focused on travel plans in workplaces. The studies suggest that information on, and the provision of facilities to support, other travel modes could reduce the number of people driving to work alone. The committee also considered a qualitative study from the UK on factors influencing the uptake of travel plans . The committee felt that this evidence was applicable to wider settings. The committee considered the evidence of effectiveness of natural and artificial barriers (see the discussion of recommendations 1.1.1 and 1.1.2 above) and the management of trees and vegetation. Five studies (4 from the USA, 1 from the UK) looked at barriers alongside major roads. All were rated as poor quality and so at high risk of bias . Members agreed that factors such as siting, pruning and species were important in determining the outcome . So it was appropriate to recommend considering these factors to avoid creating a canopy that traps air pollutants, ensuring air pollution is reduced and ensuring we gain the other benefits from sensitive use of trees and vegetation. Benefits include: New developments that do not exacerbate poor air quality or expose people to high levels of air pollution and that encourage zero- and low-emission travel (including active travel). Reduced risk of inadvertent exposure of people to poor air quality from the redistribution of air pollutants. Use of trees to encourage deposition of air pollutants, reduce heat stress, provide shade and create a more attractive environment – all of which benefit health without inadvertently creating areas of poor air pollution. Potential harms include: Using trees in areas where they do reduce ventilation. Using barriers in a way that creates poorer air quality (see also the section on additional impacts in the overview at the start of the committee discussion). Taking air pollution issues into account at the development management stage involves additional cost for training in relevant issues, assessment of planning applications and any additional impact on public consultation. However, this is likely to be relatively small. There will be a cost impact for developers. This may extend beyond the initial site if changes to infrastructure are needed. The committee agreed that urban trees and greenery play an important part in the urban landscape. They provide a number of positive benefits, including health benefits. The committee agreed that local planning and transport officers, in consultation with air quality or pollution control officers, are best placed to ensure that trees and barriers are used effectively in urban areas. The committee agreed that parking plans (including park and ride plans) are an important way to help reduce motorised trips and avoid the traffic congestion that can be caused when people are having to spend time searching for a parking space. ## The evidence The committee looked at evidence in: evidence review 1: environmental change and development planning: ES4.1a, ES4.1b, ES4.4 evidence review 3: travel planning and other initiatives providing information, advice, education and skill development: ES9.1a, ES9.1b, ES10.1 expert paper 1 (EP1): expert testimony on key issues in the epidemiology of air pollution and health expert paper 6 (EP6): expert testimony on the role of the local authority planning regime in delivering improvements to ambient air quality and in reducing public exposure to pollution. # Clean air zones The discussion below explains how the committee made recommendations 1.3.1 to 1.3.8. ## Rationale and impact Some evidence suggested that area-wide action is needed to reduce the use of polluting vehicles and to encourage a shift to zero- and low-emission travel. Some of this evidence showed that existing low-emission zones (the current nearest equivalent to a clean air zone) have only slightly improved air quality. This is partly because of the failure of new technology to reduce individual vehicle emissions under real driving conditions. But it is also probably linked to the limited scope of existing low-emission zones, in terms of class of vehicles restricted, and the failure to address the overall volume of traffic. Some evidence suggested that reducing air pollution below current EU limits would provide more health benefits. The committee agreed that stricter targets should be considered because there is a lack of evidence on how effective a lower threshold would be. They also recognised that there are likely to be greater health benefits if pollution is lower than the legislative limits, so reduction to these limits is a minimum and should not be the maximum target for reducing air pollution. Members agreed that targets should be developed with health goals in mind but that, in practice, these will be expressed as air pollution targets. Members agreed that the focus should not be limited to taking action to reduce air pollution hotspots alone. Because the evidence was uncertain the committee recommended this as an action to consider. Cost-effectiveness evidence suggested that low-emission zones could be cost effective. Committee members agreed that it was important to aim for consistency across the country, particularly in relation to the vehicle types that are restricted. Both air pollutants and their sources are mobile, so actions in one area may affect another. No evidence looked at this empirically, but the committee agreed it would be useful to take a wider geographical approach, involving cooperation across local authority boundaries. The evidence was uncertain (based on committee consensus) but the committee felt it was particularly important not to simply move the problem to another community so they made a strong recommendation. The committee noted that active travel (such as walking and cycling) was linked to a range of other health benefits. This is covered by evidence used to develop other NICE guidelines. Some evidence suggested potential benefits could be gained from using zero- and low-emission vehicles. This supported expert testimony on the actions of the Department for Environment Food and Rural Affairs to speed up the transition to a low-emission economy. The committee agreed that infrastructure (in particular, charging points) is needed to achieve significant uptake of zero- or low-emission motor vehicles. Because the evidence for all these actions was uncertain, the committee recommended these as actions to consider. There was some evidence on addressing driving style and traffic flow and this supported the committee's knowledge of how air pollution is produced. They agreed that training to reduce idling and to encourage people to change their driving style is unlikely to have any negative effects. No direct evidence was found on local deliveries or private hire vehicles. However, based on the committee's experience, they suggested action to combat the large contribution that they can both make to air pollution. They agreed that air pollution from congestion related to deliveries might be addressed by thinking about delivery schedules and by training and accreditation of fleets using a fleet recognition scheme. In addition, it may help reduce fuel use resulting in reduced emissions. Because the evidence was uncertain, they recommended this as an action to consider. Some evidence, together with the committee's experience, suggested that congestion charging could contribute to a package of measures and incentives to address air pollution where congestion was identified as a significant cause. Because the evidence was uncertain, the committee recommended this as an action to consider. Members agreed that it was important to monitor outside the zone to identify whether traffic is moving elsewhere and resulting in poor air quality in those areas. They also agreed that adjustments should be made in such cases. Because the evidence was uncertain (committee consensus), the committee recommended this as an action to consider. The committee agreed that people living in deprived areas are more likely to be exposed to higher levels of air pollution and so might gain more from changes that reduce it. But at the same time, they may be less likely to be able to afford new vehicles and so might be disadvantaged by a charging scheme. The committee agreed that the potential impact that charging may have on inequalities should be taken into account. This was based on uncertain evidence (committee consensus) but the committee felt it was particularly important so they made a strong recommendation. Piecemeal, uncoordinated actions to tackle air pollution may make the situation worse. For example, the use of single interventions such as 'alternate car days', in which half the vehicle fleet is banned from an area on alternate days, may inadvertently encourage the use of older, poor performing vehicles. Similarly, if different vehicle types are not classed in the same way in all clean air zones, then the overall impact will be diminished. Planning, transport and environment departments will need to work together across the country to ensure a consistent approach. More consistent, concerted action to change current practice will, in turn, improve people's health, by: reducing the ill effects of air pollution encouraging more people to become more active, by adopting active travel as a lifestyle choice. ## Evidence discussion The committee agreed that the most important outcomes in the absence of measured health outcomes are a reduction in the following air pollutants: Particles, especially PM2.5 and the vehicle-related components of PM2.5 (such as black carbon) NO2. Ideally these outcomes should be measured in the ambient air (the air that we breathe). But for many outcomes, changes in total emission levels or vehicle kilometres driven suffice and have been used to determine the effect of interventions. The committee noted that ambient NO2 concentrations are more sensitive to changes in local transport than total PM2.5. Other relevant outcomes include changes in number and type of vehicles in the zone. The committee considered the evidence of effectiveness for various elements of clean air zones: Six studies of low-emission zones (2 from the Netherlands, 3 from Germany and 1 from the UK) found some evidence of reductions in pollution, particularly with more stringent restrictions on vehicle classes . Four studies were rated as moderate quality and 2 as poor quality. All were at some risk of bias but overall the committee considered the evidence sufficient to support the recommendations. Two cost-effectiveness studies (1 from Italy and 1 from Sweden) that examined congestion charging zones in Milan and Stockholm, suggested that they were cost effective, although local factors mean that they are only partially applicable to the UK . Both studies were rated as moderate quality. Four modelling studies of the use of alternative fuels (3 poor quality from Spain and 1 poor quality from the UK) showed the potential for considerable improvements in air quality from fuel changes if the penetration of the technologies is large enough . As modelling studies, they involve greater uncertainty. However, the committee agreed that that they support the recommendations. Five studies of traffic restrictions (1 each from Italy, Korea and Israel, 2 from the US) suggested that vehicle restrictions or bans have little impact unless they restrict the volume of traffic substantially . All were at some risk of bias, 3 were rated as poor quality and 2 as moderate quality. Three studies (2 from the UK, 1 from Italy) looked at congestion charging schemes . All were at risk of bias (rated as poor quality) but committee members agreed with the evidence from their expert perspectives. The study from Italy found some reduction in elements of road-traffic-related air pollution. Three moderate-quality cost-effectiveness studies (from the US) looked at changes to vehicle fleets . These suggested that changes to emission-controlled diesel or compressed natural gas were not cost effective when viewed against medical interventions. However, they were within the range normally considered cost effective for interventions to address mobile or stationary air pollution. One poor-quality study from the US found that a 10% to 20% reduction in fuel consumption could be obtained by using wireless technology to inform drivers of the appropriate speed on major roads . Two studies (1 from Canada and 1 from the Netherlands) looked at the impact of information and training on driver behaviour . Both were rated as poor quality. They suggested that information and training might help reduce fuel consumption and time spent idling. The effect of anti-idling information campaigns for bus drivers was considered in 2 linked studies from the US . Both were rated as poor quality and so at risk of bias. They suggested that such campaigns could reduce the time school buses spent idling. The committee considered the evidence of effectiveness of charging zones on air quality. Three studies (2 from the UK, 1 from Italy) looked at charging schemes . All were rated as poor quality. The studies from the UK failed to find clear evidence of reductions in air pollution. This may in part be because of the failure of Euro standards to produce the modelled benefits. The study from Italy suggested that there were some reductions in particulate air pollution most heavily linked to vehicle use. However, it is possible that there are differences in the vehicle fleet between Italy and the UK, meaning that this is only partially applicable. The committee agreed that this evidence supported the recommendations. Two cost-effectiveness studies (1 from Sweden rated as moderate quality and 1 from Italy rated as moderate quality) looked at the costs and benefits of congestion charging schemes . Both were at some risk of bias. Both suggested greater benefits than costs. However, the main benefits came from changes to traffic flow, travel time savings and reductions in road injuries, rather than from air pollution savings. Local factors (such as the limited number of access points to the islands of Stockholm and differences in the vehicle fleet) mean that the evidence is partially applicable. The committee agreed that this evidence supported the recommendations. Benefits include: Discouraging use of the most polluting vehicles, by restricting their access to some areas or by encouraging zero- or low-emission travel, will improve local air quality. Increased levels of physical activity from encouraging 'active' travel. A reduction in health inequalities by reducing vulnerable groups' exposure to poor air quality. Potential harms arise from: Approaches covering only limited classes of vehicles or geographical areas not reducing emissions sufficiently, or moving the pollution elsewhere. People who depend on highly polluting vehicles or older vehicles that do not meet current emission standards not being able to afford to replace them. Large-scale schemes such as city-wide clean air zones (that can include low-emission zones) can be expensive to set up – but they can deliver substantial benefits. They also target a large population, meaning that the cost per head of population is likely to be relatively low. Much of the cost relates to setting up. Running costs are likely to be substantially lower (and potentially covered by charges or fines). Ongoing income can then be used for other activities to reduce air pollution. Demonstrating a link between income raised and funding activities to reduce air pollution is likely to encourage public support for the actions. Evidence in the economic modelling suggested an annual cost of around £2 per head for the Amsterdam low-emission zone. Although a clean air zone involving a range of interventions might be more expensive, the committee felt this was likely to have an additive positive effect. There are no data for clean air zones so the economic model considered 1 component – low-emission zones. It estimated a cost per quality-adjusted life year (QALY) of around £2,240. The committee noted this is likely to decrease as vehicle fleets progressively improve because of regulation, unless restrictions evolve to take into account improving vehicle standards. Nevertheless, because they have a benefit–cost ratio of around 29 (that is, £29 of benefit for every £1 spent) the committee considered the impact of these zones is unlikely to stop representing good value for money. Interventions to encourage reductions in vehicle idling were included in the economic modelling. Using a study that assessed the impact of a campaign to tackle bus idling at 4 schools in Cincinnati the model estimated a cost per QALY of £157 and a benefit–cost ratio of 44. The committee noted the benefit was based on the best-performing school, some schools showed no improvement The committee felt that it was reasonable to extrapolate from this to interventions aimed at reducing idling more widely. The committee heard about the draft national clean air zone framework (Department for Environment, Food and Rural Affairs' Air quality plan for nitrogen dioxide in UK) that aims to achieve compliance with the EU NO2 limit values and the implementation of clean air zones . Members noted that evidence about the effectiveness of clean air zones does not exist because they have yet to be implemented. However, they heard evidence about actions that might constitute a clean air zone (in particular low-emission zones) . The committee heard expert testimony on influencing drivers' behaviour which noted that better driving can reduce emissions and fuel consumptions. The committee noted that the contribution of diesel cars to NO2 pollution was substantial . Which vehicle types need to be restricted in a particular area to protect health would need to be assessed in light of local conditions. This would include assessing the timetable to implement changes and amending restrictions if modelled targets for health goals are not achieved, including the possibility of an introductory advisory-only restriction. Members discussed providing parking concessions for lower-emission vehicles, such as electric vehicles, as an incentive for people to buy them. But they felt that such subsidies would be going to people who can afford expensive vehicles. In addition, in areas of high housing density, off-street space for charging electric vehicles is rare. So support for on-street charging would be necessary to alleviate any potential inequalities this may cause. The committee agreed that the bulk of the actions would need to be taken by transport authorities. These are located in county council and unitary authorities. Environmental issues may be located in other authorities such as district councils. Directors of public health should sign off annual status reports and air quality management action plans. The committee felt that it was appropriate to target recommendations at these groups. The committee agreed that although road traffic was a key contributor to poor air quality, other sources would need to be tackled as well. These would depend on local circumstances but would be likely to include gas-powered domestic boilers, domestic biomass use and combined heat and power stations. The committee noted that perceptions about charging schemes risked reducing their effectiveness and antagonising the public. These include the perception that schemes are aimed at income generation rather than reducing air pollution, or that restrictions would inevitably damage economic growth and activity. It felt that emphasising the public health benefit of the schemes and adopting a consistent national approach would be important in limiting these misperceptions. ## The evidence The committee looked at evidence in: evidence review 1: environmental change and development planning: ES3.3, ES3.4 evidence review 2: traffic management and enforcement, and financial incentives and disincentives: ES5.1, ES6.1, ES6.2, ES6.3 evidence review 3: travel planning and advice: ES11.1, ES11.2, ES11.4 expert paper 1 (EP1): expert testimony on epidemiology expert paper 2 (EP2): expert testimony on national and local frameworks for action expert paper 3 (EP3): expert testimony on the use of Euro Standards to control vehicle emissions expert paper 4 (EP4): expert testimony on evidence relating to influencing driving behaviours for fleet drivers and others expert paper 5 (EP5): expert testimony on the proposed clean air zones. # Reducing emissions from public sector transport services and vehicle fleets The discussion below explains how the committee made recommendations 1.4.1 to 1.4.6. ## Rationale and impact Some evidence showed that changes to driving style may be used to lower levels of local pollution, as well as reducing fuel use. It also showed that people can be encouraged to make these changes. Some evidence suggests that if large numbers of people change their driving style this, combined with other measures to reduce traffic, could have a positive effect on the environment. An expert also told the committee that fuel consumption could be reduced by around 20% to 25% by adopting efficient driving techniques, with a realistic long-term reduction of between 5% and 10%. Based on this evidence and their own experience, the committee felt that providing support to help people change their driving style was justified. They also noted that this would be cost neutral because of the savings generated by better fuel efficiency. Because the evidence was uncertain, the committee recommended these as actions to consider. The committee was aware of NICE's guideline on behaviour change: individual approaches and added a link to this in recommendation 1.4.4 but did not specify the type of rewards for those who drive efficiently. The committee agreed by consensus that procurement of less polluting vehicles will help public sector organisations to reduce road-traffic-related air pollution. Members noted that this could be done as older vehicles are replaced. Because the evidence was uncertain, they recommended this as an action to consider. The public sector fleet is substantial. It includes various vehicle types (from local authority refuse vehicles and goods vehicles to lease cars and patient transport vehicles) many of which are highly polluting. Public sector decisions about vehicle procurement don't always take air pollution into account. In addition, many drivers are unaware of the impact their driving has on air pollution, and about practical changes they could make to reduce this. Currently only around 20% of people employed as drivers have been trained in efficient driving by their employer. Making changes will help the public sector fleet to meet its duty to address its environmental impact, reduce emissions and promote the public's health and wellbeing. ## Evidence discussion The committee agreed that although outcomes relating to ambient air quality are important for health it would be unlikely to find studies that reported these in relation to changes to driving style. Other more likely outcomes are: length of time a vehicle is left idling -verall fuel consumption. The committee considered modelling evidence from 1 poor-quality US study . This suggested that information on an appropriate speed could reduce emissions on major roads. The study was modelling only and rated as poor quality so the results were treated with caution. But the committee felt that it, together with other evidence, supported the recommendation. The committee considered evidence of effectiveness from 2 studies (1 from Canada and 1 from the Netherlands) that looked at the impact of information and training on driver behaviour . Both studies were rated as poor quality and so at risk of bias. They suggested that information and training might help reduce fuel consumption and time spent idling. The committee considered the effect of anti-idling information campaigns for bus drivers in 2 linked studies from the US . Both were rated as poor quality and so at risk of bias. It suggested that educating drivers about the importance of reducing the time they spend idling could be effective. The committee considered qualitative evidence that looked at factors that influence the likelihood of people changing their driving style. One moderate-quality study from the UK suggested several factors likely to support the uptake of 'eco driving' . The authors felt that a focus on cost savings, in-vehicle information and systems to feedback progress were key. Key elements in reducing fuel consumption were vehicle maintenance (in particular ensuring correct tyre pressure), gear selection and avoiding aggressive acceleration. Although in general the evidence was of poor quality, committee members felt that it was consistent with what they would expect from their own experience and so supported the recommendations. Benefits include: Increased knowledge about factors associated with fuel economy. Putting this knowledge into practice will result in lower fuel use and improved air quality. Energy-efficient driving with fewer rapid accelerations and decelerations. This will improve fuel consumption and reduce wear and tear on vehicles, leading to financial benefits. Energy-efficient driving with fewer rapid accelerations and decelerations may reduce road danger and encourage others to walk or cycle, resulting in lower total emissions. Training public sector staff may have the additional benefit of altering their driving habits outside work. It may also help to make these habits the norm more generally. Evidence from expert testimony suggested that efficient driving training is likely to be cost saving . Training costs are estimated at a one-off cost of £25 to £30 per driver, with an annual fuel saving of around £96. If training is provided as part of existing programmes for staff, the marginal cost is likely to be small. Use of telematics would be likely to have an additional cost. However, the committee felt these costs were likely to be small. It would be most logical to make changes to the vehicle fleet as part of the usual turnover of vehicles. Any resource impact would depend on the extent of changes and the relative cost of vehicles. This would need to be managed within available resources. The committee noted that the potential for financial savings and health benefits meant that these recommendations were highly relevant to the public sector. But the committee also felt that adoption of the recommendations by the public sector would act as an example of good practice that might be taken up in other sectors. In addition, it noted the potential for a positive knock-on effect if energy-efficient driving habits developed at work were carried over into people's personal lives. Members noted that the views of those receiving training are important in determining the potential for success. They noted that there is a perception that air pollution levels inside a vehicle are lower than outside but this may not be the case. ## The evidence The committee looked at evidence in: evidence review 3: travel planning and advice: ES11.1, ES11.2, ES11.3, ES11.4 expert paper 4 (EP4): expert testimony on influencing driving behaviours for fleet drivers and others. # Smooth driving and speed reduction The discussion below explains how the committee made recommendations 1.5.1 and 1.5.2. ## Rationale and impact Evidence on using lower speed limits, encouraging smoother driving and providing real-time information showed that reducing 'stop–go' driving could help reduce emissions of air pollutants. This was supported by the committee's understanding of air pollution and the effect of accelerations and decelerations. The committee agreed that signs displaying drivers' current speed would encourage a smoother driving style. Because the evidence was uncertain they recommended these as actions to consider. Some evidence on physical speed reduction measures like humps and bumps suggested that individual measures may increase motor vehicle emissions by encouraging decelerations and accelerations. But evidence from area-wide schemes does not back this up. So where physical measures are needed to reduce road injuries, the committee agreed that area-wide schemes should be designed to minimise the impact on air pollution. Because the evidence was uncertain, the committee recommended this as an action to consider. Speeding motor vehicles in residential areas discourages people from walking and cycling, increases the risk of injury and increases traffic-related air pollution. Ensuring motorists drive steadily at the optimum speed can help reduce stop–go driving and so improve fuel consumption as well as reducing congestion and air pollution. Reducing the speed limit in residential areas, while making sure that it does not result in an increase in vehicle emissions, will reduce road danger, injuries and air pollution. ## Evidence discussion The committee agreed that the most important outcomes are: Ambient levels of air pollutants, in particular NO2 and PM2.5. Individual vehicle emissions of these pollutants. The committee considered the evidence relating to the impact of motorway speed. Two studies examined the effect of schemes to reduce speed on urban motorways . Both were from the Netherlands; 1 was rated poor quality and 1 moderate quality. They showed that speed limits and enforcement on urban motorways have a small positive effect on PM10 and NO2. The emission reduction depends on the impact of speed management on traffic dynamics, so the larger the reduction in traffic congestion the larger the emission reduction. Although this evidence is poor quality, it supports the understanding of traffic flow dynamics and air pollution production. Although the studies are from the Netherlands they are applicable to the UK. One modelling study from the US noted savings in fuel consumption using wireless technology to inform drivers of the optimum speed on a major road . The committee agreed that these studies were in line with expectations about the effect of smoothing traffic flow by reducing speed . Members noted that where flow was not improved by changes to the speed limit (generally in less congested conditions) it would be unlikely that air quality would improve. The committee discussed the modelling study . This suggested substantial benefits were possible from changes to the behaviour of relatively small numbers of drivers. This had been achieved using wireless technology to identify the optimum speed. Although this was plausible, it would not be implementable at the moment because of lack of the necessary technology in vehicles to receive information about the current optimum speed. However, a similar effect might be obtained by the expansion of variable limit speed control using signs outside the vehicle. The committee considered the evidence on the effect on air pollution of traffic-calming schemes. Two poor-quality studies from the UK suggested that there was no significant impact on ambient NO2 concentrations from the construction of an area-wide traffic-calming scheme . Four modelling studies examined the emissions from individual vehicles . Two moderate-quality studies were from Canada and 1 each, both poor quality, were from the US and UK. Two poor-quality studies of area-wide traffic calming from the UK did not show significant changes in area-wide air quality. The changes seen were within the margin of error of the measurement techniques used. The committee noted that the modelling evidence suggested that individual traffic-calming measures tended to increase emissions from vehicles because of the increase in accelerations and decelerations. The UK modelling study cited 9 measures including road humps, pinch points, raised junctions, chicanes and mini-roundabouts. Although there are uncertainties associated with the modelling, these studies supported an increase in emissions associated with individual traffic-calming measures. One study was carried out in the UK on existing measures and so is applicable; others were carried out elsewhere and so differences in the design of measures and the make-up of the vehicle fleet mean that they are partially applicable. Benefits include: Reducing stop–go driving will lower emissions of air pollutants from accelerations and decelerations, lowering exposure of the population to poor air quality. Reduced speeds in urban areas supports a modal shift to walking and cycling. This will reduce emissions of air pollutants. Reduced speeds reduces the number and severity of road injuries. The economic modelling included examination of speed restrictions around Amsterdam. This suggested that the reduction in the speed limit on a section of motorway from 100 kph to 80 kph was highly cost effective at reducing air pollution (cost per QALY approximately £1,290, benefit–cost ratio 51). However, the committee noted costs will vary depending on the existing enforcement infrastructure already in place and whether additional speed cameras are needed. The committee noted that altering driving behaviour to reduce emissions has 2 elements: education and restriction. The committee felt that these complementary elements should both be included in the guideline separately. Education is addressed in recommendations 1.4.1 to 1.4.5. Recommendations 1.5.1 to 1.5.2 address restriction. The committee discussed the possibility of using average speed technology to reduce this risk in various areas. It noted that on major roads where there are very few (or no) route choices the cost is likely to be small because only a limited number of speed cameras would be needed. However, in other areas (such as residential streets) there were possible benefits, but implementation would be difficult or impossible because of the number of route options. Other measures (such as signs indicating current speed) were more likely to be useful in these areas. ## The evidence The committee looked at evidence in: evidence review 2: traffic management and enforcement, and financial incentives and disincentives: ES5.2, ES5.3, ES6.4 evidence review 3: travel planning and advice: ES11.1. # Walking and cycling The discussion below explains how the committee made recommendations 1.6.1 to 1.6.3. ## Rationale and impact The committee agreed that it was important to support a general shift from motor vehicles to more active travel. They also agreed that this needed doing in a way that minimises cyclists' exposure to air pollution for example, by providing a choice of cycle routes. In addition, evidence suggested that increasing the space between cyclists and motor traffic helps protect cyclists from air pollution. Although this evidence was uncertain, it agrees with the committee's understanding of the sources and dispersal of air pollutants. Some evidence suggested that where it is not possible to create cycle routes using quiet streets, separating cycle routes from motor traffic and reducing the time spent by cyclists in areas of high pollution, including busy sites, helps protect them from air pollution. Some evidence suggested that using dense foliage as a barrier may sometimes help protect cyclists from motor vehicle emissions, but the impact on the distribution of air pollutants needs to be taken into account. The committee agreed that the evidence supported its understanding of the dispersal of air pollutants. They also noted that it was important to take account of the need for cyclists to be visible to reduce the risk of collisions and to help normalise cycling. Because the evidence was uncertain the committee recommended this as an action to consider. Cyclists and pedestrians are vulnerable to road-traffic-related air pollution as well as other injuries on the road. Both factors discourage people from taking up these zero-emission modes of transport. Encouraging active travel such as walking and cycling will help reduce traffic-related air pollution and help people to be more physically active. Incorporating the rest of the recommendations at the design stage of new cycle routes will help improve the currently patchy provision across the country. It will also encourage planners to consider exposure to air pollution, which currently is not always taken into account. ## Evidence discussion Ambient levels of air pollutants, in particular NO2 and PM2.5. The committee considered the evidence of the impact of cycle route design on exposure to air pollution . This included 6 studies that examined the siting and design of cycle routes: 3 from the US, 1 each from the Netherlands, Canada and the UK. All were rated as poor quality: All 6 found exposure to PM2.5 was lower in low traffic routes and air pollution levels were reduced by increasing separation. Shelter provided by vegetation reduced levels of exposure to air pollutants; conversely, peak levels of exposure were seen in conjunction with junctions and waiting at signals. One study suggested exposure for drivers was as high as for cyclists. There is considerable variation in measurement techniques used, which introduces uncertainty. However, the results are in line with what is known about dispersion of air pollutants in general. The committee felt that although the evidence was of poor quality it was plausible. The reduction in air pollution with distance from the source is well understood and follows a simple mathematical relationship. ES4.1b examined natural barriers. One UK study found a positive effect from a dense hedge adjoining a major road. Although this was a poor-quality study the committee felt it was plausible, based on its understanding of the deposition of air pollutants. Because the evidence was uncertain, the committee recommended this as an action to consider. Benefits include: Positioning cycle routes away from areas of poor air quality will reduce the exposure of cyclists to air pollution. Perceptions of poor air quality put some people off cycling. Improving air quality will encourage more people to cycle and so further reduce air pollution. Those encouraged to cycle will also benefit from being more physically active. Potential harms could arise from collisions as a result of poorly designed cycle routes. Construction and maintenance of dedicated and separated cycle routes may entail additional costs, but it is not as expensive as constructing and maintaining vehicular roads. Modelling of the cost effectiveness of off-road cycle routes suggested that they were good value for money. The cost per QALY was estimated at around £5,080, with a benefit–cost ratio of 14. This analysis included additional monetised benefits of £64,000 resulting from increased take up of cycling. The committee noted the intervention costs and benefits calculated assume several routes are developed. Developing a single route would cost less, but may also be less effective because it is likely to reach less of the population. The committee noted that a variety of terms are used in the studies. The definitions are often not clear and may vary between studies (for example: cycle routes, paths and lanes). Members agreed that, other factors being equal, the significant factor in terms of exposure was the distance between the source (motor vehicles) and the cyclist. They also agreed to use the term 'cycle route'. The committee was aware from members' own experience that air pollution concerns were among the factors putting some people off cycling. Taking action to address this would support the overall goal of achieving a shift in transport choices and so an overall reduction in air pollution. The committee noted there was considerable uncertainty in this modelling. However, it agreed that off-road cycle paths could be cost effective in some circumstances. ## The evidence The committee looked at evidence in: evidence review 1: environmental change and development planning: ES 3.1, ES4.1b. # Awareness raising The discussion below explains how the committee made recommendations 1.7.1 to 1.7.7. ## Rationale and impact Evidence on the impact of air pollution on health provided justification for action to raise awareness of the issues and ways to mitigate the problems. The committee agreed that community support is always important when aiming for sustainable changes in behaviour. This supported the evidence on interventions to change behaviours related to air pollution. Members noted that this is in line with other NICE guidelines. The committee agreed that local, national and social media techniques are useful ways to disseminate information about the Daily Air Quality Index, particularly to vulnerable groups. Because the evidence was uncertain the committee recommended this as an action to consider. The committee agreed that it is important to give the public information on how road-traffic-related air pollution affects their health and on how their transport choices (such as driving during episodes of high pollution) contribute to this. Because the evidence was uncertain the committee recommended this as an action to consider. Some evidence relating to partial or occasional traffic restrictions suggested a limited effect. But the committee agreed that such restrictions offer the opportunity to demonstrate the positive benefits. So the consensus was that it is reasonable to use them as part of occasional awareness-raising activities. Because the evidence was uncertain the committee recommended this as an action to consider. The committee agreed that it is reasonable to make businesses aware of the need to reduce air pollution, by encouraging active travel and more energy-efficient driving. Members noted that scheduling deliveries to avoid times when streets are congested might also reduce the contribution businesses make to congestion and the resulting pollution. Because the evidence was uncertain the committee recommended this as an action to consider. The committee agreed that information provided by healthcare professionals is likely to be important in highlighting the effect of air pollution on health. So it is important to ensure health professionals are aware of the facts and can communicate them to vulnerable groups. Because the evidence was uncertain the committee recommended this as an action to consider. Many people do not understand the link between health and road-traffic-related air pollution. For example, they do not realise that long-term exposure to typical levels of air pollution causes far more health problems than short-term exposure to higher levels. In addition, they do not realise that they can help reduce this pollution, as well as their exposure to it, if they change their behaviour. Without this understanding it will be difficult to get public support for the changes needed. Without such support changes are unlikely to be sustainable and implementing them would be unethical. If healthcare professionals routinely raise air pollution as an issue affecting health, this could help prevent health conditions escalating, particularly among the most vulnerable groups. If local authorities raise awareness about air pollution with businesses and the public, this could help reduce air pollution and resulting ill health, so meeting their duty to protect people's health and wellbeing. In both cases, this would also reduce the need for potentially more expensive and less effective remedial action later. ## Evidence discussion Reduced exposure to air pollution (NO2 and particles) is the main outcome in determining health effects. Changes in knowledge and behaviours that may to lead to reduced exposure (either for the person or the wider community) are important. The committee heard expert testimony on the extent of the impact of air pollution on health . It noted that some groups are more likely to be at risk from air pollution. The committee heard expert testimony on influencing drivers' behaviour . The committee felt that members' experience of working on air pollution, together with the wider public health evidence (including NICE guidance on behaviour change and community engagement), justified these recommendations. The committee considered the evidence of effectiveness of traffic restrictions on air pollution from 5 studies of traffic restrictions (1 each from Italy, Korea and Israel, 2 from the US). The evidence suggested that vehicle restrictions or bans have little impact unless they restrict the volume of traffic substantially . All were at some risk of bias, 3 were rated as poor quality and 2 as moderate quality. Raising awareness of air pollution will: Help people, particularly those who are most vulnerable, to reduce their exposure – especially when levels of pollution are high. Help people understand how to change their behaviour to reduce emissions, thereby further reducing population-level exposure. Support the development of social networks (social capital), which can be built on for benefits in other areas. Actions to reduce the amount of polluted air from entering a home (such as closing windows) might increase indoor levels of air pollutants, if there are other sources of pollution in the house. Potential harm may also be caused if unfounded concerns are raised about the possible health effects of air pollution. No cost-effectiveness evidence or modelling was identified for this recommendation. The committee noted that local agencies were likely to have resources capable of addressing these issues by developing effective local communications strategies. Developing an effective strategy would involve a cost but this would be more likely to be successful. The committee noted that training healthcare workers about air pollution would have a cost. However, this could form part of continuing professional development so would be cost neutral. There was also the potential for cost savings if exacerbations of ill health (such as asthma), and so hospital attendances, were reduced. ## The evidence The committee looked at evidence in: evidence review 2: traffic management and enforcement, and financial incentives and disincentives: ES5.1 expert paper 1 (EP1): expert testimony on epidemiology expert paper 4 (EP4): expert testimony on influencing driving behaviours for fleet drivers and others. # Evidence statements not used to make recommendations ES2.1 – bus operations. The committee felt that this evidence (2 poor-quality modelling studies, 1 from Canada and 1 from Greece) was too uncertain to support a general recommendation. Local factors would be particularly significant in this context, and would involve considerable potential disruption. ES3.2 – alterations to bus services and technology. The committee felt that the uncertainties in both studies (2 poor-quality studies, 1 from Chile and 1 from the US) meant that this evidence was unsuitable to support a general recommendation. In particular, differences in vehicle fleets in Chile and the UK and lack of appropriate control fleets in the US study made the evidence of limited applicability. Emission standards are also addressed by recommendations relating to clean air zones. ES3.5 – bypass construction. The committee felt that this evidence (1 poor-quality UK study) did not justify a recommendation. Bypass construction is likely to be extremely expensive and only applicable in very specific circumstances. The committee felt that the reductions noted were possibly due to other factors. The age of the study (carried out in 1998) also meant that vehicle technology would be very different. ES4.2 – dust suppressants. The committee felt that this evidence (2 poor-quality studies, 1 from Spain and 1 from the USA) did not justify a recommendation. They felt that the results seen in the Spanish study would be unlikely to be replicated in the UK, partly from differences in climate. The study from the USA looked at unsealed roads so is not relevant to the UK generally. ES4.3 – street washing. The committee felt that this evidence (1 poor-quality study from Spain) did not justify a recommendation. They felt that the results would be unlikely to be replicated in the UK because of differences in climate. They felt that street washing was unlikely to have a significant effect on smaller particles most closely linked to health impacts. ES10.1 – personalised travel planning. This consisted of 1 poor-quality study of students in Japan, which suggested that vehicle mileage could be reduced substantially by using personalised approaches. Although the committee agreed that these interventions could be feasible in the UK, they felt the evidence was insufficient to base a recommendation on. The committee also noted that the linked walking and cycling guideline contains recommendations on these approaches based on evidence to promote physical activity (rather than to reduce air pollution). # Gaps in the evidence The committee's assessment of the evidence and expert testimony identified a number of gaps. These gaps are set out below. Where a gap in the evidence was identified and prioritised as a research recommendation it is included in the recommendations for research section. . Effectiveness and cost effectiveness of environmental change and development planning at reducing road-transport-related air pollution: a) Planning and land allocations, development control and planning decisions, urban space and building design: siting, layout and design of developments; and applying planning conditions or obligations. b) Developing public transport routes and services, including bus lanes, and improving bus quality. (Source: Evidence review 1: environmental change and development planning.) . Effectiveness and cost effectiveness of traffic management and enforcement, and financial incentives and disincentives to reduce road-transport-related air pollution: a) Traffic management systems and signal coordination: road signs, traffic signals and road markings lane control elements of routes (such as positioning of traffic lights) roadside emission testing. b) Parking restrictions and charges: restricted parking zones (including low-emission vehicles, car clubs and electric vehicle recharging points) higher parking charges. c) Vehicle 'idling' restrictions and charges, including waiting and loading restrictions. (Source: Evidence review 2: traffic management and enforcement, and financial incentives and disincentives.)# Recommendations for research The guideline committee has made the following recommendations for research. # Vegetation and street trees What factors influence how vegetation and street trees affect urban air quality? ## Why this is important There is limited evidence on how vegetation and trees influence urban air quality and health outcomes. Information is needed because they are often used to address air pollution or for other purposes. Research is needed on a range of factors including: impact of different species of vegetation and tree types impact of trees depending on where they are sited and how they are maintained impacts across the course of a year impact on health inequalities -ther potential health benefits. # Promoting a shift to zero- and low-emission travel What methods are effective and cost effective at promoting a shift to zero- and low-emission modes of travel, including active travel? ## Why this is important Achieving a shift to zero- and low-emission modes of travel (including active travel) is key to reducing air pollution. We also need to identify approaches that encourage more efficient, less polluting driving behaviour. Studies based on behaviour change theories are needed to identify the most effective and cost-effective approaches and messages for different groups and in different settings. Useful outcomes include: travel mode and driver behaviour. # Clean air zones How do different elements of a clean air zone interact to improve air quality and what is the overall effect on people's health? ## Why this is important At publication of this guideline, clean air zones were being introduced. These zones are likely to vary across the country and it is important to use this opportunity to identify which elements are most effective and cost effective at reducing air pollution and supporting a shift to zero- and low-emission travel. Studies are needed to evaluate: exposure to air pollution acute and chronic health outcomes impact on health inequalities. Research is also needed to look at travel behaviour in relation to different groups, to inform public awareness and social marketing approaches. # Telematics How can information about driving style gathered from telematics devices and other technologies (such as apps or in-car global positioning systems) be used to reduce individual fuel consumption and vehicle emissions? ## Why this is important Evidence suggests that information and training can help drivers change their driving style. Research is needed to evaluate how telematics devices can be most effectively used with different groups to influence driving style and so, in turn, reduce emissions and improve air quality. Specific gaps in current research include the impact on individual drivers and those driving as part of a fleet including costs, health and other benefits, and value for money. # Awareness raising What is the effectiveness and cost effectiveness of different methods of awareness raising about air pollution (including air pollution alerts) on people's behaviour and on acute and chronic health outcomes? ## Why this is important Activities to raise awareness of air pollution, including air pollution alerts (using traditional, social media and other methods) are becoming increasingly popular as a way of warning of the potential risk from episodes of poor air quality. But little is known about whether these alerts help encourage people to change their behaviour. Research on the absolute and relative effect of different approaches could be used to develop effective and cost-effective systems. Research is needed on the impact of, for example, air pollution alerts on: different groups (such as those vulnerable to air pollution and the general population) behaviours related to the production of pollution (such as changes in mode of transport) acute and chronic health. Studies are also needed on: the risk of adverse effects (such as making people worry unnecessarily, or increasing the level of motor vehicle travel after an alert) the ability of health services to respond to concerns raised by issuing alerts. # Exposure to air pollution using different modes of transport How does altering a person's mode of transport and route affect their personal exposure to air pollution? ## Why this is important Mode of transport (such as walking, cycling, using public transport or driving) influences personal exposure to air pollution. Overall, 'active' travel (such as walking or cycling) reduces emissions of air pollutants. But it could potentially increase someone's personal exposure, depending on the route they take. Research is needed to clarify the health impact of making such changes, including on health-related quality of life.# Glossary # Average speed technology Cameras with automatic number plate reading (ANPR) digital technology, placed in multiple locations (at least 2, at a minimum of 200 m apart) along a stretch of road to monitor a vehicle's average speed. # Daily Air Quality Index A number used by government agencies to tell the public how polluted the air is or will be. The number is provided with recommended actions and health advice. The index is numbered 1 to 10 and divided into 4 bands: low (1 to 3), moderate (4 to 6), high (7 to 9) and very high (10). # Euro standards Standards produced by EU Directives specifying maximum permitted emissions of various air pollutants. Light duty vehicle standards are referred to using Arabic numerals (Euro 1 to 6); standards for heavy duty vehicles use Roman numerals (Euro I to VI). # PM2.5, PM10 Particulate matter is produced by, among other things, combustion of fossil fuels or abrasion of tyres and brakes. Particles are classified by size, described using the abbreviation PM with a suffix (commonly 2.5 or 10) that gives the maximum particle size in micrometres. The mass concentration of particles is usually expressed in micrograms per m3 of air. Airborne PM10 and PM2.5 come from both primary emissions (including combustion of fossil fuels, tyre and brake wear) and secondary particles (for example, nitrates and sulphates) formed when pollutants react in the atmosphere. PM2.5 particles are sometimes referred to as 'fine particles', and PM2.5–10 as 'coarse particles'. Fine particles can penetrate deep into the lungs. # Street ventilation Air in a street flows in a pattern determined by many factors, including the shape and design of buildings. It mixes with air from outside the street. If there are sources of pollution in the street (primarily motor vehicles) the air flow is restricted. # Telematics Technologies that store and send information on the speed, position, acceleration and deceleration of road vehicles. This, together with global positioning system (GPS) data, can be used to compare driving styles and estimate the impact on fuel consumption, emissions or wear and tear. # Travel plans Travel plans are a way of assessing and then mitigating the potential negative effects that new developments could have on air pollution by generating significant amounts of motor traffic. For other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Planning\n\nInclude air pollution in 'plan making' by all tiers of local government, in line with the Department for Communities and Local Government's National Planning Policy Framework. This includes county, district and unitary authorities, as well as regional bodies and transport authorities. The Local Plan and other strategic planning processes (such as the core strategy, local transport plan, environment and health and wellbeing strategies) should include zero- and low-emission travel, for example cycling and walking (see the section on walking and cycling and NICE's guideline on physical activity: walking and cycling). Other strategies for zero- and low-emission travel could include:\n\nProviding charge points for electric vehicles in workplaces, commercial developments and residential areas.\n\nSupporting car sharing schemes or car clubs.\n\nWhen 'plan making' consider:\n\nsiting and designing new buildings, facilities and estates to reduce the need for motorised travel\n\nminimising the exposure of vulnerable groups to air pollution by not siting buildings (such as schools, nurseries and care homes) in areas where pollution levels will be high\n\nsiting living accommodation away from roadsides\n\navoiding the creation of street and building configurations (such as deep street canyons) that encourage pollution to build up where people spend time\n\nincluding landscape features such as trees and vegetation in open spaces or as 'green' walls or roofs where this does not restrict ventilation\n\nincluding information in the plan about how structures such as buildings and other physical barriers will affect the distribution of air pollutants.\n\nIf the local plan does not address air pollution, consider developing local guidance (such as supplementary planning documents, see the Department for Communities and Local Government information on local plans) on how to design buildings and spaces to improve local air quality until the local plan is amended.\n\nSee how the committee made recommendations 1.1.1 to 1.1.3.\n\n# Development management\n\nConsider ways to mitigate road-traffic-related air pollution. This could include:\n\nTaking action to reduce the number of motorised trips. For instance, by:\n\n\n\nincorporating air quality outcomes in travel plans\n\ndeveloping local parking plans\n\nsupporting car clubs\n\nsupporting active travel (see NICE's guideline on physical activity: walking and cycling).\n\n\n\nSupporting the use of zero- and low-emission vehicles for instance, by providing charging facilities for electric vehicles.\n\nManaging street trees and vegetation to reduce the risk of restricting street ventilation, where this may contribute to poor air quality (for instance, by the choice of species, siting and pruning regimes).\n\nIn consultation with local communities, consider including air quality monitoring and measures to reduce road-traffic-related emissions in the Regulation 123 list of funding options for using the Community Infrastructure Levy (see the Planning Portal information on the Community Infrastructure Levy).\n\nSee how the committee made recommendations 1.2.1 and 1.2.2.\n\n# Clean air zones\n\nConsider introducing a clean air zone that:\n\nincludes restrictions or charges on certain classes of vehicle\n\nsupports zero- and low-emission travel (including active travel)\n\nincludes targets to progressively reduce pollutant levels below EU limits and aim to meet World Health Organization air quality guidelines\n\naims to reduce exposure to air pollution across the whole zone rather than focusing on air pollution hotspots.\n\nIdentify which classes of vehicles to restrict or charge in a clean air zone (see recommendation 1.3.1) based on an understanding of local conditions (such as local sources of road-traffic-related pollution and factors influencing dispersion). Use nationally recognised vehicle types (such as the Euro classification for diesel and petrol vehicles).\n\nWork across local authority boundaries to address regional air pollution and prevent migration of traffic and emissions to other communities, resulting in areas of poor air quality.\n\nConsider support for zero- and low-emission travel. This could include:\n\nEncouraging walking and cycling (see NICE's guideline on physical activity: walking and cycling).\n\nEncouraging uptake of zero- and low-emission vehicles, for instance:\n\n\n\nProviding electric charging points.\n\nEncouraging public and private sector organisations to use zero- or low-emission vehicles for deliveries to retail, office, residential or other sites in the zone, particularly for the last mile of deliveries in city centres.\n\n\n\nDeveloping integrated public transport networks (including park and ride schemes) based on low-emission vehicles.\n\nConsider taking action to reduce emissions within the clean air zone. For instance:\n\nIntroducing fuel-efficient driving initiatives including:\n\n\n\nBylaws and other action to support 'no vehicle idling' areas, particularly where vulnerable groups congregate (such as outside schools, hospitals and care homes) and in areas where exposure to road-traffic-related air pollution is high.\n\nDriver training to reduce emissions (see the section on reducing emissions from public sector transport services and vehicle fleets).\n\nActions to smooth traffic flow (see the section on smooth driving and speed reduction).\n\n\n\nAction to minimise congestion caused by delivery schedules.\n\nUsing a fleet recognition scheme (such schemes help fleet operators improve efficiency by reducing fuel consumption and emissions: the system recognises operators who meet best operational standards).\n\nAddressing emissions from public sector transport activities (see the section on reducing emissions from public sector transport services and vehicle fleets).\n\nSpecifying emission standards for private hire and other licensed vehicles.\n\nWhere traffic congestion is contributing to poor air quality, consider incorporating a congestion charging zone within the clean air zone.\n\nConsider monitoring outside the zone to identify whether its implementation is causing problems in terms of traffic composition and flow. If so, address any issues identified. For instance, by changing the boundaries to address increased pollution at the margins of the zone or problems caused by diversion of traffic.\n\nAssess the impact of any proposed charges (including exemptions for zero- and low-emission vehicles) on vulnerable groups.\n\nSee how the committee made recommendations 1.3.1 to 1.3.8.\n\n# Reducing emissions from public sector transport services and vehicle fleets\n\n## Driver training\n\nConsider introducing fuel-efficient driving as part of any test carried out when appointing or re-appraising staff who drive as part of their work.\n\nConsider training staff drivers to reduce their vehicle emissions. This could include:\n\nreducing rapid accelerations and decelerations, and correct gear selection to improve fuel consumption\n\nswitching off engines, if practical and safe, when parked by the roadside and when dropping off people or deliveries\n\nvehicle maintenance, including pumping up tyres to the recommended pressure\n\nemphasising that lower vehicle emissions will reduce both fuel costs and air pollution.\n\nConsider using:\n\n'in-vehicle' elements, for instance to ensure vehicles display real-time information about current fuel efficiency, appropriate gear selection and speed\n\ntelematics technology to provide next-day information about driving style.\n\nConsider monitoring fuel efficiency and providing feedback to drivers after training. This could include providing support from colleagues or 'buddies' to improve their driving style and rewards for those who drive efficiently (see NICE's guideline on behaviour change: individual approaches).\n\nConsider monitoring the fleet's fuel consumption and evaluating the local effect on air pollutant emissions to demonstrate the benefits of training on fuel use and air quality.\n\n## Procuring public sector vehicles\n\nConsider making low vehicle emissions (nitrogen oxides and particles) one of the criteria when making routine procurement decisions. This could include selecting low-emission vehicles, including electric vehicles.\n\nSee how the committee made recommendations 1.4.1 to 1.4.6.\n\n# Smooth driving and speed reduction\n\nConsider promoting a smooth driving style by using:\n\nspeed limits and average speed technology on the roadside\n\nreal-time information to tell drivers what the current optimum driving speed is\n\nmph limits without physical measures to reduce speeds in urban areas where average speeds are already low (below around 24\xa0mph) to avoid unnecessary accelerations and decelerations\n\nsigns that display a driver's current speed to reduce unnecessary accelerations. See also recommendations 1.4.1 and 1.4.2.\n\nWhere physical speed reduction measures are used to reduce road danger and injuries (20\xa0mph zones – see NICE's guideline on unintentional injuries on the road), consider using them to encourage drivers to maintain a reduced, steady pace along the whole stretch of road, rather than road humps that may increase acceleration- and braking-related emissions.\n\nSee how the committee made recommendations 1.5.1 to 1.5.2.\n\n# Walking and cycling\n\nProvide support for active travel (see NICE's guidelines on physical activity: walking and cycling and physical activity and the environment).\n\nProvide a choice of cycle routes, including routes that avoid highly polluted roads. Ideally use quiet streets or segregated routes.\n\nWhere busy roads are used consider:\n\nProviding as much space as possible between the cyclist and motorised vehicles.\n\nUsing dense foliage to screen cyclists from motor vehicles, without stopping air pollution from dispersing or reducing the visibility or safety of cyclists near junctions. Also take into account concerns about personal safety.\n\nReducing the time cyclists spend at highly polluted sites, including some junctions, where this can be done without increasing the time that other groups spend exposed to poor air quality.\n\nSee how the committee made recommendations 1.6.1 to 1.6.3.\n\n# Awareness raising\n\nBase actions to raise awareness of road-traffic-related air pollution (and so change people's behaviour) on NICE's guidelines on:\n\nbehaviour change (general approaches)\n\nbehaviour change (individual approaches)\n\ncommunity engagement (in particular, the section on a local approach to making community engagement an integral part of health and wellbeing initiatives).\n\nEnsure healthcare professionals are aware that information on air quality is available, what it means for patients and what actions are recommended.\n\nConsider providing information on air quality (using the Department for Environment, Food and Rural Affairs' Daily Air Quality Index) with weather forecasts and the pollen index. This could be provided through local, national and social media.\n\nConsider providing information on:\n\nHow health is affected by exposure to air pollutants in the long term as well as during specific periods of poor air quality.\n\nThe impact of local pollution on air quality inside, as well as outside, a vehicle (levels of pollution are not always lower inside).\n\nHow to reduce air pollutants and people's exposure, including the need to:\n\n\n\nReduce the number of motor vehicle journeys, if possible.\n\nDrive in a style that minimises emissions by: avoiding rapid accelerations and decelerations, restricting the time spent with an engine 'idling' and ensuring the vehicle is correctly maintained (see the Energy Saving Trust's driving advice).\n\n\n\nChange routes to avoid highly polluted areas and adding to traffic congestion.\n\nConsider public awareness initiatives such as car-free days or National Clean Air Day to raise awareness of air pollution.\n\nConsider giving businesses information on how they can reduce road-traffic-related air pollution and improve fuel efficiency. For example, they could:\n\nhelp their drivers develop an energy-efficient driving style (see the section on reducing emissions from public sector transport services and vehicle fleets)\n\nschedule deliveries to minimise congestion\n\nencourage employees to cycle to work (see NICE's guideline on physical activity: walking and cycling).\n\n## Vulnerable groups\n\nHealthcare professionals should be aware of vulnerable groups who are particularly affected by poor outdoor air quality. When notified of poor outdoor air quality, during any contact with vulnerable groups healthcare professionals should give general advice on how to avoid contributing to levels of air pollution and raise awareness of how to minimise exposure. This could include advice to:\n\nAvoid or reduce strenuous activity outside, especially in highly polluted locations such as busy streets, and particularly if experiencing symptoms such as sore eyes, a cough or sore throat.\n\nUse an asthma reliever inhaler more often, as necessary.\n\nClose external doors and windows facing a busy street at times when traffic is heavy or congested to help stop highly polluted air getting in. (See also the Department for Environment, Food and Rural Affairs' information about the Daily Air Quality Index.)\n\nSee how the committee made recommendations 1.7.1 to 1.7.7.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.\n\n## Electric vehicles\n\nAny vehicle that uses 1 or more electric motors for propulsion. It includes electric bikes and electrically assisted pedal cycles (see the Highway Code information on electric bikes: licensing, tax and insurance).\n\n## Smooth driving\n\nDriving in a way that assesses the road ahead to avoid unnecessary braking and acceleration, which increase the amount of fuel used and emissions.\n\n## Street canyons\n\nStreets flanked by buildings on both sides. They can be categorised using the ratio of the height of the buildings to the width of the road, with a deep canyon having taller buildings relative to the width. The geometry of the canyon and its orientation to the prevailing wind influence the flow of air. This can lead to the formation of vortices and the recirculation of air that trap pollutants emitted within the canyon. It can also restrict dispersion, potentially leading to areas of high air pollution.\n\n## Vulnerable groups\n\nChildren, older people and people with chronic health problems are among the most vulnerable to air pollution. Short-term (for example day-to-day) peaks of elevated air pollution are linked with increased hospital admissions for people with respiratory and cardiovascular conditions. The Royal College of Physician's report on air pollution (Every breath we take: the lifelong impact of air pollution) noted that it can affect the growth of an unborn baby and may be linked to premature birth.", 'Context': "The major human sources of air pollution are the combustion of fuels for heat, electricity and transport. Road transport accounts for 31% of nitrogen oxides (NOx), 19.5% of PM2.5 and 18% of PM10 UK emissions. It frequently accounts for more than 64% of air pollution at urban monitoring sites (European Topic Centre on Air Pollution and Climate Change Mitigation's technical paper on road traffic's contribution to air quality in European cities). This comes from exhausts and other sources such as the wear of tyres, brakes and the road.\n\nNon-exhaust sources account for around 21% of PM2.5 from vehicles. As exhaust emissions are reduced, the relative contribution from other sources becomes more significant.\n\nIn 2008, the effect of human-produced (anthropogenic) particulate air pollution on mortality in the UK was estimated as equivalent to nearly 29,000 deaths at typical ages, and an associated loss of total life of 340,000 life years (Public Health England's report COMEAP: mortality effects of long-term exposure to particulate air pollution in the UK).\n\nIn 2010, the total mortality burden of anthropogenic PM2.5 in London was 52,630\xa0life years lost and of long-term exposure to NO2 was up to 88,113\xa0life years lost (King's College London's Understanding the health impacts of air pollution in London). This figure assumes the World Health Organization value of up to a 30% overlap between the effects of PM2.5 and NO2. The authors note that the figure for NO2 is much less certain than that for PM2.5.\n\nThe health impact of PM2.5 pollution from human activities in the UK is estimated to cost between £8.5\xa0billion and £18.6\xa0billion a year (UK Parliament's Ambient air quality).\n\nOver recent decades air pollutant emissions have reduced. But in 2013, UK levels of nitrogen dioxide (NO2) exceeded the EU directive limit in 38 of 43 geographical zones. The UK is divided into 43 zones for assessing air quality and reporting compliance with EU targets. These zones generally include more than 1 local authority (UK Government's Air quality plan for NO2 in the UK; European Parliament and Councils Directive 2008/50/EC).\n\nThe way air pollution is distributed is not straightforward. Pollutant concentrations vary:\n\nThe most deprived areas tend to have higher concentrations of NO2 and PM10.\n\nRegardless of socioeconomic status, urban areas tend to have higher pollutant levels than rural areas, which often have larger populations in the mid-range of deprivation.\n\nThe national trend shows high average concentrations in both the most and least deprived areas, and lower concentrations in the (predominantly rural) mid-decile areas.\n\nChildren (14 and under) and older people (65 and older) are more susceptible to the effects of air pollution (Department of Environment, Food and Rural Affairs' Air quality and social deprivation in the UK: an environmental inequalities analysis).\n\nAddressing air pollution by encouraging people to walk and cycle rather than drive, can help people to become fitter and healthier. Changing the way we travel can also help reduce emissions of greenhouse gases that contribute to climate change. Climate change is linked to increased risk of extreme weather and other events that have an adverse effect on health, such as floods, heatwaves and the spread of some infectious diseases (Intergovernmental Panel on Climate Change's [IPCC's] Working Group 1's Climate change 2013: the physical science basis).", 'Committee discussion': "Evidence statement numbers are given in square brackets. See 'The evidence' at the end of each section for details.\n\n# Overview\n\nThe committee discussions below relate to all the recommendations.\n\n## Key pollutants\n\nVarious air pollutants are related to road transport including carbon monoxide, benzene and volatile organic compounds (VOC). This guideline focuses on particulate matter and NO2 because these have the greatest impact on health at levels currently seen in the UK. The committee heard evidence that both long- and short-term exposure to air pollution adversely affects health and that fine particles and NO2 are both important contributors [EP1].\n\nMembers noted that various metrics are used for particulate pollution including size (such as PM2.5, PM10 and ultra-fine particles), particle numbers and particle composition (such as black carbon and elemental carbon). They also noted a possible causal relationship between road-traffic-related air pollution and negative health outcomes, and that black carbon is an indicator for such pollution.\n\nShort-term exposure (over hours or days) to elevated levels of air pollution can lead to:\n\neffects on lung function\n\nexacerbation of conditions such as asthma\n\nincreases in hospital admissions and mortality.\n\nEpidemiological studies have shown that long-term exposure (over several years) reduces life-expectancy, mainly because of increased risk of mortality from cardiovascular and respiratory causes and from lung cancer [EP1].\n\nThe committee agreed that studies of interventions related to air pollutants are important but often carried out by disciplines other than public health and focus on environmental or road-traffic-related effects rather than health outcomes.\n\nThe committee agreed that measures of particles and nitrogen oxides (NOx) were a key indicator of road-traffic-related air pollution so members focused on these as a proxy for health outcomes. The connection between fuel efficiency and emission of air pollutants is well known, so proxy measures such as fuel efficiency are also useful if other metrics are not available.\n\n## Limits, guidelines and indicator values\n\nMaximum levels of outdoor air pollutants that affect health, such as particles (PM10 and PM2.5) and NO2, are set out in the 2008 Ambient Air Quality Directive (2008/50/EC) [EP2]. This was made law in England through the Air Quality Standards Regulations 2010, which sets targets and mandatory limits for levels of outdoor air pollutants. Equivalent regulations exist in Scotland, Wales and Northern Ireland.\n\nThere is also a public health outcomes framework indicator on air pollution. The June 2017 indicator is:\n\n'fraction of all-cause adult mortality attributable to anthropogenic particulate air pollution (measured as fine particulate matter, PM2.5)'.\n\nIn addition, the committee was aware of guideline values, including for PM2.5, PM10 and NO2, in the World Health Organization's Ambient (outdoor) air quality and health.\n\nMembers noted that there is little evidence to suggest a threshold below which no adverse health effects would be anticipated. So reducing pollution below the EU limits will provide even more health benefits.\n\n## Additional impacts\n\nThe committee agreed that interventions to address air pollution are also likely to help reduce climate change from emissions of CO2. Interventions that support a shift to active transport, like walking or cycling, will also lead to potentially substantial health benefits, mainly associated with increased physical activity levels.\n\nThe committee noted that a number of recommendations, principally those on planning, might have other impacts on health as a result of changes to, and use of, the built and natural environment. For instance, physical changes (such as changes that alter temperature or provide shade) might help prevent both overexposure to heat and skin cancer.\n\nIn addition, changes in the way the environment is viewed and used could mean more people socialise in that environment. Planning changes can also influence economic activity (and so, in turn, the health) of an area. But these issues were out of scope of the current guideline.\n\nThe committee noted that it was important to link information about air pollution to other health advice, such as the benefits of physical activity and the importance of social contact (see NICE's guideline on older people: independence and mental wellbeing).\n\n## Multiple interventions\n\nGenerally, the evidence gathered for this guideline examined single interventions. The committee felt that single, small scale actions were unlikely to lead to the significant reduction in air pollution needed to protect health. Although there was no evidence to demonstrate the effect, members agreed that multiple interventions, each producing a small benefit, would be likely to act cumulatively to produce significant change.\n\n## Monitoring\n\nThe committee agreed that although evidence suggests an intervention may produce a particular effect, local factors such as the type of vehicles involved, topography and weather conditions can all have an impact. It also agreed with evidence that air quality monitoring will be an important part of most large-scale changes – before and after implementation [EP2]. The committee noted that traffic data for most roads is currently ad-hoc and of low quality. Measurements of traffic will provide the high quality information needed for planning changes.\n\nThe committee noted that there was a risk that intended changes would erode over time as drivers became used to the change and readjust their behaviours. Continual monitoring of the effect of schemes and adjustments to them will probably be needed to ensure that positive, progressive effects are achieved.\n\n## Euro standards\n\nA recognised approach to tackling air pollution has been to develop plans and initiatives to encourage cleaner vehicles and to work with transport authorities to discourage high polluting vehicles from entering certain geographical areas. This is based on the assumption that newer vehicles will produce lower emissions.\n\nThe committee heard that tail-pipe emissions from vehicles are regulated under a series of European Directives (commonly referred to as Euro standards) for all types of vehicles [EP3]. The standards currently extend from Euro 1 to Euro 6 for cars and vans, and from Euro I to Euro VI for heavy goods vehicles (HGVs), buses and coaches.\n\nThe Euro standards have introduced progressively tighter emission limits for various air pollutants, but they have not led to a corresponding reduction in concentrations of NO2. The committee heard that this is because of a difference in emissions during test procedures compared with 'real world' driving, combined with an increase in the number of diesel vehicles on the road.\n\nThe committee heard that the latest Euro standard (6/VI) requires manufacturers to adhere to tighter standards of emissions. Although NOx emissions from Euro 6/VI diesel vehicles in normal use may be higher than the standard might suggest, they will be substantially lower than Euro 5/V vehicles. From September 2017, emissions tests for cars will include on-road tests as opposed to the laboratory tests that have been used to date. This is already a requirement for heavy duty vehicles.\n\n## Equality issues\n\nThe committee heard that children, older people and those with chronic health problems are among the most vulnerable to air pollution [EP1]. In addition, more deprived urban neighbourhoods often experience higher levels than more affluent areas. So any reduction in air pollution is likely to help tackle health inequalities. But at the same time, these vulnerable groups are less likely to be able to afford a new vehicle with low emissions and could be disadvantaged by any changes to restrict older, more polluting vehicles.\n\nOverall, the committee agreed that removing older vehicles from the road would reduce health inequalities, provided these groups could get to the places and services they need.\n\n## Cost effectiveness\n\nThe economic modelling was based on assessments of specific interventions that had demonstrated effectiveness. It suggests those interventions could be highly cost effective in some settings. But both the effect and cost of any intervention will be highly dependent on factors specific to the local setting, so this may vary considerably from the case studies. A key limitation is that there were no data on pollution dispersal in relation to population for any of the case studies modelled.\n\nSome identified benefits could not be quantified, suggesting that the overall benefits might be greater than the figure given. So the committee concluded that interventions could offer good value for money.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nexpert paper 1 (EP1): expert testimony on key issues in the epidemiology of air pollution and health\n\nexpert paper 2 (EP2): expert testimony on national and local frameworks for action\n\nexpert paper 3 (EP3): expert testimony on the use of Euro Standards to control vehicle emissions.\n\n# Planning\n\nThe discussion below explains how the committee made recommendations 1.1.1 to 1.1.3.\n\n## Rationale and impact\n\nSome evidence suggests that strategic plans can have an important influence on air pollution. Based on the epidemiological evidence on the health impacts of air pollution, particularly for vulnerable groups, and committee consensus, the committee recommended several approaches. This includes action to encourage a move to zero- and low-emission travel (including active travel) by linking to the existing NICE guideline on walking and cycling.\n\nSome expert testimony, supported by the committee's own expertise, suggests that the layout of new developments will affect motorised travel.\n\nThe committee agreed that it is important to take account of how air pollution disperses and where people spend time because these factors will influence their exposure.\n\nSome evidence showed that street trees and green walls or roofs have a mixed effect on street air quality – in some cases they restrict street ventilation causing poorer air quality, in others, they improve it.\n\nBecause the evidence was uncertain, the committee recommended this as an action to consider.\n\nThe committee agreed by consensus that if air pollution is not included in the current local plan, other local policies should be developed until it is updated. Because the evidence was uncertain they recommended this as an action to consider.\n\nOur built environment can affect the emission of road-traffic-related air pollutants by influencing how, and how much, we travel. It can also affect the way air pollutants are dispersed (through street design and the resulting impact on air flow). Some areas experience poor air quality from motor vehicles passing through (rather than travel within) an area.\n\nAir pollution issues are not always incorporated into local plans, making it difficult to reject a proposal that would have adverse effects.\n\nPhysical features (such as buildings, barriers, vegetation and landscape) influence the way air pollution moves and disperses and can sometimes create high pollution levels where people spend time. For instance, trees don't always reduce air pollution: it depends on the street design, species, number and siting of trees, canopy density, time of year and wind direction relative to the street.\n\nOnly a limited amount of new building occurs at a time, but it will have an impact on road-traffic-related air pollution for decades. In addition, relatively small changes in the layout of buildings (such as the siting of air vents away from the roadside or small increases in distance from sources of pollution) might have an important impact on residents' exposure to air pollutants.\n\nAddressing these and other issues at the planning stage may reduce the need for more expensive (and probably less effective) remedial action at a later date.\n\n## Evidence discussion\n\nThe committee agreed that the most important outcomes are health outcomes (for instance, mortality or exacerbations of respiratory conditions). But these are not usually measured directly in studies of air pollution, which rely instead on examining air pollutants. The most important of these are:\n\nambient levels of particles, in particular PM2.5\n\nambient levels of NO2.\n\nOther outcomes relating to the need to travel and choice of vehicles are also likely to be relevant to planning interventions.\n\nThe committee considered evidence on the impact of air pollution on health, particularly for vulnerable groups. This was from expert paper 1 but was based on the work of the Committee on the Medical Effects of Air Pollutants (COMEAP). Members also considered evidence on the impact of planning on air pollution. This was from expert paper 6 but was based on guidance produced by Environmental Protection UK and the Institute of Air Quality Management. Members agreed that both of these represented good quality evidence that could be used to support recommendations.\n\nThe committee considered the evidence of effectiveness of natural and artificial barriers in terms of impact on air pollutants.\n\nFive studies (4 from the USA, 1 from the UK) looked at barriers alongside major roads. All were rated as poor quality and so at high risk of bias [ES4.1a, ES4.1b].\n\nTwo of these studies examined solid noise barriers. They found that although barriers reduced air pollution in the immediate lee of the barrier, levels at some distance away were higher than without the barrier [ES4.1a].\n\nThe committee considered 3 modelling studies (2 from Belgium, 1 from the UK) that examined the impact of street trees and vegetation on air pollution [ES4.4]. One study was rated as moderate quality and 2 were rated as poor quality. They found that:\n\nVegetation that does not interfere with air flow in a street canyon (such as green roofs or walls, or vegetation not situated within a street canyon) may reduce air pollution.\n\nStreet trees were unlikely to reduce air pollution in most street designs and could worsen it in some cases.\n\nThe committee felt that the studies were plausible. No effectiveness studies were found.\n\nAnother 3 studies (1 from the UK, 1 from France, 1 from the US), rated as poor quality, agreed with what the committee knew about placing and maintaining trees but did not reduce the uncertainty in the evidence about their effects in any particular direction [ES4.4]. This further supports the need for additional research and the research recommendation developed by the committee.\n\nMembers agreed that specific factors in the individual settings were highly important in determining the outcome. However, they felt it was appropriate to recommend caution when using street trees and not to consider them as always being beneficial, because if they are poorly placed or maintained this may affect ventilation at street level and inadvertently create a canopy that traps air pollutants.\n\nThe committee agreed that the limited number of effectiveness studies (and the absence of corroboration of the findings of modelling studies around the effects of street trees) represented a gap in the available evidence base.\n\nBenefits include:\n\nNew developments that do not exacerbate poor air quality or expose people to high levels of air pollution and that encourage zero- and low-emission travel (including active travel).\n\nReduced risk of inadvertent exposure of people to poor air quality from the redistribution of pollution.\n\nUse of trees to encourage deposition of air pollutants, to reduce heat stress, provide shade and create a more attractive environment – all of which benefit health without inadvertently creating areas of poor air pollution.\n\nPotential harms include:\n\nUsing trees in areas where they do reduce ventilation.\n\nUsing barriers in a way that creates poorer air quality (see also the section on additional impacts in the overview at the start of the committee discussion).\n\nThe evidence reviewed did not focus on the unintended consequence of interventions that may increase allergen levels.\n\nTaking air pollution issues into account at the plan making stage involves additional cost for training in relevant issues and could have an impact on public consultation. However, this is likely to be relatively small. There will be a cost impact for developers. This may extend beyond the initial site if changes to infrastructure are needed.\n\nThe committee did not recommend widespread use of green walls and roofs. The evidence from the reviews (based on modelling studies) suggests that these may improve air quality in some circumstances (where it does not reduce ventilation in the street). However, the committee felt that the very high resource impact for retrofitting green walls and roofs to existing buildings was not likely to be cost effective in terms of air pollution reduction alone. But they may be appropriate for new buildings.\n\nThe committee agreed that urban trees and greenery play an important part in the urban landscape. They provide a number of positive benefits, including health benefits.\n\nLeaves and branches slow air currents, causing pollutants to settle out. They may also act as 'sinks' for particles and chemicals that may have direct or indirect effects on air quality (in particular, VOCs). The extent to which this is the case depends on factors such as species, time of year and growing conditions.\n\nThe impact of trees on ventilation in a street canyon will influence their impact on air quality. Ventilation will vary according to the size, distribution and species of tree and their position within the canyon. For instance, air quality might deteriorate at street level near vehicle sources if ventilation were restricted, while improving near first floor windows above the canopy.\n\nAlthough it is important to avoid the possible negative effects, it is also important to recognise the positive benefits of properly selected, sited and managed trees.\n\nThe committee discussed the dispersion of air pollutants by solid barriers. They agreed this is complex and depends on a range of local factors. There is some evidence to suggest that barriers may result in improved air quality near to the barrier but poorer air quality at a distance. As a result, air quality may be affected downwind from a roadside barrier. The impact on health will depend on the details of this dispersion and on where people live or spend time in relation to the barrier.\n\nThe committee noted that there was a concern that some local authorities might adopt the recommendations but others may not. This could mean that developers focus on areas with fewer controls, resulting in a loss of investment for those aiming for better air quality. It noted that recommendations to all local authorities might lead to a more consistent approach, to the benefit of all. It also noted members' experience of the benefits of a good quality environment in attracting developers.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 1: environmental change and development planning: ES4.1a, ES4.1b, ES4.4\n\nexpert paper 1 (EP1): expert testimony on key issues in the epidemiology of air pollution and health\n\nexpert paper 6 (EP6): expert testimony on the role of the local authority planning regime in delivering improvements to ambient air quality and in reducing public exposure to pollution.\n\n# Development management\n\nThe discussion below explains how the committee made recommendations 1.2.1 and 1.2.2.\n\n## Rationale and impact\n\nEvidence on actions to address road-traffic-related air pollution suggested that travel plans could offer an opportunity to re-evaluate journeys to work and help a more general move away from car travel. Committee members also noted from their experience that these plans could support zero- and low-emission travel and could be implemented as part of the planning approval process.\n\nEvidence indicated that the species, siting and management of trees and vegetation is important in reducing the risk of adversely affecting air quality.\n\nBecause the evidence was uncertain the committee recommended this as an action to consider.\n\nBased on their expertise, the committee agreed that it is appropriate to use funds from developers, via the Community Infrastructure Levy, to pay for work to address air pollution issues. They also agreed that this is best carried out in consultation with local communities. Because the evidence was uncertain the committee recommended this as an action to consider.\n\nLocal development plans do not always address traffic-related air pollution.\n\nIf action to reduce traffic-related air pollution is incorporated in the development plans for new buildings and estates, this will help maintain people's health and wellbeing, both in terms of reducing pollution levels and encouraging physical activity. In turn, this may help reduce the need for NHS treatment and other support in the future.\n\n## Evidence discussion\n\nThe committee agreed that the most important outcomes are health outcomes (for instance, mortality or exacerbations of respiratory conditions). But these are not usually measured directly in studies of air pollution, which rely instead on measuring air pollutant levels. The most important of these are:\n\nambient levels of particles, in particular PM2.5\n\nambient levels of NO2.\n\nOther outcomes relating to the need to travel and choice of vehicles are also likely to be relevant.\n\nThe committee considered evidence on the impact of air pollution on health, including for vulnerable groups. This was from expert paper 1 but was based on the work of the Committee on the Medical Effects of Air Pollutants (COMEAP). Members also considered evidence on the impact of planning on air pollution. This was from expert paper 6 but was based on guidance produced by Environmental Protection UK and the Institute of Air Quality Management. Members agreed that both of these represented good quality evidence that could be used to support recommendations.\n\nEvidence relating to travel plans consisted of 2 poor-quality studies [ES9.1a]. Both were carried out in the UK so the evidence is directly applicable. Both looked at changes in mode of travel, rather than air pollutant emission or air quality data. They focused on travel plans in workplaces. The studies suggest that information on, and the provision of facilities to support, other travel modes could reduce the number of people driving to work alone.\n\nThe committee also considered a qualitative study from the UK on factors influencing the uptake of travel plans [ES9.1b]. The committee felt that this evidence was applicable to wider settings.\n\nThe committee considered the evidence of effectiveness of natural and artificial barriers (see the discussion of recommendations 1.1.1 and 1.1.2 above) and the management of trees and vegetation.\n\nFive studies (4 from the USA, 1 from the UK) looked at barriers alongside major roads. All were rated as poor quality and so at high risk of bias [ES4.1a, ES4.1b].\n\nMembers agreed that factors such as siting, pruning and species were important in determining the outcome [ES4.4]. So it was appropriate to recommend considering these factors to avoid creating a canopy that traps air pollutants, ensuring air pollution is reduced and ensuring we gain the other benefits from sensitive use of trees and vegetation.\n\nBenefits include:\n\nNew developments that do not exacerbate poor air quality or expose people to high levels of air pollution and that encourage zero- and low-emission travel (including active travel).\n\nReduced risk of inadvertent exposure of people to poor air quality from the redistribution of air pollutants.\n\nUse of trees to encourage deposition of air pollutants, reduce heat stress, provide shade and create a more attractive environment – all of which benefit health without inadvertently creating areas of poor air pollution.\n\nPotential harms include:\n\nUsing trees in areas where they do reduce ventilation.\n\nUsing barriers in a way that creates poorer air quality (see also the section on additional impacts in the overview at the start of the committee discussion).\n\nTaking air pollution issues into account at the development management stage involves additional cost for training in relevant issues, assessment of planning applications and any additional impact on public consultation. However, this is likely to be relatively small. There will be a cost impact for developers. This may extend beyond the initial site if changes to infrastructure are needed.\n\nThe committee agreed that urban trees and greenery play an important part in the urban landscape. They provide a number of positive benefits, including health benefits.\n\nThe committee agreed that local planning and transport officers, in consultation with air quality or pollution control officers, are best placed to ensure that trees and barriers are used effectively in urban areas.\n\nThe committee agreed that parking plans (including park and ride plans) are an important way to help reduce motorised trips and avoid the traffic congestion that can be caused when people are having to spend time searching for a parking space.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 1: environmental change and development planning: ES4.1a, ES4.1b, ES4.4\n\nevidence review 3: travel planning and other initiatives providing information, advice, education and skill development: ES9.1a, ES9.1b, ES10.1\n\nexpert paper 1 (EP1): expert testimony on key issues in the epidemiology of air pollution and health\n\nexpert paper 6 (EP6): expert testimony on the role of the local authority planning regime in delivering improvements to ambient air quality and in reducing public exposure to pollution.\n\n# Clean air zones\n\nThe discussion below explains how the committee made recommendations 1.3.1 to 1.3.8.\n\n## Rationale and impact\n\nSome evidence suggested that area-wide action is needed to reduce the use of polluting vehicles and to encourage a shift to zero- and low-emission travel.\n\nSome of this evidence showed that existing low-emission zones (the current nearest equivalent to a clean air zone) have only slightly improved air quality. This is partly because of the failure of new technology to reduce individual vehicle emissions under real driving conditions. But it is also probably linked to the limited scope of existing low-emission zones, in terms of class of vehicles restricted, and the failure to address the overall volume of traffic.\n\nSome evidence suggested that reducing air pollution below current EU limits would provide more health benefits. The committee agreed that stricter targets should be considered because there is a lack of evidence on how effective a lower threshold would be. They also recognised that there are likely to be greater health benefits if pollution is lower than the legislative limits, so reduction to these limits is a minimum and should not be the maximum target for reducing air pollution. Members agreed that targets should be developed with health goals in mind but that, in practice, these will be expressed as air pollution targets.\n\nMembers agreed that the focus should not be limited to taking action to reduce air pollution hotspots alone.\n\nBecause the evidence was uncertain the committee recommended this as an action to consider.\n\nCost-effectiveness evidence suggested that low-emission zones could be cost effective. Committee members agreed that it was important to aim for consistency across the country, particularly in relation to the vehicle types that are restricted.\n\nBoth air pollutants and their sources are mobile, so actions in one area may affect another. No evidence looked at this empirically, but the committee agreed it would be useful to take a wider geographical approach, involving cooperation across local authority boundaries. The evidence was uncertain (based on committee consensus) but the committee felt it was particularly important not to simply move the problem to another community so they made a strong recommendation.\n\nThe committee noted that active travel (such as walking and cycling) was linked to a range of other health benefits. This is covered by evidence used to develop other NICE guidelines.\n\nSome evidence suggested potential benefits could be gained from using zero- and low-emission vehicles. This supported expert testimony on the actions of the Department for Environment Food and Rural Affairs to speed up the transition to a low-emission economy. The committee agreed that infrastructure (in particular, charging points) is needed to achieve significant uptake of zero- or low-emission motor vehicles.\n\nBecause the evidence for all these actions was uncertain, the committee recommended these as actions to consider.\n\nThere was some evidence on addressing driving style and traffic flow and this supported the committee's knowledge of how air pollution is produced. They agreed that training to reduce idling and to encourage people to change their driving style is unlikely to have any negative effects.\n\nNo direct evidence was found on local deliveries or private hire vehicles. However, based on the committee's experience, they suggested action to combat the large contribution that they can both make to air pollution.\n\nThey agreed that air pollution from congestion related to deliveries might be addressed by thinking about delivery schedules and by training and accreditation of fleets using a fleet recognition scheme. In addition, it may help reduce fuel use resulting in reduced emissions. Because the evidence was uncertain, they recommended this as an action to consider.\n\nSome evidence, together with the committee's experience, suggested that congestion charging could contribute to a package of measures and incentives to address air pollution where congestion was identified as a significant cause. Because the evidence was uncertain, the committee recommended this as an action to consider.\n\nMembers agreed that it was important to monitor outside the zone to identify whether traffic is moving elsewhere and resulting in poor air quality in those areas. They also agreed that adjustments should be made in such cases. Because the evidence was uncertain (committee consensus), the committee recommended this as an action to consider.\n\nThe committee agreed that people living in deprived areas are more likely to be exposed to higher levels of air pollution and so might gain more from changes that reduce it. But at the same time, they may be less likely to be able to afford new vehicles and so might be disadvantaged by a charging scheme. The committee agreed that the potential impact that charging may have on inequalities should be taken into account. This was based on uncertain evidence (committee consensus) but the committee felt it was particularly important so they made a strong recommendation.\n\nPiecemeal, uncoordinated actions to tackle air pollution may make the situation worse. For example, the use of single interventions such as 'alternate car days', in which half the vehicle fleet is banned from an area on alternate days, may inadvertently encourage the use of older, poor performing vehicles.\n\nSimilarly, if different vehicle types are not classed in the same way in all clean air zones, then the overall impact will be diminished.\n\nPlanning, transport and environment departments will need to work together across the country to ensure a consistent approach. More consistent, concerted action to change current practice will, in turn, improve people's health, by:\n\nreducing the ill effects of air pollution\n\nencouraging more people to become more active, by adopting active travel as a lifestyle choice.\n\n## Evidence discussion\n\nThe committee agreed that the most important outcomes in the absence of measured health outcomes are a reduction in the following air pollutants:\n\nParticles, especially PM2.5 and the vehicle-related components of PM2.5 (such as black carbon)\n\nNO2.\n\nIdeally these outcomes should be measured in the ambient air (the air that we breathe). But for many outcomes, changes in total emission levels or vehicle kilometres driven suffice and have been used to determine the effect of interventions.\n\nThe committee noted that ambient NO2 concentrations are more sensitive to changes in local transport than total PM2.5.\n\nOther relevant outcomes include changes in number and type of vehicles in the zone.\n\nThe committee considered the evidence of effectiveness for various elements of clean air zones:\n\nSix studies of low-emission zones (2 from the Netherlands, 3 from Germany and 1 from the UK) found some evidence of reductions in pollution, particularly with more stringent restrictions on vehicle classes [ES6.3]. Four studies were rated as moderate quality and 2 as poor quality. All were at some risk of bias but overall the committee considered the evidence sufficient to support the recommendations.\n\nTwo cost-effectiveness studies (1 from Italy and 1 from Sweden) that examined congestion charging zones in Milan and Stockholm, suggested that they were cost effective, although local factors mean that they are only partially applicable to the UK [ES6.2]. Both studies were rated as moderate quality.\n\nFour modelling studies of the use of alternative fuels (3 poor quality from Spain and 1 poor quality from the UK) showed the potential for considerable improvements in air quality from fuel changes if the penetration of the technologies is large enough [ES3.3]. As modelling studies, they involve greater uncertainty. However, the committee agreed that that they support the recommendations.\n\nFive studies of traffic restrictions (1 each from Italy, Korea and Israel, 2 from the US) suggested that vehicle restrictions or bans have little impact unless they restrict the volume of traffic substantially [ES5.1]. All were at some risk of bias, 3 were rated as poor quality and 2 as moderate quality.\n\nThree studies (2 from the UK, 1 from Italy) looked at congestion charging schemes [ES6.1]. All were at risk of bias (rated as poor quality) but committee members agreed with the evidence from their expert perspectives. The study from Italy found some reduction in elements of road-traffic-related air pollution.\n\nThree moderate-quality cost-effectiveness studies (from the US) looked at changes to vehicle fleets [ES3.4]. These suggested that changes to emission-controlled diesel or compressed natural gas were not cost effective when viewed against medical interventions. However, they were within the range normally considered cost effective for interventions to address mobile or stationary air pollution.\n\nOne poor-quality study from the US found that a 10% to 20% reduction in fuel consumption could be obtained by using wireless technology to inform drivers of the appropriate speed on major roads [ES11.1].\n\nTwo studies (1 from Canada and 1 from the Netherlands) looked at the impact of information and training on driver behaviour [ES11.2]. Both were rated as poor quality. They suggested that information and training might help reduce fuel consumption and time spent idling.\n\nThe effect of anti-idling information campaigns for bus drivers was considered in 2 linked studies from the US [ES11.4]. Both were rated as poor quality and so at risk of bias. They suggested that such campaigns could reduce the time school buses spent idling.\n\nThe committee considered the evidence of effectiveness of charging zones on air quality.\n\nThree studies (2 from the UK, 1 from Italy) looked at charging schemes [ES6.1]. All were rated as poor quality. The studies from the UK failed to find clear evidence of reductions in air pollution. This may in part be because of the failure of Euro standards to produce the modelled benefits. The study from Italy suggested that there were some reductions in particulate air pollution most heavily linked to vehicle use. However, it is possible that there are differences in the vehicle fleet between Italy and the UK, meaning that this is only partially applicable. The committee agreed that this evidence supported the recommendations.\n\nTwo cost-effectiveness studies (1 from Sweden rated as moderate quality and 1 from Italy rated as moderate quality) looked at the costs and benefits of congestion charging schemes [ES6.2]. Both were at some risk of bias. Both suggested greater benefits than costs. However, the main benefits came from changes to traffic flow, travel time savings and reductions in road injuries, rather than from air pollution savings. Local factors (such as the limited number of access points to the islands of Stockholm and differences in the vehicle fleet) mean that the evidence is partially applicable. The committee agreed that this evidence supported the recommendations.\n\nBenefits include:\n\nDiscouraging use of the most polluting vehicles, by restricting their access to some areas or by encouraging zero- or low-emission travel, will improve local air quality.\n\nIncreased levels of physical activity from encouraging 'active' travel.\n\nA reduction in health inequalities by reducing vulnerable groups' exposure to poor air quality.\n\nPotential harms arise from:\n\nApproaches covering only limited classes of vehicles or geographical areas not reducing emissions sufficiently, or moving the pollution elsewhere.\n\nPeople who depend on highly polluting vehicles or older vehicles that do not meet current emission standards not being able to afford to replace them.\n\nLarge-scale schemes such as city-wide clean air zones (that can include low-emission zones) can be expensive to set up – but they can deliver substantial benefits. They also target a large population, meaning that the cost per head of population is likely to be relatively low.\n\nMuch of the cost relates to setting up. Running costs are likely to be substantially lower (and potentially covered by charges or fines). Ongoing income can then be used for other activities to reduce air pollution. Demonstrating a link between income raised and funding activities to reduce air pollution is likely to encourage public support for the actions.\n\nEvidence in the economic modelling suggested an annual cost of around £2 per head for the Amsterdam low-emission zone. Although a clean air zone involving a range of interventions might be more expensive, the committee felt this was likely to have an additive positive effect.\n\nThere are no data for clean air zones so the economic model considered 1 component – low-emission zones. It estimated a cost per quality-adjusted life year (QALY) of around £2,240. The committee noted this is likely to decrease as vehicle fleets progressively improve because of regulation, unless restrictions evolve to take into account improving vehicle standards. Nevertheless, because they have a benefit–cost ratio of around 29 (that is, £29 of benefit for every £1 spent) the committee considered the impact of these zones is unlikely to stop representing good value for money.\n\nInterventions to encourage reductions in vehicle idling were included in the economic modelling. Using a study that assessed the impact of a campaign to tackle bus idling at 4 schools in Cincinnati the model estimated a cost per QALY of £157 and a benefit–cost ratio of 44. The committee noted the benefit was based on the best-performing school, some schools showed no improvement The committee felt that it was reasonable to extrapolate from this to interventions aimed at reducing idling more widely.\n\nThe committee heard about the draft national clean air zone framework (Department for Environment, Food and Rural Affairs' Air quality plan for nitrogen dioxide in UK) that aims to achieve compliance with the EU NO2 limit values and the implementation of clean air zones [EP5]. Members noted that evidence about the effectiveness of clean air zones does not exist because they have yet to be implemented. However, they heard evidence about actions that might constitute a clean air zone (in particular low-emission zones) [EP2]. The committee heard expert testimony on influencing drivers' behaviour [EP4] which noted that better driving can reduce emissions and fuel consumptions.\n\nThe committee noted that the contribution of diesel cars to NO2 pollution was substantial [EP3]. Which vehicle types need to be restricted in a particular area to protect health would need to be assessed in light of local conditions. This would include assessing the timetable to implement changes and amending restrictions if modelled targets for health goals are not achieved, including the possibility of an introductory advisory-only restriction.\n\nMembers discussed providing parking concessions for lower-emission vehicles, such as electric vehicles, as an incentive for people to buy them. But they felt that such subsidies would be going to people who can afford expensive vehicles. In addition, in areas of high housing density, off-street space for charging electric vehicles is rare. So support for on-street charging would be necessary to alleviate any potential inequalities this may cause.\n\nThe committee agreed that the bulk of the actions would need to be taken by transport authorities. These are located in county council and unitary authorities. Environmental issues may be located in other authorities such as district councils. Directors of public health should sign off annual status reports and air quality management action plans. The committee felt that it was appropriate to target recommendations at these groups.\n\nThe committee agreed that although road traffic was a key contributor to poor air quality, other sources would need to be tackled as well. These would depend on local circumstances but would be likely to include gas-powered domestic boilers, domestic biomass use and combined heat and power stations.\n\nThe committee noted that perceptions about charging schemes risked reducing their effectiveness and antagonising the public. These include the perception that schemes are aimed at income generation rather than reducing air pollution, or that restrictions would inevitably damage economic growth and activity. It felt that emphasising the public health benefit of the schemes and adopting a consistent national approach would be important in limiting these misperceptions.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 1: environmental change and development planning: ES3.3, ES3.4\n\nevidence review 2: traffic management and enforcement, and financial incentives and disincentives: ES5.1, ES6.1, ES6.2, ES6.3\n\nevidence review 3: travel planning and advice: ES11.1, ES11.2, ES11.4\n\nexpert paper 1 (EP1): expert testimony on epidemiology\n\nexpert paper 2 (EP2): expert testimony on national and local frameworks for action\n\nexpert paper 3 (EP3): expert testimony on the use of Euro Standards to control vehicle emissions\n\nexpert paper 4 (EP4): expert testimony on evidence relating to influencing driving behaviours for fleet drivers and others\n\nexpert paper 5 (EP5): expert testimony on the proposed clean air zones.\n\n# Reducing emissions from public sector transport services and vehicle fleets\n\nThe discussion below explains how the committee made recommendations 1.4.1 to 1.4.6.\n\n## Rationale and impact\n\nSome evidence showed that changes to driving style may be used to lower levels of local pollution, as well as reducing fuel use. It also showed that people can be encouraged to make these changes.\n\nSome evidence suggests that if large numbers of people change their driving style this, combined with other measures to reduce traffic, could have a positive effect on the environment. An expert also told the committee that fuel consumption could be reduced by around 20% to 25% by adopting efficient driving techniques, with a realistic long-term reduction of between 5% and 10%.\n\nBased on this evidence and their own experience, the committee felt that providing support to help people change their driving style was justified. They also noted that this would be cost neutral because of the savings generated by better fuel efficiency. Because the evidence was uncertain, the committee recommended these as actions to consider. The committee was aware of NICE's guideline on behaviour change: individual approaches and added a link to this in recommendation 1.4.4 but did not specify the type of rewards for those who drive efficiently.\n\nThe committee agreed by consensus that procurement of less polluting vehicles will help public sector organisations to reduce road-traffic-related air pollution. Members noted that this could be done as older vehicles are replaced. Because the evidence was uncertain, they recommended this as an action to consider.\n\nThe public sector fleet is substantial. It includes various vehicle types (from local authority refuse vehicles and goods vehicles to lease cars and patient transport vehicles) many of which are highly polluting.\n\nPublic sector decisions about vehicle procurement don't always take air pollution into account. In addition, many drivers are unaware of the impact their driving has on air pollution, and about practical changes they could make to reduce this. Currently only around 20% of people employed as drivers have been trained in efficient driving by their employer.\n\nMaking changes will help the public sector fleet to meet its duty to address its environmental impact, reduce emissions and promote the public's health and wellbeing.\n\n## Evidence discussion\n\nThe committee agreed that although outcomes relating to ambient air quality are important for health it would be unlikely to find studies that reported these in relation to changes to driving style.\n\nOther more likely outcomes are:\n\nlength of time a vehicle is left idling\n\noverall fuel consumption.\n\nThe committee considered modelling evidence from 1 poor-quality US study [ES11.1]. This suggested that information on an appropriate speed could reduce emissions on major roads. The study was modelling only and rated as poor quality so the results were treated with caution. But the committee felt that it, together with other evidence, supported the recommendation.\n\nThe committee considered evidence of effectiveness from 2 studies (1 from Canada and 1 from the Netherlands) that looked at the impact of information and training on driver behaviour [ES11.2]. Both studies were rated as poor quality and so at risk of bias. They suggested that information and training might help reduce fuel consumption and time spent idling.\n\nThe committee considered the effect of anti-idling information campaigns for bus drivers in 2 linked studies from the US [ES11.4]. Both were rated as poor quality and so at risk of bias. It suggested that educating drivers about the importance of reducing the time they spend idling could be effective.\n\nThe committee considered qualitative evidence that looked at factors that influence the likelihood of people changing their driving style. One moderate-quality study from the UK suggested several factors likely to support the uptake of 'eco driving' [ES11.3]. The authors felt that a focus on cost savings, in-vehicle information and systems to feedback progress were key.\n\nKey elements in reducing fuel consumption were vehicle maintenance (in particular ensuring correct tyre pressure), gear selection and avoiding aggressive acceleration.\n\nAlthough in general the evidence was of poor quality, committee members felt that it was consistent with what they would expect from their own experience and so supported the recommendations.\n\nBenefits include:\n\nIncreased knowledge about factors associated with fuel economy. Putting this knowledge into practice will result in lower fuel use and improved air quality.\n\nEnergy-efficient driving with fewer rapid accelerations and decelerations. This will improve fuel consumption and reduce wear and tear on vehicles, leading to financial benefits.\n\nEnergy-efficient driving with fewer rapid accelerations and decelerations may reduce road danger and encourage others to walk or cycle, resulting in lower total emissions.\n\nTraining public sector staff may have the additional benefit of altering their driving habits outside work. It may also help to make these habits the norm more generally.\n\nEvidence from expert testimony suggested that efficient driving training is likely to be cost saving [EP4]. Training costs are estimated at a one-off cost of £25 to £30 per driver, with an annual fuel saving of around £96. If training is provided as part of existing programmes for staff, the marginal cost is likely to be small.\n\nUse of telematics would be likely to have an additional cost. However, the committee felt these costs were likely to be small.\n\nIt would be most logical to make changes to the vehicle fleet as part of the usual turnover of vehicles. Any resource impact would depend on the extent of changes and the relative cost of vehicles. This would need to be managed within available resources.\n\nThe committee noted that the potential for financial savings and health benefits meant that these recommendations were highly relevant to the public sector. But the committee also felt that adoption of the recommendations by the public sector would act as an example of good practice that might be taken up in other sectors. In addition, it noted the potential for a positive knock-on effect if energy-efficient driving habits developed at work were carried over into people's personal lives.\n\nMembers noted that the views of those receiving training are important in determining the potential for success. They noted that there is a perception that air pollution levels inside a vehicle are lower than outside but this may not be the case.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 3: travel planning and advice: ES11.1, ES11.2, ES11.3, ES11.4\n\nexpert paper 4 (EP4): expert testimony on influencing driving behaviours for fleet drivers and others.\n\n# Smooth driving and speed reduction\n\nThe discussion below explains how the committee made recommendations 1.5.1 and 1.5.2.\n\n## Rationale and impact\n\nEvidence on using lower speed limits, encouraging smoother driving and providing real-time information showed that reducing 'stop–go' driving could help reduce emissions of air pollutants. This was supported by the committee's understanding of air pollution and the effect of accelerations and decelerations.\n\nThe committee agreed that signs displaying drivers' current speed would encourage a smoother driving style.\n\nBecause the evidence was uncertain they recommended these as actions to consider.\n\nSome evidence on physical speed reduction measures like humps and bumps suggested that individual measures may increase motor vehicle emissions by encouraging decelerations and accelerations. But evidence from area-wide schemes does not back this up.\n\nSo where physical measures are needed to reduce road injuries, the committee agreed that area-wide schemes should be designed to minimise the impact on air pollution. Because the evidence was uncertain, the committee recommended this as an action to consider.\n\nSpeeding motor vehicles in residential areas discourages people from walking and cycling, increases the risk of injury and increases traffic-related air pollution.\n\nEnsuring motorists drive steadily at the optimum speed can help reduce stop–go driving and so improve fuel consumption as well as reducing congestion and air pollution. Reducing the speed limit in residential areas, while making sure that it does not result in an increase in vehicle emissions, will reduce road danger, injuries and air pollution.\n\n## Evidence discussion\n\nThe committee agreed that the most important outcomes are:\n\nAmbient levels of air pollutants, in particular NO2 and PM2.5.\n\nIndividual vehicle emissions of these pollutants.\n\nThe committee considered the evidence relating to the impact of motorway speed.\n\nTwo studies examined the effect of schemes to reduce speed on urban motorways [ES6.4]. Both were from the Netherlands; 1 was rated poor quality and 1 moderate quality. They showed that speed limits and enforcement on urban motorways have a small positive effect on PM10 and NO2. The emission reduction depends on the impact of speed management on traffic dynamics, so the larger the reduction in traffic congestion the larger the emission reduction. Although this evidence is poor quality, it supports the understanding of traffic flow dynamics and air pollution production. Although the studies are from the Netherlands they are applicable to the UK.\n\nOne modelling study from the US noted savings in fuel consumption using wireless technology to inform drivers of the optimum speed on a major road [ES11.1].\n\nThe committee agreed that these studies were in line with expectations about the effect of smoothing traffic flow by reducing speed [ES6.4]. Members noted that where flow was not improved by changes to the speed limit (generally in less congested conditions) it would be unlikely that air quality would improve.\n\nThe committee discussed the modelling study [ES11.1]. This suggested substantial benefits were possible from changes to the behaviour of relatively small numbers of drivers. This had been achieved using wireless technology to identify the optimum speed. Although this was plausible, it would not be implementable at the moment because of lack of the necessary technology in vehicles to receive information about the current optimum speed. However, a similar effect might be obtained by the expansion of variable limit speed control using signs outside the vehicle.\n\nThe committee considered the evidence on the effect on air pollution of traffic-calming schemes.\n\nTwo poor-quality studies from the UK suggested that there was no significant impact on ambient NO2 concentrations from the construction of an area-wide traffic-calming scheme [ES5.2].\n\nFour modelling studies examined the emissions from individual vehicles [ES5.3]. Two moderate-quality studies were from Canada and 1 each, both poor quality, were from the US and UK.\n\nTwo poor-quality studies of area-wide traffic calming from the UK did not show significant changes in area-wide air quality. The changes seen were within the margin of error of the measurement techniques used.\n\nThe committee noted that the modelling evidence suggested that individual traffic-calming measures tended to increase emissions from vehicles because of the increase in accelerations and decelerations. The UK modelling study cited 9 measures including road humps, pinch points, raised junctions, chicanes and mini-roundabouts. Although there are uncertainties associated with the modelling, these studies supported an increase in emissions associated with individual traffic-calming measures.\n\nOne study was carried out in the UK on existing measures and so is applicable; others were carried out elsewhere and so differences in the design of measures and the make-up of the vehicle fleet mean that they are partially applicable.\n\nBenefits include:\n\nReducing stop–go driving will lower emissions of air pollutants from accelerations and decelerations, lowering exposure of the population to poor air quality.\n\nReduced speeds in urban areas supports a modal shift to walking and cycling. This will reduce emissions of air pollutants.\n\nReduced speeds reduces the number and severity of road injuries.\n\nThe economic modelling included examination of speed restrictions around Amsterdam. This suggested that the reduction in the speed limit on a section of motorway from 100\xa0kph to 80\xa0kph was highly cost effective at reducing air pollution (cost per QALY approximately £1,290, benefit–cost ratio 51). However, the committee noted costs will vary depending on the existing enforcement infrastructure already in place and whether additional speed cameras are needed.\n\nThe committee noted that altering driving behaviour to reduce emissions has 2 elements: education and restriction. The committee felt that these complementary elements should both be included in the guideline separately. Education is addressed in recommendations 1.4.1 to 1.4.5. Recommendations 1.5.1 to 1.5.2 address restriction.\n\nThe committee discussed the possibility of using average speed technology to reduce this risk in various areas. It noted that on major roads where there are very few (or no) route choices the cost is likely to be small because only a limited number of speed cameras would be needed. However, in other areas (such as residential streets) there were possible benefits, but implementation would be difficult or impossible because of the number of route options. Other measures (such as signs indicating current speed) were more likely to be useful in these areas.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 2: traffic management and enforcement, and financial incentives and disincentives: ES5.2, ES5.3, ES6.4\n\nevidence review 3: travel planning and advice: ES11.1.\n\n# Walking and cycling\n\nThe discussion below explains how the committee made recommendations 1.6.1 to 1.6.3.\n\n## Rationale and impact\n\nThe committee agreed that it was important to support a general shift from motor vehicles to more active travel. They also agreed that this needed doing in a way that minimises cyclists' exposure to air pollution for example, by providing a choice of cycle routes.\n\nIn addition, evidence suggested that increasing the space between cyclists and motor traffic helps protect cyclists from air pollution. Although this evidence was uncertain, it agrees with the committee's understanding of the sources and dispersal of air pollutants.\n\nSome evidence suggested that where it is not possible to create cycle routes using quiet streets, separating cycle routes from motor traffic and reducing the time spent by cyclists in areas of high pollution, including busy sites, helps protect them from air pollution.\n\nSome evidence suggested that using dense foliage as a barrier may sometimes help protect cyclists from motor vehicle emissions, but the impact on the distribution of air pollutants needs to be taken into account. The committee agreed that the evidence supported its understanding of the dispersal of air pollutants. They also noted that it was important to take account of the need for cyclists to be visible to reduce the risk of collisions and to help normalise cycling.\n\nBecause the evidence was uncertain the committee recommended this as an action to consider.\n\nCyclists and pedestrians are vulnerable to road-traffic-related air pollution as well as other injuries on the road. Both factors discourage people from taking up these zero-emission modes of transport.\n\nEncouraging active travel such as walking and cycling will help reduce traffic-related air pollution and help people to be more physically active. Incorporating the rest of the recommendations at the design stage of new cycle routes will help improve the currently patchy provision across the country. It will also encourage planners to consider exposure to air pollution, which currently is not always taken into account.\n\n## Evidence discussion\n\nAmbient levels of air pollutants, in particular NO2 and PM2.5.\n\nThe committee considered the evidence of the impact of cycle route design on exposure to air pollution [ES3.1]. This included 6 studies that examined the siting and design of cycle routes: 3 from the US, 1 each from the Netherlands, Canada and the UK. All were rated as poor quality:\n\nAll 6 found exposure to PM2.5 was lower in low traffic routes and air pollution levels were reduced by increasing separation.\n\nShelter provided by vegetation reduced levels of exposure to air pollutants; conversely, peak levels of exposure were seen in conjunction with junctions and waiting at signals.\n\nOne study suggested exposure for drivers was as high as for cyclists.\n\nThere is considerable variation in measurement techniques used, which introduces uncertainty. However, the results are in line with what is known about dispersion of air pollutants in general.\n\nThe committee felt that although the evidence was of poor quality it was plausible. The reduction in air pollution with distance from the source is well understood and follows a simple mathematical relationship.\n\nES4.1b examined natural barriers. One UK study found a positive effect from a dense hedge adjoining a major road. Although this was a poor-quality study the committee felt it was plausible, based on its understanding of the deposition of air pollutants. Because the evidence was uncertain, the committee recommended this as an action to consider.\n\nBenefits include:\n\nPositioning cycle routes away from areas of poor air quality will reduce the exposure of cyclists to air pollution.\n\nPerceptions of poor air quality put some people off cycling. Improving air quality will encourage more people to cycle and so further reduce air pollution.\n\nThose encouraged to cycle will also benefit from being more physically active.\n\nPotential harms could arise from collisions as a result of poorly designed cycle routes.\n\nConstruction and maintenance of dedicated and separated cycle routes may entail additional costs, but it is not as expensive as constructing and maintaining vehicular roads.\n\nModelling of the cost effectiveness of off-road cycle routes suggested that they were good value for money. The cost per QALY was estimated at around £5,080, with a benefit–cost ratio of 14. This analysis included additional monetised benefits of £64,000 resulting from increased take up of cycling. The committee noted the intervention costs and benefits calculated assume several routes are developed. Developing a single route would cost less, but may also be less effective because it is likely to reach less of the population.\n\nThe committee noted that a variety of terms are used in the studies. The definitions are often not clear and may vary between studies (for example: cycle routes, paths and lanes). Members agreed that, other factors being equal, the significant factor in terms of exposure was the distance between the source (motor vehicles) and the cyclist. They also agreed to use the term 'cycle route'.\n\nThe committee was aware from members' own experience that air pollution concerns were among the factors putting some people off cycling. Taking action to address this would support the overall goal of achieving a shift in transport choices and so an overall reduction in air pollution.\n\nThe committee noted there was considerable uncertainty in this modelling. However, it agreed that off-road cycle paths could be cost effective in some circumstances.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 1: environmental change and development planning: ES 3.1, ES4.1b.\n\n# Awareness raising\n\nThe discussion below explains how the committee made recommendations 1.7.1 to 1.7.7.\n\n## Rationale and impact\n\nEvidence on the impact of air pollution on health provided justification for action to raise awareness of the issues and ways to mitigate the problems. The committee agreed that community support is always important when aiming for sustainable changes in behaviour. This supported the evidence on interventions to change behaviours related to air pollution. Members noted that this is in line with other NICE guidelines.\n\nThe committee agreed that local, national and social media techniques are useful ways to disseminate information about the Daily Air Quality Index, particularly to vulnerable groups. Because the evidence was uncertain the committee recommended this as an action to consider.\n\nThe committee agreed that it is important to give the public information on how road-traffic-related air pollution affects their health and on how their transport choices (such as driving during episodes of high pollution) contribute to this. Because the evidence was uncertain the committee recommended this as an action to consider.\n\nSome evidence relating to partial or occasional traffic restrictions suggested a limited effect. But the committee agreed that such restrictions offer the opportunity to demonstrate the positive benefits. So the consensus was that it is reasonable to use them as part of occasional awareness-raising activities. Because the evidence was uncertain the committee recommended this as an action to consider.\n\nThe committee agreed that it is reasonable to make businesses aware of the need to reduce air pollution, by encouraging active travel and more energy-efficient driving. Members noted that scheduling deliveries to avoid times when streets are congested might also reduce the contribution businesses make to congestion and the resulting pollution. Because the evidence was uncertain the committee recommended this as an action to consider.\n\nThe committee agreed that information provided by healthcare professionals is likely to be important in highlighting the effect of air pollution on health. So it is important to ensure health professionals are aware of the facts and can communicate them to vulnerable groups. Because the evidence was uncertain the committee recommended this as an action to consider.\n\nMany people do not understand the link between health and road-traffic-related air pollution. For example, they do not realise that long-term exposure to typical levels of air pollution causes far more health problems than short-term exposure to higher levels. In addition, they do not realise that they can help reduce this pollution, as well as their exposure to it, if they change their behaviour.\n\nWithout this understanding it will be difficult to get public support for the changes needed. Without such support changes are unlikely to be sustainable and implementing them would be unethical.\n\nIf healthcare professionals routinely raise air pollution as an issue affecting health, this could help prevent health conditions escalating, particularly among the most vulnerable groups. If local authorities raise awareness about air pollution with businesses and the public, this could help reduce air pollution and resulting ill health, so meeting their duty to protect people's health and wellbeing.\n\nIn both cases, this would also reduce the need for potentially more expensive and less effective remedial action later.\n\n## Evidence discussion\n\nReduced exposure to air pollution (NO2 and particles) is the main outcome in determining health effects. Changes in knowledge and behaviours that may to lead to reduced exposure (either for the person or the wider community) are important.\n\nThe committee heard expert testimony on the extent of the impact of air pollution on health [EP1]. It noted that some groups are more likely to be at risk from air pollution.\n\nThe committee heard expert testimony on influencing drivers' behaviour [EP4].\n\nThe committee felt that members' experience of working on air pollution, together with the wider public health evidence (including NICE guidance on behaviour change and community engagement), justified these recommendations.\n\nThe committee considered the evidence of effectiveness of traffic restrictions on air pollution from 5 studies of traffic restrictions (1 each from Italy, Korea and Israel, 2 from the US). The evidence suggested that vehicle restrictions or bans have little impact unless they restrict the volume of traffic substantially [ES5.1]. All were at some risk of bias, 3 were rated as poor quality and 2 as moderate quality.\n\nRaising awareness of air pollution will:\n\nHelp people, particularly those who are most vulnerable, to reduce their exposure – especially when levels of pollution are high.\n\nHelp people understand how to change their behaviour to reduce emissions, thereby further reducing population-level exposure.\n\nSupport the development of social networks (social capital), which can be built on for benefits in other areas.\n\nActions to reduce the amount of polluted air from entering a home (such as closing windows) might increase indoor levels of air pollutants, if there are other sources of pollution in the house. Potential harm may also be caused if unfounded concerns are raised about the possible health effects of air pollution.\n\nNo cost-effectiveness evidence or modelling was identified for this recommendation. The committee noted that local agencies were likely to have resources capable of addressing these issues by developing effective local communications strategies. Developing an effective strategy would involve a cost but this would be more likely to be successful.\n\nThe committee noted that training healthcare workers about air pollution would have a cost. However, this could form part of continuing professional development so would be cost neutral. There was also the potential for cost savings if exacerbations of ill health (such as asthma), and so hospital attendances, were reduced.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nevidence review 2: traffic management and enforcement, and financial incentives and disincentives: ES5.1\n\nexpert paper 1 (EP1): expert testimony on epidemiology\n\nexpert paper 4 (EP4): expert testimony on influencing driving behaviours for fleet drivers and others.\n\n# Evidence statements not used to make recommendations\n\nES2.1 – bus operations. The committee felt that this evidence (2 poor-quality modelling studies, 1 from Canada and 1 from Greece) was too uncertain to support a general recommendation. Local factors would be particularly significant in this context, and would involve considerable potential disruption.\n\nES3.2 – alterations to bus services and technology. The committee felt that the uncertainties in both studies (2 poor-quality studies, 1 from Chile and 1 from the US) meant that this evidence was unsuitable to support a general recommendation. In particular, differences in vehicle fleets in Chile and the UK and lack of appropriate control fleets in the US study made the evidence of limited applicability. Emission standards are also addressed by recommendations relating to clean air zones.\n\nES3.5 – bypass construction. The committee felt that this evidence (1 poor-quality UK study) did not justify a recommendation. Bypass construction is likely to be extremely expensive and only applicable in very specific circumstances. The committee felt that the reductions noted were possibly due to other factors. The age of the study (carried out in 1998) also meant that vehicle technology would be very different.\n\nES4.2 – dust suppressants. The committee felt that this evidence (2 poor-quality studies, 1 from Spain and 1 from the USA) did not justify a recommendation. They felt that the results seen in the Spanish study would be unlikely to be replicated in the UK, partly from differences in climate. The study from the USA looked at unsealed roads so is not relevant to the UK generally.\n\nES4.3 – street washing. The committee felt that this evidence (1 poor-quality study from Spain) did not justify a recommendation. They felt that the results would be unlikely to be replicated in the UK because of differences in climate. They felt that street washing was unlikely to have a significant effect on smaller particles most closely linked to health impacts.\n\nES10.1 – personalised travel planning. This consisted of 1 poor-quality study of students in Japan, which suggested that vehicle mileage could be reduced substantially by using personalised approaches. Although the committee agreed that these interventions could be feasible in the UK, they felt the evidence was insufficient to base a recommendation on. The committee also noted that the linked walking and cycling guideline contains recommendations on these approaches based on evidence to promote physical activity (rather than to reduce air pollution).\n\n# Gaps in the evidence\n\nThe committee's assessment of the evidence and expert testimony identified a number of gaps. These gaps are set out below. Where a gap in the evidence was identified and prioritised as a research recommendation it is included in the recommendations for research section.\n\n. Effectiveness and cost effectiveness of environmental change and development planning at reducing road-transport-related air pollution:\n\na) Planning and land allocations, development control and planning decisions, urban space and building design: siting, layout and design of developments; and applying planning conditions or obligations.\n\nb) Developing public transport routes and services, including bus lanes, and improving bus quality.\n\n(Source: Evidence review 1: environmental change and development planning.)\n\n. Effectiveness and cost effectiveness of traffic management and enforcement, and financial incentives and disincentives to reduce road-transport-related air pollution:\n\na) Traffic management systems and signal coordination:\n\nroad signs, traffic signals and road markings\n\nlane control\n\nelements of routes (such as positioning of traffic lights)\n\nroadside emission testing.\n\nb) Parking restrictions and charges:\n\nrestricted parking zones (including low-emission vehicles, car clubs and electric vehicle recharging points)\n\nhigher parking charges.\n\nc) Vehicle 'idling' restrictions and charges, including waiting and loading restrictions.\n\n(Source: Evidence review 2: traffic management and enforcement, and financial incentives and disincentives.)", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Vegetation and street trees\n\nWhat factors influence how vegetation and street trees affect urban air quality?\n\n## Why this is important\n\nThere is limited evidence on how vegetation and trees influence urban air quality and health outcomes. Information is needed because they are often used to address air pollution or for other purposes.\n\nResearch is needed on a range of factors including:\n\nimpact of different species of vegetation and tree types\n\nimpact of trees depending on where they are sited and how they are maintained\n\nimpacts across the course of a year\n\nimpact on health inequalities\n\nother potential health benefits.\n\n# Promoting a shift to zero- and low-emission travel\n\nWhat methods are effective and cost effective at promoting a shift to zero- and low-emission modes of travel, including active travel?\n\n## Why this is important\n\nAchieving a shift to zero- and low-emission modes of travel (including active travel) is key to reducing air pollution. We also need to identify approaches that encourage more efficient, less polluting driving behaviour.\n\nStudies based on behaviour change theories are needed to identify the most effective and cost-effective approaches and messages for different groups and in different settings. Useful outcomes include: travel mode and driver behaviour.\n\n# Clean air zones\n\nHow do different elements of a clean air zone interact to improve air quality and what is the overall effect on people's health?\n\n## Why this is important\n\nAt publication of this guideline, clean air zones were being introduced. These zones are likely to vary across the country and it is important to use this opportunity to identify which elements are most effective and cost effective at reducing air pollution and supporting a shift to zero- and low-emission travel. Studies are needed to evaluate:\n\nexposure to air pollution\n\nacute and chronic health outcomes\n\nimpact on health inequalities.\n\nResearch is also needed to look at travel behaviour in relation to different groups, to inform public awareness and social marketing approaches.\n\n# Telematics\n\nHow can information about driving style gathered from telematics devices and other technologies (such as apps or in-car global positioning systems) be used to reduce individual fuel consumption and vehicle emissions?\n\n## Why this is important\n\nEvidence suggests that information and training can help drivers change their driving style.\n\nResearch is needed to evaluate how telematics devices can be most effectively used with different groups to influence driving style and so, in turn, reduce emissions and improve air quality. Specific gaps in current research include the impact on individual drivers and those driving as part of a fleet including costs, health and other benefits, and value for money.\n\n# Awareness raising\n\nWhat is the effectiveness and cost effectiveness of different methods of awareness raising about air pollution (including air pollution alerts) on people's behaviour and on acute and chronic health outcomes?\n\n## Why this is important\n\nActivities to raise awareness of air pollution, including air pollution alerts (using traditional, social media and other methods) are becoming increasingly popular as a way of warning of the potential risk from episodes of poor air quality. But little is known about whether these alerts help encourage people to change their behaviour. Research on the absolute and relative effect of different approaches could be used to develop effective and cost-effective systems.\n\nResearch is needed on the impact of, for example, air pollution alerts on:\n\ndifferent groups (such as those vulnerable to air pollution and the general population)\n\nbehaviours related to the production of pollution (such as changes in mode of transport)\n\nacute and chronic health.\n\nStudies are also needed on:\n\nthe risk of adverse effects (such as making people worry unnecessarily, or increasing the level of motor vehicle travel after an alert)\n\nthe ability of health services to respond to concerns raised by issuing alerts.\n\n# Exposure to air pollution using different modes of transport\n\nHow does altering a person's mode of transport and route affect their personal exposure to air pollution?\n\n## Why this is important\n\nMode of transport (such as walking, cycling, using public transport or driving) influences personal exposure to air pollution. Overall, 'active' travel (such as walking or cycling) reduces emissions of air pollutants. But it could potentially increase someone's personal exposure, depending on the route they take. Research is needed to clarify the health impact of making such changes, including on health-related quality of life.", 'Glossary': "# Average speed technology\n\nCameras with automatic number plate reading (ANPR) digital technology, placed in multiple locations (at least 2, at a minimum of 200\xa0m apart) along a stretch of road to monitor a vehicle's average speed.\n\n# Daily Air Quality Index\n\nA number used by government agencies to tell the public how polluted the air is or will be. The number is provided with recommended actions and health advice. The index is numbered 1 to 10 and divided into 4 bands: low (1 to 3), moderate (4 to 6), high (7 to 9) and very high (10).\n\n# Euro standards\n\nStandards produced by EU Directives specifying maximum permitted emissions of various air pollutants. Light duty vehicle standards are referred to using Arabic numerals (Euro 1 to 6); standards for heavy duty vehicles use Roman numerals (Euro I to VI).\n\n# PM2.5, PM10\n\nParticulate matter is produced by, among other things, combustion of fossil fuels or abrasion of tyres and brakes. Particles are classified by size, described using the abbreviation PM with a suffix (commonly 2.5 or 10) that gives the maximum particle size in micrometres. The mass concentration of particles is usually expressed in micrograms per m3 of air.\n\nAirborne PM10 and PM2.5 come from both primary emissions (including combustion of fossil fuels, tyre and brake wear) and secondary particles (for example, nitrates and sulphates) formed when pollutants react in the atmosphere. PM2.5 particles are sometimes referred to as 'fine particles', and PM2.5–10 as 'coarse particles'. Fine particles can penetrate deep into the lungs.\n\n# Street ventilation\n\nAir in a street flows in a pattern determined by many factors, including the shape and design of buildings. It mixes with air from outside the street. If there are sources of pollution in the street (primarily motor vehicles) the air flow is restricted.\n\n# Telematics\n\nTechnologies that store and send information on the speed, position, acceleration and deceleration of road vehicles. This, together with global positioning system (GPS) data, can be used to compare driving styles and estimate the impact on fuel consumption, emissions or wear and tear.\n\n# Travel plans\n\nTravel plans are a way of assessing and then mitigating the potential negative effects that new developments could have on air pollution by generating significant amounts of motor traffic.\n\nFor other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster."}	https://www.nice.org.uk/guidance/ng70	This guideline covers road-traffic-related air pollution and its links to ill health. It aims to improve air quality and so prevent a range of health conditions and deaths.
b030554da1d21078af24dc8107a6592e4c6be296	nice	Infracoccygeal sacropexy using mesh to repair uterine prolapse	Infracoccygeal sacropexy using mesh to repair uterine prolapse Evidence-based recommendations on infracoccygeal sacropexy using mesh to repair uterine prolapse in women. This involves attaching mesh from the buttocks to the top of the vagina to hold the uterus in place. # Recommendations Current evidence on the safety of infracoccygeal sacropexy using mesh to repair uterine prolapse shows there are serious but well recognised complications. The evidence on efficacy is inadequate in quality. Therefore, this procedure should not be used unless there are special arrangements in place for clinical governance, consent and audit or research. Clinicians wishing to do infracoccygeal sacropexy using mesh to repair uterine prolapse should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety, including the risk of mesh erosion (for example, into the vagina) and the risk of recurrence, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Patient selection and treatment should only be done by specialists experienced in managing pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training. Clinicians should enter details about all patients having infracoccygeal sacropexy using mesh for uterine prolapse repair onto an appropriate registry (for example, the British Society of Urogynaecology database) and the results of the registry should be published. All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency. Clinicians are encouraged to collect long-term data on clinical outcomes and patient-reported quality-of-life outcomes using validated scales. NICE may update the guidance on publication of further evidence into infracoccygeal sacropexy using mesh to repair uterine prolapse.# Indications and current treatments Uterine prolapse is when the uterus descends from its usual position, sometimes out through the vagina opening. It can affect quality of life by causing symptoms of pressure and discomfort, and by its effect on urinary, bowel and sexual function. Treatments include pelvic floor muscle training, use of pessaries and surgery. Several surgical procedures can be used, including hysterectomy, mesh sacrocolpopexy, uterine suspension sling (including sacrohysteropexy) and uterine or vault suspension (without sling). Some of these procedures involve the use of mesh, with the aim of providing additional support.# The procedure Infracoccygeal sacropexy is usually done with the patient under general or regional anaesthesia. An incision is made in the posterior wall of the vagina and a small puncture incision is made in each buttock. A mesh tape is introduced through 1 buttock incision and using a tunnelling device, guided by a finger through the vaginal incision, the mesh is passed around the rectum. The mesh is then passed up the side of the vagina, across the top, and out through the incision in the other buttock. Both ends are cut so that they end just below the surface of the skin. The mesh is sutured to the top of the vagina and acts as a tension-free sling to suspend the uterus in its natural position. The procedure is sometimes described as posterior intravaginal slingplasty. This procedure can be combined with hysterectomy or surgery for stress urinary incontinence, such as a suburethral sling placement. Several different types of synthetic and biological mesh are available that vary in structure and in their physical properties, such as absorbability.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of surgery using mesh for uterine or vaginal vault prolapse in 7,054 patients (which included 976 patients who had infracoccygeal sacropexy), the results after a median follow‑up of 13 months were as follows: prolapse recurrence rate 5% (range 0 to 25%, n=402), rate of patient-reported persistent symptoms 9% (range 2 to 21%, n=262), and reoperation rate 8% (range 0 to 30%, n=288). For uterine prolapse only, prolapse recurrence rates were 1% (1/79 of patients, 1 non-randomised comparative study) and 10% (1/10 of patients, 1 case series). In a systematic review of 3,093 patients with uterine prolapse (which included 143 patients who had infracoccygeal sacropexy), the reoperation rate for prolapse recurrence was 3% within 6 to 30 months after the procedure. In a randomised controlled trial (RCT) of 49 patients with uterine or vaginal vault prolapse who had infracoccygeal sacropexy or sacrospinous suspension, postoperative rates of stress urinary incontinence or urgency and quality-of-life scores were not statistically significantly different between the treatment groups after a mean follow‑up of 17 months. The only statistically significant difference was for the Pelvic Organ Prolapse Distress Inventory score, which improved by 50% or more in 75% of patients who had infracoccygeal sacropexy compared with 65% for sacrospinous suspension (p=0.02). In the systematic review of 3,093 patients, the anatomical cure rates for apical support ranged from 90% to 97%. In the RCT of 49 patients who had infracoccygeal sacropexy or sacrospinous suspension, 86% and 79% of patients respectively were satisfied or very satisfied after the procedure. The specialist advisers listed the key efficacy outcomes as: patient satisfaction and comfort, quality of life, change in urinary, bowel and sexual function, objective prolapse assessment and long-term prolapse recurrence risk.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Mesh erosion at a median follow‑up of 13 months was reported in 0 to 21% of patients (median 7%, n=889 patients who had infracoccygeal sacropexy) in a systematic review of 7,054 patients who had had various types of surgery using mesh for uterine or vaginal vault prolapse. In a case series of 118 patients who had infracoccygeal sacropexy, mesh erosion happened up to 30 months after the procedure. Reoperation for mesh erosion was needed in up to 17% of patients (median 7%, n=678 patients who had infracoccygeal sacropexy), in the systematic review of 7,054 patients with uterine or vaginal vault prolapse. In an RCT of 49 patients, 10% (2/21) of patients who had infracoccygeal sacropexy had reoperation for anterior vaginal wall erosion up to a mean of 17 months after the procedure. In the case series of 118 patients, 2% (2/118) of patients had reoperation for erosion and 3% (3/118) for a fistula during a 59‑month mean follow‑up. In a case series of 577 patients, reoperation was needed in 4% (21/486) of patients to remove the mesh, in 1 patient to loosen the mesh, in 2% (12/496) of patients for stress urinary incontinence, in less than 1% (2/496) for evacuation of an abscess and in 1 patient for persistent dysfunctional uterine bleeding up to 4 years after the procedure. Blood loss during the procedure needing transfusion was reported in 0 to 2% of patients (n=383 patients who had infracoccygeal sacropexy) in the systematic review of 7,054 patients with uterine or vaginal vault prolapse. Haematoma was reported in 1% of patients (n=655 patients who had infracoccygeal sacropexy) in a systematic review of 2,653 patients who had had various types of surgery using mesh for uterine or vaginal vault prolapse. Organ damage during the procedure was reported in 0 to 3% of patients (n=684 patients who had infracoccygeal sacropexy) in the systematic review of 7,054 patients with uterine or vaginal vault prolapse. Infection was reported in 0 to 9% of patients (n=698 patients who had infracoccygeal sacropexy) in the systematic review of 7,054 patients with uterine or vaginal vault prolapse, at a median follow‑up of 13 months. Pararectal abscess was reported in 1 patient who had infracoccygeal sacropexy in the systematic review of 2,653 patients with uterine or vaginal vault prolapse (timing not reported). Gluteovaginal sinus formation 3 months after the procedure and rectocutaneous fistula 2 months after the procedure were each described in a case report, included in the review of 2,653 patients with uterine or vaginal vault prolapse. Dyspareunia was reported in 2% of patients (n=655 patients who had infracoccygeal sacropexy) in the systematic review of 2,653 patients with uterine or vaginal vault prolapse, up to a mean follow‑up of 120 weeks. Prolonged pain was reported in less than 1% of patients (4/655 patients who had infracoccygeal sacropexy) in the systematic review of 2,653 patients with uterine or vaginal vault prolapse up to a mean follow‑up of 120 weeks. Lower urinary tract symptoms were reported in 0 to 6% of patients (n=143 patients who had infracoccygeal sacropexy) in a systematic review of 3,093 patients who had had various types of surgery using mesh for uterine prolapse. De novo urge urinary incontinence or bladder overactivity symptoms were reported in 9% (10/118) of patients and de novo stress urinary incontinence was reported in 6% (7/118) of patients in the case series of 118 patients. De novo constipation after the procedure was reported in 6% (7/118) of patients in the case series of 118 patients. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any anecdotal adverse events or theoretical adverse events.# Further information For related NICE guidance, see the NICE website. NICE was unable to gather patient commentary for this procedure. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2568-1	{'Recommendations': "Current evidence on the safety of infracoccygeal sacropexy using mesh to repair uterine prolapse shows there are serious but well recognised complications. The evidence on efficacy is inadequate in quality. Therefore, this procedure should not be used unless there are special arrangements in place for clinical governance, consent and audit or research.\n\nClinicians wishing to do infracoccygeal sacropexy using mesh to repair uterine prolapse should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety, including the risk of mesh erosion (for example, into the vagina) and the risk of recurrence, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nPatient selection and treatment should only be done by specialists experienced in managing pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training.\n\nClinicians should enter details about all patients having infracoccygeal sacropexy using mesh for uterine prolapse repair onto an appropriate registry (for example, the British Society of Urogynaecology database) and the results of the registry should be published. All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nClinicians are encouraged to collect long-term data on clinical outcomes and patient-reported quality-of-life outcomes using validated scales. NICE may update the guidance on publication of further evidence into infracoccygeal sacropexy using mesh to repair uterine prolapse.", 'Indications and current treatments': 'Uterine prolapse is when the uterus descends from its usual position, sometimes out through the vagina opening. It can affect quality of life by causing symptoms of pressure and discomfort, and by its effect on urinary, bowel and sexual function.\n\nTreatments include pelvic floor muscle training, use of pessaries and surgery. Several surgical procedures can be used, including hysterectomy, mesh sacrocolpopexy, uterine suspension sling (including sacrohysteropexy) and uterine or vault suspension (without sling). Some of these procedures involve the use of mesh, with the aim of providing additional support.', 'The procedure': 'Infracoccygeal sacropexy is usually done with the patient under general or regional anaesthesia. An incision is made in the posterior wall of the vagina and a small puncture incision is made in each buttock. A mesh tape is introduced through 1\xa0buttock incision and using a tunnelling device, guided by a finger through the vaginal incision, the mesh is passed around the rectum. The mesh is then passed up the side of the vagina, across the top, and out through the incision in the other buttock. Both ends are cut so that they end just below the surface of the skin. The mesh is sutured to the top of the vagina and acts as a tension-free sling to suspend the uterus in its natural position. The procedure is sometimes described as posterior intravaginal slingplasty.\n\nThis procedure can be combined with hysterectomy or surgery for stress urinary incontinence, such as a suburethral sling placement.\n\nSeveral different types of synthetic and biological mesh are available that vary in structure and in their physical properties, such as absorbability.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of surgery using mesh for uterine or vaginal vault prolapse in 7,054\xa0patients (which included 976\xa0patients who had infracoccygeal sacropexy), the results after a median follow‑up of 13\xa0months were as follows: prolapse recurrence rate 5% (range 0 to 25%, n=402), rate of patient-reported persistent symptoms 9% (range 2 to 21%, n=262), and reoperation rate 8% (range 0 to 30%, n=288). For uterine prolapse only, prolapse recurrence rates were 1% (1/79\xa0of patients, 1\xa0non-randomised comparative study) and 10% (1/10\xa0of patients, 1\xa0case series). In a systematic review of 3,093\xa0patients with uterine prolapse (which included 143\xa0patients who had infracoccygeal sacropexy), the reoperation rate for prolapse recurrence was 3% within 6\xa0to 30\xa0months after the procedure.\n\nIn a randomised controlled trial (RCT) of 49\xa0patients with uterine or vaginal vault prolapse who had infracoccygeal sacropexy or sacrospinous suspension, postoperative rates of stress urinary incontinence or urgency and quality-of-life scores were not statistically significantly different between the treatment groups after a mean follow‑up of 17\xa0months. The only statistically significant difference was for the Pelvic Organ Prolapse Distress Inventory score, which improved by 50% or more in 75% of patients who had infracoccygeal sacropexy compared with 65% for sacrospinous suspension (p=0.02).\n\nIn the systematic review of 3,093\xa0patients, the anatomical cure rates for apical support ranged from 90% to\xa097%.\n\nIn the RCT of 49\xa0patients who had infracoccygeal sacropexy or sacrospinous suspension, 86% and 79% of patients respectively were satisfied or very satisfied after the procedure.\n\nThe specialist advisers listed the key efficacy outcomes as: patient satisfaction and comfort, quality of life, change in urinary, bowel and sexual function, objective prolapse assessment and long-term prolapse recurrence risk.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nMesh erosion at a median follow‑up of 13\xa0months was reported in 0 to 21% of patients (median 7%, n=889 patients who had infracoccygeal sacropexy) in a systematic review of 7,054\xa0patients who had had various types of surgery using mesh for uterine or vaginal vault prolapse. In a case series of 118\xa0patients who had infracoccygeal sacropexy, mesh erosion happened up to 30\xa0months after the procedure.\n\nReoperation for mesh erosion was needed in up to 17% of patients (median 7%, n=678 patients who had infracoccygeal sacropexy), in the systematic review of 7,054\xa0patients with uterine or vaginal vault prolapse. In an RCT of 49\xa0patients, 10% (2/21) of patients who had infracoccygeal sacropexy had reoperation for anterior vaginal wall erosion up to a mean of 17\xa0months after the procedure. In the case series of 118\xa0patients, 2% (2/118) of patients had reoperation for erosion and 3% (3/118) for a fistula during a 59‑month mean follow‑up. In a case series of 577\xa0patients, reoperation was needed in 4% (21/486) of patients to remove the mesh, in 1\xa0patient to loosen the mesh, in 2% (12/496) of patients for stress urinary incontinence, in less than 1% (2/496) for evacuation of an abscess and in 1\xa0patient for persistent dysfunctional uterine bleeding up to 4\xa0years after the procedure.\n\nBlood loss during the procedure needing transfusion was reported in 0 to 2% of patients (n=383 patients who had infracoccygeal sacropexy) in the systematic review of 7,054\xa0patients with uterine or vaginal vault prolapse.\n\nHaematoma was reported in 1% of patients (n=655 patients who had infracoccygeal sacropexy) in a systematic review of 2,653\xa0patients who had had various types of surgery using mesh for uterine or vaginal vault prolapse.\n\nOrgan damage during the procedure was reported in 0 to 3% of patients (n=684 patients who had infracoccygeal sacropexy) in the systematic review of 7,054\xa0patients with uterine or vaginal vault prolapse.\n\nInfection was reported in 0 to 9% of patients (n=698 patients who had infracoccygeal sacropexy) in the systematic review of 7,054\xa0patients with uterine or vaginal vault prolapse, at a median follow‑up of 13\xa0months. Pararectal abscess was reported in 1\xa0patient who had infracoccygeal sacropexy in the systematic review of 2,653\xa0patients with uterine or vaginal vault prolapse (timing not reported).\n\nGluteovaginal sinus formation 3\xa0months after the procedure and rectocutaneous fistula 2\xa0months after the procedure were each described in a case report, included in the review of 2,653\xa0patients with uterine or vaginal vault prolapse.\n\nDyspareunia was reported in 2% of patients (n=655 patients who had infracoccygeal sacropexy) in the systematic review of 2,653\xa0patients with uterine or vaginal vault prolapse, up to a mean follow‑up of 120\xa0weeks.\n\nProlonged pain was reported in less than 1% of patients (4/655 patients who had infracoccygeal sacropexy) in the systematic review of 2,653\xa0patients with uterine or vaginal vault prolapse up to a mean follow‑up of 120\xa0weeks.\n\nLower urinary tract symptoms were reported in 0 to 6% of patients (n=143 patients who had infracoccygeal sacropexy) in a systematic review of 3,093\xa0patients who had had various types of surgery using mesh for uterine prolapse. De novo urge urinary incontinence or bladder overactivity symptoms were reported in 9% (10/118) of patients and de novo stress urinary incontinence was reported in 6% (7/118) of patients in the case series of 118\xa0patients.\n\nDe novo constipation after the procedure was reported in 6% (7/118) of patients in the case series of 118\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any anecdotal adverse events or theoretical adverse events.', 'Further information': 'For related NICE guidance, see the NICE website.\n\nNICE was unable to gather patient commentary for this procedure.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2568-1'}	https://www.nice.org.uk/guidance/ipg582	Evidence-based recommendations on infracoccygeal sacropexy using mesh to repair uterine prolapse in women. This involves attaching mesh from the buttocks to the top of the vagina to hold the uterus in place.
d5e7fd3ee01e3b0cf2f21a920f3518e8a151ee30	nice	Sacrocolpopexy using mesh to repair vaginal vault prolapse	Sacrocolpopexy using mesh to repair vaginal vault prolapse Evidence-based recommendations on sacropolpopexy using mesh to repair vaginal vault prolapse in women. This involves attaching mesh, usually from the top of the vagina to the base of the spine, to support the pelvic organs. # Recommendations Current evidence on the safety of sacrocolpopexy using mesh to repair vaginal vault prolapse shows there are serious but well-recognised safety concerns. The evidence on efficacy is adequate in quantity and quality. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. During the consent process, clinicians should ensure patients understand that there is a risk of vaginal vault prolapse happening again, and of potentially serious complications, including mesh erosion (for example, into the vagina). Patients should be provided with clear written information about the procedure and its complications. In addition, the use of NICE's information for the public is recommended. Patient selection and treatment should only be done by clinicians specialising in the management of pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training and do the procedure regularly. Clinicians should enter details about all patients having sacrocolpopexy using mesh to repair vaginal vault prolapse onto an appropriate registry (for example, the British Society of Urogynaecology database). All adverse events involving the medical devices (including mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.# Indications and current treatments Vaginal vault prolapse is when the upper part of the vagina descends from its usual position, sometimes out through the vaginal opening. It is common after hysterectomy and can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function. Treatment is rarely indicated if there are no symptoms. Mild-to-moderate prolapse may be treated with conservative measures such as pelvic floor muscle training, electrical stimulation and biofeedback. Topical oestrogens and mechanical measures such as pessaries may also be used. Surgery may be needed when the prolapse is severe. Different surgical procedures are available for repairing vaginal vault prolapse using vaginal or abdominal (open, laparoscopic or robotic) approaches. Some procedures involve using mesh to provide additional support.# The procedure Sacrocolpopexy using mesh to repair vaginal vault prolapse is done with the patient under general anaesthesia, using an open or laparoscopic abdominal approach. Mesh is attached to the longitudinal ligament of the sacrum, or to the sacrum itself, most often at the level of the sacral promontory. The mesh is then attached to the apex of the vagina and sometimes to the anterior or posterior vaginal wall. The procedure can be combined with surgery for stress urinary incontinence, such as colposuspension or sub-urethral sling placement. Several different types of meshes or grafts have been used for this procedure, including synthetic meshes, allografts and xenografts. Different types of mesh may have different safety profiles.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review and meta-analysis of 3,414 women from 30 randomised control trials (RCTs) comparing surgery for apical pelvic organ prolapse, 16 studies compared surgery for vaginal vault prolapse. In 3 RCTs (n=277) sacrocolpopexy (SCP) had a statistically significantly lower rate of subjective failure than vaginal procedures (7% for SCP compared with 16% for vaginal procedures, risk ratio 2.11; 95% confidence interval 1.06 to 4.21, I2=0%). The use of mesh or biological graft for SCP did not affect the subjective failure rate. Adding colposuspension to SCP did not alter subjective failure rate in a 7‑year follow-up study. In 4 RCTs (n=390) from the systematic review of 3,414 women, SCP was associated with statistically significantly less recurrent prolapse than vaginal procedures at 1 to 2-year follow-up (19% compared with 34% , RR 1.89; 95% CI 1.33 to 2.70, I2=41%). The use of mesh or biological graft did not affect the incidence of recurrent prolapse. Recurrent prolapse was not statistically significantly different between SCP and robot-assisted sacrocolpopexy (RASC) when compared with laparoscopic sacrocolpopexy (LSC). Adding colposuspension to SCP did not alter the incidence of recurrent prolapse. In 4 RCTs from a systematic review of 1,176 women, SCP using mesh had statistically significantly better objective cure rates than native tissue vaginal repair (75% compared with 62% , odds ratio (OR) 2.04; 95% CI 1.12 to 3.72, I2=31%) at 1 to 2.5-year follow-up. In a systematic review and meta-analysis of 1,488 women, all-compartment prolapse was 6% (66/1,029) at a minimum 2-year follow-up. In an RCT of 100 women comparing SCP using polypropylene mesh with SCP using cadaveric fascia lata, overall objective anatomic success was statistically significantly higher in the polypropylene group (93% ) than in the fascia lata group (62% , p=0.02) at 5-year follow-up. In a case series of 165 women treated by LSC there was recurrent vault prolapse in 5% (7/138) of women, recurrent rectocele in 1% (1/138) and cystocele in 4% (5/138) of women at 8-year follow-up. In 2 RCTs (n=199) from the systematic review of 3,414 women, the rate of anterior compartment prolapse was statistically significantly less frequent in women treated by SCP than in women treated by vaginal procedures (6% compared with 24% , RR 4.02; 95% CI 1.71 to 9.49, I2=22%). In 3 RCTs (n=275) from the systematic review of 3,414 women, apical compartment prolapse was statistically significantly less frequent in women treated by SCP than in women treated by vaginal procedures (2% compared with 21% , RR 8.15; 95% CI 2.71 to 24.49, I2=0%). In the systematic review and meta-analysis of 1,488 women, apical prolapse rate was less than 1% (2/246). In 2 RCTs (n=199) posterior compartment prolapse was statistically significantly less frequent in women treated by SCP than in women treated by vaginal procedures (3% compared with 12% , RR 3.43; 95% CI 1.10 to 10.66, I2=0%) in the systematic review of 3,414 women. In a comparative study included in the systematic review of 1,176 women there was a statistically significantly higher recurrence of posterior wall prolapse after LSC (17% ) than after sacrospinous ligament fixation (0/51, p<0.01). In the systematic review and meta-analysis of 3,414 women, there was no statistically significant difference in quality of life measured by different types of questionnaires. In 1 RCT (n=110) a statistically significantly better quality of life was reported, as measured by the pelvic floor distress inventory (PFDI-20), in women treated by SCP than in women treated by vaginal procedures (mean difference 7.90; 95% CI 0.70 to 15.10). In a prospective case series of 70 women treated by RASC, 55% (22/40) would recommend the procedure to a relative or friend, 25% (10/40) would probably recommend the procedure and overall satisfaction was 10 (0=not at all successful, 10=very successful) at the median follow-up of 90 months. The average improvement in symptoms was 9 (0=much worse, 10=much better). In the prospective case series of 165 women treated by LSC, 83% (115/138) of women were 'quite satisfied', 12% (16/138) were 'satisfied enough' and 5% (7/138) were 'not satisfied'. In a prospective case series of 101 women treated by LSC, the quality-of-life score improved from 5.6 at baseline to 9.1 at 12 months and 8.3 at 60 months (measured on a visual analogue scale between 1 and 10). In the prospective case series of 165 women, constipation rates increased from 7% (10/138) before surgery to 13% (18/138) at the end of follow-up. Obstructed defaecation increased from 1% (2/138) to 6% (8/138). Urgency was not reported by any women before surgery and it was reported in 2% (3/138) of women at 43 months. The incidence of pelvic pressure symptoms reduced from 67% (92/138) to 9% (12/138) at the end of follow-up. Similarly, the incidence of false urge to defaecate reduced from 51% (70/138) of women at baseline to 5% (7/138) at 43 months. In a systematic review and meta-analysis of 5,954 women from 56 RCTs, in 3 RCTs reduction in postoperative dyspareunia was greater in the SCP group than in the VSC group (16% for VSC compared with 36% for SCP, RR 0.39; 95%CI 0.18 to 0.86). The specialist advisers listed the key efficacy outcomes as patient satisfaction, elimination of the bulge in the vagina, and bladder, bowel and sexual function changes. Fourteen commentaries from women who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Incidence of death was not statistically significantly different between women treated by abdominal sacrocolpopexy (SCP) using mesh (0/503) and women treated using native tissue (less than 1% , odds ratio 0.14; 95% confidence interval 0.003 to 6.97) in the analysis of comparative studies reported in a systematic review and meta-analysis of 1,176 women. Postoperative admission to intensive care was not statistically significantly different between the SCP using mesh group (1% ) and the native tissue repair group (0/506, OR 4.64; 95% CI 0.42 to 50.6) in the analysis of comparative studies in the same systematic review. Deep vein thrombosis or pulmonary embolism was not statistically significantly different between the SCP using mesh group (less than 1% ) and the native tissue repair group (less than 1% , OR 1.36; 95% CI 0.14 to 13.7) in the same analysis of comparative studies. Mesh or suture complications were statistically significantly more frequent in women treated by SCP using mesh (4% ) than in women who had native tissue repair (1% , OR 3.26; 95% CI 1.62 to 6.56) in an analysis of comparative studies in the systematic review of 1,176 women. Mesh or suture complications were statistically significantly more frequent in women treated by SCP using mesh (4% ) than in women treated by native tissue repair (less than 1% , p<0.001) in an analysis of 40 SCP compared with 11 native tissue repair non-comparative studies. Mesh erosion was not statistically significantly different between robot-assisted sacrocolpopexy (RASC) and laparoscopic sacrocolpopexy (LSC; OR 1.82; 95% CI 0.51 to 6.45 , I2=0%, p=0.86) in a systematic review of 1,488 women. Mesh erosion was statistically significantly lower in women treated by RASC with supracervical hysterectomy (0%) than in women treated by RASC after total hysterectomy (14%, p=0.008) in 1 comparative study included in the same systematic review. Mesh erosion was reported in 1% (1/99) of women treated by LSC at 12 months and in 3% (2/85) at 60 months in a prospective case series of 101 women. Reoperation rates were similar for women treated by SCP or sacrospinous ligament fixation (13% compared with 16% , p=0.67) in an RCT (reported in the systematic review of 1,176 women) with follow-up of 6 to 66 months. Pooled reoperation rates were 7% (46/615) for SCP and 10% (51/511) for native tissue repair (OR 0.76, 95% CI 0.28 to 1.09) in 7 comparative studies from the same systematic review and meta-analysis. Pooled reoperation rates in non-comparative studies were 5% (367/7,218) for SCP and 3% (114/3,872) for native tissue repair (p=0.28) in the systematic review of 1,176 women. The reoperation rate was 3% (23/687) in women treated by RASC in the systematic review and meta-analysis of 1,488 women from 27 studies. A feeling of traction needing reoperation was reported in less than 1% (2/1,118) of the women treated by RASC in the same systematic review. Reoperation for stress urinary incontinence in women treated by LSC was reported in 15% (15/99) and 19% (16/85) of women at 12 and 60 months respectively in the prospective case series of 101 women. Reoperation rates in women treated by RASC were 2%, 5% and 10% at years 1, 3 and 6 respectively in a prospective case series of 70 women. The vaginotomy rate in women treated by RASC was 1% (14/1,488) in the systematic review and meta-analysis of 1,488 women from 27 studies. Urinary tract injury was not statistically significantly different in women treated by SCP using mesh (2% ) compared with women treated by native tissue repair (1% , OR 1.68; 95% CI 0.79 to 3.55) in 8 comparative studies from the systematic review of 1,176 women. Urinary tract injury was statistically significantly higher in women treated by SCP using mesh (2% ) compared with native tissue repair (1% , p<0.05) in the analysis of non-comparative studies from the same review. Bladder injury in women treated by RASC was 2% (26/1,488) in the systematic review of 1,488 women. Ureteral injury was less than 1% (1/1,488) in women from the same systematic review. Bowel injury in women treated by RASC was less than 1% (4/1,488) in the systematic review of 1,488 women. Stress incontinence in women who had not had it before and who were treated by LSC was 24% (24/99) and 38% (32/85) at 12 and 60 months respectively in the case series of 101 women. Postoperative voiding disorders occurred in 8% (8/99) and 13% (11/85) of women at 12 and 60 months respectively in the same patient group. Urge incontinence in women who had not had it before occurred in 2% (2/99) women at 12 months and in 8% (7/85) at 60 months. The detrusor muscle overactivity rate was 9% (15/165) in a case series of 165 women. Dyspareunia was statistically significantly lower in women treated by SCP using mesh (5% ) than in women treated by native tissue repair (12% , OR 0.42; 95% CI 0.25 to 0.72) from the analysis of 5 comparative studies reported in the systematic review and meta-analysis of 1,176 women. The rate of dyspareunia was similar for SCP using mesh (12% ) and native tissue repair (9% ; p=0.48) in the analysis of non-comparative studies in the same systematic review. Dyspareunia in women who had not had this before who were treated by LSC was 2% (1/47) and 24% (10/41) at 12 and 60 months respectively in the prospective case series of 101 women. Rectocele and cystocele incidence in women who had not had these before and who were treated by LSC was 12% (16/138) and 8% (11/183) respectively at 8-year follow-up in the case series of 165 women. Infection rates were not statistically significantly different between women treated by SCP using mesh (3% ) and women treated by native tissue repair (1% OR 2.01; 95% CI 0.91 to 4.45) in the analysis of comparative studies reported in the systematic review and meta-analysis of 1,176 women. Infection rates were not statistically significantly different between women treated by mesh SCP (2% ) and women treated by native tissue repair (12% , p=0.6) in the analysis of non-comparative studies for the same systematic review. Abscess formation in women treated by RASC was less than 1% (3/1,118) in the systematic review of 1,488 women. Peritonitis caused by bowel injury was reported in less than 1% (2/1,118) of women in the same review. Bleeding rates were not statistically significantly different between women treated by SCP using mesh (3% ) and women treated by native tissue repair (2% OR 1.00; 95% CI 0.63 to 1.59) in the comparative studies reported in the systematic review of 1,176 women. Bleeding rates were statistically significantly lower in women treated by SCP using mesh (2% ) than in women treated by native tissue repair (5% , p=0.05) in the analysis of non-comparative studies in the same systematic review. Ileus or small bowel obstruction was statistically significantly higher in women treated by SCP using mesh (2% ) than in women treated by native tissue repair (less than 1% , OR 9.45; 95% CI 3.39 to 26.4) in the analysis of comparative studies reported in the systematic review of 1,176 women. Ileus or small bowel obstruction was also statistically significantly higher in women treated by SCP using mesh (3% ) than in women treated by native tissue repair (less than 1% , p<0.01) in the analysis of non-comparative studies for the same systematic review. Bowel obstruction in women treated by RASC was less than 1% (5/1,118) in the systematic review of 1,488 women. Postoperative constipation in women treated by LSC was 1% (1/99) and 5% (4/85) at 12 and 60 months respectively, in the case series of 101 women. Lumbosciatica pain was reported in 3% (5/165) of women treated by LSC in the case series of 165 women. Intraoperative complication rates were not statistically significantly different between women treated by RASC and women treated by LSC (OR 1.05; 95% CI 0.52 to 2.12 , I2=0%, p=0.94) in the systematic review of 1,488 women. Surgical conversion to open surgery was also not statistically significantly different between the RASC and LSC treatment groups (OR 0.89; 95% CI 0.25 to 3.19 , I2=0%, p=0.72). The incidence of all postoperative complications was not statistically significant between RASC and LSC (OR 1.85; 95% CI 0.96 to 3.75 , I2=37%, p=0.18) and this was also true for severe postoperative complications (of grade 3 or higher; OR 0.56; 95% CI 0.36 to 2.83 , I2=24%, p=0.73). In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). The anecdotal adverse events reported for the procedure were osteomyelitis of the sacrum and haemorrhage from left iliac vein. Fourteen commentaries from women who had experience of this procedure were received, which were discussed by the committee.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2570-4	{'Recommendations': "Current evidence on the safety of sacrocolpopexy using mesh to repair vaginal vault prolapse shows there are serious but well-recognised safety concerns. The evidence on efficacy is adequate in quantity and quality. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit.\n\nDuring the consent process, clinicians should ensure patients understand that there is a risk of vaginal vault prolapse happening again, and of potentially serious complications, including mesh erosion (for example, into the vagina). Patients should be provided with clear written information about the procedure and its complications. In addition, the use of NICE's information for the public is recommended.\n\nPatient selection and treatment should only be done by clinicians specialising in the management of pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training and do the procedure regularly.\n\nClinicians should enter details about all patients having sacrocolpopexy using mesh to repair vaginal vault prolapse onto an appropriate registry (for example, the British Society of Urogynaecology database). All adverse events involving the medical devices (including mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.", 'Indications and current treatments': 'Vaginal vault prolapse is when the upper part of the vagina descends from its usual position, sometimes out through the vaginal opening. It is common after hysterectomy and can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function.\n\nTreatment is rarely indicated if there are no symptoms. Mild-to-moderate prolapse may be treated with conservative measures such as pelvic floor muscle training, electrical stimulation and biofeedback. Topical oestrogens and mechanical measures such as pessaries may also be used. Surgery may be needed when the prolapse is severe. Different surgical procedures are available for repairing vaginal vault prolapse using vaginal or abdominal (open, laparoscopic or robotic) approaches. Some procedures involve using mesh to provide additional support.', 'The procedure': 'Sacrocolpopexy using mesh to repair vaginal vault prolapse is done with the patient under general anaesthesia, using an open or laparoscopic abdominal approach. Mesh is attached to the longitudinal ligament of the sacrum, or to the sacrum itself, most often at the level of the sacral promontory. The mesh is then attached to the apex of the vagina and sometimes to the anterior or posterior vaginal wall.\n\nThe procedure can be combined with surgery for stress urinary incontinence, such as colposuspension or sub-urethral sling placement. Several different types of meshes or grafts have been used for this procedure, including synthetic meshes, allografts and xenografts. Different types of mesh may have different safety profiles.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review and meta-analysis of 3,414\xa0women from 30\xa0randomised control trials (RCTs) comparing surgery for apical pelvic organ prolapse, 16\xa0studies compared surgery for vaginal vault prolapse. In 3\xa0RCTs (n=277) sacrocolpopexy (SCP) had a statistically significantly lower rate of subjective failure than vaginal procedures (7% [10/139] for SCP compared with 16% [22/138] for vaginal procedures, risk ratio [RR] 2.11; 95% confidence interval [CI] 1.06 to 4.21, I2=0%). The use of mesh or biological graft for SCP did not affect the subjective failure rate. Adding colposuspension to SCP did not alter subjective failure rate in a 7‑year follow-up study.\n\nIn 4\xa0RCTs (n=390) from the systematic review of 3,414\xa0women, SCP was associated with statistically significantly less recurrent prolapse than vaginal procedures at 1 to 2-year follow-up (19% [35/189] compared with 34% [68/201], RR 1.89; 95% CI 1.33 to 2.70, I2=41%). The use of mesh or biological graft did not affect the incidence of recurrent prolapse. Recurrent prolapse was not statistically significantly different between SCP and robot-assisted sacrocolpopexy (RASC) when compared with laparoscopic sacrocolpopexy (LSC). Adding colposuspension to SCP did not alter the incidence of recurrent prolapse. In 4\xa0RCTs from a systematic review of 1,176\xa0women, SCP using mesh had statistically significantly better objective cure rates than native tissue vaginal repair (75% [132/177] compared with 62% [119/192], odds ratio (OR) 2.04; 95% CI 1.12 to 3.72, I2=31%) at 1 to 2.5-year follow-up. In a systematic review and meta-analysis of 1,488\xa0women, all-compartment prolapse was 6% (66/1,029) at a minimum 2-year follow-up. In an RCT of 100\xa0women comparing SCP using polypropylene mesh with SCP using cadaveric fascia lata, overall objective anatomic success was statistically significantly higher in the polypropylene group (93% [27/29]) than in the fascia lata group (62% [18/29], p=0.02) at 5-year follow-up. In a case series of 165\xa0women treated by LSC there was recurrent vault prolapse in 5% (7/138) of women, recurrent rectocele in 1% (1/138) and cystocele in 4% (5/138) of women at 8-year follow-up.\n\nIn 2\xa0RCTs (n=199) from the systematic review of 3,414\xa0women, the rate of anterior compartment prolapse was statistically significantly less frequent in women treated by SCP than in women treated by vaginal procedures (6% [6/102] compared with 24% [23/97], RR 4.02; 95% CI 1.71 to 9.49, I2=22%).\n\nIn 3\xa0RCTs (n=275) from the systematic review of 3,414\xa0women, apical compartment prolapse was statistically significantly less frequent in women treated by SCP than in women treated by vaginal procedures (2% [3/134] compared with 21% [29/141], RR 8.15; 95% CI 2.71 to 24.49, I2=0%). In the systematic review and meta-analysis of 1,488\xa0women, apical prolapse rate was less than 1% (2/246).\n\nIn 2\xa0RCTs (n=199) posterior compartment prolapse was statistically significantly less frequent in women treated by SCP than in women treated by vaginal procedures (3% [3/99] compared with 12% [12/100], RR 3.43; 95% CI 1.10 to 10.66, I2=0%) in the systematic review of 3,414\xa0women. In a comparative study included in the systematic review of 1,176\xa0women there was a statistically significantly higher recurrence of posterior wall prolapse after LSC (17% [10/60]) than after sacrospinous ligament fixation (0/51, p<0.01).\n\nIn the systematic review and meta-analysis of 3,414\xa0women, there was no statistically significant difference in quality of life measured by different types of questionnaires. In 1\xa0RCT (n=110) a statistically significantly better quality of life was reported, as measured by the pelvic floor distress inventory (PFDI-20), in women treated by SCP than in women treated by vaginal procedures (mean difference 7.90; 95% CI 0.70 to 15.10). In a prospective case series of 70\xa0women treated by RASC, 55% (22/40) would recommend the procedure to a relative or friend, 25% (10/40) would probably recommend the procedure and overall satisfaction was 10 (0=not at all successful, 10=very successful) at the median follow-up of 90\xa0months. The average improvement in symptoms was 9 (0=much worse, 10=much better). In the prospective case series of 165\xa0women treated by LSC, 83% (115/138) of women were 'quite satisfied', 12% (16/138) were 'satisfied enough' and 5% (7/138) were 'not satisfied'. In a prospective case series of 101\xa0women treated by LSC, the quality-of-life score improved from 5.6 at baseline to 9.1 at 12\xa0months and 8.3 at 60\xa0months (measured on a visual analogue scale between 1 and 10).\n\nIn the prospective case series of 165\xa0women, constipation rates increased from 7% (10/138) before surgery to 13% (18/138) at the end of follow-up. Obstructed defaecation increased from 1% (2/138) to 6% (8/138). Urgency was not reported by any women before surgery and it was reported in 2% (3/138) of women at 43\xa0months. The incidence of pelvic pressure symptoms reduced from 67% (92/138) to 9% (12/138) at the end of follow-up. Similarly, the incidence of false urge to defaecate reduced from 51% (70/138) of women at baseline to 5% (7/138) at 43\xa0months.\n\nIn a systematic review and meta-analysis of 5,954\xa0women from 56\xa0RCTs, in 3\xa0RCTs reduction in postoperative dyspareunia was greater in the SCP group than in the VSC group (16% [7/45] for VSC compared with 36% [22/61] for SCP, RR 0.39; 95%CI 0.18 to 0.86).\n\nThe specialist advisers listed the key efficacy outcomes as patient satisfaction, elimination of the bulge in the vagina, and bladder, bowel and sexual function changes.\n\nFourteen commentaries from women who had experience of this procedure were received, which were discussed by the committee.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIncidence of death was not statistically significantly different between women treated by abdominal sacrocolpopexy (SCP) using mesh (0/503) and women treated using native tissue (less than 1% [1/582], odds ratio [OR] 0.14; 95% confidence interval [CI] 0.003 to 6.97) in the analysis of comparative studies reported in a systematic review and meta-analysis of 1,176\xa0women. Postoperative admission to intensive care was not statistically significantly different between the SCP using mesh group (1% [3/561]) and the native tissue repair group (0/506, OR 4.64; 95% CI 0.42 to 50.6) in the analysis of comparative studies in the same systematic review.\n\nDeep vein thrombosis or pulmonary embolism was not statistically significantly different between the SCP using mesh group (less than 1% [2/569]) and the native tissue repair group (less than 1% [1/599], OR 1.36; 95% CI 0.14 to 13.7) in the same analysis of comparative studies.\n\nMesh or suture complications were statistically significantly more frequent in women treated by SCP using mesh (4% [28/650]) than in women who had native tissue repair (1% [6/537], OR 3.26; 95% CI 1.62 to 6.56) in an analysis of comparative studies in the systematic review of 1,176\xa0women. Mesh or suture complications were statistically significantly more frequent in women treated by SCP using mesh (4% [348/7,831]) than in women treated by native tissue repair (less than 1% [13/1,169], p<0.001) in an analysis of 40\xa0SCP compared with 11\xa0native tissue repair non-comparative studies. Mesh erosion was not statistically significantly different between robot-assisted sacrocolpopexy (RASC) and laparoscopic sacrocolpopexy (LSC; OR 1.82; 95% CI 0.51 to 6.45 [n=438], I2=0%, p=0.86) in a systematic review of 1,488\xa0women. Mesh erosion was statistically significantly lower in women treated by RASC with supracervical hysterectomy (0%) than in women treated by RASC after total hysterectomy (14%, p=0.008) in 1\xa0comparative study included in the same systematic review. Mesh erosion was reported in 1% (1/99) of women treated by LSC at 12\xa0months and in 3% (2/85) at 60\xa0months in a prospective case series of 101\xa0women.\n\nReoperation rates were similar for women treated by SCP or sacrospinous ligament fixation (13% [6/46] compared with 16% [7/43], p=0.67) in an RCT (reported in the systematic review of 1,176\xa0women) with follow-up of 6 to 66\xa0months. Pooled reoperation rates were 7% (46/615) for SCP and 10% (51/511) for native tissue repair (OR 0.76, 95% CI 0.28 to 1.09) in 7\xa0comparative studies from the same systematic review and meta-analysis. Pooled reoperation rates in non-comparative studies were 5% (367/7,218) for SCP and 3% (114/3,872) for native tissue repair (p=0.28) in the systematic review of 1,176\xa0women. The reoperation rate was 3% (23/687) in women treated by RASC in the systematic review and meta-analysis of 1,488\xa0women from 27\xa0studies. A feeling of traction needing reoperation was reported in less than 1% (2/1,118) of the women treated by RASC in the same systematic review. Reoperation for stress urinary incontinence in women treated by LSC was reported in 15% (15/99) and 19% (16/85) of women at 12 and 60\xa0months respectively in the prospective case series of 101\xa0women. Reoperation rates in women treated by RASC were 2%, 5% and 10% at years 1, 3 and 6 respectively in a prospective case series of 70\xa0women.\n\nThe vaginotomy rate in women treated by RASC was 1% (14/1,488) in the systematic review and meta-analysis of 1,488\xa0women from 27\xa0studies.\n\nUrinary tract injury was not statistically significantly different in women treated by SCP using mesh (2% [20/1,068]) compared with women treated by native tissue repair (1% [9/1,108], OR 1.68; 95% CI 0.79 to 3.55) in 8\xa0comparative studies from the systematic review of 1,176\xa0women. Urinary tract injury was statistically significantly higher in women treated by SCP using mesh (2% [113/6,894]) compared with native tissue repair (1% [46/5,111], p<0.05) in the analysis of non-comparative studies from the same review. Bladder injury in women treated by RASC was 2% (26/1,488) in the systematic review of 1,488\xa0women. Ureteral injury was less than 1% (1/1,488) in women from the same systematic review.\n\nBowel injury in women treated by RASC was less than 1% (4/1,488) in the systematic review of 1,488\xa0women.\n\nStress incontinence in women who had not had it before and who were treated by LSC was 24% (24/99) and 38% (32/85) at 12 and 60\xa0months respectively in the case series of 101\xa0women. Postoperative voiding disorders occurred in 8% (8/99) and 13% (11/85) of women at 12 and 60\xa0months respectively in the same patient group. Urge incontinence in women who had not had it before occurred in 2% (2/99) women at 12\xa0months and in 8% (7/85) at 60\xa0months. The detrusor muscle overactivity rate was 9% (15/165) in a case series of 165\xa0women.\n\nDyspareunia was statistically significantly lower in women treated by SCP using mesh (5% [23/445]) than in women treated by native tissue repair (12% [46/384], OR 0.42; 95% CI 0.25 to 0.72) from the analysis of 5\xa0comparative studies reported in the systematic review and meta-analysis of 1,176\xa0women. The rate of dyspareunia was similar for SCP using mesh (12% [371/2,986]) and native tissue repair (9% [200/2,180]; p=0.48) in the analysis of non-comparative studies in the same systematic review. Dyspareunia in women who had not had this before who were treated by LSC was 2% (1/47) and 24% (10/41) at 12 and 60\xa0months respectively in the prospective case series of 101\xa0women.\n\nRectocele and cystocele incidence in women who had not had these before and who were treated by LSC was 12% (16/138) and 8% (11/183) respectively at 8-year follow-up in the case series of 165\xa0women.\n\nInfection rates were not statistically significantly different between women treated by SCP using mesh (3% [17/676]) and women treated by native tissue repair (1% [9/617] OR 2.01; 95% CI 0.91 to 4.45) in the analysis of comparative studies reported in the systematic review and meta-analysis of 1,176\xa0women. Infection rates were not statistically significantly different between women treated by mesh SCP (2% [114/5,519]) and women treated by native tissue repair (12% [558/4,743], p=0.6) in the analysis of non-comparative studies for the same systematic review. Abscess formation in women treated by RASC was less than 1% (3/1,118) in the systematic review of 1,488\xa0women. Peritonitis caused by bowel injury was reported in less than 1% (2/1,118) of women in the same review.\n\nBleeding rates were not statistically significantly different between women treated by SCP using mesh (3% [43/1,317]) and women treated by native tissue repair (2% [37/1,863] OR 1.00; 95% CI 0.63 to 1.59) in the comparative studies reported in the systematic review of 1,176\xa0women. Bleeding rates were statistically significantly lower in women treated by SCP using mesh (2% [128/6,555]) than in women treated by native tissue repair (5% [367/7,044], p=0.05) in the analysis of non-comparative studies in the same systematic review.\n\nIleus or small bowel obstruction was statistically significantly higher in women treated by SCP using mesh (2% [16/814]) than in women treated by native tissue repair (less than 1% [2/780], OR 9.45; 95% CI 3.39 to 26.4) in the analysis of comparative studies reported in the systematic review of 1,176\xa0women. Ileus or small bowel obstruction was also statistically significantly higher in women treated by SCP using mesh (3% [137/4,168]) than in women treated by native tissue repair (less than 1% [3/1,449], p<0.01) in the analysis of non-comparative studies for the same systematic review. Bowel obstruction in women treated by RASC was less than 1% (5/1,118) in the systematic review of 1,488\xa0women. Postoperative constipation in women treated by LSC was 1% (1/99) and 5% (4/85) at 12 and 60\xa0months respectively, in the case series of 101\xa0women.\n\nLumbosciatica pain was reported in 3% (5/165) of women treated by LSC in the case series of 165\xa0women.\n\nIntraoperative complication rates were not statistically significantly different between women treated by RASC and women treated by LSC (OR 1.05; 95% CI 0.52 to 2.12 [n=443], I2=0%, p=0.94) in the systematic review of 1,488\xa0women. Surgical conversion to open surgery was also not statistically significantly different between the RASC and LSC treatment groups (OR 0.89; 95% CI 0.25 to 3.19 [n=443], I2=0%, p=0.72). The incidence of all postoperative complications was not statistically significant between RASC and LSC (OR 1.85; 95% CI 0.96 to 3.75 [n=350], I2=37%, p=0.18) and this was also true for severe postoperative complications (of grade 3 or higher; OR 0.56; 95% CI 0.36 to 2.83 [n=430], I2=24%, p=0.73).\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). The anecdotal adverse events reported for the procedure were osteomyelitis of the sacrum and haemorrhage from left iliac vein.\n\nFourteen commentaries from women who had experience of this procedure were received, which were discussed by the committee.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2570-4'}	https://www.nice.org.uk/guidance/ipg583	Evidence-based recommendations on sacropolpopexy using mesh to repair vaginal vault prolapse in women. This involves attaching mesh, usually from the top of the vagina to the base of the spine, to support the pelvic organs.
9390c4de45cd6657603d0139905e83377c788ea4	nice	Uterine suspension using mesh (including sacrohysteropexy) to repair uterine prolapse	Uterine suspension using mesh (including sacrohysteropexy) to repair uterine prolapse Evidence-based recommendations on uterine suspension using mesh (including sacrohysteropexy) to repair uterine prolapse in women. This involves attaching mesh from the uterus or cervix either to the bone at the base of the spine or to a ligament in the pelvis to hold the uterus in place. # Recommendations Current evidence on the safety of uterine suspension using mesh (including sacrohysteropexy) to repair uterine prolapse shows there are serious and well-recognised complications. The evidence on efficacy is adequate in quantity and quality. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit. During the consent process, clinicians should ensure that patients understand the risk of uterine prolapse happening again and of potentially serious complications, including mesh erosion (for example, into the bladder). Patients should be told about all treatment options and provided with clear written information about the procedure and its complications. In addition, the use of NICE's information for the public is recommended. Patient selection should be done by a multidisciplinary team with experience in managing pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training and do the procedure regularly. Clinicians should enter details about all patients having mesh uterine suspension (including sacrohysteropexy) to repair uterine prolapse onto an appropriate registry (for example, the British Society of Urogynaecology database). All adverse events involving the medical devices (including mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.# Indications and current treatments Uterine prolapse is when the uterus descends from its usual position, into and sometimes through the vagina. It can affect quality of life by causing symptoms of pressure and discomfort, and by its effects on urinary, bowel and sexual function. Current treatment options include pelvic floor muscle training, use of pessaries and surgery. Some surgical procedures involve the use of mesh, with the aim of providing additional support.# The procedure Uterine suspension using mesh to repair uterine prolapse involves attaching the uterus (or cervix) either to the sacrum (sacrohysteropexy) or to the ileopectineal ligaments. This procedure can also be used for women with cervical prolapse after supracervical hysterectomy. The procedure is done with the patient under general anaesthesia by an open or laparoscopic abdominal approach. In sacrohysteropexy the mesh can be attached to the uterus either in the midline of the posterior cervix or bilaterally, where the uterosacral ligaments join the uterus (in both cases the other end of the mesh is attached to the sacrum). Another mesh suspension technique involves attaching the mesh to the front of the uterine cervix and to the lateral ileopectineal ligaments. Each of the above procedures can be described as a 'uterine suspension using mesh'. This procedure can be combined with surgery for stress urinary incontinence, such as colposuspension or minimally invasive sling placement. Several different types of synthetic and biological mesh are available that vary in structure and in their physical properties, such as absorbability.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of surgery for women with apical prolapse including 183 women with uterine prolapse (2 randomised controlled trials ) comparing abdominal sacrohysteropexy (open or laparoscopic approach) with vaginal hysterectomy and vault repair/support, there was no difference in repeat prolapse surgery between the groups at 1 to 8‑year follow‑up (risk ratio 0.68, 95% confidence interval 0.36 to 1.31, n=182, low quality evidence). In a retrospective case series of 507 women with uterine prolapse treated by laparoscopic sacrohysteropexy, 3% (14/507) of women had further apical prolapse at a median follow‑up of 12 months (range 6 to 84 months) because the mesh had stretched. Of these, 10 women had plication of mesh and 3 had cervical amputation for elongation. Ongoing uterine prolapse was reported in 2 women and treated by vaginal hysterectomy; 7% (36/507) of women had further vaginal wall repair. In a case series of 194 premenopausal women with uterine prolapse treated by pectineal ligament hysteropexy (PLH) by open or laparoscopic approach, the overall reoperation rate after PLH was 15% (29/194) at a mean follow‑up of 6.5 years; 6% (10/176) of women had grade 3 uterine prolapse recurrence (7 occurred in pregnant women after vaginal delivery; 3 in non-pregnant women, of which 1 was a tape erosion into the bladder). Twelve women developed cystocele and 7 developed cervical elongation. Laparoscopic procedures had no recurrence of prolapse over 2 years. In the systematic review including 183 women with uterine prolapse, evidence from 1 RCT (n=82) did not show a statistically significant difference between vaginal hysterectomy with vault support and abdominal sacrohysteropexy for objective failure of anterior vaginal compartment (RR 1.04, 95% CI 0.60 to 1.82), apical compartment (RR 1.00, 95% CI 0.15 to 6.76) or posterior vaginal compartment (RR 3.07, 95% CI 0.66 to 14.35) at 1‑year follow‑up. In a non-randomised comparative study of 151 women comparing laparoscopic sacral hysteropexy (n=74) with vaginal mesh hysteropexy (n=77), there was no difference between groups in the rate of apical failure (19% laparoscopic hysteropexy compared with 16% vaginal mesh hysteropexy, p=0.16) or anterior failure (9% laparoscopic hysteropexy compared with 6% vaginal mesh hysteropexy, p=0.93) at 1‑year follow‑up. In the systematic review including 183 women with uterine prolapse, 1 RCT reported that awareness of prolapse (defined as any positive response to questions related to awareness of prolapse or vaginal bulge) was less likely after vaginal hysterectomy than after abdominal sacrohysteropexy at 8‑year follow‑up, but this result was not statistically significant (RR 0.38, 95% CI 0.15 to 0.98, n=84, moderate quality evidence). In the case series of 507 women there was significant improvement for pelvic organ prolapse quantification point C assessment (p<0.001), with a mean change of 7.9 cm between preoperative and postoperative scores at 3‑month follow‑up; 94% (379/404) of women felt that their prolapse (assessed using 7‑point Patient Global Impression of Improvement subjective measure) was 'very much' or 'much' better and 2% (6/404) felt there was no change in symptoms. No women described their symptoms as worse. In the non-randomised comparative study of 151 women comparing laparoscopic sacral hysteropexy with vaginal mesh hysteropexy, prolapse stage was similar but laparoscopic hysteropexy was associated with increased vaginal length (p<0.001), increased perineal body length (p=0.02) and better apical support (p=0.05) at 1‑year follow‑up. Overall satisfaction (measured on PGI‑I scale) was high and 79% of women in each group rated prolapse symptoms as 'very much better' and 16% 'much better' at 1‑year follow‑up. In a case series of 100 women with uterovaginal prolapse treated by robotic sacrohysteropexy, overall quality of life (measured using the validated urogenital distress inventory and incontinence impact questionnaires , with scores ranging from 0 to 6) improved from a mean score of 4.5 to 5.12 (p<0.05), and overall health status (based on a visual analogue scale of 0 to 100) improved from 73% to 82% (p<0.05), 6 weeks after surgery. Postoperatively women also experienced less feelings of nervousness (p=0.01), shame (p<0.05) and frustration (p<0.05). After 5 years the positive effects of these feelings remained and quality of life and overall health status remained stable. In the case series of 194 premenopausal women with uterine prolapse, there were 46 births (32 vaginal and 14 caesarean deliveries) in 40 women after PLH. Prolapse recurred (tape avulsed from the uterus) in 7 women after vaginal delivery and was treated by vaginal hysterectomy. There were no recurrences after caesarean deliveries. The specialist advisers listed key efficacy outcomes as resolution of prolapse symptoms and recurrent apical prolapse. Twenty one commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Mesh complications were reported in 3% (2/74) of women in the laparoscopic hysteropexy group (1 excision and 1 spontaneous resolution) and in 7% (5/77) of women in the vaginal mesh hysteropexy group (treated by excision in 3 and observation in 2) in a non-randomised comparative study of 151 patients. Tape erosion into the bladder occurred in 1 non-pregnant woman who had grade 3 uterine prolapse recurrence after open sacrohysteropexy, in a case series of 194 premenopausal women with uterine prolapse treated by pectineal ligament hysteropexy (PLH). Further treatment details were not reported. In a systematic review of surgery for women with apical prolapse including 183 women with uterine prolapse (2 randomised controlled trials ) comparing abdominal sacrohysteropexy (open or laparoscopic approach) with vaginal hysterectomy and vault repair/support, evidence from 1 RCT (n=82) did not show a statistically significant difference between vaginal hysterectomy with vault support and abdominal sacrohysteropexy in the rate of mesh exposure (risk ratio 0.20, 95% confidence interval 0.01 to 4.04), or the need for repeat operation for mesh exposure (RR 0.20, 95% CI 0.01 to 4.04). In the systematic review including 183 women with uterine prolapse, evidence from 1 RCT (n=82) did not show a statistically significant difference in the rate of bowel injury between vaginal hysterectomy with vault support and abdominal sacrohysteropexy (RR 3.00, 95% CI 0.13 to 71.56). Small bowel injuries were reported in 3% (2/74) of women in the laparoscopic hysteropexy group and bladder injuries were reported in 4% (3/77) of women in the vaginal mesh hysteropexy group, in the non-randomised comparative study of 151 women. Bowel obstructions were reported in 2 women in a case series of 159 women treated by modified single-sheet mesh sacrohysteropexy. Both needed surgical re-intervention to release bowel adhesions. Adhesions were noted between bowel and non-peritonised mesh in less than 1% (3/507) of women who reported lower abdominal pain 4 to 8 months after surgery, in a case series of 507 women treated by laparoscopic hysteropexy. These were carefully divided. Damage to surrounding organs causing haemorrhage was reported in less than 1% (3/507) of women in the same study. Infections were reported in 1 RCT, 1 non-randomised comparative study, and 1 case series included in a systematic review of 239 women. In the RCT, infections were reported as vault abscess during admission (2/41), infected implant needing surgery (2/41) and fever of unknown origin (3/41). In total, 17% (7/41) of women had an infection after sacrohysteropexy compared with 5% (2/41) in the vaginal hysterectomy group. The outcome was reported as wound infection and fever in the non-randomised comparative study. Three cases of infection (3/39) occurred in the hysterectomy followed by sacrocolpopexy group, and 1 (1/36) occurred in the sacrohysteropexy group. In the case series, 1 urinary tract infection (1/30) and 1 wound infection (1/30) were reported after sacrohysteropexy. In the systematic review including 183 women with uterine prolapse, evidence from 1 RCT (n=82) did not show a statistically significant difference between vaginal hysterectomy with vault support and abdominal sacrohysteropexy in the need for a blood transfusion (RR 2.00, 95% CI 0.19 to 21.21). Other serious adverse effects reported in the systematic review of 239 women included incisional hernia in 4 women and 1 intestinal occlusion by the mesh after sacrohysteropexy. Pulmonary embolism was reported in 2 women in the case series of 507 women treated by laparoscopic sacrohysteropexy. Other complications including perineal infection in 3% (16/507) of women, urinary tract infections in 1% (6/507) and voiding difficulties in 2% (11/507) were reported in the case series of 507 women treated by laparoscopic sacrohysteropexy. In a case series of 245 patients, after 1 year, 2% of women had urinary retention needing treatment, 2% had de novo stress urinary incontinence, 5% had urgency, 5% developed de novo constipation and 5% reported de novo dyspareunia. Overactive bladder occurred in 6% (3/54) of women treated by robotic or laparoscopic sacrohysteropexy and in 18% (10/57) treated by open sacrohysteropexy in the non-randomised study of 111 women (median follow‑up of 30 months). One patient reported a feeling of traction in the abdomen that reduced after the mesh was partially removed several weeks after robotic sacrohysteropexy, in a case series of 100 women. The study also reported ileus (n=1), oedema of the right arm leading to temporary sensitive malfunction (n=1) and de novo stress urinary incontinence (n=13). All patients reported postoperative dragging pain, at the points where the mesh was fixed to the abdominal wall, in a case series of 28 women. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: sacral discitis. They considered that the following were theoretical adverse events: risk related to sacral promontory mesh fixation (vascular damage and discitis) and risk of performing a hysterectomy after a hysteropexy. Twenty one commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2572-8	{'Recommendations': "Current evidence on the safety of uterine suspension using mesh (including sacrohysteropexy) to repair uterine prolapse shows there are serious and well-recognised complications. The evidence on efficacy is adequate in quantity and quality. Therefore, this procedure can be used provided that standard arrangements are in place for clinical governance, consent and audit.\n\nDuring the consent process, clinicians should ensure that patients understand the risk of uterine prolapse happening again and of potentially serious complications, including mesh erosion (for example, into the bladder). Patients should be told about all treatment options and provided with clear written information about the procedure and its complications. In addition, the use of NICE's information for the public is recommended.\n\nPatient selection should be done by a multidisciplinary team with experience in managing pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training and do the procedure regularly.\n\nClinicians should enter details about all patients having mesh uterine suspension (including sacrohysteropexy) to repair uterine prolapse onto an appropriate registry (for example, the British Society of Urogynaecology database). All adverse events involving the medical devices (including mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.", 'Indications and current treatments': 'Uterine prolapse is when the uterus descends from its usual position, into and sometimes through the vagina. It can affect quality of life by causing symptoms of pressure and discomfort, and by its effects on urinary, bowel and sexual function.\n\nCurrent treatment options include pelvic floor muscle training, use of pessaries and surgery. Some surgical procedures involve the use of mesh, with the aim of providing additional support.', 'The procedure': "Uterine suspension using mesh to repair uterine prolapse involves attaching the uterus (or cervix) either to the sacrum (sacrohysteropexy) or to the ileopectineal ligaments. This procedure can also be used for women with cervical prolapse after supracervical hysterectomy. The procedure is done with the patient under general anaesthesia by an open or laparoscopic abdominal approach. In sacrohysteropexy the mesh can be attached to the uterus either in the midline of the posterior cervix or bilaterally, where the uterosacral ligaments join the uterus (in both cases the other end of the mesh is attached to the sacrum). Another mesh suspension technique involves attaching the mesh to the front of the uterine cervix and to the lateral ileopectineal ligaments. Each of the above procedures can be described as a 'uterine suspension using mesh'.\n\nThis procedure can be combined with surgery for stress urinary incontinence, such as colposuspension or minimally invasive sling placement. Several different types of synthetic and biological mesh are available that vary in structure and in their physical properties, such as absorbability.", 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of surgery for women with apical prolapse including 183\xa0women with uterine prolapse (2\xa0randomised controlled trials [RCTs]) comparing abdominal sacrohysteropexy (open or laparoscopic approach) with vaginal hysterectomy and vault repair/support, there was no difference in repeat prolapse surgery between the groups at 1\xa0to 8‑year follow‑up (risk ratio [RR] 0.68, 95% confidence interval [CI] 0.36 to 1.31, n=182, low quality evidence). In a retrospective case series of 507\xa0women with uterine prolapse treated by laparoscopic sacrohysteropexy, 3% (14/507) of women had further apical prolapse at a median follow‑up of 12\xa0months (range 6\xa0to 84\xa0months) because the mesh had stretched. Of these, 10\xa0women had plication of mesh and 3\xa0had cervical amputation for elongation. Ongoing uterine prolapse was reported in 2\xa0women and treated by vaginal hysterectomy; 7% (36/507) of women had further vaginal wall repair. In a case series of 194\xa0premenopausal women with uterine prolapse treated by pectineal ligament hysteropexy (PLH) by open or laparoscopic approach, the overall reoperation rate after PLH was 15% (29/194) at a mean follow‑up of 6.5\xa0years; 6% (10/176) of women had grade\xa03 uterine prolapse recurrence (7\xa0occurred in pregnant women after vaginal delivery; 3\xa0in non-pregnant women, of which 1\xa0was a tape erosion into the bladder). Twelve women developed cystocele and 7\xa0developed cervical elongation. Laparoscopic procedures had no recurrence of prolapse over 2\xa0years.\n\nIn the systematic review including 183\xa0women with uterine prolapse, evidence from 1\xa0RCT (n=82) did not show a statistically significant difference between vaginal hysterectomy with vault support and abdominal sacrohysteropexy for objective failure of anterior vaginal compartment (RR 1.04, 95% CI 0.60 to 1.82), apical compartment (RR 1.00, 95% CI 0.15 to 6.76) or posterior vaginal compartment (RR 3.07, 95% CI 0.66 to 14.35) at 1‑year follow‑up. In a non-randomised comparative study of 151\xa0women comparing laparoscopic sacral hysteropexy (n=74) with vaginal mesh hysteropexy (n=77), there was no difference between groups in the rate of apical failure (19% [12/64] laparoscopic hysteropexy compared with 16% [9/61] vaginal mesh hysteropexy, p=0.16) or anterior failure (9% [6/65] laparoscopic hysteropexy compared with 6% [4/61] vaginal mesh hysteropexy, p=0.93) at 1‑year follow‑up.\n\nIn the systematic review including 183\xa0women with uterine prolapse, 1\xa0RCT reported that awareness of prolapse (defined as any positive response to questions related to awareness of prolapse or vaginal bulge) was less likely after vaginal hysterectomy than after abdominal sacrohysteropexy at 8‑year follow‑up, but this result was not statistically significant (RR 0.38, 95% CI 0.15 to 0.98, n=84, moderate quality evidence). In the case series of 507\xa0women there was significant improvement for pelvic organ prolapse quantification point\xa0C assessment (p<0.001), with a mean change of 7.9\xa0cm between preoperative and postoperative scores at 3‑month follow‑up; 94% (379/404) of women felt that their prolapse (assessed using 7‑point Patient Global Impression of Improvement [PGI‑I] subjective measure) was 'very much' or 'much' better and 2% (6/404) felt there was no change in symptoms. No women described their symptoms as worse. In the non-randomised comparative study of 151\xa0women comparing laparoscopic sacral hysteropexy with vaginal mesh hysteropexy, prolapse stage was similar but laparoscopic hysteropexy was associated with increased vaginal length (p<0.001), increased perineal body length (p=0.02) and better apical support (p=0.05) at 1‑year follow‑up. Overall satisfaction (measured on PGI‑I scale) was high and 79% of women in each group rated prolapse symptoms as 'very much better' and 16% 'much better' at 1‑year follow‑up.\n\nIn a case series of 100\xa0women with uterovaginal prolapse treated by robotic sacrohysteropexy, overall quality of life (measured using the validated urogenital distress inventory and incontinence impact questionnaires [UDI/IIQ], with scores ranging from 0 to 6) improved from a mean score of 4.5 to 5.12 (p<0.05), and overall health status (based on a visual analogue scale of 0 to 100) improved from 73% to 82% (p<0.05), 6\xa0weeks after surgery. Postoperatively women also experienced less feelings of nervousness (p=0.01), shame (p<0.05) and frustration (p<0.05). After 5\xa0years the positive effects of these feelings remained and quality of life and overall health status remained stable.\n\nIn the case series of 194\xa0premenopausal women with uterine prolapse, there were 46\xa0births (32\xa0vaginal and 14\xa0caesarean deliveries) in 40\xa0women after PLH. Prolapse recurred (tape avulsed from the uterus) in 7\xa0women after vaginal delivery and was treated by vaginal hysterectomy. There were no recurrences after caesarean deliveries.\n\nThe specialist advisers listed key efficacy outcomes as resolution of prolapse symptoms and recurrent apical prolapse.\n\nTwenty one commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nMesh complications were reported in 3% (2/74) of women in the laparoscopic hysteropexy group (1\xa0excision and 1\xa0spontaneous resolution) and in 7% (5/77) of women in the vaginal mesh hysteropexy group (treated by excision in\xa03 and observation in\xa02) in a non-randomised comparative study of 151\xa0patients. Tape erosion into the bladder occurred in 1\xa0non-pregnant woman who had grade\xa03 uterine prolapse recurrence after open sacrohysteropexy, in a case series of 194\xa0premenopausal women with uterine prolapse treated by pectineal ligament hysteropexy (PLH). Further treatment details were not reported. In a systematic review of surgery for women with apical prolapse including 183\xa0women with uterine prolapse (2\xa0randomised controlled trials [RCTs]) comparing abdominal sacrohysteropexy (open or laparoscopic approach) with vaginal hysterectomy and vault repair/support, evidence from 1\xa0RCT (n=82) did not show a statistically significant difference between vaginal hysterectomy with vault support and abdominal sacrohysteropexy in the rate of mesh exposure (risk ratio [RR] 0.20, 95% confidence interval [CI] 0.01 to 4.04), or the need for repeat operation for mesh exposure (RR 0.20, 95% CI 0.01 to\xa04.04).\n\nIn the systematic review including 183\xa0women with uterine prolapse, evidence from 1\xa0RCT (n=82) did not show a statistically significant difference in the rate of bowel injury between vaginal hysterectomy with vault support and abdominal sacrohysteropexy (RR 3.00, 95% CI 0.13 to 71.56). Small bowel injuries were reported in 3% (2/74) of women in the laparoscopic hysteropexy group and bladder injuries were reported in 4% (3/77) of women in the vaginal mesh hysteropexy group, in the non-randomised comparative study of 151\xa0women.\n\nBowel obstructions were reported in 2\xa0women in a case series of 159\xa0women treated by modified single-sheet mesh sacrohysteropexy. Both needed surgical re-intervention to release bowel adhesions. Adhesions were noted between bowel and non-peritonised mesh in less than 1% (3/507) of women who reported lower abdominal pain 4\xa0to 8\xa0months after surgery, in a case series of 507\xa0women treated by laparoscopic hysteropexy. These were carefully divided. Damage to surrounding organs causing haemorrhage was reported in less than 1% (3/507) of women in the same study.\n\nInfections were reported in 1\xa0RCT, 1\xa0non-randomised comparative study, and 1\xa0case series included in a systematic review of 239\xa0women. In the RCT, infections were reported as vault abscess during admission (2/41), infected implant needing surgery (2/41) and fever of unknown origin (3/41). In total, 17% (7/41) of women had an infection after sacrohysteropexy compared with 5% (2/41) in the vaginal hysterectomy group. The outcome was reported as wound infection and fever in the non-randomised comparative study. Three cases of infection (3/39) occurred in the hysterectomy followed by sacrocolpopexy group, and 1\xa0(1/36) occurred in the sacrohysteropexy group. In the case series, 1\xa0urinary tract infection (1/30) and 1\xa0wound infection (1/30) were reported after sacrohysteropexy.\n\nIn the systematic review including 183\xa0women with uterine prolapse, evidence from 1\xa0RCT (n=82) did not show a statistically significant difference between vaginal hysterectomy with vault support and abdominal sacrohysteropexy in the need for a blood transfusion (RR 2.00, 95% CI 0.19 to\xa021.21).\n\nOther serious adverse effects reported in the systematic review of 239\xa0women included incisional hernia in 4\xa0women and 1\xa0intestinal occlusion by the mesh after sacrohysteropexy. Pulmonary embolism was reported in 2\xa0women in the case series of 507\xa0women treated by laparoscopic sacrohysteropexy.\n\nOther complications including perineal infection in 3% (16/507) of women, urinary tract infections in 1% (6/507) and voiding difficulties in 2% (11/507) were reported in the case series of 507\xa0women treated by laparoscopic sacrohysteropexy. In a case series of 245\xa0patients, after 1\xa0year, 2% of women had urinary retention needing treatment, 2% had de novo stress urinary incontinence, 5% had urgency, 5% developed de novo constipation and 5% reported de novo dyspareunia. Overactive bladder occurred in 6% (3/54) of women treated by robotic or laparoscopic sacrohysteropexy and in 18% (10/57) treated by open sacrohysteropexy in the non-randomised study of 111\xa0women (median follow‑up of 30\xa0months). One\xa0patient reported a feeling of traction in the abdomen that reduced after the mesh was partially removed several weeks after robotic sacrohysteropexy, in a case series of 100\xa0women. The study also reported ileus (n=1), oedema of the right arm leading to temporary sensitive malfunction (n=1) and de novo stress urinary incontinence (n=13). All patients reported postoperative dragging pain, at the points where the mesh was fixed to the abdominal wall, in a case series of 28\xa0women.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: sacral discitis. They considered that the following were theoretical adverse events: risk related to sacral promontory mesh fixation (vascular damage and discitis) and risk of performing a hysterectomy after a hysteropexy.\n\nTwenty one commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2572-8'}	https://www.nice.org.uk/guidance/ipg584	Evidence-based recommendations on uterine suspension using mesh (including sacrohysteropexy) to repair uterine prolapse in women. This involves attaching mesh from the uterus or cervix either to the bone at the base of the spine or to a ligament in the pelvis to hold the uterus in place.
ca936cfdf43ab8956baea55f633ce0d597a32000	nice	Infracoccygeal sacropexy using mesh to repair vaginal vault prolapse	Infracoccygeal sacropexy using mesh to repair vaginal vault prolapse Evidence-based recommendations on infracoccygeal sacropexy using mesh to repair vaginal vault prolapse in women. This involves attaching mesh from the buttocks to the top of the vagina to hold the vagina in place. # Recommendations Current evidence on the safety of infracoccygeal sacropexy using mesh to repair vaginal vault prolapse shows there are serious but well-recognised complications. The evidence on efficacy is inadequate in quality. Therefore, this procedure should not be used unless there are special arrangements in place for clinical governance, consent, and audit or research. Clinicians wishing to do infracoccygeal sacropexy using mesh to repair vaginal vault prolapse should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety, including the risk of mesh erosion (for example, into the vagina) and the risk of recurrence, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Patient selection and treatment should only be done by specialists experienced in managing pelvic organ prolapse and urinary incontinence in women. Clinicians doing this procedure should have specific up-to-date training. Clinicians should enter details about all patients having infracoccygeal sacropexy using mesh for vaginal vault prolapse repair onto an appropriate registry (for example, the British Society of Urogynaecology database) and the results of the registry should be published. All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency. Clinicians are encouraged to collect long-term data on clinical outcomes and patient-reported quality-of-life outcomes using validated scales. NICE may update the guidance on publication of further evidence.# Indications and current treatments Vaginal vault prolapse is when the upper part of the vagina descends from its usual position, sometimes out through the vaginal opening. It is common after hysterectomy and can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function. Treatment is rarely indicated if there are no symptoms. Mild-to-moderate prolapse may be treated with conservative measures such as pelvic floor muscle training, electrical stimulation and biofeedback. Topical oestrogens and mechanical measures such as pessaries may also be used. Surgery may be needed when the prolapse is severe. Different surgical procedures are available using vaginal or abdominal (open, laparoscopic or robotic) approaches. Some procedures involve the use of mesh, with the aim of providing additional support.# The procedure Infracoccygeal sacropexy is done with the patient under regional or general anaesthesia. An incision is made in the posterior wall of the vagina and a small puncture incision is made in each buttock. A mesh tape is introduced through 1 buttock incision and, using a tunnelling device, guided by a finger through the vaginal incision, the mesh is passed around the rectum. The mesh is then passed up the side of the vagina, across the top, and down the other side, and out through the incision in the other buttock. Both ends are cut so that they end just below the surface of the skin. The mesh is sutured to the top of the vagina to act as a tension-free sling that aims to support the vaginal vault. The procedure is sometimes described as posterior intravaginal slingplasty. This procedure can be combined with surgery for stress urinary incontinence, such as a sub-urethral sling placement. Several different types of synthetic and biological mesh are available that vary in structure and in physical properties such as absorbability.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of surgery using mesh for vaginal vault or uterine prolapse in 7,054 patients (which included 976 patients treated by infracoccygeal sacropexy) the results after a median follow-up of 13 months were as follows: prolapse recurrence rate 5% (range 0 to 25%; n=402), rate of patient-reported persistent symptoms 9% (range 2 to 21%; n=262), and reoperation rate 8% (range 0 to 30%; n=288). For vaginal vault prolapse only, recurrent prolapse at the original site was 7% (4/60 patients). In a case series of 118 patients with vaginal vault or uterine prolapse, the reoperation rate for recurrent prolapse was 2% (2/118) of patients after a mean follow-up of 59 months. In a case series of 577 patients, 4% (20/496) of patients had another operation for recurrent prolapse within 10 to 96 weeks. In a systematic review of 2,653 patients with vaginal vault or uterine prolapse (655 patients treated by infracoccygeal sacropexy), the mean objective success rate was 88% (range 37 to 99%; 95% confidence interval 87.2 to 89.1). In a randomised controlled trial (RCT) of 49 patients with vaginal vault or uterine prolapse treated by infracoccygeal sacropexy or sacrospinous suspension, anatomical success rates were 95% (20/21) and 100% (24/24) respectively (p=0.94) after a mean follow-up of 17 months. In a case series of 44 patients with vaginal vault or uterine prolapse, the success rate was 93% (41/44 patients) at 9-year follow-up. In the case series of 577 patients, anatomical results at median 7-week follow-up were assessed as good or excellent in 88% of patients (436/496); functional results were assessed as good or excellent in 83% (412/496) of patients. In the RCT of 49 patients treated by infracoccygeal sacropexy or sacrospinous suspension, postoperative rates of urinary stress incontinence were 0% (0/21) and 8% (2/24) respectively, compared with preoperative rates of 52% (11/21) and 29% (7/24) respectively. Postoperative rates of urgency were 14% (3/21) and 25% (6/24) respectively, compared with preoperative rates of 52% (11/21) and 50% (12/24) respectively. The differences between the treatment groups were not statistically significant. In the case series of 118 patients, persistent urinary stress incontinence, urge incontinence and bladder overactivity symptoms were reported in 3% (3/118), 3% (4/118) and 4% (5/118) of patients respectively, after a mean follow-up of 59 months. In the case series of 44 patients, none of the 18 patients who had nocturia at baseline and none of the 12 patients who had urgency at baseline reported these at 9-year follow-up (p=0.003 and 0.04 respectively). In the RCT of 49 patients, quality-of-life scores improved similarly in both treatment groups; the only statistically significant difference was for the Pelvic Organ Prolapse Distress Inventory score, which improved by 50% or more in 75% of patients treated by infracoccygeal sacropexy compared with 65% for sacrospinous suspension (p=0.02). In the case series of 118 patients, the Urinary Impact questionnaire scores improved from 134.6 at baseline to 115.7 after surgery (p<0.05) and the Pelvic Organ Prolapse Impact questionnaire scores improved from 164.3 at baseline to 108.4 after surgery (p<0.05), at a mean follow-up of 59 months. In the RCT of 49 patients treated by infracoccygeal sacropexy or sacrospinous suspension, 86% and 79% of patients respectively were satisfied or very satisfied after the procedure (p=0.85). In the case series of 44 patients, all patients noted that their quality of life had improved and they would recommend the surgery to their friends. The specialist advisers listed the key efficacy outcomes as patient satisfaction and comfort, quality of life, change in urinary, bowel and sexual function, objective prolapse assessment and long-term prolapse recurrence risk. Thirteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Mesh erosion was reported in 11 studies (n=889) of infracoccygeal sacropexy, with rates of 0 to 21% of patients (median 7%), in a systematic review of 7,054 patients. Reoperation for mesh erosion was needed in up to 17% of patients (median 7%, n=678). Mesh erosion was reported in 8% of patients treated by infracoccygeal sacropexy (n=655) in a systematic review of 2,653 patients. Vaginal tape exposure was reported in 10% (50/496) of patients in a case series of 577 patients and surgery to remove the tape was reported in 4% (21/496) of patients. Reoperation for anterior vaginal wall erosion was reported in 10% (2/21) of patients treated by infracoccygeal sacropexy and 8% (2/24) of patients treated by sacrospinous suspension, in an RCT of 49 patients. Blood loss needing transfusion was reported in 7 studies (n=383) of infracoccygeal sacropexy, with rates ranging from 0 to 2%, in the systematic review of 7,054 patients. Haematoma was reported in 1% of patients treated by infracoccygeal sacropexy (n=655) in the systematic review of 2,653 patients. Haematoma was reported in 3% (4/118) of all patients in the case series of 118 patients with vaginal cuff or utero-vaginal prolapse; 1 patient needed surgical evacuation and blood transfusion. Organ damage during the procedure was reported in 0 to 3% of patients (n=684 patients who had infracoccygeal sacropexy) in the systematic review of 7,054 patients. Bladder injury was reported in 2 patients treated by infracoccygeal sacropexy and 1 patient treated by sacrospinous suspension in the RCT of 49 patients. Infection was reported in 8 studies (n=698) of infracoccygeal sacropexy, with rates of 0 to 9%, in the systematic review of 7,054 patients. Pararectal abscess was reported in 1 patient treated by infracoccygeal sacropexy in the systematic review of 2,653 patients. Abscess or fistula was reported in 3% (3/118) of patients in the case series of 118 patients; all 3 patients needed surgery. Gluteovaginal sinus formation 3 months after infracoccygeal sacropexy and rectocutaneous fistula 2 months postoperatively were each described in a case report, included in the review of 2,653 patients. Dyspareunia was reported in 2% of patients treated by infracoccygeal sacropexy (n=655) in the systematic review of 2,653 patients. De novo dyspareunia was reported in 7% (25/348) of sexually active patients in the case series of 577 patients. Prolonged pain was reported in less than 1% of patients (4/655) who had infracoccygeal sacropexy in the systematic review of 2,653 patients. De novo urinary urge incontinence or bladder overactivity symptoms were reported in 9% (10/118) of patients and de novo urinary stress incontinence was reported in 6% (7/118) of patients in the case series of 118 patients. De novo urinary symptoms were reported in 6% (29/496) of patients in the case series of 577 patients. De novo constipation after the procedure was reported in 6% (7/118) of patients in the case series of 118 patients. Constipation was reported in 2% (2/92) of patients treated by infracoccygeal sacropexy and 9% (9/98) of patients treated by abdominal sacrocolpopexy (p=0.039) in the non-randomised comparative study of 190 patients. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any additional anecdotal or theoretical adverse events. Thirteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2566-7	{'Recommendations': "Current evidence on the safety of infracoccygeal sacropexy using mesh to repair vaginal vault prolapse shows there are serious but well-recognised complications. The evidence on efficacy is inadequate in quality. Therefore, this procedure should not be used unless there are special arrangements in place for clinical governance, consent, and audit or research.\n\nClinicians wishing to do infracoccygeal sacropexy using mesh to repair vaginal vault prolapse should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety, including the risk of mesh erosion (for example, into the vagina) and the risk of recurrence, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nPatient selection and treatment should only be done by specialists experienced in managing pelvic organ prolapse and urinary incontinence in women. Clinicians doing this procedure should have specific up-to-date training.\n\nClinicians should enter details about all patients having infracoccygeal sacropexy using mesh for vaginal vault prolapse repair onto an appropriate registry (for example, the British Society of Urogynaecology database) and the results of the registry should be published. All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nClinicians are encouraged to collect long-term data on clinical outcomes and patient-reported quality-of-life outcomes using validated scales. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Vaginal vault prolapse is when the upper part of the vagina descends from its usual position, sometimes out through the vaginal opening. It is common after hysterectomy and can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function.\n\nTreatment is rarely indicated if there are no symptoms. Mild-to-moderate prolapse may be treated with conservative measures such as pelvic floor muscle training, electrical stimulation and biofeedback. Topical oestrogens and mechanical measures such as pessaries may also be used. Surgery may be needed when the prolapse is severe. Different surgical procedures are available using vaginal or abdominal (open, laparoscopic or robotic) approaches. Some procedures involve the use of mesh, with the aim of providing additional support.', 'The procedure': 'Infracoccygeal sacropexy is done with the patient under regional or general anaesthesia. An incision is made in the posterior wall of the vagina and a small puncture incision is made in each buttock. A mesh tape is introduced through 1\xa0buttock incision and, using a tunnelling device, guided by a finger through the vaginal incision, the mesh is passed around the rectum. The mesh is then passed up the side of the vagina, across the top, and down the other side, and out through the incision in the other buttock. Both ends are cut so that they end just below the surface of the skin. The mesh is sutured to the top of the vagina to act as a tension-free sling that aims to support the vaginal vault. The procedure is sometimes described as posterior intravaginal slingplasty.\n\nThis procedure can be combined with surgery for stress urinary incontinence, such as a sub-urethral sling placement.\n\nSeveral different types of synthetic and biological mesh are available that vary in structure and in physical properties such as absorbability.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of surgery using mesh for vaginal vault or uterine prolapse in 7,054\xa0patients (which included 976\xa0patients treated by infracoccygeal sacropexy) the results after a median follow-up of 13\xa0months were as follows: prolapse recurrence rate 5% (range 0 to 25%; n=402), rate of patient-reported persistent symptoms 9% (range 2 to 21%; n=262), and reoperation rate 8% (range 0 to 30%; n=288). For vaginal vault prolapse only, recurrent prolapse at the original site was 7% (4/60\xa0patients). In a case series of 118\xa0patients with vaginal vault or uterine prolapse, the reoperation rate for recurrent prolapse was 2% (2/118) of patients after a mean follow-up of 59\xa0months. In a case series of 577\xa0patients, 4% (20/496) of patients had another operation for recurrent prolapse within 10 to 96\xa0weeks.\n\nIn a systematic review of 2,653\xa0patients with vaginal vault or uterine prolapse (655\xa0patients treated by infracoccygeal sacropexy), the mean objective success rate was 88% (range 37 to 99%; 95% confidence interval [CI] 87.2 to 89.1). In a randomised controlled trial (RCT) of 49\xa0patients with vaginal vault or uterine prolapse treated by infracoccygeal sacropexy or sacrospinous suspension, anatomical success rates were 95% (20/21) and 100% (24/24) respectively (p=0.94) after a mean follow-up of 17\xa0months. In a case series of 44\xa0patients with vaginal vault or uterine prolapse, the success rate was 93% (41/44\xa0patients) at 9-year follow-up. In the case series of 577\xa0patients, anatomical results at median 7-week follow-up were assessed as good or excellent in 88% of patients (436/496); functional results were assessed as good or excellent in 83% (412/496) of patients.\n\nIn the RCT of 49\xa0patients treated by infracoccygeal sacropexy or sacrospinous suspension, postoperative rates of urinary stress incontinence were 0% (0/21) and 8% (2/24) respectively, compared with preoperative rates of 52% (11/21) and 29% (7/24) respectively. Postoperative rates of urgency were 14% (3/21) and 25% (6/24) respectively, compared with preoperative rates of 52% (11/21) and 50% (12/24) respectively. The differences between the treatment groups were not statistically significant. In the case series of 118\xa0patients, persistent urinary stress incontinence, urge incontinence and bladder overactivity symptoms were reported in 3% (3/118), 3% (4/118) and 4% (5/118) of patients respectively, after a mean follow-up of 59\xa0months. In the case series of 44\xa0patients, none of the 18\xa0patients who had nocturia at baseline and none of the 12\xa0patients who had urgency at baseline reported these at 9-year follow-up (p=0.003 and 0.04 respectively).\n\nIn the RCT of 49\xa0patients, quality-of-life scores improved similarly in both treatment groups; the only statistically significant difference was for the Pelvic Organ Prolapse Distress Inventory score, which improved by 50% or more in 75% of patients treated by infracoccygeal sacropexy compared with 65% for sacrospinous suspension (p=0.02). In the case series of 118\xa0patients, the Urinary Impact questionnaire scores improved from 134.6 at baseline to 115.7 after surgery (p<0.05) and the Pelvic Organ Prolapse Impact questionnaire scores improved from 164.3 at baseline to 108.4 after surgery (p<0.05), at a mean follow-up of 59\xa0months.\n\nIn the RCT of 49\xa0patients treated by infracoccygeal sacropexy or sacrospinous suspension, 86% and 79% of patients respectively were satisfied or very satisfied after the procedure (p=0.85). In the case series of 44\xa0patients, all patients noted that their quality of life had improved and they would recommend the surgery to their friends.\n\nThe specialist advisers listed the key efficacy outcomes as patient satisfaction and comfort, quality of life, change in urinary, bowel and sexual function, objective prolapse assessment and long-term prolapse recurrence risk.\n\nThirteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nMesh erosion was reported in 11\xa0studies (n=889) of infracoccygeal sacropexy, with rates of 0 to 21% of patients (median 7%), in a systematic review of 7,054\xa0patients. Reoperation for mesh erosion was needed in up to 17% of patients (median 7%, n=678). Mesh erosion was reported in 8% of patients treated by infracoccygeal sacropexy (n=655) in a systematic review of 2,653\xa0patients. Vaginal tape exposure was reported in 10% (50/496) of patients in a case series of 577\xa0patients and surgery to remove the tape was reported in 4% (21/496) of patients. Reoperation for anterior vaginal wall erosion was reported in 10% (2/21) of patients treated by infracoccygeal sacropexy and 8% (2/24) of patients treated by sacrospinous suspension, in an RCT of 49\xa0patients.\n\nBlood loss needing transfusion was reported in 7\xa0studies (n=383) of infracoccygeal sacropexy, with rates ranging from 0 to 2%, in the systematic review of 7,054\xa0patients.\n\nHaematoma was reported in 1% of patients treated by infracoccygeal sacropexy (n=655) in the systematic review of 2,653\xa0patients. Haematoma was reported in 3% (4/118) of all patients in the case series of 118\xa0patients with vaginal cuff or utero-vaginal prolapse; 1\xa0patient needed surgical evacuation and blood transfusion.\n\nOrgan damage during the procedure was reported in 0 to 3% of patients (n=684 patients who had infracoccygeal sacropexy) in the systematic review of 7,054\xa0patients. Bladder injury was reported in 2\xa0patients treated by infracoccygeal sacropexy and 1\xa0patient treated by sacrospinous suspension in the RCT of 49\xa0patients.\n\nInfection was reported in 8\xa0studies (n=698) of infracoccygeal sacropexy, with rates of 0 to 9%, in the systematic review of 7,054\xa0patients. Pararectal abscess was reported in 1\xa0patient treated by infracoccygeal sacropexy in the systematic review of 2,653\xa0patients. Abscess or fistula was reported in 3% (3/118) of patients in the case series of 118\xa0patients; all 3\xa0patients needed surgery. Gluteovaginal sinus formation 3\xa0months after infracoccygeal sacropexy and rectocutaneous fistula 2\xa0months postoperatively were each described in a case report, included in the review of 2,653\xa0patients.\n\nDyspareunia was reported in 2% of patients treated by infracoccygeal sacropexy (n=655) in the systematic review of 2,653\xa0patients. De novo dyspareunia was reported in 7% (25/348) of sexually active patients in the case series of 577\xa0patients.\n\nProlonged pain was reported in less than 1% of patients (4/655) who had infracoccygeal sacropexy in the systematic review of 2,653\xa0patients.\n\nDe novo urinary urge incontinence or bladder overactivity symptoms were reported in 9% (10/118) of patients and de novo urinary stress incontinence was reported in 6% (7/118) of patients in the case series of 118\xa0patients. De novo urinary symptoms were reported in 6% (29/496) of patients in the case series of 577\xa0patients.\n\nDe novo constipation after the procedure was reported in 6% (7/118) of patients in the case series of 118\xa0patients. Constipation was reported in 2% (2/92) of patients treated by infracoccygeal sacropexy and 9% (9/98) of patients treated by abdominal sacrocolpopexy (p=0.039) in the non-randomised comparative study of 190\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any additional anecdotal or theoretical adverse events.\n\nThirteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2566-7'}	https://www.nice.org.uk/guidance/ipg581	Evidence-based recommendations on infracoccygeal sacropexy using mesh to repair vaginal vault prolapse in women. This involves attaching mesh from the buttocks to the top of the vagina to hold the vagina in place.
56ffe0d41a5a642c68aba06ec8d66cbb3a1c10a8	nice	Etelcalcetide for treating secondary hyperparathyroidism	Etelcalcetide for treating secondary hyperparathyroidism Evidence-based recommendations on etelcalcetide (Parsabiv) for treating secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis. # Recommendations Etelcalcetide is recommended as an option for treating secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis, only if: treatment with a calcimimetic is indicated but cinacalcet is not suitable and the company provides etelcalcetide with the discount agreed in the patient access scheme. This guidance is not intended to affect the position of patients whose treatment with etelcalcetide was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Etelcalcetide (Parsabiv, Amgen) is a calcimimetic. It binds directly to the extracellular domain of the calcium-sensing receptor and activates it at a site distinct from the calcium-activating site. This suppresses secretion of parathyroid hormone because of an increased sensitivity of the receptor to calcium, and leads to a decrease in calcium levels. Etelcalcetide is given by intravenous injection. Marketing authorisation Etelcalcetide is indicated for the treatment of secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis. Adverse reactions Very common adverse reactions with etelcalcetide are decreased blood calcium, muscle spasms, diarrhoea, nausea and vomiting. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended initial dose of etelcalcetide is 5 mg administered by bolus injection 3 times per week. Corrected serum calcium should be at or above the lower limit of the normal range before administration of the first dose of etelcalcetide. Etelcalcetide should be titrated so that doses are individualised between 2.5 mg and 15 mg. Price NHS list prices: £136.87 per pack of 6 vials of 2.5 mg in 0.5 ml solution (£9.12 per mg; excluding VAT). £163.92 per pack of 6 vials of 5 mg in 1 ml solution (£5.46 per mg). £327.84 per pack of 6 vials of 10 mg in 1 ml solution (£5.46 per mg). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of etelcalcetide, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of etelcalcetide, having considered evidence on the nature of secondary hyperparathyroidism and the value placed on the benefits of etelcalcetide by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness ## Clinical management of secondary hyperparathyroidism The committee considered the effect of secondary hyperparathyroidism on people with chronic kidney disease on haemodialysis. The committee heard from the patient experts that the main symptoms are bone pain, reduced mobility, stomach pain and depression. The patient experts also stated that most people with the condition have a substantial number of tablets to take, including phosphate binders that can be unpleasant because they are difficult to swallow and produce nausea, making adherence to treatment challenging. People with secondary hyperparathyroidism would welcome a treatment that could be given at the same time as dialysis with no additional tablets to take. The clinical experts stated that they spend a lot of time talking to people who have difficulty adhering to treatment, in order to find ways to improve adherence. For these reasons, the clinical and patient experts commented that an intravenous calcimimetic could improve adherence because it would be given at the end of haemodialysis sessions. Taking into account the chronic nature of the condition, the availability of an additional treatment with a different mode of administration would be a valued option for people with secondary hyperparathyroidism. The committee understood the importance of having different treatment options available for treating secondary hyperparathyroidism. The committee discussed how secondary hyperparathyroidism is treated in clinical practice. It heard from the clinical experts that the aim of treatment is to correct levels of parathyroid hormone, serum calcium and phosphate. Initial treatment comprises dietary changes (to restrict phosphate), oral phosphate binders and active vitamin D such as alfacalcidol, calcitriol or paricalcitol. The clinical experts stated that active vitamin D treatment can lead to an increase in the level of serum calcium, limiting the amount of vitamin D that can be given. When calcium levels are considered to be too high clinicians will consider treatment with a calcimimetic such as cinacalcet, in combination with phosphate binders and vitamin D. The clinical experts confirmed that rising serum calcium and uncontrolled parathyroid hormone levels, despite phosphate binders and vitamin D, could be considered as 'refractory' secondary hyperparathyroidism. The committee heard that surgery to remove the parathyroid glands (parathyroidectomy) can be a good treatment option for people with more severe hyperparathyroidism, but this is more likely to be offered after treatment with phosphate binders, vitamin D and a calcimimetic. The patient experts highlighted a patient survey, which revealed that most people prefer to avoid surgery if possible. The committee noted the wording of the marketing authorisation for etelcalcetide, which is for the treatment of secondary hyperparathyroidism in people with chronic kidney disease on haemodialysis. It heard from the clinical experts that etelcalcetide is unlikely to be used as a first-line treatment because clinicians have a lot of experience with using phosphate binders and active vitamin D, and they would only offer a calcimimetic to people with refractory secondary hyperparathyroidism; that is, people with rising serum calcium and uncontrolled parathyroid hormone levels despite taking phosphate binders and vitamin D. The committee concluded that the most likely place in the treatment pathway for etelcalcetide would be for people with refractory secondary hyperparathyroidism, not as a first-line therapy. ## Generalisability of the clinical trial results The committee discussed the patient populations in the 2 clinical trials that compared etelcalcetide with placebo (Study 20120229 and Study 20120230) and the active comparator trial that compared etelcalcetide with cinacalcet (Study 20120360). It acknowledged that the trials included a broad population of people with secondary hyperparathyroidism, rather than those specifically with refractory disease to whom a calcimimetic would be offered in current clinical practice. The committee noted that around 46% of patients in the placebo-controlled trials, and 25% in the cinacalcet-controlled trial, had previously had treatment with cinacalcet. The committee concluded that people included in these trials were generally representative of those with secondary hyperparathyroidism in the UK, but it noted that they did not specifically represent the population who would be considered for etelcalcetide in current clinical practice; that is, people with inadequately controlled calcium and parathyroid hormone levels on standard first-line treatment. The committee considered the primary outcome (more than 30% reduction in parathyroid hormone level) from the pooled results of the 2 trials of etelcalcetide compared with placebo. It noted that etelcalcetide resulted in a statistically significantly higher proportion of people having more than 30% reduction compared with placebo (74.7% for etelcalcetide compared with 8.9% for placebo; odds ratio 31.60, 95% confidence interval 21.59 to 46.25, p<0.001).The committee noted that in the active comparator-controlled trial, in which etelcalcetide was compared with cinacalcet, etelcalcetide met its non-inferiority endpoint (a difference of no more than 12% in the upper bound of the 95% CI for the proportion of patients achieving more than 30% reduction in parathyroid hormone level): 77.9% of people in the etelcalcetide group had more than 30% reduction in parathyroid hormone levels compared with 63.9% in the cinacalcet group (treatment difference −10.48%, 95% CI −17.45 to −3.51). The committee also noted that etelcalcetide showed a statistically significantly higher proportion of people achieving a reduction of more than 30% and more than 50% reduction in mean parathyroid hormone levels compared with cinacalcet. The committee agreed that etelcalcetide is effective in terms of reducing parathyroid hormone levels by the target percentages in the trial. However it was uncertain of the generalisability of this specific surrogate outcome to long-term outcomes such as cardiovascular events and death. It heard from the clinical experts that the aim of treatment in secondary hyperparathyroidism is to control the levels of phosphate, calcium and parathyroid hormone with the aim of reducing both immediate and longer-term harm; but a directly proportional relationship between a specific percentage reduction in parathyroid hormone with long-term outcomes such as mortality is not clear. The committee concluded that the relationship between a 30% reduction in parathyroid hormone (from a variable baseline level) and long-term outcomes such as survival, incidence of fractures, incidence of cardiovascular events and need for parathyroidectomy, which were not measured in the trials, is unclear. The committee discussed the key secondary outcome in the placebo-controlled trials of etelcalcetide, which was the attainment of a parathyroid hormone level of 300 picograms/ml (31.8 picomoles/litre) or less. The clinical experts explained that in clinical practice target levels for parathyroid hormone can be very broad (the Kidney Disease Improving Global Outcomes guideline suggests 2 to 9 times the upper limit of normal for the reference limit of the laboratory test used, which translates to a parathyroid hormone range of around 130 to 600 picograms/ml or 13.8 to 63.6 picomoles/litre). The committee heard from the clinical experts that the range is broad because people tolerate high levels of parathyroid hormone differently, and the approach to treatment varies for each person depending on their symptoms and other parameters such as serum calcium and phosphate levels. The committee concluded that the primary outcome of more than 30% reduction in parathyroid hormone is a good indicator of the effectiveness of a treatment on the blood biochemistry and therefore a clinically relevant outcome. But it recalled its previous conclusion that such a percentage reduction may not be directly proportional to a reduction in incidence of long-term outcomes such as mortality, cardiovascular events and fractures. ## Adverse effects of etelcalcetide The committee discussed the adverse effects associated with etelcalcetide. It noted that the most common adverse event in the etelcalcetide studies was low serum calcium. The committee noted the ERG's comments that the higher rate of hypocalcaemia observed for etelcalcetide than cinacalcet could result in the use of more health care resources in order to manage the effects of hypocalcaemia. The committee was concerned that the evidence for etelcalcetide came from relatively short-term studies (26 weeks duration initially, followed by a 52‑week open-label extension to studies 201202229 and 2012230), whereas people with secondary hyperparathyroidism may be taking this treatment long-term. It heard from the clinical experts that although etelcalcetide acts on a different binding site to cinacalcet, it acts on the same calcium-sensing receptor. Therefore they would not expect the adverse effects to be very different for cinacalcet and etelcalcetide. The committee concluded that etelcalcetide's adverse effect profile is acceptable, but acknowledged that there may be some uncertainty in understanding the long-term risks associated with its use. # Cost effectiveness ## The company's economic model The committee considered the company's economic model, which used a Markov-type health state transition model. The model used 4 health states, which reflected the principal long-term adverse outcomes associated with secondary hyperparathyroidism: all-cause mortality, non-fatal clinical fractures and non-fatal cardiovascular events (such as heart failure and myocardial infarction). The committee agreed that the inclusion of these health states was reasonable for the modelling of cost effectiveness over a lifetime horizon, although in clinical practice the success of treatment is judged on shorter-term biochemical outcomes. The committee acknowledged the challenges in modelling long-term outcomes such as mortality on the basis of biochemical outcomes from trials of limited duration, but concluded that the structure of the model was acceptable. The committee considered the clinical-effectiveness estimates used in the company's model. The committee was aware that the primary outcome in the etelcalcetide trials was the proportion of people with more than 30% reduction in parathyroid hormone levels, but that the model used data on long-term effects including mortality, cardiovascular events, fractures and parathyroidectomy. It noted that the company derived hazard ratio estimates for etelcalcetide and the comparators for these long-term outcomes from the EVOLVE trial. This was a large international trial that compared cinacalcet with placebo, with a follow up of 64 months. All patients in the trial could also have phosphate binders, vitamin D, or both. The committee understood that the unadjusted intention-to-treat analysis in the publication of the EVOLVE trial showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events compared with placebo. However, when the trial results were adjusted for imbalance in the 2 arms (principally a 13‑month difference in the mean age in the arms of the trial) statistical significance was reached. The committee considered that the evidence for a long‑term benefit for cinacalcet on mortality and cardiovascular events from EVOLVE was not particularly strong. However, the committee accepted that EVOLVE also had high rates of both discontinuation and treatment switching. The company had explored several approaches to correct for this when deriving hazard ratio estimates for etelcalcetide and the comparators for each of the outcomes in the model. In order to derive hazard ratios for estimating the long-term treatment effects of etelcalcetide, the committee understood that the company used hazard ratio estimates from EVOLVE (a cinacalcet trial), linked to outcomes from the etelcalcetide trials. The company assumed a linear relationship between the hazard ratios and the proportion of people experiencing more than 30% reduction in parathyroid hormone levels. The committee agreed with the ERG that EVOLVE was the best available source of evidence for the long-term effects of calcimimetics, but it had concerns about the robustness of the estimates. It was concerned that there were adjustments made to the EVOLVE data to derive treatment effects, and it was unclear how valid they were. The data were also further adjusted for high rates of discontinuation and switching, although the committee acknowledged that the lag-censored approach used in the company's base case was pre-specified. The ERG commented that the company's approach to pooling the placebo-controlled etelcalcetide trials broke randomisation and the ERG suggested that a preferred approach would be a simple chained indirect comparison. The committee was aware that the company's approach assumed that the rate of achieving a 30% reduction in parathyroid hormone level would translate into a directly proportional effect on mortality, fractures, cardiovascular events and the need for parathyroidectomy. It concluded that the company's estimates of the long-term benefits of etelcalcetide were highly uncertain because of the reliance on a trial of another treatment (cinacalcet), the results of which had been extensively adjusted, and the assumption that a higher rate of reduction in parathyroid hormone levels for etelcalcetide than cinacalcet would translate into a directly proportionally greater reduction in mortality, fractures, cardiovascular events and parathyroidectomy. The committee considered the company's approach to estimating utility values used in the model. It noted that no utility data were available for etelcalcetide because EQ-5D data were not collected in the etelcalcetide trials. The committee noted that the utility estimates used in the economic model were derived from EVOLVE, which estimated utilities using EQ-5D questionnaires given to 3,547 people who took part in the trial. The committee noted that a utility value of 0.71 for the baseline utility for people on haemodialysis could be considered relatively high compared with the general population. However, the committee agreed that EVOLVE is the most robust source of utility data and concluded that the company's approach was acceptable. The committee discussed the company's base-case cost-effectiveness estimates for etelcalcetide. It noted that the company had provided a comparison of etelcalcetide (plus phosphate binders and vitamin D) with phosphate binders and vitamin D alone for a broad population; that is, people with secondary hyperparathyroidism on haemodialysis. The cost-effectiveness results included the patient access scheme discount agreed between the company and the Department of Health. The committee recalled its previous discussion that etelcalcetide would not be used as a first-line treatment in the NHS, although noting comments from clinical experts that there might be some advantages to starting calcimimetics earlier rather than later. The committee therefore confined its further consideration to when etelcalcetide would be used in clinical practice; that is, for raised calcium and uncontrolled parathyroid hormone levels despite routine first-line treatment. The committee discussed the company's base-case incremental cost-effectiveness ratios (ICERs) for etelcalcetide compared with cinacalcet in people with refractory secondary hyperparathyroidism on haemodialysis. The committee agreed that this comparison is the most appropriate, based on how etelcalcetide would be used in clinical practice (see sections 4.2 and 4.10). The committee noted that the company's base-case deterministic ICER for this comparison was £14,778 per quality-adjusted life year (QALY) gained and the probabilistic ICER was £15,058 per QALY gained. The committee was aware of the multiple uncertainties in relation to the extrapolation of the hazard ratios from EVOLVE (see section 4.8). The company's deterministic sensitivity analysis, varying the hazard ratio for mortality, which was the key driver in the cost-effectiveness analysis, increased the ICER from £14,778 to £26,647 per QALY gained. The ERG's exploratory analysis (using a simple indirect comparison of the etelcalcetide trials rather than pooling, and using an alternative method for adjusting the data from EVOLVE for non-adherence to treatment) increased the ICER from £14,778 to £22,400 per QALY gained. The committee noted that several estimates were above £20,000 per QALY gained, and these still assumed a directly proportional effect of a 30% reduction in parathyroid hormone on long-term outcomes. The company considered that etelcalcetide was 'highly likely' to be cost effective, but the committee considered that it was highly uncertain because of uncertainties in extrapolating short-term surrogate outcomes from the etelcalcetide trials to long-term outcomes such as mortality. The committee considered the company's comments that the appraisal consultation document overstated the uncertainty associated with estimates of the cost-effectiveness of etelcalcetide compared with cinacalcet. The committee was aware that the parameter uncertainty associated with the hazard ratio for mortality alone increased the deterministic ICER by more than £10,000 per QALY gained. In addition, this does not include the uncertainty in the extrapolation from the EVOLVE trial and therefore this uncertainty is not reflected in the ICER estimates nor in the probabilistic sensitivity analyses. The committee noted that the company presented an alternative method for modelling outcomes, using risk-based equations, and although this alternative method was welcomed by the committee, it understood that this approach had not been validated and therefore uncertainty remained. However, the committee accepted the advantages of having an intravenous calcimimetic option available for patients. It agreed that because there is uncertainty in establishing the long-term benefits of etelcalcetide compared with cinacalcet (for outcomes such as mortality, fracture and cardiovascular events) and higher associated costs, etelcalcetide should be recommended as an option for people with secondary hyperparathyroidism for whom a calcimimetic is indicated, only if cinacalcet is not considered suitable. # Equality issues The committee noted the potential equality issue raised by patient experts about people not on dialysis, who are taking calcimimetics and still have symptomatic secondary hyperparathyroidism. The committee noted that the marketing authorisation does not cover this population and that the recommendations made for this technology appraisal would not affect current practice for these people. The committee concluded that this did not constitute an equalities issue. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the PPRS 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA448 Appraisal title: Etelcalcetide for treating secondary hyperparathyroidism Section Key conclusion Etelcalcetide is recommended as an option for treating secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis, only if: treatment with a calcimimetic is indicated but cinacalcet is not suitable and the company provides etelcalcetide with the discount agreed in the patient access scheme. The committee noted that although the company's incremental cost-effectiveness ratios (ICERs) were below £30,000 per quality-adjusted life year (QALY) gained, these cost-effectiveness estimates are highly uncertain because of uncertainties in extrapolating short-term surrogate outcomes from the etelcalcetide trials to long-term outcomes such as mortality. However, the committee accepted the advantages of having an intravenous calcimimetic option available. Given that there is uncertainty in establishing the long-term benefits of etelcalcetide compared with cinacalcet (for outcomes such as mortality, fracture and cardiovascular events) and higher associated costs, the committee considered that it should be recommended as an option for people with secondary hyperparathyroidism for whom a calcimimetic is indicated, only if cinacalcet is not considered suitable. Current practice Clinical need of patients, including the availability of alternative treatments The patient experts stated that most people with the condition have a substantial number of tablets to take, including phosphate binders that can be unpleasant because they are difficult to swallow and produce nausea, making adherence to treatment challenging. The patient experts highlighted that people with secondary hyperparathyroidism would welcome a treatment that could be given at the same time as dialysis with no additional tablets to take. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? People with secondary hyperparathyroidism would welcome a treatment that could be given at the same time as dialysis with no additional tablets to take, which may improve adherence to treatment. The patient experts highlighted a patient survey, which revealed that most people would prefer to avoid surgery if possible. The committee accepted the advantages of having an intravenous calcimimetic option available. What is the position of the treatment in the pathway of care for the condition? The clinical experts stated that they would only offer a calcimimetic to people with refractory secondary hyperparathyroidism; that is, people with rising serum calcium and uncontrolled parathyroid hormone levels despite taking phosphate binders and vitamin D. The committee concluded that the most likely place in the treatment pathway for etelcalcetide would be for people with refractory secondary hyperparathyroidism, not as a first-line therapy. Adverse reactions The committee concluded that etelcalcetide's adverse effect profile is acceptable, but acknowledged that there may be some uncertainty in understanding the long-term risks associated with its use. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee concluded that the trials were of good quality but acknowledged that they included a broad population of people with secondary hyperparathyroidism, rather than those specifically with refractory disease to whom a calcimimetic would be offered in current clinical practice. The committee concluded that the primary outcome of a 30% reduction in parathyroid hormone level is a clinically important and meaningful outcome, but may not be directly proportional to the reduction in incidence of outcomes such as mortality, cardiovascular events and fractures. Relevance to general clinical practice in the NHS The committee concluded that people included in the trials were generally representative of those with secondary hyperparathyroidism in the UK, but it noted that they did not specifically represent the population who would be offered etelcalcetide in clinical practice; that is, people with inadequately controlled calcium and parathyroid hormone levels on standard first-line treatment. Uncertainties generated by the evidence The committee concluded that it was highly uncertain whether a 30% reduction in parathyroid hormone levels translates into directly proportional improvements in long-term outcomes such as survival, cardiovascular events and fractures. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable. Estimate of the size of the clinical effectiveness including strength of supporting evidence In the placebo-controlled trials, treatment with etelcalcetide resulted in a statistically significantly higher proportion of people with more than 30% reduction in parathyroid hormone level compared with placebo (74.7% for etelcalcetide compared with 8.9% for placebo; stratified odds ratio 31.60, 95% confidence interval 21.59 to 46.25, p<0.001). In the trial comparing etelcalcetide with cinacalcet (20120360), which had the same primary outcome measure, 77.9% of people in the etelcalcetide group experienced a more than 30% reduction in parathyroid hormone levels compared with 63.9% in the cinacalcet group (stratified treatment difference −10.48%, 95% CI −17.45% to −3.51%). Evidence for cost effectiveness Availability and nature of evidence The model used 4 health states, which reflected the principal adverse events associated with secondary hyperparathyroidism: all-cause mortality; non-fatal clinical fractures; and non-fatal cardiovascular events (such as, heart failure, myocardial infarction). To estimate treatment effects, the company model assumed that the rate of achieving a 30% reduction in the parathyroid hormone level would translate into a directly proportional effect on mortality, fractures, cardiovascular events and the need for parathyroidectomy. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee concluded that the company's estimates of the long-term benefits of etelcalcetide were highly uncertain because of the reliance on a trial of another treatment (cinacalcet), the results of which had been extensively adjusted and also the assumption that a higher rate of reduction in parathyroid hormone levels for etelcalcetide than cinacalcet, would translate into a directly proportional reduction in mortality, fractures, cardiovascular events and parathyroidectomy. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee noted that a utility value of 0.71 for the baseline utility for people on haemodialysis could be considered relatively high compared with the general population, but agreed that the EVOLVE trial was the most robust source of utility data and concluded that the company's approach was acceptable. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? Hazard ratios for mortality. Most likely cost-effectiveness estimate (given as an ICER) The most plausible ICER for the comparison of etelcalcetide and cinacalcet is between £14,778 to £26,647 per QALY gained, but the committee considered that it was highly uncertain because of uncertainties in extrapolating short-term surrogate outcomes from the etelcalcetide trials to long-term outcomes such as mortality. The committee was aware that the parameter uncertainty associated with the hazard ratio for mortality alone increased the deterministic ICER by more than £10,000 per QALY gained. In addition, this does not include the uncertainty in the extrapolation from the EVOLVE trial and therefore this uncertainty is not reflected in the ICER estimates nor in the probabilistic sensitivity analyses. Additional factors taken into account Patient access schemes (PPRS) The committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. Equalities considerations and social value judgements None identified.	{'Recommendations': 'Etelcalcetide is recommended as an option for treating secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis, only if:\n\ntreatment with a calcimimetic is indicated but cinacalcet is not suitable and\n\nthe company provides etelcalcetide with the discount agreed in the patient access scheme.\n\nThis guidance is not intended to affect the position of patients whose treatment with etelcalcetide was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': 'Description of the technology\n\nEtelcalcetide (Parsabiv, Amgen) is a calcimimetic. It binds directly to the extracellular domain of the calcium-sensing receptor and activates it at a site distinct from the calcium-activating site. This suppresses secretion of parathyroid hormone because of an increased sensitivity of the receptor to calcium, and leads to a decrease in calcium levels. Etelcalcetide is given by intravenous injection.\n\nMarketing authorisation\n\nEtelcalcetide is indicated for the treatment of secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis.\n\nAdverse reactions\n\nVery common adverse reactions with etelcalcetide are decreased blood calcium, muscle spasms, diarrhoea, nausea and vomiting. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended initial dose of etelcalcetide is 5\xa0mg administered by bolus injection 3\xa0times per week. Corrected serum calcium should be at or above the lower limit of the normal range before administration of the first dose of etelcalcetide. Etelcalcetide should be titrated so that doses are individualised between 2.5\xa0mg and 15\xa0mg.\n\nPrice\n\nNHS list prices:\n\n£136.87 per pack of 6\xa0vials of 2.5\xa0mg in 0.5\xa0ml solution (£9.12 per mg; excluding VAT).\n\n£163.92 per pack of 6\xa0vials of 5\xa0mg in 1\xa0ml solution (£5.46 per mg).\n\n£327.84 per pack of 6\xa0vials of 10\xa0mg in 1\xa0ml solution (£5.46 per mg).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of etelcalcetide, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Evidence': 'The appraisal committee (section 6) considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of etelcalcetide, having considered evidence on the nature of secondary hyperparathyroidism and the value placed on the benefits of etelcalcetide by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\n## Clinical management of secondary hyperparathyroidism\n\nThe committee considered the effect of secondary hyperparathyroidism on people with chronic kidney disease on haemodialysis. The committee heard from the patient experts that the main symptoms are bone pain, reduced mobility, stomach pain and depression. The patient experts also stated that most people with the condition have a substantial number of tablets to take, including phosphate binders that can be unpleasant because they are difficult to swallow and produce nausea, making adherence to treatment challenging. People with secondary hyperparathyroidism would welcome a treatment that could be given at the same time as dialysis with no additional tablets to take. The clinical experts stated that they spend a lot of time talking to people who have difficulty adhering to treatment, in order to find ways to improve adherence. For these reasons, the clinical and patient experts commented that an intravenous calcimimetic could improve adherence because it would be given at the end of haemodialysis sessions. Taking into account the chronic nature of the condition, the availability of an additional treatment with a different mode of administration would be a valued option for people with secondary hyperparathyroidism. The committee understood the importance of having different treatment options available for treating secondary hyperparathyroidism.\n\nThe committee discussed how secondary hyperparathyroidism is treated in clinical practice. It heard from the clinical experts that the aim of treatment is to correct levels of parathyroid hormone, serum calcium and phosphate. Initial treatment comprises dietary changes (to restrict phosphate), oral phosphate binders and active vitamin D such as alfacalcidol, calcitriol or paricalcitol. The clinical experts stated that active vitamin D treatment can lead to an increase in the level of serum calcium, limiting the amount of vitamin D that can be given. When calcium levels are considered to be too high clinicians will consider treatment with a calcimimetic such as cinacalcet, in combination with phosphate binders and vitamin D. The clinical experts confirmed that rising serum calcium and uncontrolled parathyroid hormone levels, despite phosphate binders and vitamin D, could be considered as 'refractory' secondary hyperparathyroidism. The committee heard that surgery to remove the parathyroid glands (parathyroidectomy) can be a good treatment option for people with more severe hyperparathyroidism, but this is more likely to be offered after treatment with phosphate binders, vitamin D and a calcimimetic. The patient experts highlighted a patient survey, which revealed that most people prefer to avoid surgery if possible. The committee noted the wording of the marketing authorisation for etelcalcetide, which is for the treatment of secondary hyperparathyroidism in people with chronic kidney disease on haemodialysis. It heard from the clinical experts that etelcalcetide is unlikely to be used as a first-line treatment because clinicians have a lot of experience with using phosphate binders and active vitamin D, and they would only offer a calcimimetic to people with refractory secondary hyperparathyroidism; that is, people with rising serum calcium and uncontrolled parathyroid hormone levels despite taking phosphate binders and vitamin D. The committee concluded that the most likely place in the treatment pathway for etelcalcetide would be for people with refractory secondary hyperparathyroidism, not as a first-line therapy.\n\n## Generalisability of the clinical trial results\n\nThe committee discussed the patient populations in the 2\xa0clinical trials that compared etelcalcetide with placebo (Study 20120229 and Study 20120230) and the active comparator trial that compared etelcalcetide with cinacalcet (Study 20120360). It acknowledged that the trials included a broad population of people with secondary hyperparathyroidism, rather than those specifically with refractory disease to whom a calcimimetic would be offered in current clinical practice. The committee noted that around 46% of patients in the placebo-controlled trials, and 25% in the cinacalcet-controlled trial, had previously had treatment with cinacalcet. The committee concluded that people included in these trials were generally representative of those with secondary hyperparathyroidism in the UK, but it noted that they did not specifically represent the population who would be considered for etelcalcetide in current clinical practice; that is, people with inadequately controlled calcium and parathyroid hormone levels on standard first-line treatment.\n\nThe committee considered the primary outcome (more than 30% reduction in parathyroid hormone level) from the pooled results of the 2\xa0trials of etelcalcetide compared with placebo. It noted that etelcalcetide resulted in a statistically significantly higher proportion of people having more than 30% reduction compared with placebo (74.7% for etelcalcetide compared with 8.9% for placebo; odds ratio 31.60, 95% confidence interval [CI] 21.59 to 46.25, p<0.001).The committee noted that in the active comparator-controlled trial, in which etelcalcetide was compared with cinacalcet, etelcalcetide met its non-inferiority endpoint (a difference of no more than 12% in the upper bound of the 95% CI for the proportion of patients achieving more than 30% reduction in parathyroid hormone level): 77.9% of people in the etelcalcetide group had more than 30% reduction in parathyroid hormone levels compared with 63.9% in the cinacalcet group (treatment difference −10.48%, 95% CI −17.45 to −3.51). The committee also noted that etelcalcetide showed a statistically significantly higher proportion of people achieving a reduction of more than 30% and more than 50% reduction in mean parathyroid hormone levels compared with cinacalcet. The committee agreed that etelcalcetide is effective in terms of reducing parathyroid hormone levels by the target percentages in the trial. However it was uncertain of the generalisability of this specific surrogate outcome to long-term outcomes such as cardiovascular events and death. It heard from the clinical experts that the aim of treatment in secondary hyperparathyroidism is to control the levels of phosphate, calcium and parathyroid hormone with the aim of reducing both immediate and longer-term harm; but a directly proportional relationship between a specific percentage reduction in parathyroid hormone with long-term outcomes such as mortality is not clear. The committee concluded that the relationship between a 30% reduction in parathyroid hormone (from a variable baseline level) and long-term outcomes such as survival, incidence of fractures, incidence of cardiovascular events and need for parathyroidectomy, which were not measured in the trials, is unclear.\n\nThe committee discussed the key secondary outcome in the placebo-controlled trials of etelcalcetide, which was the attainment of a parathyroid hormone level of 300\xa0picograms/ml (31.8\xa0picomoles/litre) or less. The clinical experts explained that in clinical practice target levels for parathyroid hormone can be very broad (the Kidney Disease Improving Global Outcomes guideline suggests 2\xa0to 9\xa0times the upper limit of normal for the reference limit of the laboratory test used, which translates to a parathyroid hormone range of around 130\xa0to\xa0600\xa0picograms/ml or 13.8\xa0to\xa063.6\xa0picomoles/litre). The committee heard from the clinical experts that the range is broad because people tolerate high levels of parathyroid hormone differently, and the approach to treatment varies for each person depending on their symptoms and other parameters such as serum calcium and phosphate levels. The committee concluded that the primary outcome of more than 30% reduction in parathyroid hormone is a good indicator of the effectiveness of a treatment on the blood biochemistry and therefore a clinically relevant outcome. But it recalled its previous conclusion that such a percentage reduction may not be directly proportional to a reduction in incidence of long-term outcomes such as mortality, cardiovascular events and fractures.\n\n## Adverse effects of etelcalcetide\n\nThe committee discussed the adverse effects associated with etelcalcetide. It noted that the most common adverse event in the etelcalcetide studies was low serum calcium. The committee noted the ERG's comments that the higher rate of hypocalcaemia observed for etelcalcetide than cinacalcet could result in the use of more health care resources in order to manage the effects of hypocalcaemia. The committee was concerned that the evidence for etelcalcetide came from relatively short-term studies (26\xa0weeks duration initially, followed by a 52‑week open-label extension to studies 201202229 and 2012230), whereas people with secondary hyperparathyroidism may be taking this treatment long-term. It heard from the clinical experts that although etelcalcetide acts on a different binding site to cinacalcet, it acts on the same calcium-sensing receptor. Therefore they would not expect the adverse effects to be very different for cinacalcet and etelcalcetide. The committee concluded that etelcalcetide's adverse effect profile is acceptable, but acknowledged that there may be some uncertainty in understanding the long-term risks associated with its use.\n\n# Cost effectiveness\n\n## The company's economic model\n\nThe committee considered the company's economic model, which used a Markov-type health state transition model. The model used 4 health states, which reflected the principal long-term adverse outcomes associated with secondary hyperparathyroidism: all-cause mortality, non-fatal clinical fractures and non-fatal cardiovascular events (such as heart failure and myocardial infarction). The committee agreed that the inclusion of these health states was reasonable for the modelling of cost effectiveness over a lifetime horizon, although in clinical practice the success of treatment is judged on shorter-term biochemical outcomes. The committee acknowledged the challenges in modelling long-term outcomes such as mortality on the basis of biochemical outcomes from trials of limited duration, but concluded that the structure of the model was acceptable.\n\nThe committee considered the clinical-effectiveness estimates used in the company's model. The committee was aware that the primary outcome in the etelcalcetide trials was the proportion of people with more than 30% reduction in parathyroid hormone levels, but that the model used data on long-term effects including mortality, cardiovascular events, fractures and parathyroidectomy. It noted that the company derived hazard ratio estimates for etelcalcetide and the comparators for these long-term outcomes from the EVOLVE trial. This was a large international trial that compared cinacalcet with placebo, with a follow up of 64\xa0months. All patients in the trial could also have phosphate binders, vitamin D, or both. The committee understood that the unadjusted intention-to-treat analysis in the publication of the EVOLVE trial showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events compared with placebo. However, when the trial results were adjusted for imbalance in the 2\xa0arms (principally a 13‑month difference in the mean age in the arms of the trial) statistical significance was reached. The committee considered that the evidence for a long‑term benefit for cinacalcet on mortality and cardiovascular events from EVOLVE was not particularly strong. However, the committee accepted that EVOLVE also had high rates of both discontinuation and treatment switching. The company had explored several approaches to correct for this when deriving hazard ratio estimates for etelcalcetide and the comparators for each of the outcomes in the model. In order to derive hazard ratios for estimating the long-term treatment effects of etelcalcetide, the committee understood that the company used hazard ratio estimates from EVOLVE (a cinacalcet trial), linked to outcomes from the etelcalcetide trials. The company assumed a linear relationship between the hazard ratios and the proportion of people experiencing more than 30% reduction in parathyroid hormone levels. The committee agreed with the ERG that EVOLVE was the best available source of evidence for the long-term effects of calcimimetics, but it had concerns about the robustness of the estimates. It was concerned that there were adjustments made to the EVOLVE data to derive treatment effects, and it was unclear how valid they were. The data were also further adjusted for high rates of discontinuation and switching, although the committee acknowledged that the lag-censored approach used in the company's base case was pre-specified. The ERG commented that the company's approach to pooling the placebo-controlled etelcalcetide trials broke randomisation and the ERG suggested that a preferred approach would be a simple chained indirect comparison. The committee was aware that the company's approach assumed that the rate of achieving a 30% reduction in parathyroid hormone level would translate into a directly proportional effect on mortality, fractures, cardiovascular events and the need for parathyroidectomy. It concluded that the company's estimates of the long-term benefits of etelcalcetide were highly uncertain because of the reliance on a trial of another treatment (cinacalcet), the results of which had been extensively adjusted, and the assumption that a higher rate of reduction in parathyroid hormone levels for etelcalcetide than cinacalcet would translate into a directly proportionally greater reduction in mortality, fractures, cardiovascular events and parathyroidectomy.\n\nThe committee considered the company's approach to estimating utility values used in the model. It noted that no utility data were available for etelcalcetide because EQ-5D data were not collected in the etelcalcetide trials. The committee noted that the utility estimates used in the economic model were derived from EVOLVE, which estimated utilities using EQ-5D questionnaires given to 3,547 people who took part in the trial. The committee noted that a utility value of 0.71 for the baseline utility for people on haemodialysis could be considered relatively high compared with the general population. However, the committee agreed that EVOLVE is the most robust source of utility data and concluded that the company's approach was acceptable.\n\nThe committee discussed the company's base-case cost-effectiveness estimates for etelcalcetide. It noted that the company had provided a comparison of etelcalcetide (plus phosphate binders and vitamin D) with phosphate binders and vitamin D alone for a broad population; that is, people with secondary hyperparathyroidism on haemodialysis. The cost-effectiveness results included the patient access scheme discount agreed between the company and the Department of Health. The committee recalled its previous discussion that etelcalcetide would not be used as a first-line treatment in the NHS, although noting comments from clinical experts that there might be some advantages to starting calcimimetics earlier rather than later. The committee therefore confined its further consideration to when etelcalcetide would be used in clinical practice; that is, for raised calcium and uncontrolled parathyroid hormone levels despite routine first-line treatment.\n\nThe committee discussed the company's base-case incremental cost-effectiveness ratios (ICERs) for etelcalcetide compared with cinacalcet in people with refractory secondary hyperparathyroidism on haemodialysis. The committee agreed that this comparison is the most appropriate, based on how etelcalcetide would be used in clinical practice (see sections 4.2 and 4.10). The committee noted that the company's base-case deterministic ICER for this comparison was £14,778 per quality-adjusted life year (QALY) gained and the probabilistic ICER was £15,058 per QALY gained. The committee was aware of the multiple uncertainties in relation to the extrapolation of the hazard ratios from EVOLVE (see section 4.8). The company's deterministic sensitivity analysis, varying the hazard ratio for mortality, which was the key driver in the cost-effectiveness analysis, increased the ICER from £14,778 to £26,647 per QALY gained. The ERG's exploratory analysis (using a simple indirect comparison of the etelcalcetide trials rather than pooling, and using an alternative method for adjusting the data from EVOLVE for non-adherence to treatment) increased the ICER from £14,778 to £22,400 per QALY gained. The committee noted that several estimates were above £20,000 per QALY gained, and these still assumed a directly proportional effect of a 30% reduction in parathyroid hormone on long-term outcomes. The company considered that etelcalcetide was 'highly likely' to be cost effective, but the committee considered that it was highly uncertain because of uncertainties in extrapolating short-term surrogate outcomes from the etelcalcetide trials to long-term outcomes such as mortality. The committee considered the company's comments that the appraisal consultation document overstated the uncertainty associated with estimates of the cost-effectiveness of etelcalcetide compared with cinacalcet. The committee was aware that the parameter uncertainty associated with the hazard ratio for mortality alone increased the deterministic ICER by more than £10,000 per QALY gained. In addition, this does not include the uncertainty in the extrapolation from the EVOLVE trial and therefore this uncertainty is not reflected in the ICER estimates nor in the probabilistic sensitivity analyses. The committee noted that the company presented an alternative method for modelling outcomes, using risk-based equations, and although this alternative method was welcomed by the committee, it understood that this approach had not been validated and therefore uncertainty remained. However, the committee accepted the advantages of having an intravenous calcimimetic option available for patients. It agreed that because there is uncertainty in establishing the long-term benefits of etelcalcetide compared with cinacalcet (for outcomes such as mortality, fracture and cardiovascular events) and higher associated costs, etelcalcetide should be recommended as an option for people with secondary hyperparathyroidism for whom a calcimimetic is indicated, only if cinacalcet is not considered suitable.\n\n# Equality issues\n\nThe committee noted the potential equality issue raised by patient experts about people not on dialysis, who are taking calcimimetics and still have symptomatic secondary hyperparathyroidism. The committee noted that the marketing authorisation does not cover this population and that the recommendations made for this technology appraisal would not affect current practice for these people. The committee concluded that this did not constitute an equalities issue.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the PPRS 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA448\n\nAppraisal title: Etelcalcetide for treating secondary hyperparathyroidism\n\nSection\n\nKey conclusion\n\nEtelcalcetide is recommended as an option for treating secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis, only if:\n\ntreatment with a calcimimetic is indicated but cinacalcet is not suitable and\n\nthe company provides etelcalcetide with the discount agreed in the patient access scheme.\n\nThe committee noted that although the company's incremental cost-effectiveness ratios (ICERs) were below £30,000 per quality-adjusted life year (QALY) gained, these cost-effectiveness estimates are highly uncertain because of uncertainties in extrapolating short-term surrogate outcomes from the etelcalcetide trials to long-term outcomes such as mortality. However, the committee accepted the advantages of having an intravenous calcimimetic option available. Given that there is uncertainty in establishing the long-term benefits of etelcalcetide compared with cinacalcet (for outcomes such as mortality, fracture and cardiovascular events) and higher associated costs, the committee considered that it should be recommended as an option for people with secondary hyperparathyroidism for whom a calcimimetic is indicated, only if cinacalcet is not considered suitable.\n\n, 4.11\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe patient experts stated that most people with the condition have a substantial number of tablets to take, including phosphate binders that can be unpleasant because they are difficult to swallow and produce nausea, making adherence to treatment challenging. The patient experts highlighted that people with secondary hyperparathyroidism would welcome a treatment that could be given at the same time as dialysis with no additional tablets to take.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nPeople with secondary hyperparathyroidism would welcome a treatment that could be given at the same time as dialysis with no additional tablets to take, which may improve adherence to treatment.\n\nThe patient experts highlighted a patient survey, which revealed that most people would prefer to avoid surgery if possible.\n\nThe committee accepted the advantages of having an intravenous calcimimetic option available.\n\n, 4.2, 4.11\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe clinical experts stated that they would only offer a calcimimetic to people with refractory secondary hyperparathyroidism; that is, people with rising serum calcium and uncontrolled parathyroid hormone levels despite taking phosphate binders and vitamin D. The committee concluded that the most likely place in the treatment pathway for etelcalcetide would be for people with refractory secondary hyperparathyroidism, not as a first-line therapy.\n\n\n\nAdverse reactions\n\nThe committee concluded that etelcalcetide's adverse effect profile is acceptable, but acknowledged that there may be some uncertainty in understanding the long-term risks associated with its use.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee concluded that the trials were of good quality but acknowledged that they included a broad population of people with secondary hyperparathyroidism, rather than those specifically with refractory disease to whom a calcimimetic would be offered in current clinical practice.\n\nThe committee concluded that the primary outcome of a 30% reduction in parathyroid hormone level is a clinically important and meaningful outcome, but may not be directly proportional to the reduction in incidence of outcomes such as mortality, cardiovascular events and fractures.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that people included in the trials were generally representative of those with secondary hyperparathyroidism in the UK, but it noted that they did not specifically represent the population who would be offered etelcalcetide in clinical practice; that is, people with inadequately controlled calcium and parathyroid hormone levels on standard first-line treatment.\n\n\n\nUncertainties generated by the evidence\n\nThe committee concluded that it was highly uncertain whether a 30% reduction in parathyroid hormone levels translates into directly proportional improvements in long-term outcomes such as survival, cardiovascular events and fractures.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nIn the placebo-controlled trials, treatment with etelcalcetide resulted in a statistically significantly higher proportion of people with more than 30% reduction in parathyroid hormone level compared with placebo (74.7% for etelcalcetide compared with 8.9% for placebo; stratified odds ratio 31.60, 95% confidence interval [CI] 21.59 to 46.25, p<0.001). In the trial comparing etelcalcetide with cinacalcet (20120360), which had the same primary outcome measure, 77.9% of people in the etelcalcetide group experienced a more than 30% reduction in parathyroid hormone levels compared with 63.9% in the cinacalcet group (stratified treatment difference −10.48%, 95% CI −17.45% to −3.51%).\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe model used 4 health states, which reflected the principal adverse events associated with secondary hyperparathyroidism: all-cause mortality; non-fatal clinical fractures; and non-fatal cardiovascular events (such as, heart failure, myocardial infarction).\n\nTo estimate treatment effects, the company model assumed that the rate of achieving a 30% reduction in the parathyroid hormone level would translate into a directly proportional effect on mortality, fractures, cardiovascular events and the need for parathyroidectomy.\n\n, 4.8\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee concluded that the company's estimates of the long-term benefits of etelcalcetide were highly uncertain because of the reliance on a trial of another treatment (cinacalcet), the results of which had been extensively adjusted and also the assumption that a higher rate of reduction in parathyroid hormone levels for etelcalcetide than cinacalcet, would translate into a directly proportional reduction in mortality, fractures, cardiovascular events and parathyroidectomy.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that a utility value of 0.71 for the baseline utility for people on haemodialysis could be considered relatively high compared with the general population, but agreed that the EVOLVE trial was the most robust source of utility data and concluded that the company's approach was acceptable.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nHazard ratios for mortality.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe most plausible ICER for the comparison of etelcalcetide and cinacalcet is between £14,778 to £26,647 per QALY gained, but the committee considered that it was highly uncertain because of uncertainties in extrapolating short-term surrogate outcomes from the etelcalcetide trials to long-term outcomes such as mortality.\n\nThe committee was aware that the parameter uncertainty associated with the hazard ratio for mortality alone increased the deterministic ICER by more than £10,000 per QALY gained. In addition, this does not include the uncertainty in the extrapolation from the EVOLVE trial and therefore this uncertainty is not reflected in the ICER estimates nor in the probabilistic sensitivity analyses.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nNone identified.\n\n"}	https://www.nice.org.uk/guidance/ta448	Evidence-based recommendations on etelcalcetide (Parsabiv) for treating secondary hyperparathyroidism in adults with chronic kidney disease on haemodialysis.
87bd5a3af044b447562e8f062bc851381cb7741f	nice	Everolimus and sunitinib for treating unresectable or metastatic neuroendocrine tumours in people with progressive disease	Everolimus and sunitinib for treating unresectable or metastatic neuroendocrine tumours in people with progressive disease Evidence-based recommendations on everolimus (Afinitor) and sunitinib (Sutent) for treating neuroendocrine tumours in adults. # Recommendations Everolimus and sunitinib are recommended, within their marketing authorisations, as options for treating well- or moderately differentiated unresectable or metastatic neuroendocrine tumours (NETs) of pancreatic origin in adults with progressive disease. Everolimus is recommended, within its marketing authorisation, as an option for treating well-differentiated (grade 1 or grade 2) non-functional unresectable or metastatic NETs of gastrointestinal or lung origin in adults with progressive disease. Everolimus is recommended only when the company provides it with the discount agreed in the patient access scheme. # Why the committee made these recommendations NETs can affect the pancreas, gastrointestinal tissue and lungs and are difficult to diagnose and treat. They can significantly affect emotional health and often mean that people are unable to work. There is particularly high unmet need for people with NETs that affect the lungs. Clinical trial evidence shows that everolimus and sunitinib are effective for treating pancreatic NETs compared with current treatment (best supportive care). Everolimus is effective for treating gastrointestinal and lung NETs compared with current treatment (best supportive care). For treating pancreatic NETs, everolimus and sunitinib were recommended because they met NICE's end-of-life criteria. The cost effectiveness estimates varied, from below £20,000 up to £30,000 per quality-adjusted life year (QALY) gained. For treating gastrointestinal NETs, everolimus did not meet the end-of-life criteria but was recommended because it is cost effective, at below £20,000 per QALY gained. For treating lung NETs, everolimus did not meet the end-of-life criteria. The cost-effectiveness estimates for everolimus varied, from below £20,000 up to £30,000 per QALY gained. It was recommended because of the cost-effectiveness estimates and the limited treatment options available for people with lung NETs. NICE's end-of-life criteria are that life expectancy for people with the condition should be less than 24 months and that treatment should extend life by more than 3 months.# The technologies Everolimus (Afinitor, Novartis) Sunitinib (Sutent, Pfizer) Marketing authorisations Everolimus has a marketing authorisation for 'unresectable or metastatic, well- or moderately differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease' and 'unresectable or metastatic, well differentiated (grade 1 or grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with progressive disease'. Sunitinib has a marketing authorisation for 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults'. Recommended doses and schedules Everolimus is taken orally, 10 mg once daily. Sunitinib is taken orally, 37.5 mg once daily. Prices £2,673.00 per 30-tablet (10 mg) pack (excluding VAT). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of everolimus with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. £784.70 per 28-tablet (12.5 mg) pack (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts. A complex patient access scheme for sunitinib is available in the NHS for other indications. However, the company did not request approval from the Department of Health for it to be considered in this appraisal. This appraisal only considered the list price.# Committee discussion The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence. # Clinical need and current practice ## People with NETs will welcome new treatment options because of high unmet need The committee understood that neuroendocrine tumours (NETs) can affect the pancreas, gastrointestinal tissue and lungs. They are difficult to diagnose and treat, can significantly affect emotional health and often mean that people are unable to work. It also heard from a patient expert that there is increasing frustration among people with advanced progressive NETs because of the recent restriction on targeted treatments that were previously available through the Cancer Drugs Fund. The clinical experts explained that few treatment options are available for lung NETs, meaning there is particularly high unmet need for this group of people. The committee concluded that there is a recognised need for treatment for NETs at different sites. ## Everolimus, sunitinib and best supportive care are appropriate comparators The committee heard from the clinical experts that managing NETs in the NHS mostly follows the European Neuroendocrine Tumor Society's guidelines. For treating pancreatic NETs causing symptoms (functional NETs) in people with progressive disease, options include everolimus and 177Lu-dotatate. For non-functional pancreatic NETs, the guidelines suggest 177Lu-dotatate or chemotherapy for progressive disease after offering everolimus or sunitinib. For treating functional and non-functional advanced gastrointestinal NETs in people with progressive disease, the guidelines suggest 177Lu-dotatate as an option with everolimus, and interferons. The clinical experts explained that although interferons may be considered after disease progression, they are not routinely used in England because of their toxicity. The clinical experts further explained that chemotherapy is sometimes used if people have symptoms because of the bulk of their disease (mainly people with a high disease burden with a Ki-67 proliferative index of around 20% or more, that is, grade 3 tumours). This is most often people with pancreatic NETs; chemotherapy is rarely used for people with well-differentiated gastrointestinal NETs. The committee understood that everolimus and 177Lu-dotatate are no longer available through the Cancer Drugs Fund. It was aware that only sunitinib is currently available through the Cancer Drugs Fund, meaning that current alternative treatment options are limited to best supportive care. The committee concluded that interferons and chemotherapy are not relevant comparators for everolimus and sunitinib, and that the most appropriate comparisons are of everolimus and sunitinib with each other and of both technologies with best supportive care for the specific sites covered by their marketing authorisations. # Clinical trial evidence ## Everolimus and sunitinib are effective for treating pancreatic NETs The clinical trial evidence for pancreatic NETs came from 2 double-blind, randomised controlled trials: RADIANT-3 (everolimus plus best supportive care compared with placebo plus best supportive care) and A6181111 (sunitinib plus best supportive care compared with placebo plus best supportive care).The trials included people whose disease had progressed on surgery, radiotherapy, chemotherapy, somatostatin analogues and targeted therapies. The committee noted that only a small number of people had disease that progressed on targeted therapies, which included everolimus (in RADIANT-3) and sunitinib (in A6181111). The results from the clinical trials showed significant improvements in progression-free survival for both treatments, with hazard ratios of 0.35 (95% confidence interval 0.27 to 0.45) for everolimus compared with placebo and 0.42 (95% CI 0.26 to 0.66) for sunitinib compared with placebo. The committee noted that the overall survival results were confounded by high levels of crossover in the comparator arms of both trials (73% in RADIANT-3 and 69% in A6181111). Both companies used the rank-preserving structural failure time model to adjust for crossover, which resulted in hazard ratios of 0.60 (95% CI 0.09 to 3.95) for everolimus compared with placebo and 0.34 (95% CI 0.14 to 1.28) for sunitinib compared with placebo. The median overall survival gain for sunitinib compared with placebo was 25.4 months, but this could not be determined for everolimus compared with placebo after adjusting for crossover. The committee heard from the assessment group that the companies' crossover adjustment method was appropriate. The committee concluded that despite the non-significant overall survival results and high levels of crossover, both everolimus and sunitinib are clinically effective for treating pancreatic NETs. ## Everolimus is effective for treating gastrointestinal and lung NETs For gastrointestinal and lung NETs, the evidence came from a double-blind, randomised controlled trial of everolimus plus best supportive care compared with placebo plus best supportive care (RADIANT-4). For gastrointestinal and lung NETs combined, the progression-free survival hazard ratio for everolimus compared with best supportive care was 0.48 (95% CI 0.35 to 0.67); the overall survival hazard ratio was 0.73 (95% CI 0.48 to 1.11). Separate analyses by tumour site showed significant reductions in the risk of progression or death with everolimus compared with placebo for both gastrointestinal NETs (hazard ratio 0.56, 95% CI 0.37 to 0.84) and lung NETs (hazard ratio 0.50, 95% CI 0.28 to 0.88). The overall survival results by tumour site are considered confidential by the company and cannot be reported here. The committee concluded that everolimus is a clinically effective treatment for both gastrointestinal and lung NETs. # Indirect treatment comparison ## The indirect treatment comparison is appropriate for decision-making The assessment group did an indirect treatment comparison of everolimus and sunitinib for pancreatic NETs using data from RADIANT-3 and A6181111. Based on the evidence presented, the committee considered that the 2 trials were generally comparable. However, it was concerned that the Bucher method used by the assessment group is a fixed-effects model, meaning that any heterogeneity between the trials was not accounted for. It was aware that using a different method that accounted for heterogeneity is likely to have led to wider confidence intervals than those reported. The assessment group explained that it had accounted for this by using the confidence intervals to inform the distributions that it applied to the estimates in the probabilistic cost-effectiveness sensitivity analyses. The committee concluded that although there was uncertainty associated with the indirect treatment comparison, it was appropriate for decision-making. ## Everolimus and sunitinib have similar benefits for treating pancreatic NETs The committee noted that the hazard ratio for progression-free survival for everolimus compared with sunitinib was 1.06 (95% CI 0.57 to 1.97). When adjusted for crossover, the hazard ratio for overall survival was 1.76 (95% CI 0.20 to 15.78). The committee noted that the confidence intervals were wide, and suggested that there may be no statistically significant difference between sunitinib and everolimus. The clinical experts explained that based on the progression-free survival data from the trials, they would consider the clinical benefit of everolimus and sunitinib to be similar. They noted that a recent crossover study of both treatments for renal cell carcinoma had reported similar effectiveness, providing further evidence for this assumption. However, the experts emphasised that although both treatments are comparable in clinical effectiveness, they are not considered interchangeable because of their different mechanisms of action and safety profiles. Having heard from the clinical experts and with no robust evidence of a difference in effectiveness, the committee concluded that everolimus and sunitinib have similar clinical benefits for treating pancreatic NETs. # Economic models ## The assessment group's economic model is the most appropriate for decision-making The committee discussed the economic models presented by Novartis and the assessment group. These were all partitioned survival models with health states corresponding to pre-progression, post-progression and death. The models for pancreatic NETs were driven by the indirect treatment comparisons of everolimus and sunitinib and head-to-head data from the respective trials, whereas the models for gastrointestinal and lung NETs were based solely on data from RADIANT-4. The committee noted that the assessment group identified some flaws with the company's model including: no comparison with best supportive care for pancreatic NETs using indirect treatment comparison results based on outdated trial data utility data for everolimus estimated from a vignette in the absence of trial data incorrect treatment duration for sunitinib no separate analysis for gastrointestinal NETs and lung NETs and limitations with the implementation of costs of subsequent treatments.The assessment group also noted that the lack of resource use data collected in RADIANT-4 limited the company model. The committee agreed with the assessment group that best supportive care should be included as a comparator for pancreatic NETs and that the most current trial data should be incorporated in the analyses for all tumour sites. Therefore, it concluded that the assessment group's economic model was the most appropriate for decision-making. # Health-related quality of life ## The assessment group's estimates are the most appropriate The committee considered the different approaches used to estimate utilities in the models. It noted that the main difference lay in the source of utility values for pancreatic NETs. Novartis used condition-specific valuations that were assigned to treatment arms using a time-trade off utility study (Swinburn et al. 2012), whereas the assessment group used EQ-5D valuations from A6181111 and assumed that the utilities for stable disease for everolimus and sunitinib were equal. The clinical experts explained that both everolimus and sunitinib are offered at the same point in the treatment pathway, and they have similar clinical effectiveness. Despite different safety profiles, it is reasonable to assume that health-related quality of life would be similar. In addition, the committee noted that the assessment group's values for pancreatic NETs were consistently lower than those for gastrointestinal and lung NETs from RADIANT-4. The clinical experts explained that pancreatic NETs are associated with more comorbidities (such as diabetes and pancreatic obstruction) than gastrointestinal NETs, so a lower utility value is plausible. The committee concluded that the assessment group's estimates had superior methodological and clinical validity and were, therefore, the most appropriate. # Cost-effectiveness results The assessment group's base-case results, which were used in the committee's decision-making, include the confidential patient access scheme discount for everolimus. As such, the exact cost-effectiveness results cannot be reported here. ## The ICERs for everolimus and sunitinib for pancreatic NETs are less than £30,000 per QALY gained The committee considered 3 cost-effectiveness analyses for pancreatic NETs: everolimus compared with best supportive care sunitinib compared with best supportive care sunitinib compared with everolimus.All of the pairwise deterministic and probabilistic incremental cost-effectiveness ratios (ICERs) were either less than £20,000 per quality-adjusted life year (QALY) gained or between £20,000 and £30,000 per QALY gained. The committee noted that most of the scenario analyses (including using alternative curves to model survival) also produced ICERs between £20,000 and £30,000 per QALY gained for both treatments. ## Separate cost-effectiveness analyses for gastrointestinal and lung NETs are appropriate for decision-making For gastrointestinal and lung NETs, the committee also considered 3 sets of cost-effectiveness analyses: an analysis with gastrointestinal and lung NETs combined and separate analyses for each tumour site (based on subgroup data from RADIANT-4 provided by the company). The committee understood that prognosis and quality of life can differ by tumour site and agreed that these factors are likely to affect the cost-effectiveness estimates. The committee concluded that the analyses specific to each tumour site were more appropriate for decision-making. ## The ICERs for everolimus for gastrointestinal NETs are less than £20,000 per QALY gained For gastrointestinal NETs, the committee considered everolimus compared with best supportive care. The deterministic and probabilistic ICERs as well as the ICERs for most of the scenario analyses were less than £20,000 per QALY gained. ## The ICERs for everolimus for lung NETs are less than £30,000 per QALY gained For lung NETs, the committee considered everolimus compared with best supportive care. The deterministic and probabilistic ICERs as well as the ICERs for most of the scenario analyses were either less than £20,000 per QALY gained or between £20,000 and £30,000 per QALY gained. # Innovation ## All significant health-related benefits were captured in the analyses The committee discussed whether sunitinib and everolimus were innovative. It heard from the clinical experts that there are limited alternative treatment options available for NETs, especially for lung NETs. It noted the comment from the companies that both treatments are tolerable options which provide meaningful improvements in life expectancy and health-related quality of life. However, the committee concluded that there were no additional health-related quality-of-life benefits that had not been captured in the QALY calculations. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. ## Everolimus and sunitinib for pancreatic NETs meet the end-of-life criteria For pancreatic NETs, the committee noted that the extrapolated survival of the best supportive care group was 20.5 months from A6181111 and 41.6 months from RADIANT-3. The assessment group explained that the choice of parametric extrapolation could have led to different results, so the estimates were very uncertain. The clinical experts stated that they would expect survival to be similar, given that the technologies are indicated for people at the same point in the treatment pathway. They further explained that in clinical practice they would expect survival to be closer to 20.5 months than 41.6 months for this group of people, meaning that they would have a life expectancy of less than 24 months (the first end-of-life criterion). For both everolimus and sunitinib, the extrapolated survival benefit compared with best supportive care was over 3 months (14.7 and 38.5 months respectively), meaning that the second end-of-life criterion, of extending life by at least 3 months, was met. The committee accepted the clinical experts' views about life expectancy and concluded that both everolimus and sunitinib met the end-of-life criteria for pancreatic NETs in people with progressive disease. ## Everolimus for gastrointestinal NETs does not meet the end-of-life criteria For gastrointestinal NETs, the committee noted that the extrapolated survival from the best supportive care arm was 51.4 months. It heard from the clinical experts that life expectancy for people with advanced gastrointestinal NETs was around 5 to 6 years and survival of less than 24 months, as would be necessary to meet the first end-of-life criterion, is not seen in practice. Therefore, although everolimus met the second criterion (it gave an extension to life compared with best supportive care of 26.6 months based on the survival extrapolation), the committee concluded that the end-of-life criteria were not met for gastrointestinal NETs. ## Everolimus for lung NETs does not meet the end-of-life criteria For lung NETs, the committee noted that the extrapolated survival from the best supportive care arm was 35.5 months (so the first end-of-life criterion was not met). Everolimus met the second end-of-life criterion (it gave extension to life compared with best supportive care of 25.9 months) but the committee concluded that the end-of-life criteria were not met for lung NETs because the life expectancy was shown to be greater than 24 months. # Summary of recommendations ## Everolimus and sunitinib are recommended for treating pancreatic NETS For pancreatic NETs, given that everolimus and sunitinib met the end-of-life criteria (see section 3.16) and all the ICERs were either below £20,000 per QALY gained or between £20,000 and £30,000 per QALY gained (see section 3.10), the committee concluded that it could recommend both everolimus and sunitinib as a cost-effective use of NHS resources for treating pancreatic NETs in people with progressive disease. ## Everolimus is recommended for treating gastrointestinal and lung NETs The committee had concluded that everolimus did not meet the end-of-life criteria for gastrointestinal NETs and lung NETs (see section 3.17 and section 3.18). However, the ICERs for gastrointestinal NETs were below £20,000 per QALY gained (see section 3.12), which is normally considered cost effective. Although some of the ICERs for everolimus compared with best supportive care for lung NETs were above £20,000 per QALY gained, the committee noted that they were all below £30,000 per QALY gained. It also considered the comments from the clinical experts that there is a high unmet need for treatment for lung NETs because there are limited treatment options available for this group of people (see section 3.1). Based on the ICER estimates for the 2 populations and the limited treatment options for lung NETs, the committee concluded that it could recommend everolimus as a cost-effective use of NHS resources for treating gastrointestinal NETs and lung NETs in people with progressive disease.	{'Recommendations': "Everolimus and sunitinib are recommended, within their marketing authorisations, as options for treating well- or moderately differentiated unresectable or metastatic neuroendocrine tumours (NETs) of pancreatic origin in adults with progressive disease.\n\nEverolimus is recommended, within its marketing authorisation, as an option for treating well-differentiated (grade\xa01 or grade\xa02) non-functional unresectable or metastatic NETs of gastrointestinal or lung origin in adults with progressive disease.\n\nEverolimus is recommended only when the company provides it with the discount agreed in the patient access scheme.\n\n# Why the committee made these recommendations\n\nNETs can affect the pancreas, gastrointestinal tissue and lungs and are difficult to diagnose and treat. They can significantly affect emotional health and often mean that people are unable to work. There is particularly high unmet need for people with NETs that affect the lungs.\n\nClinical trial evidence shows that everolimus and sunitinib are effective for treating pancreatic NETs compared with current treatment (best supportive care). Everolimus is effective for treating gastrointestinal and lung NETs compared with current treatment (best supportive care).\n\nFor treating pancreatic NETs, everolimus and sunitinib were recommended because they met NICE's end-of-life criteria. The cost effectiveness estimates varied, from below £20,000 up to £30,000 per quality-adjusted life year (QALY) gained.\n\nFor treating gastrointestinal NETs, everolimus did not meet the end-of-life criteria but was recommended because it is cost effective, at below £20,000 per QALY gained.\n\nFor treating lung NETs, everolimus did not meet the end-of-life criteria. The cost-effectiveness estimates for everolimus varied, from below £20,000 up to £30,000 per QALY gained. It was recommended because of the cost-effectiveness estimates and the limited treatment options available for people with lung NETs.\n\nNICE's end-of-life criteria are that life expectancy for people with the condition should be less than 24\xa0months and that treatment should extend life by more than 3\xa0months.", 'The technologies': "Everolimus (Afinitor, Novartis)\n\nSunitinib (Sutent, Pfizer)\n\nMarketing authorisations\n\nEverolimus has a marketing authorisation for 'unresectable or metastatic, well- or moderately differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease' and 'unresectable or metastatic, well differentiated (grade 1 or grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with progressive disease'.\n\nSunitinib has a marketing authorisation for 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults'.\n\nRecommended doses and schedules\n\nEverolimus is taken orally, 10\xa0mg once daily.\n\nSunitinib is taken orally, 37.5\xa0mg once daily.\n\nPrices\n\n£2,673.00 per 30-tablet (10\xa0mg) pack (excluding VAT).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of everolimus with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n£784.70 per 28-tablet (12.5\xa0mg) pack (excluding VAT).\n\nCosts may vary in different settings because of negotiated procurement discounts.\n\nA complex patient access scheme for sunitinib is available in the NHS for other indications. However, the company did not request approval from the Department of Health for it to be considered in this appraisal. This appraisal only considered the list price.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Clinical need and current practice\n\n## People with NETs will welcome new treatment options because of high unmet need\n\nThe committee understood that neuroendocrine tumours (NETs) can affect the pancreas, gastrointestinal tissue and lungs. They are difficult to diagnose and treat, can significantly affect emotional health and often mean that people are unable to work. It also heard from a patient expert that there is increasing frustration among people with advanced progressive NETs because of the recent restriction on targeted treatments that were previously available through the Cancer Drugs Fund. The clinical experts explained that few treatment options are available for lung NETs, meaning there is particularly high unmet need for this group of people. The committee concluded that there is a recognised need for treatment for NETs at different sites.\n\n## Everolimus, sunitinib and best supportive care are appropriate comparators\n\nThe committee heard from the clinical experts that managing NETs in the NHS mostly follows the European Neuroendocrine Tumor Society's guidelines. For treating pancreatic NETs causing symptoms (functional NETs) in people with progressive disease, options include everolimus and 177Lu-dotatate. For non-functional pancreatic NETs, the guidelines suggest 177Lu-dotatate or chemotherapy for progressive disease after offering everolimus or sunitinib. For treating functional and non-functional advanced gastrointestinal NETs in people with progressive disease, the guidelines suggest 177Lu-dotatate as an option with everolimus, and interferons. The clinical experts explained that although interferons may be considered after disease progression, they are not routinely used in England because of their toxicity. The clinical experts further explained that chemotherapy is sometimes used if people have symptoms because of the bulk of their disease (mainly people with a high disease burden with a Ki-67 proliferative index of around 20% or more, that is, grade\xa03 tumours). This is most often people with pancreatic NETs; chemotherapy is rarely used for people with well-differentiated gastrointestinal NETs. The committee understood that everolimus and 177Lu-dotatate are no longer available through the Cancer Drugs Fund. It was aware that only sunitinib is currently available through the Cancer Drugs Fund, meaning that current alternative treatment options are limited to best supportive care. The committee concluded that interferons and chemotherapy are not relevant comparators for everolimus and sunitinib, and that the most appropriate comparisons are of everolimus and sunitinib with each other and of both technologies with best supportive care for the specific sites covered by their marketing authorisations.\n\n# Clinical trial evidence\n\n## Everolimus and sunitinib are effective for treating pancreatic NETs\n\nThe clinical trial evidence for pancreatic NETs came from 2\xa0double-blind, randomised controlled trials:\n\nRADIANT-3 (everolimus plus best supportive care compared with placebo plus best supportive care) and\n\nA6181111 (sunitinib plus best supportive care compared with placebo plus best supportive care).The trials included people whose disease had progressed on surgery, radiotherapy, chemotherapy, somatostatin analogues and targeted therapies. The committee noted that only a small number of people had disease that progressed on targeted therapies, which included everolimus (in RADIANT-3) and sunitinib (in A6181111). The results from the clinical trials showed significant improvements in progression-free survival for both treatments, with hazard ratios of 0.35 (95% confidence interval [CI] 0.27 to 0.45) for everolimus compared with placebo and 0.42 (95% CI 0.26 to 0.66) for sunitinib compared with placebo. The committee noted that the overall survival results were confounded by high levels of crossover in the comparator arms of both trials (73% in RADIANT-3 and 69% in A6181111). Both companies used the rank-preserving structural failure time model to adjust for crossover, which resulted in hazard ratios of 0.60 (95% CI 0.09 to 3.95) for everolimus compared with placebo and 0.34 (95% CI 0.14 to 1.28) for sunitinib compared with placebo. The median overall survival gain for sunitinib compared with placebo was 25.4\xa0months, but this could not be determined for everolimus compared with placebo after adjusting for crossover. The committee heard from the assessment group that the companies' crossover adjustment method was appropriate. The committee concluded that despite the non-significant overall survival results and high levels of crossover, both everolimus and sunitinib are clinically effective for treating pancreatic NETs.\n\n## Everolimus is effective for treating gastrointestinal and lung NETs\n\nFor gastrointestinal and lung NETs, the evidence came from a double-blind, randomised controlled trial of everolimus plus best supportive care compared with placebo plus best supportive care (RADIANT-4). For gastrointestinal and lung NETs combined, the progression-free survival hazard ratio for everolimus compared with best supportive care was 0.48 (95% CI 0.35 to 0.67); the overall survival hazard ratio was 0.73 (95% CI 0.48 to 1.11). Separate analyses by tumour site showed significant reductions in the risk of progression or death with everolimus compared with placebo for both gastrointestinal NETs (hazard ratio 0.56, 95% CI 0.37 to 0.84) and lung NETs (hazard ratio 0.50, 95% CI 0.28 to 0.88). The overall survival results by tumour site are considered confidential by the company and cannot be reported here. The committee concluded that everolimus is a clinically effective treatment for both gastrointestinal and lung NETs.\n\n# Indirect treatment comparison\n\n## The indirect treatment comparison is appropriate for decision-making\n\nThe assessment group did an indirect treatment comparison of everolimus and sunitinib for pancreatic NETs using data from RADIANT-3 and A6181111. Based on the evidence presented, the committee considered that the 2\xa0trials were generally comparable. However, it was concerned that the Bucher method used by the assessment group is a fixed-effects model, meaning that any heterogeneity between the trials was not accounted for. It was aware that using a different method that accounted for heterogeneity is likely to have led to wider confidence intervals than those reported. The assessment group explained that it had accounted for this by using the confidence intervals to inform the distributions that it applied to the estimates in the probabilistic cost-effectiveness sensitivity analyses. The committee concluded that although there was uncertainty associated with the indirect treatment comparison, it was appropriate for decision-making.\n\n## Everolimus and sunitinib have similar benefits for treating pancreatic NETs\n\nThe committee noted that the hazard ratio for progression-free survival for everolimus compared with sunitinib was 1.06 (95% CI 0.57 to 1.97). When adjusted for crossover, the hazard ratio for overall survival was 1.76 (95% CI 0.20 to 15.78). The committee noted that the confidence intervals were wide, and suggested that there may be no statistically significant difference between sunitinib and everolimus. The clinical experts explained that based on the progression-free survival data from the trials, they would consider the clinical benefit of everolimus and sunitinib to be similar. They noted that a recent crossover study of both treatments for renal cell carcinoma had reported similar effectiveness, providing further evidence for this assumption. However, the experts emphasised that although both treatments are comparable in clinical effectiveness, they are not considered interchangeable because of their different mechanisms of action and safety profiles. Having heard from the clinical experts and with no robust evidence of a difference in effectiveness, the committee concluded that everolimus and sunitinib have similar clinical benefits for treating pancreatic NETs.\n\n# Economic models\n\n## The assessment group's economic model is the most appropriate for decision-making\n\nThe committee discussed the economic models presented by Novartis and the assessment group. These were all partitioned survival models with health states corresponding to pre-progression, post-progression and death. The models for pancreatic NETs were driven by the indirect treatment comparisons of everolimus and sunitinib and head-to-head data from the respective trials, whereas the models for gastrointestinal and lung NETs were based solely on data from RADIANT-4. The committee noted that the assessment group identified some flaws with the company's model including:\n\nno comparison with best supportive care for pancreatic NETs\n\nusing indirect treatment comparison results based on outdated trial data\n\nutility data for everolimus estimated from a vignette in the absence of trial data\n\nincorrect treatment duration for sunitinib\n\nno separate analysis for gastrointestinal NETs and lung NETs and\n\nlimitations with the implementation of costs of subsequent treatments.The assessment group also noted that the lack of resource use data collected in RADIANT-4 limited the company model. The committee agreed with the assessment group that best supportive care should be included as a comparator for pancreatic NETs and that the most current trial data should be incorporated in the analyses for all tumour sites. Therefore, it concluded that the assessment group's economic model was the most appropriate for decision-making.\n\n# Health-related quality of life\n\n## The assessment group's estimates are the most appropriate\n\nThe committee considered the different approaches used to estimate utilities in the models. It noted that the main difference lay in the source of utility values for pancreatic NETs. Novartis used condition-specific valuations that were assigned to treatment arms using a time-trade off utility study (Swinburn et al. 2012), whereas the assessment group used EQ-5D valuations from A6181111 and assumed that the utilities for stable disease for everolimus and sunitinib were equal. The clinical experts explained that both everolimus and sunitinib are offered at the same point in the treatment pathway, and they have similar clinical effectiveness. Despite different safety profiles, it is reasonable to assume that health-related quality of life would be similar. In addition, the committee noted that the assessment group's values for pancreatic NETs were consistently lower than those for gastrointestinal and lung NETs from RADIANT-4. The clinical experts explained that pancreatic NETs are associated with more comorbidities (such as diabetes and pancreatic obstruction) than gastrointestinal NETs, so a lower utility value is plausible. The committee concluded that the assessment group's estimates had superior methodological and clinical validity and were, therefore, the most appropriate.\n\n# Cost-effectiveness results\n\nThe assessment group's base-case results, which were used in the committee's decision-making, include the confidential patient access scheme discount for everolimus. As such, the exact cost-effectiveness results cannot be reported here.\n\n## The ICERs for everolimus and sunitinib for pancreatic NETs are less than £30,000 per QALY gained\n\nThe committee considered 3\xa0cost-effectiveness analyses for pancreatic NETs:\n\neverolimus compared with best supportive care\n\nsunitinib compared with best supportive care\n\nsunitinib compared with everolimus.All of the pairwise deterministic and probabilistic incremental cost-effectiveness ratios (ICERs) were either less than £20,000 per quality-adjusted life year (QALY) gained or between £20,000 and £30,000 per QALY gained. The committee noted that most of the scenario analyses (including using alternative curves to model survival) also produced ICERs between £20,000 and £30,000 per QALY gained for both treatments.\n\n## Separate cost-effectiveness analyses for gastrointestinal and lung NETs are appropriate for decision-making\n\nFor gastrointestinal and lung NETs, the committee also considered 3\xa0sets of cost-effectiveness analyses: an analysis with gastrointestinal and lung NETs combined and separate analyses for each tumour site (based on subgroup data from RADIANT-4 provided by the company). The committee understood that prognosis and quality of life can differ by tumour site and agreed that these factors are likely to affect the cost-effectiveness estimates. The committee concluded that the analyses specific to each tumour site were more appropriate for decision-making.\n\n## The ICERs for everolimus for gastrointestinal NETs are less than £20,000 per QALY gained\n\nFor gastrointestinal NETs, the committee considered everolimus compared with best supportive care. The deterministic and probabilistic ICERs as well as the ICERs for most of the scenario analyses were less than £20,000 per QALY gained.\n\n## The ICERs for everolimus for lung NETs are less than £30,000 per QALY gained\n\nFor lung NETs, the committee considered everolimus compared with best supportive care. The deterministic and probabilistic ICERs as well as the ICERs for most of the scenario analyses were either less than £20,000 per QALY gained or between £20,000 and £30,000 per QALY gained.\n\n# Innovation\n\n## All significant health-related benefits were captured in the analyses\n\nThe committee discussed whether sunitinib and everolimus were innovative. It heard from the clinical experts that there are limited alternative treatment options available for NETs, especially for lung NETs. It noted the comment from the companies that both treatments are tolerable options which provide meaningful improvements in life expectancy and health-related quality of life. However, the committee concluded that there were no additional health-related quality-of-life benefits that had not been captured in the QALY calculations.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\n## Everolimus and sunitinib for pancreatic NETs meet the end-of-life criteria\n\nFor pancreatic NETs, the committee noted that the extrapolated survival of the best supportive care group was 20.5\xa0months from A6181111 and 41.6\xa0months from RADIANT-3. The assessment group explained that the choice of parametric extrapolation could have led to different results, so the estimates were very uncertain. The clinical experts stated that they would expect survival to be similar, given that the technologies are indicated for people at the same point in the treatment pathway. They further explained that in clinical practice they would expect survival to be closer to 20.5\xa0months than 41.6\xa0months for this group of people, meaning that they would have a life expectancy of less than 24\xa0months (the first end-of-life criterion). For both everolimus and sunitinib, the extrapolated survival benefit compared with best supportive care was over 3\xa0months (14.7 and 38.5\xa0months respectively), meaning that the second end-of-life criterion, of extending life by at least 3\xa0months, was met. The committee accepted the clinical experts' views about life expectancy and concluded that both everolimus and sunitinib met the end-of-life criteria for pancreatic NETs in people with progressive disease.\n\n## Everolimus for gastrointestinal NETs does not meet the end-of-life criteria\n\nFor gastrointestinal NETs, the committee noted that the extrapolated survival from the best supportive care arm was 51.4\xa0months. It heard from the clinical experts that life expectancy for people with advanced gastrointestinal NETs was around 5 to 6\xa0years and survival of less than 24\xa0months, as would be necessary to meet the first end-of-life criterion, is not seen in practice. Therefore, although everolimus met the second criterion (it gave an extension to life compared with best supportive care of 26.6\xa0months based on the survival extrapolation), the committee concluded that the end-of-life criteria were not met for gastrointestinal NETs.\n\n## Everolimus for lung NETs does not meet the end-of-life criteria\n\nFor lung NETs, the committee noted that the extrapolated survival from the best supportive care arm was 35.5\xa0months (so the first end-of-life criterion was not met). Everolimus met the second end-of-life criterion (it gave extension to life compared with best supportive care of 25.9\xa0months) but the committee concluded that the end-of-life criteria were not met for lung NETs because the life expectancy was shown to be greater than 24\xa0months.\n\n# Summary of recommendations\n\n## Everolimus and sunitinib are recommended for treating pancreatic NETS\n\nFor pancreatic NETs, given that everolimus and sunitinib met the end-of-life criteria (see section\xa03.16) and all the ICERs were either below £20,000 per QALY gained or between £20,000 and £30,000 per QALY gained (see section\xa03.10), the committee concluded that it could recommend both everolimus and sunitinib as a cost-effective use of NHS resources for treating pancreatic NETs in people with progressive disease.\n\n## Everolimus is recommended for treating gastrointestinal and lung NETs\n\nThe committee had concluded that everolimus did not meet the end-of-life criteria for gastrointestinal NETs and lung NETs (see section\xa03.17 and section\xa03.18). However, the ICERs for gastrointestinal NETs were below £20,000 per QALY gained (see section\xa03.12), which is normally considered cost effective. Although some of the ICERs for everolimus compared with best supportive care for lung NETs were above £20,000 per QALY gained, the committee noted that they were all below £30,000 per QALY gained. It also considered the comments from the clinical experts that there is a high unmet need for treatment for lung NETs because there are limited treatment options available for this group of people (see section\xa03.1). Based on the ICER estimates for the 2\xa0populations and the limited treatment options for lung NETs, the committee concluded that it could recommend everolimus as a cost-effective use of NHS resources for treating gastrointestinal NETs and lung NETs in people with progressive disease."}	https://www.nice.org.uk/guidance/ta449	Evidence-based recommendations on everolimus (Afinitor) and sunitinib (Sutent) for treating neuroendocrine tumours in adults.
bf62b5834e90c5068342a6d28a931967f749cc19	nice	Blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia	Blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia Evidence-based recommendations on blinatumomab (Blincyto) for treating Philadelphia-chromosome-negative precursor B-cell acute lymphoblastic leukaemia in adults. # Recommendations Blinatumomab is recommended within its marketing authorisation as an option for treating Philadelphia-chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukaemia in adults, only if the company provides it with the discount agreed in the patient access scheme.# The technology Description of the technology Blinatumomab (Blincyto, Amgen) is a T-cell engager antibody targeting CD19 and the CD3/T-cell receptor. Marketing authorisation Blinatumomab is indicated for the treatment of adults with Philadelphia-chromosome-negative relapsed or refractory B-precursor acute lymphoblastic leukaemia. Adverse reactions The most common frequently reported adverse reactions are infusion-related reactions, infections, pyrexia, headache and febrile neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Patients may have 2 cycles of treatment. A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval. Patients who experience complete remission after 2 treatment cycles may have up to 3 additional cycles of consolidation treatment, based on an individual benefits-risks assessment. Blinatumomab is administered at a dose of 9 micrograms per day for the first 7 days of the first cycle. All doses after that are 28 micrograms per day. Price Blinatumomab costs £2,017 per 38.5‑microgram vial (excluding VAT, BNF online March 2017). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of blinatumomab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of blinatumomab, having considered evidence on the nature of acute lymphoblastic leukaemia and the value placed on the benefits of blinatumomab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical management The committee heard from a patient expert that living with precursor B-cell acute lymphoblastic leukaemia, particularly when the condition has failed to respond to first line chemotherapy, can have a profound effect on a person's physical and psychological wellbeing. The committee acknowledged that acute lymphoblastic leukaemia does not affect the patient in isolation, but also places emotional strain on their families and friends. The committee heard from the patient expert that patients whose disease responds to blinatumomab can live a relatively normal life during treatment, with minimal side effects. The clinical experts emphasised that the side effects of blinatumomab are much less severe than currently available therapies such as fludarabine, cytarabine and granulocyte stimulating factor (FLAG) based regimens. The committee noted that the aim of treatment is to induce remission so that people who are fit enough can have allogeneic stem cell transplantation, which could cure the disease. Clinical experts advised that although the summary of product characteristics stipulates minimum inpatient treatment for 9 days in the first cycle and 2 days in subsequent cycles, in clinical practice blinatumomab is so well tolerated that most patients are treated as inpatients for only 4 days in cycle 1 and 2 days in cycle 2. This means that they can have treatment mostly in the outpatient setting, apart from attending hospital for the intravenous infusion bag to be changed every 4 days. The committee concluded that the availability of an effective treatment that could be delivered primarily in the outpatient setting was hugely beneficial to patients and would have a major impact on their quality of life. The committee considered the most appropriate comparators for blinatumomab for treating relapsed or refractory acute lymphoblastic leukaemia and the likely position of blinatumomab in the treatment pathway. It heard from the patient expert and clinical experts that people with relapsed or refractory acute lymphoblastic leukaemia will have combination chemotherapy. In most cases this would be FLAG with idarubicin (FLAG-IDA), which involves prolonged hospitalisation for treatment and is associated with debilitating side effects. It heard that clofarabine is sometimes used instead, but noted that its marketing authorisation is only for children. The clinical experts stated that in clinical practice blinatumomab would be most useful at first relapse, before other salvage therapies that are poorly tolerated. The committee concluded that blinatumomab would be used before other salvage therapies and that FLAG-IDA was the most appropriate comparator for this appraisal. # Clinical effectiveness of blinatumomab The clinical evidence for blinatumomab in people with relapsed or refractory precursor B-cell acute lymphoblastic leukaemia is from 2 clinical trials, TOWER and Study MT103-211: TOWER (n=405) was a phase III randomised controlled trial, comparing blinatumomab with one of 4 different standard of care chemotherapy regimens. Study MT103-211 was a phase II single-arm trial, assessing the safety and effectiveness of blinatumomab. The company used an historical cohort (Study 21020310) to allow comparison with 4 different standard of care chemotherapy regimens, which were similar to those in the control arm of TOWER. ## Generalisability of the trial results to the NHS The committee noted that TOWER included patients with refractory precursor B-cell acute lymphoblastic leukaemia that was refractory to primary induction therapy or relapsed within 12 months of first line chemotherapy, or after subsequent therapy, or after allogenic stem cell transplantation. The committee heard from the clinical experts that the trial specifically recruited people with a poor prognosis. People who relapsed 12 months or more after primary induction therapy were excluded from the trial, but would have a better prognosis than those who relapsed earlier. The committee also noted that TOWER compared blinatumomab with standard of care (FLAG with or without an anthracycline such as idarubicin, a high-dose methotrexate based regimen or high-dose cytarabine with or without anthracycline). Most people in the trial had FLAG-IDA, which is consistent with clinical practice in England. The committee noted that the marketing authorisation specifies a maximum of 5 cycles of blinatumomab, but some patients in TOWER had more than 5 cycles. The committee also considered the generalisability of Study MT103-211. Similarly to TOWER, patients were excluded if they had relapsed following a remission that lasted over 12 months. The committee concluded that the trial populations broadly correspond with those in clinical practice but reflect people with a relatively poor prognosis. ## Clinical effectiveness results – TOWER In the trial, blinatumomab increased overall survival compared with standard of care chemotherapy (hazard ratio 0.71; 95% confidence interval 0.55 to 0.93). The committee noted that although blinatumomab was associated with improved overall survival up to 15 months, the Kaplan–Meier curves of the 2 treatment arms came together at this point. However it also noted that the data were immature and that there were very small numbers of patients alive at 15 months. The committee concluded that blinatumomab is clinically effective in improving overall survival compared with standard care in the short term, but there is uncertainty about the long-term overall survival benefit. Results of a pre-specified subgroup analysis suggested that blinatumomab is more effective in people who have had no, or only 1 salvage therapy. The committee noted that the study was not powered to detect differences in efficacy between these subgroups but it appeared that blinatumomab was more effective if given earlier, and it recalled the clinical experts' view that blinatumomab would be used as the first salvage therapy (see section 4.3). The committee noted that the rates of allogeneic stem cell transplants were similar in the blinatumomab and standard of care chemotherapy arms (24.0% compared to 23.9% respectively). The committee heard from the clinical experts that these may not be directly comparable because treatment decisions were made on an individual basis and may be affected by multiple factors. For example, some patients in the chemotherapy arm of TOWER may have had a stem cell transplantation despite not achieving a complete remission, which would not happen in the NHS. It also heard that that there may have been other confounding factors, such as a delay in offering transplantation to people who responded well to blinatumomab (time to transplant was longer in the blinatumomab than standard of care arm in the trial). The committee concluded that it was uncertain from the available evidence whether blinatumomab would enable more patients to undergo allogeneic stem cell transplantation. However given the higher rate of complete remission with blinatumomab than standard of care (33.6% compared with 15.7%) this would be expected. Blinatumomab was associated with fewer serious (grade 3 and above) adverse events than standard of care chemotherapy. The committee recalled hearing from the patient experts that the side effects of blinatumomab are minimal (see section 4.1) and it concluded that blinatumomab would be well-tolerated compared with standard of care chemotherapy. ## Clinical effectiveness results – Study MT103-211 The committee noted that the ERG only regarded the comparison with the historical cohort as relevant and therefore it did not consider further the results of Study MT103-211 alone. To account for the different populations in the trial and the historical comparator, the company used 2 different methods to match patients based on their characteristics: a reweighted analysis and an inverse probability of treatment weighting analysis. The committee noted that the arms were not significantly different once matched, except for by region. The committee concluded that the matched analysis was appropriate for comparing blinatumomab with standard of care based on a historical cohort. # Cost effectiveness The company used a 4-state partitioned-survival economic model, representing an initial pre-response state, a response state, a refractory/relapsed state and death. All clinical parameters in the model were derived from TOWER. The committee agreed that the model structure was appropriate. In the model, patients had either blinatumomab or FLAG-IDA. The company used the results of the whole standard of care chemotherapy arm of TOWER to estimate the effectiveness of FLAG-IDA. The committee noted that clinical advisers to the ERG thought it plausible for the efficacy of the whole standard of care arm to be similar to FLAG-IDA, and that the trial was not powered to assess the relative clinical effectiveness of different chemotherapy regimens. It noted that FLAG-IDA was the most common chemotherapy regimen in the trial. The committee concluded that the chemotherapy arm of TOWER offered a reasonable representation of the clinical effectiveness of FLAG-IDA. ## Modelling of overall survival The committee recalled that the data on overall survival from TOWER were immature (see section 4.6). The company fitted parametric survival curves to the observed blinatumomab data and used a Gompertz distribution, based on clinical plausibility and visual inspection. The committee noted that the company's extrapolation of overall survival was subject to uncertainty because in TOWER the overall survival curves converged at around 15 months, which suggested that the proportional hazards assumption was not met. However the committee also noted that the number of patients at this time point in the trial was very small. It heard from the ERG that they were unable to identify a more clinically plausible survival curve for use in the economic model. The committee noted that the proportional hazards assumption did appear to be met in the first 12 months but there is uncertainty about the long-term extrapolation of overall survival. It concluded that the company's extrapolation was acceptable for the purposes of decision making. The committee discussed the time point at which it is reasonable to assume a survivor is cured, which has a substantial impact on the incremental cost-effectiveness ratios (ICERs). It noted that the company base case assumed 48 months, while the ERG argued that 60 months would be more appropriate. It heard from the clinical experts that the time point considered to be 'cure' was debatable, but would be much less than 48 months. The committee noted that the overall survival curves in the model appeared to plateau at around 36 months and that the sooner a cure was achieved, the lower the ICER. The committee concluded that the company's assumption of patients being cured at 48 months was potentially a conservative estimate. ## Utility values The committee heard that the quality-of-life data was mapped from EORTC QLQ-C30 data collected in TOWER. It noted that the company had not adjusted for the baseline differences in utility between treatment arms. The committee concluded that although it would have preferred adjusted values, the utility estimates used in the model were acceptable. ## Cost of treatment in the model The committee discussed the resource use assumed in the company's and the ERG's models. It noted that in both models the administration costs were assumed to be the same as in TOWER, in which patients had up to 9 cycles of blinatumomab. It heard from the clinical experts that although the marketing authorisation for blinatumomab recommends a maximum of 5 cycles, most people would have 2 cycles of treatment. If the disease responded, they would proceed to transplantation. If the disease responded after 2 cycles but a suitable donor match was not immediately available, or if stem cell transplantation was not appropriate, they might have more than 2 cycles. The company assumed hospitalisation requirements for blinatumomab as per the minimum specified in the marketing authorisation, while the ERG had assumed in their preferred base case that patients would be hospitalised for the entirety of the first 2 treatment cycles. The committee noted that the hospitalisation requirements would be considerably less than either of these assumptions in clinical practice (see section 4.2). The committee also noted that the company assumed that intravenous bags were changed every 4 days, while the ERG assumed they were changed daily. It heard from the patient expert, clinical experts and NHS England that daily bag changes would be unlikely in clinical practice. The committee concluded that it preferred the company's assumptions for healthcare utilisation, but that these would overestimate the administration costs of blinatumomab. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee concluded that the end-of-life criteria were met in the overall population based on the following discussions: The committee discussed whether life expectancy without blinatumomab would be less than 24 months. It noted that life expectancy was 4 months for standard of care chemotherapy in TOWER and concluded that the short life-expectancy criterion was met. The committee discussed whether a survival benefit of over 3 months can be expected for blinatumomab compared to its comparators. It noted that blinatumomab was associated with a median overall survival gain of 3.7 months over standard of care chemotherapy and concluded that the extension to life criterion was met. # Cost-effectiveness results The committee considered the company's base case ICERs using the patient access scheme price for blinatumomab. It noted that the deterministic ICERs were £55,501 per quality-adjusted life year (QALY) gained for the overall population (probabilistic ICER of £57,600 per QALY gained) and £49,190 per QALY gained for people who had not had previous salvage therapy (probabilistic ICER of £58,900 per QALY gained). However, the committee considered these ICERs to have been overestimated. It was aware that the costs of blinatumomab were overestimated because up to 9 cycles of treatment had been modelled, when the marketing authorisation is for a maximum of 5 cycles. The committee also considered that the hospitalisation requirements in clinical practice (see section 4.2) are less than those modelled, and the assumption that patients were cured at 48 months was potentially conservative (see section 4.14). The committee considered the ICER for people who had not had previous salvage therapy to be most appropriate for the purposes of decision making, because it represents the treatment position in which blinatumomab will be used in clinical practice. As blinatumomab becomes established in clinical practice the number of people who have had previous salvage chemotherapy will diminish over time. The committee also noted that there is significant unmet clinical need for people with relapsed or refractory acute lymphoblastic leukaemia, because of the shortcomings of existing regimens (see section 4.3). The committee concluded that, despite substantial uncertainty, the ICER for blinatumomab is within the range normally considered a cost-effective use of NHS resources given that the end-of-life criteria apply (see section 4.17). # Innovation The committee considered whether blinatumomab is innovative. It heard from the patient and clinical experts that there is significant unmet need for people with relapsed or refractory acute lymphoblastic leukaemia because of the ineffective and toxic chemotherapy regimens currently available. It noted that the company considers blinatumomab to be an innovative treatment and a step-change in treatment of a very rare illness. The committee concluded that blinatumomab would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of quality-adjusted life years (QALYs). # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the PPRS 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA450 Appraisal title: Blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia Section Key conclusion Blinatumomab is recommended within its marketing authorisation as an option for treating Philadelphia-chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukaemia in adults, only if the company provides it with the discount agreed in the patient access scheme. The committee considered the end-of-life criteria to be met because life expectancy in the standard of care arm in the TOWER trial was 4 months and blinatumomab was associated with an overall survival benefit of 3.7 months. The deterministic incremental cost-effectiveness ratio (ICER) for people who had not had previous salvage therapy was £49,190 per quality-adjusted life year (QALY) gained, when a patient access scheme was included. However the ICER is likely to be lower if the reduced hospitalisation requirements are taken into account, and is therefore likely to be within the range normally considered a cost-effective use of NHS resources. The committee considered the ICER for people who had not had previous salvage therapy to be most appropriate for the purposes of decision making, because it represents the treatment position in which blinatumomab will be used in clinical practice. The committee concluded that, despite substantial uncertainty, the ICER for blinatumomab is within the range normally considered a cost-effective use of NHS resources given that the end-of-life criteria apply. Current practice Clinical need of patients, including the availability of alternative treatments Living with precursor B-cell acute lymphoblastic leukaemia, particularly when the condition has failed to respond to first line chemotherapy, can have a profound effect on a person's physical and psychological wellbeing. The clinical experts emphasised that the side effects of blinatumomab are much less severe than alternative therapies currently available such as fludarabine, cytarabine and granulocyte stimulating factor based regimens with idarubicin (FLAG-IDA). Blinatumomab can also be delivered mostly in the outpatient setting. The committee concluded that the availability of an effective treatment that could be delivered primarily in the outpatient setting was hugely beneficial to patients and would have a major impact on their quality of life. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Blinatumomab was associated with a statistically significant overall survival gain of 3.7 months and an increase in the proportion of patients with complete remission, compared with standard of care chemotherapy in the TOWER trial. The committee concluded that the results of TOWER are generalisable to the UK population, and noted that blinatumomab appears to be more clinically effective in the subgroup of people who have not had previous salvage therapy. The committee heard from clinical experts that blinatumomab would be used as first salvage therapy because people would then be in a better positon to respond to allogenic stem cell transplantation. The committee concluded that people who have had no salvage therapy are the most relevant population for this appraisal. The committee noted that the company considers blinatumomab to be innovative because it is a step-change in a very rare illness. However it concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculations. to 4.8, 4.18, 4.19 What is the position of the treatment in the pathway of care for the condition? Clinical experts suggested that blinatumomab would be used as first salvage therapy in practice, noting the lack of alternative options. Adverse reactions Blinatumomab is associated with fewer adverse reactions than the standard of care chemotherapy regimens that are its comparators. Evidence for clinical effectiveness Availability, nature and quality of evidence The clinical evidence for blinatumomab compared with standard of care chemotherapy comes mainly from TOWER. The committee noted that the company presented data for the whole trial population and for a subgroup of people who had not had previous salvage therapy. Relevance to general clinical practice in the NHS People who relapsed 12 months or more after primary induction therapy (who have a better prognosis than those who relapsed earlier) were excluded from the trials. The committee concluded that the trial populations broadly correspond with those in clinical practice but reflect people with a relatively poor prognosis. Uncertainties generated by the evidence The committee noted that although in TOWER blinatumomab was associated with improved overall survival up to 15 months, the Kaplan–Meier curves of the 2 treatment arms came together at this point. The data were immature and there were very small numbers of patients alive at 15‑month follow-up. The committee concluded that blinatumomab is clinically effective in improving overall survival compared with standard care in the short term, but there is uncertainty about the long-term overall survival benefit. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Blinatumomab appears to be more clinically effective in people who have not had previous salvage therapy. Estimate of the size of the clinical effectiveness including strength of supporting evidence Blinatumomab was associated with a statistically significant overall survival benefit of 3.7 months compared with standard of care chemotherapy. Evidence for cost effectiveness Availability and nature of evidence The company submitted a partitioned-survival economic model, representing an initial pre-response state, a response state, a refractory/relapsed state and death. The committee agreed that the model structure was appropriate. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee considered the following key areas of uncertainty: extrapolation of overall survival time at which a patient is considered to be cured healthcare utilisation costs. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee heard that the quality-of-life data was mapped from EORTC QLQ-C30 data collected in TOWER. The company considers blinatumomab to be innovative because it is a step-change in treatment of a very rare illness. However the committee did not identify any specific health-related benefit that had not already been captured in the QALY calculation. Are there specific groups of people for whom the technology is particularly cost effective? Blinatumomab is more cost effective in people who have not had previous salvage therapy. This represents the expected position in which blinatumomab will be used in clinical practice in the NHS. What are the key drivers of cost effectiveness? The key drivers of cost effectiveness in the company's model were the extrapolation of overall survival, the time at which a patient is considered to be cured and healthcare utilisation costs. Most likely cost-effectiveness estimate (given as an ICER) The committee considered the ICER in people who had not had previous salvage therapy to be most appropriate for the purposes of decision making, because it represents the treatment position in which blinatumomab will be used in clinical practice. The committee concluded that the most plausible ICER for blinatumomab compared with standard of care chemotherapy in the subgroup of people who had not had previous salvage therapy is likely to be lower than the company's base case ICER of £49,190 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) The PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. End-of-life considerations The committee concluded that the end-of-life criteria were met in the overall population: Blinatumomab met the short life-expectancy criteria (less than 24 months) because life expectancy in the standard of care chemotherapy arm of TOWER was 4 months. Blinatumomab was associated with a median overall survival gain of 3.7 months over standard of care chemotherapy and therefore met the criterion for extension to life of greater than 3 months. Equalities considerations and social value judgements No equality issues were raised during the appraisal.	{'Recommendations': 'Blinatumomab is recommended within its marketing authorisation as an option for treating Philadelphia-chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukaemia in adults, only if the company provides it with the discount agreed in the patient access scheme.', 'The technology': 'Description of the technology\n\nBlinatumomab (Blincyto, Amgen) is a T-cell engager antibody targeting CD19 and the CD3/T-cell receptor.\n\nMarketing authorisation\n\nBlinatumomab is indicated for the treatment of adults with Philadelphia-chromosome-negative relapsed or refractory B-precursor acute lymphoblastic leukaemia.\n\nAdverse reactions\n\nThe most common frequently reported adverse reactions are infusion-related reactions, infections, pyrexia, headache and febrile neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nPatients may have 2\xa0cycles of treatment. A single cycle of treatment is 28\xa0days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14\xa0day (2 week) treatment-free interval.\n\nPatients who experience complete remission after 2\xa0treatment cycles may have up to 3\xa0additional cycles of consolidation treatment, based on an individual benefits-risks assessment.\n\nBlinatumomab is administered at a dose of 9\xa0micrograms per day for the first 7\xa0days of the first cycle. All doses after that are 28\xa0micrograms per day.\n\nPrice\n\nBlinatumomab costs £2,017 per 38.5‑microgram vial (excluding VAT, BNF online March 2017).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of blinatumomab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Evidence': 'The appraisal committee (section 6) considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of blinatumomab, having considered evidence on the nature of acute lymphoblastic leukaemia and the value placed on the benefits of blinatumomab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management\n\nThe committee heard from a patient expert that living with precursor B-cell acute lymphoblastic leukaemia, particularly when the condition has failed to respond to first line chemotherapy, can have a profound effect on a person's physical and psychological wellbeing. The committee acknowledged that acute lymphoblastic leukaemia does not affect the patient in isolation, but also places emotional strain on their families and friends. The committee heard from the patient expert that patients whose disease responds to blinatumomab can live a relatively normal life during treatment, with minimal side effects. The clinical experts emphasised that the side effects of blinatumomab are much less severe than currently available therapies such as fludarabine, cytarabine and granulocyte stimulating factor (FLAG) based regimens.\n\nThe committee noted that the aim of treatment is to induce remission so that people who are fit enough can have allogeneic stem cell transplantation, which could cure the disease. Clinical experts advised that although the summary of product characteristics stipulates minimum inpatient treatment for 9\xa0days in the first cycle and 2\xa0days in subsequent cycles, in clinical practice blinatumomab is so well tolerated that most patients are treated as inpatients for only 4\xa0days in cycle\xa01 and 2\xa0days in cycle\xa02. This means that they can have treatment mostly in the outpatient setting, apart from attending hospital for the intravenous infusion bag to be changed every 4\xa0days. The committee concluded that the availability of an effective treatment that could be delivered primarily in the outpatient setting was hugely beneficial to patients and would have a major impact on their quality of life.\n\nThe committee considered the most appropriate comparators for blinatumomab for treating relapsed or refractory acute lymphoblastic leukaemia and the likely position of blinatumomab in the treatment pathway. It heard from the patient expert and clinical experts that people with relapsed or refractory acute lymphoblastic leukaemia will have combination chemotherapy. In most cases this would be FLAG with idarubicin (FLAG-IDA), which involves prolonged hospitalisation for treatment and is associated with debilitating side effects. It heard that clofarabine is sometimes used instead, but noted that its marketing authorisation is only for children. The clinical experts stated that in clinical practice blinatumomab would be most useful at first relapse, before other salvage therapies that are poorly tolerated. The committee concluded that blinatumomab would be used before other salvage therapies and that FLAG-IDA was the most appropriate comparator for this appraisal.\n\n# Clinical effectiveness of blinatumomab\n\nThe clinical evidence for blinatumomab in people with relapsed or refractory precursor B-cell acute lymphoblastic leukaemia is from 2\xa0clinical trials, TOWER and Study\xa0MT103-211:\n\nTOWER (n=405) was a phase\xa0III randomised controlled trial, comparing blinatumomab with one of 4\xa0different standard of care chemotherapy regimens.\n\nStudy\xa0MT103-211 was a phase\xa0II single-arm trial, assessing the safety and effectiveness of blinatumomab. The company used an historical cohort (Study\xa021020310) to allow comparison with 4\xa0different standard of care chemotherapy regimens, which were similar to those in the control arm of TOWER.\n\n## Generalisability of the trial results to the NHS\n\nThe committee noted that TOWER included patients with refractory precursor B-cell acute lymphoblastic leukaemia that was refractory to primary induction therapy or relapsed within 12\xa0months of first line chemotherapy, or after subsequent therapy, or after allogenic stem cell transplantation. The committee heard from the clinical experts that the trial specifically recruited people with a poor prognosis. People who relapsed 12\xa0months or more after primary induction therapy were excluded from the trial, but would have a better prognosis than those who relapsed earlier. The committee also noted that TOWER compared blinatumomab with standard of care (FLAG with or without an anthracycline such as idarubicin, a high-dose methotrexate based regimen or high-dose cytarabine with or without anthracycline). Most people in the trial had FLAG-IDA, which is consistent with clinical practice in England. The committee noted that the marketing authorisation specifies a maximum of 5\xa0cycles of blinatumomab, but some patients in TOWER had more than 5\xa0cycles. The committee also considered the generalisability of Study\xa0MT103-211. Similarly to TOWER, patients were excluded if they had relapsed following a remission that lasted over 12\xa0months. The committee concluded that the trial populations broadly correspond with those in clinical practice but reflect people with a relatively poor prognosis.\n\n## Clinical effectiveness results – TOWER\n\nIn the trial, blinatumomab increased overall survival compared with standard of care chemotherapy (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.55 to 0.93). The committee noted that although blinatumomab was associated with improved overall survival up to 15\xa0months, the Kaplan–Meier curves of the 2\xa0treatment arms came together at this point. However it also noted that the data were immature and that there were very small numbers of patients alive at 15\xa0months. The committee concluded that blinatumomab is clinically effective in improving overall survival compared with standard care in the short term, but there is uncertainty about the long-term overall survival benefit.\n\nResults of a pre-specified subgroup analysis suggested that blinatumomab is more effective in people who have had no, or only 1 salvage therapy. The committee noted that the study was not powered to detect differences in efficacy between these subgroups but it appeared that blinatumomab was more effective if given earlier, and it recalled the clinical experts' view that blinatumomab would be used as the first salvage therapy (see section\xa04.3).\n\nThe committee noted that the rates of allogeneic stem cell transplants were similar in the blinatumomab and standard of care chemotherapy arms (24.0% compared to 23.9% respectively). The committee heard from the clinical experts that these may not be directly comparable because treatment decisions were made on an individual basis and may be affected by multiple factors. For example, some patients in the chemotherapy arm of TOWER may have had a stem cell transplantation despite not achieving a complete remission, which would not happen in the NHS. It also heard that that there may have been other confounding factors, such as a delay in offering transplantation to people who responded well to blinatumomab (time to transplant was longer in the blinatumomab than standard of care arm in the trial). The committee concluded that it was uncertain from the available evidence whether blinatumomab would enable more patients to undergo allogeneic stem cell transplantation. However given the higher rate of complete remission with blinatumomab than standard of care (33.6% compared with 15.7%) this would be expected.\n\nBlinatumomab was associated with fewer serious (grade 3 and above) adverse events than standard of care chemotherapy. The committee recalled hearing from the patient experts that the side effects of blinatumomab are minimal (see section\xa04.1) and it concluded that blinatumomab would be well-tolerated compared with standard of care chemotherapy.\n\n## Clinical effectiveness results – Study\xa0MT103-211\n\nThe committee noted that the ERG only regarded the comparison with the historical cohort as relevant and therefore it did not consider further the results of Study\xa0MT103-211 alone. To account for the different populations in the trial and the historical comparator, the company used 2\xa0different methods to match patients based on their characteristics: a reweighted analysis and an inverse probability of treatment weighting analysis. The committee noted that the arms were not significantly different once matched, except for by region. The committee concluded that the matched analysis was appropriate for comparing blinatumomab with standard of care based on a historical cohort.\n\n# Cost effectiveness\n\nThe company used a 4-state partitioned-survival economic model, representing an initial pre-response state, a response state, a refractory/relapsed state and death. All clinical parameters in the model were derived from TOWER. The committee agreed that the model structure was appropriate.\n\nIn the model, patients had either blinatumomab or FLAG-IDA. The company used the results of the whole standard of care chemotherapy arm of TOWER to estimate the effectiveness of FLAG-IDA. The committee noted that clinical advisers to the ERG thought it plausible for the efficacy of the whole standard of care arm to be similar to FLAG-IDA, and that the trial was not powered to assess the relative clinical effectiveness of different chemotherapy regimens. It noted that FLAG-IDA was the most common chemotherapy regimen in the trial. The committee concluded that the chemotherapy arm of TOWER offered a reasonable representation of the clinical effectiveness of FLAG-IDA.\n\n## Modelling of overall survival\n\nThe committee recalled that the data on overall survival from TOWER were immature (see section\xa04.6). The company fitted parametric survival curves to the observed blinatumomab data and used a Gompertz distribution, based on clinical plausibility and visual inspection. The committee noted that the company's extrapolation of overall survival was subject to uncertainty because in TOWER the overall survival curves converged at around 15\xa0months, which suggested that the proportional hazards assumption was not met. However the committee also noted that the number of patients at this time point in the trial was very small. It heard from the ERG that they were unable to identify a more clinically plausible survival curve for use in the economic model. The committee noted that the proportional hazards assumption did appear to be met in the first 12\xa0months but there is uncertainty about the long-term extrapolation of overall survival. It concluded that the company's extrapolation was acceptable for the purposes of decision making.\n\nThe committee discussed the time point at which it is reasonable to assume a survivor is cured, which has a substantial impact on the incremental cost-effectiveness ratios (ICERs). It noted that the company base case assumed 48\xa0months, while the ERG argued that 60\xa0months would be more appropriate. It heard from the clinical experts that the time point considered to be 'cure' was debatable, but would be much less than 48\xa0months. The committee noted that the overall survival curves in the model appeared to plateau at around 36\xa0months and that the sooner a cure was achieved, the lower the ICER. The committee concluded that the company's assumption of patients being cured at 48\xa0months was potentially a conservative estimate.\n\n## Utility values\n\nThe committee heard that the quality-of-life data was mapped from EORTC QLQ-C30 data collected in TOWER. It noted that the company had not adjusted for the baseline differences in utility between treatment arms. The committee concluded that although it would have preferred adjusted values, the utility estimates used in the model were acceptable.\n\n## Cost of treatment in the model\n\nThe committee discussed the resource use assumed in the company's and the ERG's models. It noted that in both models the administration costs were assumed to be the same as in TOWER, in which patients had up to 9\xa0cycles of blinatumomab. It heard from the clinical experts that although the marketing authorisation for blinatumomab recommends a maximum of 5\xa0cycles, most people would have 2\xa0cycles of treatment. If the disease responded, they would proceed to transplantation. If the disease responded after 2\xa0cycles but a suitable donor match was not immediately available, or if stem cell transplantation was not appropriate, they might have more than 2\xa0cycles. The company assumed hospitalisation requirements for blinatumomab as per the minimum specified in the marketing authorisation, while the ERG had assumed in their preferred base case that patients would be hospitalised for the entirety of the first 2\xa0treatment cycles. The committee noted that the hospitalisation requirements would be considerably less than either of these assumptions in clinical practice (see section\xa04.2). The committee also noted that the company assumed that intravenous bags were changed every 4\xa0days, while the ERG assumed they were changed daily. It heard from the patient expert, clinical experts and NHS England that daily bag changes would be unlikely in clinical practice. The committee concluded that it preferred the company's assumptions for healthcare utilisation, but that these would overestimate the administration costs of blinatumomab.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee concluded that the end-of-life criteria were met in the overall population based on the following discussions:\n\nThe committee discussed whether life expectancy without blinatumomab would be less than 24\xa0months. It noted that life expectancy was 4\xa0months for standard of care chemotherapy in TOWER and concluded that the short life-expectancy criterion was met.\n\nThe committee discussed whether a survival benefit of over 3\xa0months can be expected for blinatumomab compared to its comparators. It noted that blinatumomab was associated with a median overall survival gain of 3.7\xa0months over standard of care chemotherapy and concluded that the extension to life criterion was met.\n\n# Cost-effectiveness results\n\nThe committee considered the company's base case ICERs using the patient access scheme price for blinatumomab. It noted that the deterministic ICERs were £55,501 per quality-adjusted life year (QALY) gained for the overall population (probabilistic ICER of £57,600 per QALY gained) and £49,190 per QALY gained for people who had not had previous salvage therapy (probabilistic ICER of £58,900 per QALY gained). However, the committee considered these ICERs to have been overestimated. It was aware that the costs of blinatumomab were overestimated because up to 9 cycles of treatment had been modelled, when the marketing authorisation is for a maximum of 5 cycles. The committee also considered that the hospitalisation requirements in clinical practice (see section\xa04.2) are less than those modelled, and the assumption that patients were cured at 48 months was potentially conservative (see section\xa04.14). The committee considered the ICER for people who had not had previous salvage therapy to be most appropriate for the purposes of decision making, because it represents the treatment position in which blinatumomab will be used in clinical practice. As blinatumomab becomes established in clinical practice the number of people who have had previous salvage chemotherapy will diminish over time. The committee also noted that there is significant unmet clinical need for people with relapsed or refractory acute lymphoblastic leukaemia, because of the shortcomings of existing regimens (see section\xa04.3). The committee concluded that, despite substantial uncertainty, the ICER for blinatumomab is within the range normally considered a cost-effective use of NHS resources given that the end-of-life criteria apply (see section\xa04.17).\n\n# Innovation\n\nThe committee considered whether blinatumomab is innovative. It heard from the patient and clinical experts that there is significant unmet need for people with relapsed or refractory acute lymphoblastic leukaemia because of the ineffective and toxic chemotherapy regimens currently available. It noted that the company considers blinatumomab to be an innovative treatment and a step-change in treatment of a very rare illness. The committee concluded that blinatumomab would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of quality-adjusted life years (QALYs).\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the PPRS 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA450\n\nAppraisal title: Blinatumomab for previously treated Philadelphia-chromosome-negative acute lymphoblastic leukaemia\n\nSection\n\nKey conclusion\n\nBlinatumomab is recommended within its marketing authorisation as an option for treating Philadelphia-chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukaemia in adults, only if the company provides it with the discount agreed in the patient access scheme.\n\nThe committee considered the end-of-life criteria to be met because life expectancy in the standard of care arm in the TOWER trial was 4\xa0months and blinatumomab was associated with an overall survival benefit of 3.7\xa0months.\n\nThe deterministic incremental cost-effectiveness ratio (ICER) for people who had not had previous salvage therapy was £49,190 per quality-adjusted life year (QALY) gained, when a patient access scheme was included. However the ICER is likely to be lower if the reduced hospitalisation requirements are taken into account, and is therefore likely to be within the range normally considered a cost-effective use of NHS resources.\n\nThe committee considered the ICER for people who had not had previous salvage therapy to be most appropriate for the purposes of decision making, because it represents the treatment position in which blinatumomab will be used in clinical practice. The committee concluded that, despite substantial uncertainty, the ICER for blinatumomab is within the range normally considered a cost-effective use of NHS resources given that the end-of-life criteria apply.\n\n, 4.17, 4.18\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nLiving with precursor B-cell acute lymphoblastic leukaemia, particularly when the condition has failed to respond to first line chemotherapy, can have a profound effect on a person's physical and psychological wellbeing. The clinical experts emphasised that the side effects of blinatumomab are much less severe than alternative therapies currently available such as fludarabine, cytarabine and granulocyte stimulating factor based regimens with idarubicin (FLAG-IDA). Blinatumomab can also be delivered mostly in the outpatient setting. The committee concluded that the availability of an effective treatment that could be delivered primarily in the outpatient setting was hugely beneficial to patients and would have a major impact on their quality of life.\n\n, 4.2\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nBlinatumomab was associated with a statistically significant overall survival gain of 3.7\xa0months and an increase in the proportion of patients with complete remission, compared with standard of care chemotherapy in the TOWER trial. The committee concluded that the results of TOWER are generalisable to the UK population, and noted that blinatumomab appears to be more clinically effective in the subgroup of people who have not had previous salvage therapy. The committee heard from clinical experts that blinatumomab would be used as first salvage therapy because people would then be in a better positon to respond to allogenic stem cell transplantation. The committee concluded that people who have had no salvage therapy are the most relevant population for this appraisal.\n\nThe committee noted that the company considers blinatumomab to be innovative because it is a step-change in a very rare illness. However it concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculations.\n\nto 4.8, 4.18, 4.19\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nClinical experts suggested that blinatumomab would be used as first salvage therapy in practice, noting the lack of alternative options.\n\n, 4.7\n\nAdverse reactions\n\nBlinatumomab is associated with fewer adverse reactions than the standard of care chemotherapy regimens that are its comparators.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe clinical evidence for blinatumomab compared with standard of care chemotherapy comes mainly from TOWER. The committee noted that the company presented data for the whole trial population and for a subgroup of people who had not had previous salvage therapy.\n\n\n\nRelevance to general clinical practice in the NHS\n\nPeople who relapsed 12\xa0months or more after primary induction therapy (who have a better prognosis than those who relapsed earlier) were excluded from the trials. The committee concluded that the trial populations broadly correspond with those in clinical practice but reflect people with a relatively poor prognosis.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that although in TOWER blinatumomab was associated with improved overall survival up to 15\xa0months, the Kaplan–Meier curves of the 2 treatment arms came together at this point. The data were immature and there were very small numbers of patients alive at 15‑month follow-up. The committee concluded that blinatumomab is clinically effective in improving overall survival compared with standard care in the short term, but there is uncertainty about the long-term overall survival benefit.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nBlinatumomab appears to be more clinically effective in people who have not had previous salvage therapy.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nBlinatumomab was associated with a statistically significant overall survival benefit of 3.7\xa0months compared with standard of care chemotherapy.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company submitted a partitioned-survival economic model, representing an initial pre-response state, a response state, a refractory/relapsed state and death. The committee agreed that the model structure was appropriate.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee considered the following key areas of uncertainty:\n\nextrapolation of overall survival\n\ntime at which a patient is considered to be cured\n\nhealthcare utilisation costs.\n\n, 4.14, 4.16\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee heard that the quality-of-life data was mapped from EORTC QLQ-C30 data collected in TOWER.\n\nThe company considers blinatumomab to be innovative because it is a step-change in treatment of a very rare illness. However the committee did not identify any specific health-related benefit that had not already been captured in the QALY calculation.\n\n, 4.19\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nBlinatumomab is more cost effective in people who have not had previous salvage therapy. This represents the expected position in which blinatumomab will be used in clinical practice in the NHS.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of cost effectiveness in the company's model were the extrapolation of overall survival, the time at which a patient is considered to be cured and healthcare utilisation costs.\n\n, 4.14, 4.16\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee considered the ICER in people who had not had previous salvage therapy to be most appropriate for the purposes of decision making, because it represents the treatment position in which blinatumomab will be used in clinical practice.\n\nThe committee concluded that the most plausible ICER for blinatumomab compared with standard of care chemotherapy in the subgroup of people who had not had previous salvage therapy is likely to be lower than the company's base case ICER of £49,190 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n\n\nEnd-of-life considerations\n\nThe committee concluded that the end-of-life criteria were met in the overall population:\n\nBlinatumomab met the short life-expectancy criteria (less than 24\xa0months) because life expectancy in the standard of care chemotherapy arm of TOWER was 4\xa0months.\n\nBlinatumomab was associated with a median overall survival gain of 3.7\xa0months over standard of care chemotherapy and therefore met the criterion for extension to life of greater than 3\xa0months.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the appraisal.\n\n–"}	https://www.nice.org.uk/guidance/ta450	Evidence-based recommendations on blinatumomab (Blincyto) for treating Philadelphia-chromosome-negative precursor B-cell acute lymphoblastic leukaemia in adults.
38549137f925fa16ea7b6a3b0fbc7b6dccd682b5	nice	Ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia	Ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia Evidence-based recommendations on ponatinib (Iclusig) for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia in adults. # Recommendations Ponatinib is recommended, within its marketing authorisation, as an option for treating chronic‑, accelerated‑ or blast‑phase chronic myeloid leukaemia in adults when: the disease is resistant to dasatinib or nilotinib or they cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate or the T315I gene mutation is present. Ponatinib is recommended, within its marketing authorisation, as an option for treating Philadelphia-chromosome-positive acute lymphoblastic leukaemia in adults when: the disease is resistant to dasatinib or they cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or the T315I gene mutation is present. Ponatinib is recommended only if the company provides the drug with the discount agreed in the patient access scheme.# The technology Description of the technology Ponatinib (Iclusig, Incyte Corporation) is a third-generation antineoplastic protein kinase inhibitor that acts on the breakpoint cluster region-Abelson oncogene that leads to chronic myeloid leukaemia and Philadelphia-chromosome-positive acute lymphoblastic leukaemia. Marketing authorisation Ponatinib has a marketing authorisation for 'adult patients with: chronic‑phase, accelerated‑phase, or blast‑phase chronic myeloid leukaemia who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation Philadelphia-chromosome-positive acute lymphoblastic leukaemia who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.' Recommended dose and schedule Once‑daily oral doses: 15 mg, 30 mg or 45 mg. Dose levels and dose adjustments are determined by time on treatment, treatment response, and adverse reactions to treatment. For full details about treatment discontinuation and dose reduction, see the summary of product characteristics. Price Ponatinib is available at a cost of £5,050 for 60 15‑mg tablets, or 30 45‑mg tablets (excluding VAT; British national formulary online, accessed January 2017). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ponatinib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Incyte and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of ponatinib, having considered evidence on the nature of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) and the value placed on the benefits of ponatinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical management of CML The committee considered the views of the patient expert on their experience of ponatinib as a treatment for CML. It heard that people whose disease had not responded to initial treatment with a tyrosine kinase inhibitor (TKI) would value ponatinib as an option to control their condition. The committee heard from the patient expert that patients whose disease responds to ponatinib can live a 'normal' life, treatment can be maintained and the risk of side effects can be minimised by adjusting the dosage and frequency at which ponatinib is taken. The committee considered the current guidance on CML. It noted that NICE technology appraisal guidance recommends dasatinib and nilotinib for Philadelphia-chromosome-positive (Ph+) chronic‑ or accelerated‑phase CML in adults who cannot tolerate or whose disease is resistant to imatinib, and bosutinib for chronic‑, accelerated‑ or blast‑phase CML after at least 1 TKI when imatinib, nilotinib and dasatinib are not clinically appropriate. The committee noted that approximately 95% of people with CML have Ph+ disease. The committee considered the summary of product characteristics for ponatinib and it noted that ponatinib is indicated for use in adults with 'chronic‑phase, accelerated‑phase, or blast‑phase chronic myeloid leukaemia who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation'. The committee noted that this was the same population used in the scope issued by NICE, and was aware that any recommendations it made on the use of ponatinib would be within the marketing authorisation. The committee considered that in the current treatment pathway, ponatinib may be an option when the TKIs imatinib, nilotinib and dasatinib are not clinically appropriate. The committee heard from the clinical experts that ponatinib can have various severe side effects, and in particular there is an increased risk of severe cardiovascular occlusive events. However, both the clinical and patient experts explained that although some people will not be able to tolerate ponatinib because of toxicity, the most common side effects are generally tolerable in this patient population. The committee heard that side effects are likely related to drug dosage, and that their risk could be reduced by lowering the dose and frequency of treatment. It noted that for people with chronic‑phase CML, the summary of product characteristics suggests stopping ponatinib if there has not been a complete haematological response by 3 months, and reducing the dose to 15 mg if there has been a major cytogenetic response. The committee heard from the clinical experts that it was important to distinguish between resistance and intolerance. It heard that certain types of CML can be resistant to treatment with a particular TKI resulting in non-response, and would be unlikely to respond to treatment with similar TKIs. On the other hand, some people may be unable to tolerate treatment with a particular TKI because of the associated side effects, despite their disease responding to the treatment (but these people may be able to tolerate a different TKI). The committee heard from clinical experts that response to treatment is measured using a sensitive molecular assay, real-time quantitative polymerase chain reaction (RQ-PCR), and that a result of less than 10% at 3 months is considered to be an important milestone in predicting long-term survival. It heard that around 70% of people with newly diagnosed CML having imatinib will reach this milestone; this rises to 90% in people having a second-generation TKI (dasatinib, nilotinib or bosutinib). Some people may not reach this milestone because they cannot tolerate imatinib, rather than because their disease is resistant to treatment. Around 50% of people who cannot tolerate imatinib have an RQ-PCR of less than 10% 3 months after starting a second-generation TKI. The other 50% need further treatment with ponatinib or an allogeneic stem cell transplant. # Clinical management of Philadelphia-chromosome-positive ALL The committee considered the current guidance on ALL. It noted that NICE technology appraisal guidance on pegaspargase for treating acute lymphoblastic leukaemia recommends pegaspargase as part of antineoplastic combination therapy for newly diagnosed ALL in people of all ages. It noted that although there was no other NICE guidance currently available, and none specifically for people with Ph+ ALL, imatinib and dasatinib are available for people with Ph+ ALL and dasatinib was previously available for this indication through the Cancer Drugs Fund. It noted the population in both ponatinib's marketing authorisation and the NICE scope (section 4.2) and was aware that any recommendations it made on the use of ponatinib would be within the marketing authorisation. The committee concluded that it was appropriate to consider ponatinib as an option in adults with Ph+ ALL whose disease is resistant to, or who cannot tolerate, imatinib and dasatinib. The committee heard from the clinical experts that before TKIs became available, Philadelphia-chromosome-positive (Ph+) ALL was considered the most severe form of leukaemia. The TKIs have changed the treatment pathway for people with ALL, who now have more tolerable treatment options than the previous standard of care (chemotherapy). # Clinical effectiveness in CML The committee considered the clinical evidence presented by the company. It noted that the clinical evidence for ponatinib in CML came from the PACE study. This is a phase II, single-arm, open-label, non-comparative study involving 66 sites across 12 countries, including 5 from the UK. The committee noted concerns about the lack of a comparator in the PACE study, but was aware of the ethical considerations (offering placebo to patients who have not responded to previous treatment) which prevented the company from designing the trial as a randomised control trial design. The committee was aware that for some patients in the trial, the dosage was changed or treatment was stopped which led to uncertainties about the best dosing level, the duration of treatment, and the generalisability of the reported outcomes. The committee concluded that despite these uncertainties the evidence presented was sufficient for decision-making in this case. The committee considered the results of the PACE study for people with CML. For patients with chronic‑phase CML, the primary outcome was the proportion of patients achieving major cytogenetic response (MCyR, defined as complete cytogenetic response or partial cytogenetic response) within 12 months of starting treatment. For patients with accelerated‑phase and blast‑phase CML, the primary outcome was the proportion of patients achieving a major haematologic response (MaHR, defined as complete haematologic response or no evidence of leukaemia, confirmed by blood analyses) within 6 months of starting treatment. Patients in the study had 1 to 4 TKIs (imatinib, dasatinib, nilotinib or bosutinib) and conventional therapy, before having ponatinib. For patients with chronic‑phase CML, 56% of patients having ponatinib after 1 TKI achieved a MCyR at 12 months; this increased to 67% for patients having 2 previous TKIs, 45% for 3 TKIs and 58% for 4 TKIs. At 12 months overall survival was 94% and progression-free survival was 80%. For patients with accelerated‑phase CML, 55% of patients having ponatinib after 1 TKI achieved a MaHR by 6 months; this increased to 61% for patients having 2 previous TKIs, 50% for 3 TKIs and 67% for 4 TKIs. At 12 months overall survival was 84% and progression-free survival was 55%. For patients with blast‑phase CML, 31% achieved a MaHR by 6 months. Overall survival was 29% and progression-free survival was 19%.The committee also considered results at 4-year follow-up, provided as commercial in confidence by the company. The committee concluded that the PACE study demonstrated ponatinib to be an effective treatment for CML. The committee discussed the matching adjusted indirect comparison carried out by the company to allow an indirect comparison of ponatinib with bosutinib. The approach was only used for patients with chronic‑phase CML because theirs were the only data comprehensive enough to allow the matching technique to be used. The committee discussed the appropriateness of the approach used by the company. It noted the concerns of the ERG that individual patient data from the PACE trial were matched with aggregate data from Khoury et al. (2012). It heard from the clinical experts that Khoury et al. was representative of UK practice, and had been used in a recent Cancer Drugs Fund reconsideration of the NICE technology appraisal guidance on bosutinib for previously treated chronic myeloid leukaemia. The committee heard from the ERG that using the company's weightings for patients in its analysis had made little difference to the results of the matching adjusted indirect comparison. It heard from the company that none of the other comparators provided similar data relevant to this evaluation. It also heard that there were limitations in this approach, including that it involved several assumptions to allow for matching patient characteristics across a range of covariates and to account for unobserved heterogeneity. The committee noted that considerable overlap between the 2 populations is needed to prevent all the weighting being given to a few patients. It noted comments received during consultation highlighting evidence that ponatinib is more effective than dasatinib, nilotinib and bosutinib when compared with imatinib in newly diagnosed disease. The committee considered that despite the uncertainty about the matching adjusted indirect comparison, it could be used for decision-making in this case. The committee considered the results of the PACE study in light of ponatinib's role in treating CML in people with the T315I gene mutation. For patients with chronic‑phase CML, 70% achieved an MCyR by 12 months, overall survival was 92% and progression-free survival was 83%. For patients with accelerated‑phase CML, 50% achieved an MaHR by 6 months. For patients with blast‑phase CML, 29% achieved an MaHR by 6 months. Overall and progression-free survival was not reported. The committee noted that these results were at least as good as those as patients without the T315I gene mutation. The committee noted that although ponatinib is the only drug licensed for use in people with the T315I gene mutation, it generally works better than other treatments in people without the T315I gene mutation. The committee concluded that the clinical-effectiveness evidence for ponatinib in people with the T315I gene mutation showed it to be an effective treatment, and was sufficient for its decision-making. The committee discussed the comparators listed in the scope issued by NICE. It noted that interferon alfa was included as a comparator in the company's submission for chronic‑phase CML only, because it is rarely used to treat CML in the UK and there was no evidence for its effectiveness in accelerated‑ and blast‑phase CML. The committee heard from the clinical and patient experts that best supportive care should not be considered as a relevant comparator because of its limited clinical effectiveness. The committee noted comments received during consultation which suggested that best supportive care should be considered as a comparator, because bosutinib may be ineffective at this stage of the disease and best supportive care would represent the only treatment option. The committee heard from the clinical and patient experts that although allogeneic stem cell transplant can be curative, it is usually most suitable when there are no other treatment options. The committee also heard that allogeneic stem cell transplant would not be suitable for some people with chronic‑phase CML because of either fitness or the availability of a suitable donor, and that there are substantial allogeneic stem cell transplant-associated risks. The committee concluded that bosutinib was the most appropriate comparator based on the current treatment pathway but noted that best supportive care would be the only option for some people, so it should also be a comparator. # Clinical effectiveness in Philadelphia-chromosome-positive ALL The committee noted that the clinical evidence for ponatinib in Ph+ ALL came from the PACE study. The committee noted that because of the small number of patients in the Ph+ ALL subgroup (n=32), the results lacked statistical power. The committee heard from the ERG that patients in the study had received nilotinib, which is not representative of NHS practice. It heard from the clinical experts that because many patients in PACE had already had several ineffective treatments before the study, the results for ponatinib were less favourable than they may be in practice. The committee acknowledged the limitations of the evidence base in this population, but concluded that it was sufficient for its decision-making. The committee considered the results of the PACE study. For patients with Ph+ ALL, 41% achieved the primary outcome (that is, a MaHR within 6 months of starting treatment). At 12 months, overall survival was 40% and progression-free survival was 7%. The primary outcome was not reported by line of therapy; the committee noted results at 4-year follow-up, provided as commercial in confidence by the company, which did report results by line of therapy but merged Ph+ ALL with blast‑phase CML. The committee concluded that the results of the PACE study demonstrated that ponatinib is an effective treatment in Ph+ ALL patients. The committee considered the comparators in the scope issued by NICE. It noted that because allogeneic stem cell transplant would only be considered after ponatinib in those people for whom it is suitable, it was not a relevant comparator. The committee considered that for people for whom a transplant was suitable, the relevant comparators for ponatinib would be best supportive care and induction chemotherapy. However, it noted that chemotherapy would only be used to induce remission in people for whom an allogeneic stem cell transplant is suitable; for people who can have ponatinib but for whom an allogeneic stem cell transplant is unsuitable, the only other treatment option (and so the relevant comparator) was best supportive care. The committee considered that, as for CML, ponatinib was at least as effective in treating Ph+ ALL in people without the T315I gene mutation as it was in people with the mutation (section 4.11). It considered the results from the PACE study in this population, and noted the results reported at 12 months which showed that 36% achieved a MaHR by 6 months. The committee noted that although ponatinib is the only drug that is licensed for the T315I gene mutation, it is generally also more effective than other treatments in those people who do not have the T315I gene mutation. The committee concluded that the clinical-effectiveness evidence for ponatinib in people with the T315I gene mutation showed it to be an effective treatment, and was sufficient for its decision-making. # Cost effectiveness in CML The committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. It noted that because no studies were identified that were relevant to the decision problem, the company constructed a de novo model. During consultation, the company submitted a revised patient access scheme (PAS). The committee discussed the limitations in the company's model. It heard from the ERG that the probabilistic sensitivity analyses done by the company were not robust because of the inappropriate characterisation of uncertainty in the curves, lack of correlation and the arbitrary choice of standard error used for many parameters. It noted this but accepted the structure of the company's economic model and considered it appropriate for its decision-making. The PACE trial did not collect quality-of-life data. The company therefore used the values reported in Szabo et al. (2010), and applied utility decrements to set them to the UK population norm. The committee noted that this approach meant that neither the absolute, nor relative, differences in the health states compared with the baseline health state applied in the model matched those seen in Szabo et al. It accepted the approach taken by the company and considered it appropriate for its decision-making. The committee considered the company's base-case deterministic incremental cost-effectiveness ratios (ICERs) for people with CML, using the revised PAS price for ponatinib and list prices for the comparators. The committee noted that these ICERs were different to those which would be used for decision-making. This was because of the confidential PASs in place for bosutinib, dasatinib and nilotinib. The ICERs for CML in this guidance all use the price for ponatinib including the revised PAS and list prices for the comparators. The committee discussed the ERG's exploratory analyses on the deterministic ICERs in the company's original submission. It heard from the ERG that the parametric distributions, fitted where individual patient data were unavailable, were inappropriate and that the company had not explored the effect of alternative distributions on the ICER. The committee noted that the company chose its parametric distributions based on the Akaike information criterion and Bayesian information criterion, but did not take into account clinical expert advice on the plausibility of the survival curves that it used in its base case. The company had provided additional analyses using the Guyot methodology in response to a clarification letter from the ERG. The committee concluded that the company had neither properly explored the effect of alternative parametric distributions nor justified its chosen distribution. The committee considered the ERG's investigation of parameter uncertainty in the company's model. It heard that the choice of curves of best fit for survival functions and duration of response had a big effect on the ICER, and that the ERG had fitted additional combinations of curves to explore this uncertainty, resulting in a range of potential ICERs. The committee heard responses from the company about the appropriate curve for progression-free survival, and that the choice of log normal led to a clinically implausible result in which patients whose condition did not respond had better outcomes than those whose condition did respond. The committee noted that because of limited data there was considerable parameter uncertainty and no curve provided a definitive fit, including the company's preferred exponential curve for progression-free survival. It therefore concluded that the ERG's fitting of alternative distributions was appropriate. The committee considered the ERG's additional exploratory analyses and noted that the ICERs also increased when a 3‑month stopping rule for bosutinib was applied in the chronic‑ and blast‑phase CML models, to align it with ponatinib. The committee heard from the clinical experts that it would be reasonable to assume that the 3‑month stopping rule would be used in clinical practice, as suggested in the summary of product characteristics (section 4.3), because clinicians would stop treatment with bosutinib or ponatinib as soon as possible if the disease were no longer responding to treatment. The committee concluded that a 3‑month stopping rule should be applied to bosutinib in the models. The committee considered ponatinib drug wastage in the chronic‑phase CML model. It heard from the ERG that assuming drug wastage in the company model increased the ICER. The committee heard from experts that drug wastage would be rare in people with chronic‑phase CML because they are generally well informed about their disease and are aware of the seriousness of the effect of missed doses on maintaining treatment response. The clinical experts also stated that people whose disease responded to treatment would have prescriptions for several months but would be monitored during that period to ensure a response was being maintained. However, the committee considered that zero wastage is unlikely for any drug and that some allowance should have been made in the model for this, although it noted that this had only a small effect on the ICER. The committee considered the company's revised PAS discount and the ERG's exploratory ICERs, using the revised PAS for ponatinib and list price for comparators. It heard from the ERG that the ICERs could be anywhere within its exploratory range, and it was not possible to specify a likely value within it. For chronic‑phase CML, the ICERs for ponatinib were: compared with best supportive care: £18,246 to £27,667 per quality-adjusted life year (QALY) gained compared with bosutinib: £19,680 to £37,381 per QALY gained compared with allogeneic stem cell transplant: £18,279 to dominated (that is, ponatinib was both less effective and more costly than transplant) per QALY gained.The ERG considered it unlikely that the comparison with interferon alfa would not be cost effective, so did no additional analyses. For accelerated‑phase CML, the ICERs for ponatinib were: compared with best supportive care: £7,123 to £17,625 per QALY gained compared with bosutinib: generally ponatinib was dominant (no further analyses were done) compared with allogeneic stem cell transplant: dominant (that is, transplant was both less effective and more costly than ponatinib) to £61,896 per QALY gained. For blast‑phase CML, the ICERs for ponatinib were: compared with best supportive care: dominant compared with bosutinib: £16,209 to £21,404 per QALY gained compared with allogeneic stem cell transplant: £5,033 per QALY gained to dominant.The committee noted that the ICERs for ponatinib compared with allogeneic stem cell transplant in accelerated‑phase CML and ponatinib compared with bosutinib in blast‑phase CML, using the revised PAS for ponatinib and list price for comparators mostly fell within a range usually considered to be a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained). For people with chronic‑phase CML, even though some of the ICERs in the ERG's analyses using the revised PAS for ponatinib and list price for comparators for ponatinib compared with bosutinib were above £30,000 per QALY gained, the ICERs were mostly within the range usually considered to be cost effective. The committee then considered the inclusion of the comparators' confidential PAS discounts in the analysis. It noted that for chronic‑phase CML, the range using the revised PAS for ponatinib and PAS price for comparators included values of less than £20,000 per QALY gained and, given the uncertainty of the true value within the range, it was possible that ponatinib was a cost-effective option in these patients. It also considered the ICER range for ponatinib compared with best supportive care to be relevant, because without ponatinib best supportive care could be the only treatment option in patients whose condition did not respond to a second-generation TKI. The precise decision-making ICERs cannot be reported because of a confidential PAS for the comparators. The committee concluded that ponatinib was cost effective compared with best supportive care and potentially cost effective compared with bosutinib, so recommended ponatinib for chronic‑phase CML as a cost-effective use of NHS resources. # Cost effectiveness in Philadelphia-chromosome-positive ALL The committee discussed the company's de novo model for Ph+ ALL. The ICERs discussed in this population are those used in the committee's decision-making, because there were no confidential PASs for the comparators. The committee understood that the ERG considered the company's model for ALL had underestimated the uncertainty around the ICER in the same way as its model for CML (that is, it did not adequately explore the effect of alternative distributions and values for its model parameters). The committee noted that the company had done indirect comparisons because of a lack of direct comparative evidence. The committee noted that the company's base-case ICERs for ponatinib were: compared with induction chemotherapy: £29,812 per QALY gained compared with best supportive care in people for whom allogeneic stem cell transplant is suitable: £26,319 per QALY gained compared with best supportive care in people for whom allogeneic stem cell transplant is unsuitable: £31,210 per QALY gained.The committee concluded that there was sufficient evidence for its decision-making. The committee considered the company's indirect comparison of ponatinib and best supportive care. It noted that the company's model resulted in different overall survival rates for patients in the ponatinib group compared with those in the best supportive care group. The committee understood that non-response in either treatment arm should give the same overall survival results. The committee noted that to account for this discrepancy, the ERG did 2 separate scenario analyses in which the overall survival rates were set at the same value for both ponatinib and best supportive care. In the first, the ERG used the overall survival figure for ponatinib, and in the second it used the overall survival figure for best supportive care. In the group for whom allogeneic stem cell transplant is suitable, ponatinib dominated induction chemotherapy (that is, it was less expensive and more effective) in both scenarios. In the same group of patients the ICERs dropped to £12,661 per QALY gained when using the overall survival figure for ponatinib, and £18,690 per QALY gained for ponatinib compared with best supportive care. In the group for whom allogeneic stem cell transplant is unsuitable, ponatinib dominated best supportive care in both scenarios. The committee concluded that assuming overall survival after non-response was the same for ponatinib and best supportive care, and using either overall survival value for ponatinib or best supportive care, adequately accounted for the uncertainty around this comparison in this case. The committee also considered the choice of parametric distribution in the company's Ph+ ALL model. It heard from the ERG that it explored a range of alternative parametric distributions which affected the ICER in both directions. The committee concluded that there was some uncertainty about which parametric distributions were most plausible and clinically appropriate. The committee considered the ICER range calculated by the ERG, taking into account the overall survival adjustment for people whose disease did not respond to ponatinib or best supportive care, assuming no half cycle correction of intervention cost, removal of immortality for a small subset of patients, (for group suitable for allogeneic stem cell transplant only) as well as the highest and lowest values from the combinations of alternative parametric distributions used by the ERG. In people for whom allogeneic stem cell transplant is suitable, the ICER for ponatinib compared with best supportive care was £7,156 to £29,995 per QALY gained; compared with induction therapy, the ICER was less than £5,000 per QALY gained. In people for whom allogeneic stem cell transplant was unsuitable, ponatinib dominated best supportive care. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. # People with chronic‑phase CML The company's model estimated that patients' life expectancy is, on average, more than 4 years regardless of treatment. Therefore the committee concluded that the end-of-life criteria, which apply to people with a life expectancy of 2 years or less, were not satisfied for the population with chronic‑phase CML. ## People with accelerated‑phase CML The company's model estimated that, on average, patients having bosutinib would live for more than 6 years, those having allogeneic stem cell transplant would live for more than 3 years, and those having best supportive care would live for slightly less than 2 years. The committee noted that the company's model predicted a large extension to life for ponatinib compared with best supportive care of more than 6 years. The committee concluded that the end-of-life criteria were met for people with accelerated‑phase CML for whom allogeneic stem cell transplant or bosutinib are not appropriate. ## People with blast‑phase CML The company's model estimated that patients having bosutinib, allogeneic stem cell transplant or best supportive care have a life expectancy of less than 2 years. The committee noted that in the model, ponatinib extends life by more than 3 months compared with all the comparators. The committee concluded that the end-of-life criteria were satisfied for people with blast‑phase CML. ## People with Ph+ ALL The company's model estimated that patients having best supportive care only had a life expectancy of less than 6 months. The committee noted that the model predicted that patients for whom allogeneic stem cell transplant is suitable and who were having ponatinib had an extension of life of more than 7 years. It also noted that the model predicted an extension of life of nearly 1 year for patients for whom allogeneic stem cell transplant is unsuitable and who were having ponatinib. The committee concluded that the end-of-life criteria were met for people with Ph+ ALL regardless of allogeneic stem cell transplantation suitability. The committee considered that the ERG's exploratory ranges, taking into account the end-of-life conclusions it had made for each population. The committee concluded that the end-of-life criteria were not met for the chronic‑phase CML population, but because the ERG's exploratory ICER ranges for ponatinib compared with bosutinib largely included values considered to be cost effective, and the values compared with best supportive care were cost effective (usually £20,000 to £30,000 per QALY gained), ponatinib could be considered a cost-effective use of NHS resources. The committee concluded that in those groups in whom the end-of-life criteria were met, the ICERs for ponatinib compared with its relevant comparator were less than £50,000 per QALY gained, so it recommended ponatinib for chronic‑, accelerated‑ and blast‑phase CML, and Ph+ ALL, as a cost-effective use of NHS resources. # Summary of appraisal committee's key conclusions TA451 Appraisal title: Ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia Section Key conclusion Ponatinib is recommended, within its marketing authorisation, as an option for treating chronic, accelerated or blast‑phase chronic myeloid leukaemia (CML) in adults when: the disease is resistant to dasatinib or nilotinib or they cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate or the T315I gene mutation is present. Ponatinib is recommended, within its marketing authorisation, as an option for treating Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL) in adults when: the disease is resistant to dasatinib or they cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or the T315I gene mutation is present. Ponatinib is recommended only if the company provides the drug with the discount agreed in the patient access scheme. The committee concluded that bosutinib was the most appropriate comparator based on the current treatment pathway, but noted that best supportive care would be the only option for some people, so it should also be a comparator. The clinical-effectiveness evidence came from the PACE study which was a single-arm, open-label, non-comparative study. For patients with accelerated‑phase, blast‑phase and chronic‑phase CML, results at 1 year and 4 years showed that ponatinib was an effective treatment. To allow for a comparison with bosutinib, the company presented a matching adjusted indirect comparison for patients with chronic‑phase CML. The committee noted the limitations of the company's matching adjusted indirect comparison but accepted that it could be used for decision-making. For people with ALL, the results from the PACE study showed that at 12 months and 4 years, ponatinib was an effective treatment. For the cost-effectiveness results, the end-of-life criteria were met for people with accelerated and blast‑phase CML. For these populations the most plausible ICERs were below £50,000 per QALY gained. For people with chronic‑phase CML, even though some of the ICERs in the ERG's analyses for ponatinib compared with bosutinib were above £20,000 per QALY gained, the range did contain values below £20,000 per QALY gained. The precise ICERs could not be reported because of a confidential patient access scheme for the comparators. The committee therefore recommended ponatinib for people with chronic‑phase CML because it was potentially cost effective compared with bosutinib and was cost effective compared with best supportive care. The end-of-life criteria were met for people with Ph+ ALL regardless of allogeneic stem cell transplantation suitability. For people with Ph+ ALL for whom allogeneic stem cell transplant is suitable, the ICER for ponatinib compared with best supportive care ranged between £7,156 and £29,995 per QALY gained, and for ponatinib compared with induction was likely to be below £5,000 per QALY gained (dominant to £4,138 per QALY gained). The committee noted that in people with Ph+ ALL for whom allogeneic stem cell transplant was unsuitable, ponatinib dominated best supportive care. The committee recommended ponatinib for people with ALL. , 4.12, 4.8 to 4.10, 4.14, 4.29, 4.30 to 4.35 Current practice Clinical need of patients, including the availability of alternative treatments The committee heard that prognosis for people with CML and Ph+ ALL could be poor, and that treatments liked ponatinib could help them to live a 'normal' life. It understood that while allogeneic stem cell transplant could be curative it had significant risks and side effects, and there were issues around availability of donors, which meant that it was not a suitable treatment for all people. It also understood that for those suitable for allogeneic stem cell transplant, they would first need to stabilise their condition using ponatinib. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee concluded that ponatinib was the only treatment licensed for people with CML or Ph+ ALL with the T315I gene mutation. It heard that ponatinib offers advantages over bosutinib even in people who do not have the T315I mutation. What is the position of the treatment in the pathway of care for the condition? The committee considered the place of ponatinib in the current pathway for CML was in patients who were resistant or intolerant to imatinib, dasatinib and nilotinib. The committee considered that bosutinib was the most appropriate comparator based on the current treatment pathway, but noted that best supportive care would be the only option for some people, so it should also be a comparator. The committee considered the place of ponatinib in the current pathway for Ph+ ALL was in patients who were resistant or intolerant to imatinib and dasatinib. The committee considered that for people for whom a transplant was suitable, the relevant comparators to ponatinib would be best supportive care and induction chemotherapy. Adverse reactions The committee heard from clinical experts that people having ponatinib can have various severe side effects, and in particular there is an increased risk of severe cardiovascular events. However, both the clinical and patient experts explained that although some people will not be able to tolerate ponatinib because of toxicity, the most common side effects are generally tolerable in this patient population. It heard that side effects are likely related to drug dosage, and that their risk could be reduced by lowering the dose and frequency of treatment. Evidence for clinical effectiveness Availability, nature and quality of evidence The clinical evidence was the PACE trial. The committee noted that this was a non-comparative study, and that, without comparative evidence, the company had made an indirect comparison with bosutinib. The committee considered the limitations in both the evidence and company's chosen technique to make an indirect comparison, but considered both appropriate for decision-making. to 4.11, 4.13, 4.14 Relevance to general clinical practice in the NHS The committee concluded that evidence from the PACE trial and Khoury et al. (2012) were relevant to clinical practice in the NHS and this evaluation. Uncertainties generated by the evidence The evidence was limited and had the potential for biases. In the Ph+ ALL group, and in some of the CML subgroups, patient numbers were small, and lacked statistical power. The main uncertainties in the evidence related to optimal dosing, duration of treatment, and in the results from the matching adjusted indirect comparison. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee considered the results from the PACE study. For patients with chronic‑phase CML, the primary outcome was the proportion of patients achieving major cytogenetic response (MCyR) within 12 months of treatment initiation. For patients with accelerated‑phase and blast‑phase CML, the primary outcome was the proportion of patients achieving a major haematologic response (MaHR) within 6 months of treatment initiation. Patients in the study were pre-treated with up to 4 TKIs (imatinib, dasatinib, nilotinib or bosutinib) and conventional therapy, before having ponatinib. For patients with chronic‑phase CML 56% of patients having ponatinib after 1 TKI achieved a MCyR at 12 months, this increased to 67% for patients after 2 previous TKIs, 45% after 3 TKIs, and 58% after 4 TKIs. At 12 months overall survival was 94%, and progression-free survival was 80%. For patients with accelerated‑phase CML, 55% of patients having ponatinib after 1 TKI achieved a MaHR by 6 months, this increased to 61% for patients after 2 previous TKIs, 50% after 3, and 67% after 4. At 12 months overall survival was 84% and progression-free survival was 55%. For patients with blast‑phase CML 31% achieved a MaHR by 6 months. Overall survival was 29% and progression-free survival was 19%. The committee also considered results at 4 years follow-up provided as commercial in confidence by the company. For patients with Ph+ ALL, the primary outcome was the proportion of patients achieving a MaHR within 6 months of treatment initiation; 41% achieved a MaHR by 6 months. At 12 months overall survival was 40% and progression-free survival was 7%. The primary outcome was not reported by line of therapy but the committee noted results, provided by the company as commercial in confidence at 4 year follow-up, which did include this breakdown though merged with blast‑phase CML. The committee considered the results for those patients with the T315I gene mutation which were similar. It concluded that the results from this study demonstrated that ponatinib was effective in CML and Ph+ALL patients, including those with the T315I gene mutation. Evidence for cost effectiveness Availability and nature of evidence No cost-effectiveness evidence relevant to the decision problem was identified and the company submitted a de novo model. The committee considered the model to be appropriate for decision-making. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee agreed with the company's modelling approach, and its choice of economic inputs. However, it considered that the company had not adequately explored the effect of uncertainty in its selection of survival curves in its probabilistic sensitivity analyses. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The PACE trial did not collect quality-of-life data. The company used the values reported in Szabo et al. (2010), and applied utility decrements to set them to the UK population norm. The committee noted that this approach meant that neither the absolute nor relative differences compared with the baseline health state applied in the model matched those seen in Szabo et al. Are there specific groups of people for whom the technology is particularly cost effective? No. What are the key drivers of cost effectiveness? The key driver of cost effectiveness in all the models was the choice of distribution for measures of survival and treatment response. Most likely cost-effectiveness estimate (given as an ICER) The committee recognised that there was considerable uncertainty in the value of the ICERs, and therefore their most likely value fell within a range. It noted that the value of the ICER could fall anywhere within that range. The committee concluded that in all instances this range included cost-effective values, and therefore ponatinib was a cost-effective use of NHS resources. The committee further concluded for those groups in whom the end-of-life criteria were met, the range of ICERs for ponatinib compared with its relevant comparator were below £50,000 per quality-adjusted life year gained. The committee concluded that ponatinib could be recommended for people with chronic, accelerated and blast‑phase-CML, and Ph+ ALL. , 4.29, 4.30 to 4.35 Additional factors taken into account Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health. This scheme provides a discount to the list price of ponatinib applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS. End-of-life considerations The committee concluded that the end-of-life criteria had been met in people with accelerated and blast‑phase CML, and Ph+ ALL. to 4.35 Equalities considerations and social value judgements There were no equality issues to be addressed during the appraisal. N/A	{'Recommendations': 'Ponatinib is recommended, within its marketing authorisation, as an option for treating chronic‑, accelerated‑ or blast‑phase chronic myeloid leukaemia in adults when:\n\nthe disease is resistant to dasatinib or nilotinib or\n\nthey cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate or\n\nthe T315I\xa0gene mutation is present.\n\nPonatinib is recommended, within its marketing authorisation, as an option for treating Philadelphia-chromosome-positive acute lymphoblastic leukaemia in adults when:\n\nthe disease is resistant to dasatinib or\n\nthey cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or\n\nthe T315I\xa0gene mutation is present.\n\nPonatinib is recommended only if the company provides the drug with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nPonatinib (Iclusig, Incyte Corporation) is a third-generation antineoplastic protein kinase inhibitor that acts on the breakpoint cluster region-Abelson oncogene that leads to chronic myeloid leukaemia and Philadelphia-chromosome-positive acute lymphoblastic leukaemia.\n\nMarketing authorisation\n\nPonatinib has a marketing authorisation for 'adult patients with:\n\nchronic‑phase, accelerated‑phase, or blast‑phase chronic myeloid leukaemia who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I\xa0mutation\n\nPhiladelphia-chromosome-positive acute lymphoblastic leukaemia who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I\xa0mutation.'\n\nRecommended dose and schedule\n\nOnce‑daily oral doses: 15\xa0mg, 30\xa0mg or 45\xa0mg. Dose levels and dose adjustments are determined by time on treatment, treatment response, and adverse reactions to treatment. For full details about treatment discontinuation and dose reduction, see the summary of product characteristics.\n\nPrice\n\nPonatinib is available at a cost of £5,050 for 60 15‑mg tablets, or 30 45‑mg tablets (excluding VAT; British national formulary online, accessed January 2017).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ponatinib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Incyte and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of ponatinib, having considered evidence on the nature of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) and the value placed on the benefits of ponatinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management of CML\n\nThe committee considered the views of the patient expert on their experience of ponatinib as a treatment for CML. It heard that people whose disease had not responded to initial treatment with a tyrosine kinase inhibitor (TKI) would value ponatinib as an option to control their condition. The committee heard from the patient expert that patients whose disease responds to ponatinib can live a 'normal' life, treatment can be maintained and the risk of side effects can be minimised by adjusting the dosage and frequency at which ponatinib is taken.\n\nThe committee considered the current guidance on CML. It noted that NICE technology appraisal guidance recommends dasatinib and nilotinib for Philadelphia-chromosome-positive (Ph+) chronic‑ or accelerated‑phase CML in adults who cannot tolerate or whose disease is resistant to imatinib, and bosutinib for chronic‑, accelerated‑ or blast‑phase CML after at least 1\xa0TKI when imatinib, nilotinib and dasatinib are not clinically appropriate. The committee noted that approximately 95% of people with CML have Ph+\xa0disease. The committee considered the summary of product characteristics for ponatinib and it noted that ponatinib is indicated for use in adults with 'chronic‑phase, accelerated‑phase, or blast‑phase chronic myeloid leukaemia who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I\xa0mutation'. The committee noted that this was the same population used in the scope issued by NICE, and was aware that any recommendations it made on the use of ponatinib would be within the marketing authorisation. The committee considered that in the current treatment pathway, ponatinib may be an option when the\xa0TKIs imatinib, nilotinib and dasatinib are not clinically appropriate.\n\nThe committee heard from the clinical experts that ponatinib can have various severe side effects, and in particular there is an increased risk of severe cardiovascular occlusive events. However, both the clinical and patient experts explained that although some people will not be able to tolerate ponatinib because of toxicity, the most common side effects are generally tolerable in this patient population. The committee heard that side effects are likely related to drug dosage, and that their risk could be reduced by lowering the dose and frequency of treatment. It noted that for people with chronic‑phase CML, the summary of product characteristics suggests stopping ponatinib if there has not been a complete haematological response by 3\xa0months, and reducing the dose to 15\xa0mg if there has been a major cytogenetic response.\n\nThe committee heard from the clinical experts that it was important to distinguish between resistance and intolerance. It heard that certain types of CML can be resistant to treatment with a particular\xa0TKI resulting in non-response, and would be unlikely to respond to treatment with similar\xa0TKIs. On the other hand, some people may be unable to tolerate treatment with a particular\xa0TKI because of the associated side effects, despite their disease responding to the treatment (but these people may be able to tolerate a different\xa0TKI).\n\nThe committee heard from clinical experts that response to treatment is measured using a sensitive molecular assay, real-time quantitative polymerase chain reaction (RQ-PCR), and that a result of less than 10% at 3\xa0months is considered to be an important milestone in predicting long-term survival. It heard that around 70% of people with newly diagnosed CML having imatinib will reach this milestone; this rises to 90% in people having a second-generation\xa0TKI (dasatinib, nilotinib or bosutinib). Some people may not reach this milestone because they cannot tolerate imatinib, rather than because their disease is resistant to treatment. Around 50% of people who cannot tolerate imatinib have an RQ-PCR of less than 10% 3\xa0months after starting a second-generation\xa0TKI. The other 50% need further treatment with ponatinib or an allogeneic stem cell transplant.\n\n# Clinical management of Philadelphia-chromosome-positive ALL\n\nThe committee considered the current guidance on ALL. It noted that NICE technology appraisal guidance on pegaspargase for treating acute lymphoblastic leukaemia recommends pegaspargase as part of antineoplastic combination therapy for newly diagnosed ALL in people of all ages. It noted that although there was no other NICE guidance currently available, and none specifically for people with Ph+\xa0ALL, imatinib and dasatinib are available for people with Ph+\xa0ALL and dasatinib was previously available for this indication through the Cancer Drugs Fund. It noted the population in both ponatinib's marketing authorisation and the NICE scope (section\xa04.2) and was aware that any recommendations it made on the use of ponatinib would be within the marketing authorisation. The committee concluded that it was appropriate to consider ponatinib as an option in adults with Ph+\xa0ALL whose disease is resistant to, or who cannot tolerate, imatinib and dasatinib.\n\nThe committee heard from the clinical experts that before\xa0TKIs became available, Philadelphia-chromosome-positive (Ph+) ALL was considered the most severe form of leukaemia. The\xa0TKIs have changed the treatment pathway for people with ALL, who now have more tolerable treatment options than the previous standard of care (chemotherapy).\n\n# Clinical effectiveness in CML\n\nThe committee considered the clinical evidence presented by the company. It noted that the clinical evidence for ponatinib in CML came from the PACE study. This is a phase\xa0II, single-arm, open-label, non-comparative study involving 66\xa0sites across 12\xa0countries, including 5 from the UK. The committee noted concerns about the lack of a comparator in the PACE study, but was aware of the ethical considerations (offering placebo to patients who have not responded to previous treatment) which prevented the company from designing the trial as a randomised control trial design. The committee was aware that for some patients in the trial, the dosage was changed or treatment was stopped which led to uncertainties about the best dosing level, the duration of treatment, and the generalisability of the reported outcomes. The committee concluded that despite these uncertainties the evidence presented was sufficient for decision-making in this case.\n\nThe committee considered the results of the PACE study for people with CML. For patients with chronic‑phase CML, the primary outcome was the proportion of patients achieving major cytogenetic response (MCyR, defined as complete cytogenetic response or partial cytogenetic response) within 12\xa0months of starting treatment. For patients with accelerated‑phase and blast‑phase CML, the primary outcome was the proportion of patients achieving a major haematologic response (MaHR, defined as complete haematologic response or no evidence of leukaemia, confirmed by blood analyses) within 6\xa0months of starting treatment. Patients in the study had 1 to 4\xa0TKIs (imatinib, dasatinib, nilotinib or bosutinib) and conventional therapy, before having ponatinib. For patients with chronic‑phase CML, 56% of patients having ponatinib after 1\xa0TKI achieved a MCyR at 12\xa0months; this increased to 67% for patients having 2 previous\xa0TKIs, 45% for 3\xa0TKIs and 58% for 4\xa0TKIs. At 12\xa0months overall survival was 94% and progression-free survival was 80%. For patients with accelerated‑phase CML, 55% of patients having ponatinib after 1\xa0TKI achieved a MaHR by 6\xa0months; this increased to 61% for patients having 2 previous\xa0TKIs, 50% for 3\xa0TKIs and 67% for 4\xa0TKIs. At 12\xa0months overall survival was 84% and progression-free survival was 55%. For patients with blast‑phase CML, 31% achieved a MaHR by 6\xa0months. Overall survival was 29% and progression-free survival was 19%.The committee also considered results at 4-year follow-up, provided as commercial in confidence by the company. The committee concluded that the PACE study demonstrated ponatinib to be an effective treatment for CML.\n\nThe committee discussed the matching adjusted indirect comparison carried out by the company to allow an indirect comparison of ponatinib with bosutinib. The approach was only used for patients with chronic‑phase CML because theirs were the only data comprehensive enough to allow the matching technique to be used. The committee discussed the appropriateness of the approach used by the company. It noted the concerns of the ERG that individual patient data from the PACE trial were matched with aggregate data from Khoury et al. (2012). It heard from the clinical experts that Khoury et al. was representative of UK practice, and had been used in a recent Cancer Drugs Fund reconsideration of the NICE technology appraisal guidance on bosutinib for previously treated chronic myeloid leukaemia. The committee heard from the ERG that using the company's weightings for patients in its analysis had made little difference to the results of the matching adjusted indirect comparison. It heard from the company that none of the other comparators provided similar data relevant to this evaluation. It also heard that there were limitations in this approach, including that it involved several assumptions to allow for matching patient characteristics across a range of covariates and to account for unobserved heterogeneity. The committee noted that considerable overlap between the 2\xa0populations is needed to prevent all the weighting being given to a few patients. It noted comments received during consultation highlighting evidence that ponatinib is more effective than dasatinib, nilotinib and bosutinib when compared with imatinib in newly diagnosed disease. The committee considered that despite the uncertainty about the matching adjusted indirect comparison, it could be used for decision-making in this case.\n\nThe committee considered the results of the PACE study in light of ponatinib's role in treating CML in people with the T315I\xa0gene mutation. For patients with chronic‑phase CML, 70% achieved an MCyR by 12\xa0months, overall survival was 92% and progression-free survival was 83%. For patients with accelerated‑phase CML, 50% achieved an MaHR by 6\xa0months. For patients with blast‑phase CML, 29% achieved an MaHR by 6\xa0months. Overall and progression-free survival was not reported. The committee noted that these results were at least as good as those as patients without the T315I\xa0gene mutation. The committee noted that although ponatinib is the only drug licensed for use in people with the T315I\xa0gene mutation, it generally works better than other treatments in people without the T315I\xa0gene mutation. The committee concluded that the clinical-effectiveness evidence for ponatinib in people with the T315I\xa0gene mutation showed it to be an effective treatment, and was sufficient for its decision-making.\n\nThe committee discussed the comparators listed in the scope issued by NICE. It noted that interferon alfa was included as a comparator in the company's submission for chronic‑phase CML only, because it is rarely used to treat CML in the UK and there was no evidence for its effectiveness in accelerated‑ and blast‑phase CML. The committee heard from the clinical and patient experts that best supportive care should not be considered as a relevant comparator because of its limited clinical effectiveness. The committee noted comments received during consultation which suggested that best supportive care should be considered as a comparator, because bosutinib may be ineffective at this stage of the disease and best supportive care would represent the only treatment option. The committee heard from the clinical and patient experts that although allogeneic stem cell transplant can be curative, it is usually most suitable when there are no other treatment options. The committee also heard that allogeneic stem cell transplant would not be suitable for some people with chronic‑phase CML because of either fitness or the availability of a suitable donor, and that there are substantial allogeneic stem cell transplant-associated risks. The committee concluded that bosutinib was the most appropriate comparator based on the current treatment pathway but noted that best supportive care would be the only option for some people, so it should also be a comparator.\n\n# Clinical effectiveness in Philadelphia-chromosome-positive ALL\n\nThe committee noted that the clinical evidence for ponatinib in Ph+\xa0ALL came from the PACE study. The committee noted that because of the small number of patients in the Ph+\xa0ALL subgroup (n=32), the results lacked statistical power. The committee heard from the ERG that patients in the study had received nilotinib, which is not representative of NHS practice. It heard from the clinical experts that because many patients in PACE had already had several ineffective treatments before the study, the results for ponatinib were less favourable than they may be in practice. The committee acknowledged the limitations of the evidence base in this population, but concluded that it was sufficient for its decision-making.\n\nThe committee considered the results of the PACE study. For patients with Ph+\xa0ALL, 41% achieved the primary outcome (that is, a MaHR within 6\xa0months of starting treatment). At 12\xa0months, overall survival was 40% and progression-free survival was 7%. The primary outcome was not reported by line of therapy; the committee noted results at 4-year follow-up, provided as commercial in confidence by the company, which did report results by line of therapy but merged Ph+\xa0ALL with blast‑phase CML. The committee concluded that the results of the PACE study demonstrated that ponatinib is an effective treatment in Ph+\xa0ALL patients.\n\nThe committee considered the comparators in the scope issued by NICE. It noted that because allogeneic stem cell transplant would only be considered after ponatinib in those people for whom it is suitable, it was not a relevant comparator. The committee considered that for people for whom a transplant was suitable, the relevant comparators for ponatinib would be best supportive care and induction chemotherapy. However, it noted that chemotherapy would only be used to induce remission in people for whom an allogeneic stem cell transplant is suitable; for people who can have ponatinib but for whom an allogeneic stem cell transplant is unsuitable, the only other treatment option (and so the relevant comparator) was best supportive care.\n\nThe committee considered that, as for CML, ponatinib was at least as effective in treating Ph+\xa0ALL in people without the T315I\xa0gene mutation as it was in people with the mutation (section\xa04.11). It considered the results from the PACE study in this population, and noted the results reported at 12\xa0months which showed that 36% achieved a MaHR by 6\xa0months. The committee noted that although ponatinib is the only drug that is licensed for the T315I\xa0gene mutation, it is generally also more effective than other treatments in those people who do not have the T315I\xa0gene mutation. The committee concluded that the clinical-effectiveness evidence for ponatinib in people with the T315I\xa0gene mutation showed it to be an effective treatment, and was sufficient for its decision-making.\n\n# Cost effectiveness in CML\n\nThe committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. It noted that because no studies were identified that were relevant to the decision problem, the company constructed a de novo model. During consultation, the company submitted a revised patient access scheme (PAS). The committee discussed the limitations in the company's model. It heard from the ERG that the probabilistic sensitivity analyses done by the company were not robust because of the inappropriate characterisation of uncertainty in the curves, lack of correlation and the arbitrary choice of standard error used for many parameters. It noted this but accepted the structure of the company's economic model and considered it appropriate for its decision-making.\n\nThe PACE trial did not collect quality-of-life data. The company therefore used the values reported in Szabo et al. (2010), and applied utility decrements to set them to the UK population norm. The committee noted that this approach meant that neither the absolute, nor relative, differences in the health states compared with the baseline health state applied in the model matched those seen in Szabo et al. It accepted the approach taken by the company and considered it appropriate for its decision-making.\n\nThe committee considered the company's base-case deterministic incremental cost-effectiveness ratios (ICERs) for people with CML, using the revised PAS price for ponatinib and list prices for the comparators. The committee noted that these ICERs were different to those which would be used for decision-making. This was because of the confidential PASs in place for bosutinib, dasatinib and nilotinib. The ICERs for CML in this guidance all use the price for ponatinib including the revised PAS and list prices for the comparators.\n\nThe committee discussed the ERG's exploratory analyses on the deterministic ICERs in the company's original submission. It heard from the ERG that the parametric distributions, fitted where individual patient data were unavailable, were inappropriate and that the company had not explored the effect of alternative distributions on the ICER. The committee noted that the company chose its parametric distributions based on the Akaike information criterion and Bayesian information criterion, but did not take into account clinical expert advice on the plausibility of the survival curves that it used in its base case. The company had provided additional analyses using the Guyot methodology in response to a clarification letter from the ERG. The committee concluded that the company had neither properly explored the effect of alternative parametric distributions nor justified its chosen distribution.\n\nThe committee considered the ERG's investigation of parameter uncertainty in the company's model. It heard that the choice of curves of best fit for survival functions and duration of response had a big effect on the ICER, and that the ERG had fitted additional combinations of curves to explore this uncertainty, resulting in a range of potential ICERs. The committee heard responses from the company about the appropriate curve for progression-free survival, and that the choice of log normal led to a clinically implausible result in which patients whose condition did not respond had better outcomes than those whose condition did respond. The committee noted that because of limited data there was considerable parameter uncertainty and no curve provided a definitive fit, including the company's preferred exponential curve for progression-free survival. It therefore concluded that the ERG's fitting of alternative distributions was appropriate.\n\nThe committee considered the ERG's additional exploratory analyses and noted that the ICERs also increased when a 3‑month stopping rule for bosutinib was applied in the chronic‑ and blast‑phase CML models, to align it with ponatinib. The committee heard from the clinical experts that it would be reasonable to assume that the 3‑month stopping rule would be used in clinical practice, as suggested in the summary of product characteristics (section\xa04.3), because clinicians would stop treatment with bosutinib or ponatinib as soon as possible if the disease were no longer responding to treatment. The committee concluded that a 3‑month stopping rule should be applied to bosutinib in the models.\n\nThe committee considered ponatinib drug wastage in the chronic‑phase CML model. It heard from the ERG that assuming drug wastage in the company model increased the ICER. The committee heard from experts that drug wastage would be rare in people with chronic‑phase CML because they are generally well informed about their disease and are aware of the seriousness of the effect of missed doses on maintaining treatment response. The clinical experts also stated that people whose disease responded to treatment would have prescriptions for several\xa0months but would be monitored during that period to ensure a response was being maintained. However, the committee considered that zero wastage is unlikely for any drug and that some allowance should have been made in the model for this, although it noted that this had only a small effect on the ICER.\n\nThe committee considered the company's revised PAS discount and the ERG's exploratory ICERs, using the revised PAS for ponatinib and list price for comparators. It heard from the ERG that the ICERs could be anywhere within its exploratory range, and it was not possible to specify a likely value within it.\n\nFor chronic‑phase CML, the ICERs for ponatinib were:\n\n\n\ncompared with best supportive care: £18,246 to £27,667 per quality-adjusted life year (QALY) gained\n\ncompared with bosutinib: £19,680 to £37,381 per QALY gained\n\ncompared with allogeneic stem cell transplant: £18,279 to dominated (that is, ponatinib was both less effective and more costly than transplant) per QALY gained.The ERG considered it unlikely that the comparison with interferon alfa would not be cost effective, so did no additional analyses.\n\n\n\nFor accelerated‑phase CML, the ICERs for ponatinib were:\n\n\n\ncompared with best supportive care: £7,123 to £17,625 per QALY gained\n\ncompared with bosutinib: generally ponatinib was dominant (no further analyses were done)\n\ncompared with allogeneic stem cell transplant: dominant (that is, transplant was both less effective and more costly than ponatinib) to £61,896 per QALY gained.\n\n\n\nFor blast‑phase CML, the ICERs for ponatinib were:\n\n\n\ncompared with best supportive care: dominant\n\ncompared with bosutinib: £16,209 to £21,404 per QALY gained\n\ncompared with allogeneic stem cell transplant: £5,033 per QALY gained to dominant.The committee noted that the ICERs for ponatinib compared with allogeneic stem cell transplant in accelerated‑phase CML and ponatinib compared with bosutinib in blast‑phase CML, using the revised PAS for ponatinib and list price for comparators mostly fell within a range usually considered to be a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained). For people with chronic‑phase CML, even though some of the ICERs in the ERG's analyses using the revised PAS for ponatinib and list price for comparators for ponatinib compared with bosutinib were above £30,000 per QALY gained, the ICERs were mostly within the range usually considered to be cost effective. The committee then considered the inclusion of the comparators' confidential PAS discounts in the analysis. It noted that for chronic‑phase CML, the range using the revised PAS for ponatinib and PAS price for comparators included values of less than £20,000 per QALY gained and, given the uncertainty of the true value within the range, it was possible that ponatinib was a cost-effective option in these patients. It also considered the ICER range for ponatinib compared with best supportive care to be relevant, because without ponatinib best supportive care could be the only treatment option in patients whose condition did not respond to a second-generation\xa0TKI. The precise decision-making ICERs cannot be reported because of a confidential PAS for the comparators. The committee concluded that ponatinib was cost effective compared with best supportive care and potentially cost effective compared with bosutinib, so recommended ponatinib for chronic‑phase CML as a cost-effective use of NHS resources.\n\n\n\n# Cost effectiveness in Philadelphia-chromosome-positive ALL\n\nThe committee discussed the company's de novo model for Ph+\xa0ALL. The ICERs discussed in this population are those used in the committee's decision-making, because there were no confidential PASs for the comparators.\n\nThe committee understood that the ERG considered the company's model for ALL had underestimated the uncertainty around the ICER in the same way as its model for CML (that is, it did not adequately explore the effect of alternative distributions and values for its model parameters). The committee noted that the company had done indirect comparisons because of a lack of direct comparative evidence. The committee noted that the company's base-case ICERs for ponatinib were:\n\ncompared with induction chemotherapy: £29,812 per QALY gained\n\ncompared with best supportive care in people for whom allogeneic stem cell transplant is suitable: £26,319 per QALY gained\n\ncompared with best supportive care in people for whom allogeneic stem cell transplant is unsuitable: £31,210 per QALY gained.The committee concluded that there was sufficient evidence for its decision-making.\n\nThe committee considered the company's indirect comparison of ponatinib and best supportive care. It noted that the company's model resulted in different overall survival rates for patients in the ponatinib group compared with those in the best supportive care group. The committee understood that non-response in either treatment arm should give the same overall survival results. The committee noted that to account for this discrepancy, the ERG did 2\xa0separate scenario analyses in which the overall survival rates were set at the same value for both ponatinib and best supportive care. In the first, the ERG used the overall survival figure for ponatinib, and in the second it used the overall survival figure for best supportive care. In the group for whom allogeneic stem cell transplant is suitable, ponatinib dominated induction chemotherapy (that is, it was less expensive and more effective) in both scenarios. In the same group of patients the ICERs dropped to £12,661 per QALY gained when using the overall survival figure for ponatinib, and £18,690 per QALY gained for ponatinib compared with best supportive care. In the group for whom allogeneic stem cell transplant is unsuitable, ponatinib dominated best supportive care in both scenarios. The committee concluded that assuming overall survival after non-response was the same for ponatinib and best supportive care, and using either overall survival value for ponatinib or best supportive care, adequately accounted for the uncertainty around this comparison in this case.\n\nThe committee also considered the choice of parametric distribution in the company's Ph+\xa0ALL model. It heard from the ERG that it explored a range of alternative parametric distributions which affected the ICER in both directions. The committee concluded that there was some uncertainty about which parametric distributions were most plausible and clinically appropriate.\n\nThe committee considered the ICER range calculated by the ERG, taking into account the overall survival adjustment for people whose disease did not respond to ponatinib or best supportive care, assuming no half cycle correction of intervention cost, removal of immortality for a small subset of patients, (for group suitable for allogeneic stem cell transplant only) as well as the highest and lowest values from the combinations of alternative parametric distributions used by the ERG.\n\nIn people for whom allogeneic stem cell transplant is suitable, the ICER for ponatinib compared with best supportive care was £7,156 to £29,995 per QALY gained; compared with induction therapy, the ICER was less than £5,000 per QALY gained.\n\nIn people for whom allogeneic stem cell transplant was unsuitable, ponatinib dominated best supportive care.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\n# People with chronic‑phase CML\n\nThe company's model estimated that patients' life expectancy is, on average, more than 4\xa0years regardless of treatment. Therefore the committee concluded that the end-of-life criteria, which apply to people with a life expectancy of 2\xa0years or less, were not satisfied for the population with chronic‑phase CML.\n\n## People with accelerated‑phase CML\n\nThe company's model estimated that, on average, patients having bosutinib would live for more than 6\xa0years, those having allogeneic stem cell transplant would live for more than 3\xa0years, and those having best supportive care would live for slightly less than 2\xa0years. The committee noted that the company's model predicted a large extension to life for ponatinib compared with best supportive care of more than 6\xa0years. The committee concluded that the end-of-life criteria were met for people with accelerated‑phase CML for whom allogeneic stem cell transplant or bosutinib are not appropriate.\n\n## People with blast‑phase CML\n\nThe company's model estimated that patients having bosutinib, allogeneic stem cell transplant or best supportive care have a life expectancy of less than 2\xa0years. The committee noted that in the model, ponatinib extends life by more than 3\xa0months compared with all the comparators. The committee concluded that the end-of-life criteria were satisfied for people with blast‑phase CML.\n\n## People with Ph+\xa0ALL\n\nThe company's model estimated that patients having best supportive care only had a life expectancy of less than 6\xa0months. The committee noted that the model predicted that patients for whom allogeneic stem cell transplant is suitable and who were having ponatinib had an extension of life of more than 7\xa0years. It also noted that the model predicted an extension of life of nearly 1\xa0year for patients for whom allogeneic stem cell transplant is unsuitable and who were having ponatinib. The committee concluded that the end-of-life criteria were met for people with Ph+\xa0ALL regardless of allogeneic stem cell transplantation suitability.\n\nThe committee considered that the ERG's exploratory ranges, taking into account the end-of-life conclusions it had made for each population. The committee concluded that the end-of-life criteria were not met for the chronic‑phase CML population, but because the ERG's exploratory ICER ranges for ponatinib compared with bosutinib largely included values considered to be cost effective, and the values compared with best supportive care were cost effective (usually £20,000 to £30,000 per QALY gained), ponatinib could be considered a cost-effective use of NHS resources. The committee concluded that in those groups in whom the end-of-life criteria were met, the ICERs for ponatinib compared with its relevant comparator were less than £50,000 per QALY gained, so it recommended ponatinib for chronic‑, accelerated‑ and blast‑phase CML, and Ph+\xa0ALL, as a cost-effective use of NHS resources.\n\n# Summary of appraisal committee's key conclusions\n\nTA451\n\nAppraisal title: Ponatinib for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia\n\nSection\n\nKey conclusion\n\nPonatinib is recommended, within its marketing authorisation, as an option for treating chronic, accelerated or blast‑phase chronic myeloid leukaemia (CML) in adults when:\n\nthe disease is resistant to dasatinib or nilotinib or\n\nthey cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate or\n\nthe T315I\xa0gene mutation is present.\n\nPonatinib is recommended, within its marketing authorisation, as an option for treating Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL) in adults when:\n\nthe disease is resistant to dasatinib or\n\nthey cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or\n\nthe T315I\xa0gene mutation is present.\n\nPonatinib is recommended only if the company provides the drug with the discount agreed in the patient access scheme.\n\nThe committee concluded that bosutinib was the most appropriate comparator based on the current treatment pathway, but noted that best supportive care would be the only option for some people, so it should also be a comparator.\n\nThe clinical-effectiveness evidence came from the PACE study which was a single-arm, open-label, non-comparative study. For patients with accelerated‑phase, blast‑phase and chronic‑phase CML, results at 1 year and 4\xa0years showed that ponatinib was an effective treatment. To allow for a comparison with bosutinib, the company presented a matching adjusted indirect comparison for patients with chronic‑phase CML. The committee noted the limitations of the company's matching adjusted indirect comparison but accepted that it could be used for decision-making. For people with ALL, the results from the PACE study showed that at 12\xa0months and 4\xa0years, ponatinib was an effective treatment.\n\nFor the cost-effectiveness results, the end-of-life criteria were met for people with accelerated and blast‑phase CML. For these populations the most plausible ICERs were below £50,000 per QALY gained. For people with chronic‑phase CML, even though some of the ICERs in the ERG's analyses for ponatinib compared with bosutinib were above £20,000 per QALY gained, the range did contain values below £20,000 per QALY gained. The precise ICERs could not be reported because of a confidential patient access scheme for the comparators. The committee therefore recommended ponatinib for people with chronic‑phase CML because it was potentially cost effective compared with bosutinib and was cost effective compared with best supportive care.\n\nThe end-of-life criteria were met for people with Ph+\xa0ALL regardless of allogeneic stem cell transplantation suitability. For people with Ph+\xa0ALL for whom allogeneic stem cell transplant is suitable, the ICER for ponatinib compared with best supportive care ranged between £7,156 and £29,995 per QALY gained, and for ponatinib compared with induction was likely to be below £5,000 per QALY gained (dominant to £4,138 per QALY gained). The committee noted that in people with Ph+\xa0ALL for whom allogeneic stem cell transplant was unsuitable, ponatinib dominated best supportive care. The committee recommended ponatinib for people with ALL.\n\n, 4.12, 4.8 to 4.10, 4.14, 4.29, 4.30 to 4.35\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard that prognosis for people with CML and Ph+\xa0ALL could be poor, and that treatments liked ponatinib could help them to live a 'normal' life. It understood that while allogeneic stem cell transplant could be curative it had significant risks and side effects, and there were issues around availability of donors, which meant that it was not a suitable treatment for all people. It also understood that for those suitable for allogeneic stem cell transplant, they would first need to stabilise their condition using ponatinib.\n\n, 4.12\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that ponatinib was the only treatment licensed for people with CML or Ph+\xa0ALL with the T315I\xa0gene mutation. It heard that ponatinib offers advantages over bosutinib even in people who do not have the T315I\xa0mutation.\n\n, 4.16\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee considered the place of ponatinib in the current pathway for CML was in patients who were resistant or intolerant to imatinib, dasatinib and nilotinib. The committee considered that bosutinib was the most appropriate comparator based on the current treatment pathway, but noted that best supportive care would be the only option for some people, so it should also be a comparator.\n\nThe committee considered the place of ponatinib in the current pathway for Ph+\xa0ALL was in patients who were resistant or intolerant to imatinib and dasatinib. The committee considered that for people for whom a transplant was suitable, the relevant comparators to ponatinib would be best supportive care and induction chemotherapy.\n\n, 4.12, 4.15\n\nAdverse reactions\n\nThe committee heard from clinical experts that people having ponatinib can have various severe side effects, and in particular there is an increased risk of severe cardiovascular events. However, both the clinical and patient experts explained that although some people will not be able to tolerate ponatinib because of toxicity, the most common side effects are generally tolerable in this patient population. It heard that side effects are likely related to drug dosage, and that their risk could be reduced by lowering the dose and frequency of treatment.\n\n, 4.3\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe clinical evidence was the PACE trial. The committee noted that this was a non-comparative study, and that, without comparative evidence, the company had made an indirect comparison with bosutinib. The committee considered the limitations in both the evidence and company's chosen technique to make an indirect comparison, but considered both appropriate for decision-making.\n\nto 4.11, 4.13, 4.14\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that evidence from the PACE trial and Khoury et al. (2012) were relevant to clinical practice in the NHS and this evaluation.\n\n, 4.10, 4.13\n\nUncertainties generated by the evidence\n\nThe evidence was limited and had the potential for biases. In the Ph+\xa0ALL group, and in some of the CML subgroups, patient numbers were small, and lacked statistical power. The main uncertainties in the evidence related to optimal dosing, duration of treatment, and in the results from the matching adjusted indirect comparison.\n\n, 4.10, 4.13\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee considered the results from the PACE study. For patients with chronic‑phase CML, the primary outcome was the proportion of patients achieving major cytogenetic response (MCyR) within 12\xa0months of treatment initiation. For patients with accelerated‑phase and blast‑phase CML, the primary outcome was the proportion of patients achieving a major haematologic response (MaHR) within 6\xa0months of treatment initiation. Patients in the study were pre-treated with up to 4\xa0TKIs (imatinib, dasatinib, nilotinib or bosutinib) and conventional therapy, before having ponatinib. For patients with chronic‑phase CML 56% of patients having ponatinib after 1\xa0TKI achieved a MCyR at 12\xa0months, this increased to 67% for patients after 2 previous\xa0TKIs, 45% after 3\xa0TKIs, and 58% after 4\xa0TKIs. At 12\xa0months overall survival was 94%, and progression-free survival was 80%. For patients with accelerated‑phase CML, 55% of patients having ponatinib after 1\xa0TKI achieved a MaHR by 6\xa0months, this increased to 61% for patients after 2 previous\xa0TKIs, 50% after 3, and 67% after 4. At 12\xa0months overall survival was 84% and progression-free survival was 55%. For patients with blast‑phase CML 31% achieved a MaHR by 6\xa0months. Overall survival was 29% and progression-free survival was 19%. The committee also considered results at 4\xa0years follow-up provided as commercial in confidence by the company.\n\nFor patients with Ph+\xa0ALL, the primary outcome was the proportion of patients achieving a MaHR within 6\xa0months of treatment initiation; 41% achieved a MaHR by 6\xa0months. At 12\xa0months overall survival was 40% and progression-free survival was 7%. The primary outcome was not reported by line of therapy but the committee noted results, provided by the company as commercial in confidence at 4 year follow-up, which did include this breakdown though merged with blast‑phase CML.\n\nThe committee considered the results for those patients with the T315I\xa0gene mutation which were similar. It concluded that the results from this study demonstrated that ponatinib was effective in CML and Ph+ALL patients, including those with the T315I\xa0gene mutation.\n\n, 4.11, 4.14, 4.17\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nNo cost-effectiveness evidence relevant to the decision problem was identified and the company submitted a de novo model. The committee considered the model to be appropriate for decision-making.\n\n, 4.25\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee agreed with the company's modelling approach, and its choice of economic inputs. However, it considered that the company had not adequately explored the effect of uncertainty in its selection of survival curves in its probabilistic sensitivity analyses.\n\n, 4.26\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe PACE trial did not collect quality-of-life data. The company used the values reported in Szabo et al. (2010), and applied utility decrements to set them to the UK population norm. The committee noted that this approach meant that neither the absolute nor relative differences compared with the baseline health state applied in the model matched those seen in Szabo et al.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key driver of cost effectiveness in all the models was the choice of distribution for measures of survival and treatment response.\n\n, 4.28\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee recognised that there was considerable uncertainty in the value of the ICERs, and therefore their most likely value fell within a range. It noted that the value of the ICER could fall anywhere within that range. The committee concluded that in all instances this range included cost-effective values, and therefore ponatinib was a cost-effective use of NHS resources.\n\nThe committee further concluded for those groups in whom the end-of-life criteria were met, the range of ICERs for ponatinib compared with its relevant comparator were below £50,000 per quality-adjusted life year gained. The committee concluded that ponatinib could be recommended for people with chronic, accelerated and blast‑phase-CML, and Ph+\xa0ALL.\n\n, 4.29, 4.30 to 4.35\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a discount to the list price of ponatinib applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nThe committee concluded that the end-of-life criteria had been met in people with accelerated and blast‑phase CML, and Ph+\xa0ALL.\n\nto 4.35\n\nEqualities considerations and social value judgements\n\nThere were no equality issues to be addressed during the appraisal.\n\nN/A"}	https://www.nice.org.uk/guidance/ta451	Evidence-based recommendations on ponatinib (Iclusig) for treating chronic myeloid leukaemia and acute lymphoblastic leukaemia in adults.
5ffff325dca9f9195181332e4d2aa3dcae2e948a	nice	Multiple frequency bioimpedance devices to guide fluid management in people with chronic kidney disease having dialysis	Multiple frequency bioimpedance devices to guide fluid management in people with chronic kidney disease having dialysis Evidence-based recommendations on multiple frequency bioimpedance devices to guide fluid management in people with chronic kidney disease having dialysis. # Recommendations There is currently not enough evidence to recommend the routine adoption of the BCM – Body Composition Monitor to guide fluid management in people with chronic kidney disease having dialysis in the NHS. Further research is recommended to show the effect of using the BCM – Body Composition Monitor on clinical outcomes (see section 6.1).Centres that are currently using the BCM – Body Composition Monitor to guide fluid management are encouraged to take part in research and data collection (see section 5.18).Centres that do not currently use the BCM – Body Composition Monitor to guide fluid management should only do so as part of a research study, such as the BISTRO trial.NICE will support this guidance through a range of activities to promote the recommendations for further research (see section 7). There is currently not enough validation or clinical-outcome data to recommend the routine adoption of the InBody S10 or the MultiScan 5000 to guide fluid management in people with chronic kidney disease having dialysis in the NHS.# Clinical need and practice # The problem addressed The purpose of this assessment is to evaluate the clinical and cost effectiveness of using multiple frequency bioimpedance devices to monitor the hydration status of a person with chronic kidney disease who is having either haemodialysis or peritoneal dialysis treatment. Dialysis is used to replace renal function in people with severe chronic kidney disease, including removing excess fluid from the blood. It is important that a correct volume of fluid is removed; removing too little will result in the person becoming overhydrated and may lead to oedema, increased blood pressure and an increased risk of cardiovascular events. Alternatively, if too much fluid is removed during dialysis the person will become underhydrated, which can result in the loss of residual renal function and an increased incidence of symptoms such as cramps, nausea and dizziness. In current practice, the fluid status of a person on dialysis is usually determined by clinical assessment, taking into account clinical features and symptoms that suggest overhydration or underhydration. People who are over or underhydrated are often asymptomatic, so clinical assessment may not identify this. Multiple frequency bioimpedance devices give an objective assessment of a person's fluid status which, when used with clinical assessment, may help make decisions about the amount of fluid to remove in dialysis. Using the devices may help reduce the incidence of overhydration or underhydration and their associated clinical consequences. # The condition ## Chronic kidney disease and dialysis Chronic kidney disease can be categorised into 5 stages of severity, in accordance with NICE's clinical guideline on chronic kidney disease. If chronic kidney disease progresses to the most severe stage (stage 5), kidney failure occurs and renal replacement therapy (transplantation or dialysis) is needed for survival. Dialysis replicates many of the functions of a healthy kidney, for example, filtering waste products and excess water from the blood, and is available in 2 types: haemodialysis and peritoneal dialysis. When used as longer-term renal replacement therapy, dialysis can be delivered in an outpatient setting or at home (see NICE's technology appraisal guidance on home compared with hospital haemodialysis for patients with end-stage renal failure). # The diagnostic and care pathways ## Management of chronic kidney disease The management of chronic kidney disease and renal replacement therapy is described in NICE's guidelines on chronic kidney disease, peritoneal dialysis, anaemia management in chronic kidney disease and hyperphosphatemia management in chronic kidney disease. ## Determining fluid volumes to remove by dialysis One of the main aims of dialysis is to remove fluid which builds up because of reduced renal function. Determining the volume of fluid to be removed by dialysis involves identifying a target weight for a person. This is often defined as how much a person should weigh at the end of a haemodialysis session or, for people who have peritoneal dialysis, how much they should weigh in the morning. Comparing a person's current and target weight helps to decide the amount of fluid to be removed during dialysis. Assessing fluid status to set, or adjust, a person's target dialysis weight is usually based on clinical judgement and identifying symptoms of over or underhydration. Clinical parameters assessed include blood pressure, the presence of oedema, weight and any intradialytic or interdialytic symptoms that could suggest overhydration or underhydration (such as cramps, fatigue or nausea). Identification of a person's first target weight often involves gradually reducing a person's post-dialysis weight over successive dialysis sessions until it is as low as can be tolerated.# The diagnostic tests The assessment compared 3 intervention devices with 1 comparator. # The interventions Multiple frequency bioimpedance devices send small, painless electrical signals through the body by way of electrodes. The electrodes also measure the opposition to the flow of the electric current from body tissues (bioimpedance). Each of the devices included in this assessment are portable and could be used by a healthcare professional in either a clinic or the patient's home. Built-in software uses bioimpedance values to calculate parameters relating to hydration, such as volumes of extracellular, intracellular and total body water. Based on these parameters, multiple frequency bioimpedance devices can also produce estimates of a person's target dialysis weight, using models or algorithms that differ between devices. These outputs should be used with clinical assessment to make decisions about the amount of fluid to be removed during dialysis. ## BCM – Body Composition Monitor (Fresenius Medical Care) The BCM – Body Composition Monitor uses bioimpedance spectroscopy and measures bioimpedance across 50 frequencies between 5 and 1,000 kilohertz (kHz). The technology includes a BCM – Body Composition Monitor unit with an output display screen. It is connected by cables to disposable electrodes which are attached to the body. A computer software application is provided for further analysis, and external data storage devices (PatientCards) can be used to transfer outputs from the device to a computer using a card reader. The device calculates parameters relating to hydration, such as volumes of extracellular, intracellular and total body water, and the ratio of extracellular to intracellular water volumes. It also estimates fluid overload using 2 physiological models adapted from techniques published by Chamney et al. (2007) and Moissl et al. (2006). This is the estimated volume that a person is above, or below, their predicted normally hydrated volume. ## InBody S10 (InBody) The InBody S10 model is a multifrequency bioimpedance device that measures bioimpedance across 6 different frequencies (1, 5, 50, 250, 500 and 1,000 kHz). The device consists of an InBody S10 unit which contains a display monitor. The unit is connected by cables to electrodes which are attached to the body. Two types of electrode can be used with this device: disposable adhesive type electrodes and reusable touch type electrodes which can be clipped to a person's hand and foot. As well as whole body measurements, bioimpedance measurements can also be made in 5 areas of the body; right arm, left arm, trunk, right leg, left leg. The device calculates hydration-related outputs including water volumes (extracellular water and intracellular water) and ratio of extracellular to total body water. A suggested standard range of values is given, to help identify people who may be overhydrated or underhydrated. Accompanying software can estimate several suggested dry weight values for use, depending on any complications which may alter extracellular fluid volumes, such as diabetes or hypoalbuminaemia. ## MultiScan 5000 (Bodystat) The MultiScan 5000 uses bioimpedance spectroscopy and measures bioimpedance across 50 frequencies between 5 and 1,000 kHz. The system consists of a bioimpedance spectroscopy hardware unit which is connected by leads to disposable electrodes. Outputs are displayed on a colour touchscreen display. Results for up to 1,000 tests can be stored on the device, with additional data storage available through a Wi-Fi or Bluetooth connection to a computer. A calibrator unit and analytical software are also provided. As well as whole body measurements, bioimpedance can also be measured in different body areas by attaching electrodes in different positions on the body. The device calculates hydration-related parameters such as the volumes of total body water and intracellular and extracellular water, as well as the ratio of total body to extracellular water volumes. The device also displays an estimate of the volume of fluid excess or deficit in a person, which is reported as the volume of overhydration in litres. This value is estimated using models based on methods set out in published literature (Chamney et al. 2007; Moissl et al. 2006). The device can also do a bioelectrical impedance vector analysis. # The comparator ## Clinical assessment The comparator is clinical assessment to determine fluid status and set, or adjust, target weights for people with chronic kidney disease who are on dialysis. Clinical assessment may include blood pressure measurements, changes in weight, the presence of oedema, assessment of residual renal function, any pre-existing cardiovascular conditions and also any reported symptoms of overhydration or underhydration (such as dizziness or nausea). There is no generally accepted gold standard for identifying a person's target weight for assessing the accuracy of the comparator or interventions.# Evidence The diagnostics advisory committee (section 9) considered evidence on the use of the BCM – Body Composition Monitor, InBody S10 and MultiScan 5000 to guide fluid management in people with chronic kidney disease having dialysis from several sources. Full details of all the evidence are in the committee papers. # Clinical effectiveness Six randomised controlled trials (RCTs) met the inclusion criteria for the systematic review, all of which assessed use of the BCM – Body Composition Monitor (Huan-Sheng et al. 2016; Hur et al. 2013; Luo et al. 2011; Onofriescu et al. 2012; Onofriescu et al. 2014; Ponce et al. 2014). Two of these trials (Onofriescu et al. 2012 and Onofriescu et al. 2014) may have reported the same trial or outcomes from an overlapping patient population. The possible effect of this was explored by reporting the meta-analyses with and without Onofriescu et al. (2012). The Cochrane risk of bias tool was used to assess the risk of bias in the included RCTs. One of the RCTs was judged to be at low risk of overall bias (Onofriescu et al. 2012) and 1 was at high risk of bias (Luo et al. 2011). The remaining 4 RCTs did not give enough information to make a judgement on the risk of bias. The frequency of BCM – Body Composition Monitor use varied between studies, from twice monthly to every 3 months. All of the RCTs were done outside the UK. Only 1 study included people having peritoneal dialysis (Luo et al. 2011); the remaining studies enrolled people having haemodialysis. Five trials included people aged 18 years or over and the remaining trial did not give the age-related exclusion criteria, but the mean age of participants was 52.4 years (standard deviation 13.1 years; Onofriescu et al. 2012). Other groups excluded from some of these studies were people with limb amputations, pregnant women and people with coronary stents, pacemakers or metallic implants. No RCTs were identified for the InBody S10 or the MultiScan 5000. Eight non-randomised cohort studies, reported in 9 papers, were also included in the systematic review (Castellano et al. 2014; Hoppe et al. 2015; Kim et al. 2012; Kim et al. 2015; Oei et al. 2016; O'Lone et al. 2014; Onofriescu et al. 2015; Santhakumaran et al. 2016; Wizemann et al. 2009), all of which assessed the BCM – Body Composition Monitor device. Studies were included if they involved at least 100 participants. Two of these studies may have overlapping patient populations (1 was reported in both O'Lone et al. 2014 and Santhakumaran et al. 2016, and the other was reported in Oei et al. 2016). All participants included in the non-randomised studies had monitoring using the BCM – Body Composition Monitor. The frequency of device use varied widely between studies, from just once in the first week of dialysis to 3 assessments per week. Two studies were done in the UK (reported in O'Lone et al. 2014 and Santhakumaran et al. 2016, and Oei et al. 2016) and none of the studies enrolled paediatric patients. Most of the studies included people having haemodialysis (6 studies) rather than peritoneal dialysis (2 studies). The risk of bias in the non-randomised studies was assessed using the Review Body for Interventional Procedures tool. None of the studies included blinded participants or study personnel, and the characteristics of participants who withdrew from the studies were not reported. ## Evidence on clinical outcomes Three RCTs reported data on mortality (Onofriescu et al. 2014; Ponce et al. 2014; Huan-Sheng et al. 2016). Use of the BCM – Body Composition Monitor device had no significant effect on mortality rates (pooled hazard ratio 0.69; 95% confidence interval 0.23 to 2.08; p=0.51) and there was moderate statistical heterogeneity between trials. Three non-randomised studies had results for the effects of hydration status on mortality in subgroups of participants monitored with the BCM – Body Composition Monitor device. Kim et al. (2015) reported a higher incidence of mortality in overhydrated participants (defined by relative hydration state; odds ratio 2.57; 95% CI 1.08 to 6.13; p=0.033). In O'Lone et al. (2014), absolute overhydration had a significant effect on the risk of mortality (hazard ratio 1.10; 95% CI 1.01 to 1.20; p=0.025) and Wizemann et al. (2009) reported that hydration state was an important predictor of mortality in patients having haemodialysis (adjusted hazard ratio 2.10; 90% CI 1.39 to 3.18; p=0.003). Huan-Sheng et al. (2016) reported significant differences in intradialytic complications between people monitored with and without the BCM – Body Composition Monitor device. But incidences were not consistently higher in 1 group. For people monitored using BCM – Body Composition Monitor, significantly higher incidences of cramping, chest tightness and headaches were reported. However, significantly lower incidences of complications caused by hypotension during dialysis sessions and skin itching were reported. The difference in the number of patient-reported events of intradialytic fatigue in participants monitored with and without the BCM – Body Composition Monitor was not statistically significant (p=0.7). Hur et al. (2013) reported no significant difference in the frequency of intradialytic events between groups monitored with and without the BCM – Body Composition Monitor device at 12 months (66.6 and 63.9 events per 1,000 dialysis sessions respectively; p=0.4). Similarly, Onofriescu et al. (2014) found no significant difference in the incidence of hypotension or cramps (p=0.6). Ponce et al. (2014) reported no significant difference in the incidence of hypotensive events (defined as a drop in systolic blood pressure during dialysis by at least 30 mm of mercury or to below 90 mm Hg) at 12 months. One RCT (Huan-Sheng et al. 2016) reported the incidence of cardiovascular-related events, although this was in combination with the incidence of acute fluid overload events. The incidence rate in people monitored with the BCM – Body Composition Monitor device was significantly lower than the control group (incidence rate ratio 0.50 per patient-year; 95% CI 0.26 to 0.94; p=0.03). Three non-randomised studies gave the incidence of cardiovascular events among subgroups of people monitored using the BCM – Body Composition Monitor device. Kim et al. (2015) reported no statistically significant difference in the number of cardiovascular events per year between overhydrated and non-overhydrated subgroups as determined by the level of relative overhydration (p=0.13). Onofriescu et al. (2015) also found no statistically significant difference in the incidence of coronary heart disease, peripheral vascular disease, heart failure or stroke between subgroups with lower relative fluid overload (less than 17.4%) and higher relative fluid overload (over 17.4%). Hoppe et al. (2015) reported a non-significant difference in the incidence of acute myocardial infarction and stroke between people who had been having dialysis for a shorter length of time (short dialysis vintage) and people who had been having dialysis for a longer length of time (long dialysis vintage). No RCTs gave data on residual renal function, although 2 reported urinary output which could be used as a surrogate measure. Hur et al. (2013) found a significant increase in the proportion of patients with anuria, that is when the kidneys no longer produce urine, and a significant decrease in urine output in patients without anuria in a group monitored using the BCM – Body Composition Monitor device. In the corresponding control group, there was no change in the proportion of patients with anuria and the decrease in urine output seen in patients without anuria was not significant. Luo et al. (2011) reported non-significant decreases in urine volume in groups monitored with and without the BCM – Body Composition Monitor device. ## Evidence on intermediate outcomes All 6 included RCTs reported systolic blood pressure measurements. Use of the BCM – Body Composition Monitor device was associated with a significantly lower systolic blood pressure in a meta-analysis (pooled mean difference −3.48 mm Hg; 95% CI −5.96 to −1.00; p=0.006). When data from Onofriescu et al. (2012) was removed from the meta-analysis, the effect size of BCM – Body Composition Monitor-guided monitoring was reduced and was no longer significant (pooled mean difference −2.46 mm Hg; 95% CI −5.07 to 0.15; p=0.06). The external assessment group (EAG) also did a subgroup analysis of systolic blood pressure according to the type of dialysis: peritoneal dialysis (1 RCT) or haemodialysis (5 RCTs). In the haemodialysis subgroup, use of the BCM – Body Composition Monitor device was associated with a significant decrease in systolic blood pressure (pooled mean difference −3.09 mm Hg; 95% CI −5.88 to −0.31; p=0.03). For patients having peritoneal dialysis, Luo et al. (2011) reported a mean decrease in systolic blood pressure of −6.08 mm Hg (95% CI −12.57 to 0.41) associated with use of the BCM – Body Composition Monitor device. Four non-randomised studies gave data on blood pressure among subgroups of people monitored using the BCM – Body Composition Monitor device. No statistically significant differences in blood pressure were seen in the following subgroup comparisons: patients in whom the average overhydration decreased within 6 months compared with those in whom it did not decrease (Castellano et al. 2014), patients who had been having dialysis for a short length of time compared with those who had been having it for longer (Hoppe et al. 2015), and patients with a high relative fluid overload (more than 17.4%) compared with those in whom it was low (less than 17.4%; Onofriescu et al. 2015). Kim et al. (2012) reported that systolic blood pressure was higher in hyperhydrated patients when compared with dehydrated patients (significance not stated). Three RCTs gave data on carotid-femoral pulse wave velocity as a surrogate for arterial stiffness (Hur et al. 2013; Onofriescu et al. 2012; Onofriescu et al. 2014) and were included in a meta-analysis. Arterial stiffness is thought to be associated with an increased risk of cardiovascular events in the longer term. Pulse wave velocity was significantly reduced in patients who were monitored using the BCM – Body Composition Monitor device and standard clinical assessment compared with standard clinical assessment alone (mean difference −1.53 meters per second ; 95% CI −3.00 to −0.07; p=0.04). There was high statistical heterogeneity between the studies. If data from Onofriescu et al. (2012) were removed from the meta-analysis, the pooled effect was no longer significant (mean difference −1.18 m/s; 95% CI −3.14 to 0.78; p=0.24). Five RCTs (Huan-Sheng et al. 2016; Hur et al. 2013; Luo et al. 2011; Onofriescu et al. 2012; Ponce et al. 2014) assessed absolute overhydration; that is, the volume of fluid by which the participants were above their target volume (as assessed by the BCM – Body Composition Monitor device). No data on underhydration were available. A meta-analysis of the mean difference in absolute overhydration volumes showed that absolute overhydration was significantly lower in groups monitored with the BCM – Body Composition Monitor device (mean difference = −0.39 litres, 95% CI −0.62 to −0.15, p=0.001). The EAG did a subgroup analysis for absolute overhydration, as assessed by the BCM – Body Composition Monitor device, according to type of dialysis. They compared the pooled effect of using the BCM – Body Composition Monitor device on absolute overhydration in the overall group (all 5 studies) and a subgroup of studies on people having haemodialysis (4 of these studies). A difference in effect between the overall and haemodialysis subgroup was seen, but the EAG stated that this was not large enough to suggest a significant dialysis effect. Four RCTs had results for relative overhydration (Huan-Sheng et al. 2016; Onofriescu et al. 2012; Onofriescu et al. 2014; Ponce et al. 2014); that is, a person's absolute overhydration volume normalised against their total extracellular body water volume (both volumes assessed by the BCM – Body Composition Monitor device). A meta-analysis of the reported mean differences in the relative overhydration between groups monitored with and without the BCM – Body Composition Monitor device showed that relative overhydration was significantly lower when the BCM – Body Composition Monitor device was used (mean difference = −1.54; 95%CI −3.01 to −0.07; p=0.04). Three RCTs gave data on hospitalisations. Huan-Sheng et al. (2016) reported that the difference in all-cause hospitalisation in patient groups monitored with and without the BCM – Body Composition Monitor device was not significant (hazard ratio 1.19; 95% CI 0.79 to 1.80). Hur et al. (2013) found that the difference in rates of hospitalisation caused by new cardiovascular events in the control and BCM – Body Composition Monitor monitored groups was not statistically significant. In Ponce et al. (2014), 39.6% of participants in the BCM – Body Composition Monitor monitored group and 31.8% of the standard clinical assessment group were hospitalised at least once. Two non-randomised studies gave data on hospitalisation. Kim et al. (2015) found no significant differences in the number of hospital days per event between overhydrated and non-overhydrated groups (as determined by the BCM – Body Composition Monitor device). Onofriescu et al. (2015) found a significantly higher all-cause hospitalisation rate for patients classified as overhydrated when a relative overhydration value of 17.4% was used as a cut-off to define people as overhydrated, but not when a value of 15% was used. Measures of left ventricular hypertrophy, and surrogates of this, such as left ventricular mass index, may be associated with longer-term cardiac morbidity. Hur et al. (2013) reported that left ventricular hypertrophy was present at 12 months in 44% of participants monitored using the BCM – Body Composition Monitor device and in 50% of participants monitored using standard clinical assessment alone. This was a non-significant reduction from baseline in both groups (67% and 53% respectively). But there was a statistically significant reduction in left ventricular mass index from baseline in the group monitored using the BCM – Body Composition Monitor device (p<0.001), although not in the group monitored using standard clinical assessment (p=0.9). Two non-randomised studies gave data on the use of antihypertensive medication in subgroups of people monitored using the BCM – Body Composition Monitor device. In Castellano et al. (2014), consumption of antihypertensive medication was significantly higher in a subgroup of patients who did not have reduced relative overhydration after 6 months of monitoring. Kim et al. (2012) found no significant difference in medication use between people who were dehydrated or hyperhydrated. ## People under 18 years Three non-randomised studies that enrolled people under 18 years were identified by the EAG (all of which assessed the BCM – Body Composition Monitor). One of these studies (reported in Zaloszyc et al. and Zaloszyc et al. ) investigated the association between relative hydration status (measured using the BCM – Body Composition Monitor device) and blood pressure in children having dialysis. The study authors concluded that hypertension was not always related to overhydration; and that using bioimpedance spectroscopy could prevent incorrect reduction of a child's target weight to try and reduce hypertension, when it is not caused by excess fluid. ## Ongoing trials Four ongoing trials that will report outcomes which may be relevant to this assessment were identified. One of these trials, the BioImpedance Spectroscopy to maintain Renal Output (the BISTRO trial), will be UK based. This multi-centre study, funded by the National Institute for Health Research, has a primary outcome of time to anuria (loss of urine output). The study will involve random allocation of participants (adults starting haemodialysis because of chronic kidney disease stage 5) for either regular assessment with a bioimpedance device plus standard treatment or standard treatment alone. Secondary outcomes will include the rate of kidney function reduction, vascular access failure, cardiovascular events, hospital admissions, death and patient-reported outcomes, such as quality of life, dialysis symptoms and functional status (measured at baseline, then every 3 months for up to 24 months). The trial is scheduled to start recruiting in March 2017, with a planned publication date of February 2020. # Cost effectiveness ## Review of economic evidence The EAG did a systematic review to identify existing studies on the cost effectiveness of using multiple frequency bioimpedance devices to monitor the fluid status of people with chronic kidney disease who are on dialysis. No studies reporting full economic evaluations relevant to the scope of this assessment were identified. ## Modelling approach The EAG developed a de novo economic model to assess the cost effectiveness of using multiple frequency bioimpedance testing to help guide fluid management decisions in people having dialysis for chronic kidney disease. The model took the perspective of NHS and personal social services. A Markov model was developed to simulate the effects of monitoring the fluid status of cohorts of people on dialysis, using a multiple frequency bioimpedance device with standard assessment or by standard assessment alone. The model was run as a cohort simulation over a 30‑year time horizon for a 66 year old mixed dialysis population in the base-case analyses. All future costs and benefits included in modelling were discounted at a rate of 3.5% per annum. In the model, people started in a stable state on either haemodialysis or peritoneal dialysis and over time could either stay in that state or move to others when events (such as a kidney transplant, cardiovascular event or death) happened. These events could occur in each cycle of the model, which was set as 3 months. The characteristics of the cohort of patients modelled (for example, their age, the proportion of people on haemodialysis or peritoneal dialysis, gender, and incidence of comorbidities) were based on the UK Renal Registry Report (2015). Mortality rates and hospitalisation rates were informed by a combination of European (ERA-EDTA Registry Annual Report 2013) and UK Renal Registry data, and other published sources. The model also had an option to allow people in the 'stable' and 'post-CV event' dialysis states to be further classified as either severely overhydrated or normohydrated (based on their relative overhydration). This allowed scenarios to be run in the model in which mortality and hospitalisation rates were increased for dialysis patients who were overhydrated. No 'underhydrated' state was included because of a lack of evidence on the prevalence of underhydration in UK dialysis cohorts, the effect of underhydration on the risk of adverse events and quality of life, and the effectiveness of the BCM – Body Composition Monitor device in reducing the incidence of underhydration. Parameter values used in the model were taken from focused reviews of the literature to identify baseline risks for mortality and hospitalisation, and also sources for cost and utility data, and the clinical-effectiveness review. Several possible outcomes that may be affected by using the BCM – Body Composition Monitor device were not included in base-case modelling because of a lack of evidence. These included changes in quality of life (independent of effects of hospitalisation and cardiovascular events), maintenance of residual renal function and effects on dialysis requirements (number and duration of sessions). The clinical-effectiveness review only found data on using the BCM – Body Composition Monitor, therefore only this device has been assessed in base-case analyses. Several scenarios were used to model the effect of BCM – Body Composition Monitor-guided fluid management on baseline model parameters. Direct evidence was only available for the effect of BCM – Body Composition Monitor-guided monitoring on all-cause mortality. Several identified trials also reported the effects of BCM – Body Composition Monitor-guided monitoring on surrogate endpoints, such as pulse wave velocity as a measure of arterial stiffness. The EAG did a further literature search to identify evidence that could be used to link changes in these surrogate endpoints to final health outcomes. Using this linked approach, estimated effects of BCM – Body Composition Monitor-guided monitoring on mortality and non-fatal cardiovascular events were calculated. The EAG also modelled an effect of assuming that BCM – Body Composition Monitor-guided monitoring reduced the proportion of people who were seriously overhydrated (with relative overhydration over 15%). This was applied by classifying people in dialysis states in the model as either severely overhydrated or normohydrated, which allowed mortality and hospitalisation rates to be adjusted upwards for proportions of people in the dialysis cohorts who were estimated to be severely overhydrated. Table 1 gives a summary of the relative effects applied to different parameters in the base-case scenario analyses. Scenario Relative effect on all-cause mortality (HR; 95% CI) Relative effect on hospitalisation for non-fatal CV (HR; 95% CI) Effect on blood pressure medication costs (£ mean reduction) Proportional reduction in severe overhydration Scenario 1 (0.23 to 2.08) Scenario 2 (0.23 to 2.08) (0.82 to 1.01) Scenario 3 (0.82 to 1.01) (0.82 to 1.01) Scenario 4 (0.82 to 1.01) (0.82 to 1.01) Scenario 5 Scenario 6 Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio. The model incorporates health service costs associated with maintenance dialysis, blood pressure medication, erythropoietin stimulating agents, all-cause inpatient hospitalisation, renal transplantation (including work-up, surgery and follow-up), post-transplantation immunosuppression and outpatient visits. Dialysis costs, per session (haemodialysis) or per day (peritoneal dialysis), were taken from NHS reference costs (2014 to 2015). For haemodialysis, the average cost of £154 per haemodialysis session was calculated based on the cost per type of session, at home or at a unit, weighted by relative incidence. For peritoneal dialysis, the average cost per day of £69 was taken from the NHS reference costs. Costs of bioimpedance monitoring included in modelling were purchase costs for devices (annuitised over 5 years), maintenance costs, staff costs related to using the device, training costs and device consumable costs (such as electrodes). The costs of the bioimpedance devices are shown in table 2. Bioimpedance device Cost Expected service life Maintenance cost Estimated annual cost of device consumables Estimated annual cost per patient per year (assuming a test every 3 months) BCM – Body Composition Monitor years £13.26 (assuming use of patient cards) £96.50 (including maintenance contract without parts and labour) InBody S10 years No maintenance costs provided £2.08 (assuming use of reusable electrodes and cost of results sheets) MultiScan 5000 years £70 (assuming a replacement set of leads annually) Health state utility values for people on dialysis and post-renal transplant were identified through a focused search of the literature. Two systematic reviews were found that published EQ‑5D data for UK patients (Liem et al. 2008; Wyld et al. 2012). Further searches did not identify any other studies reporting EQ‑5D data for UK patients after 2010 (the end date for searches in the most recent systematic review). Short and longer-term utility multipliers associated with cardiovascular events were calculated based on data from the Health Survey for England (2003 and 2006). Decreases in health state utilities resulting from hospitalisations were taken from the NICE guideline on peritoneal dialysis. ## Base-case results The following main assumptions were applied in the base-case analysis: Hydration status was assessed with a bioimpedance device every 3 months and, if needed, people had their target weight modified in line with the results. Any effect of BCM – Body Composition Monitor-guided monitoring on the length and frequency of dialysis sessions was assumed to be cost neutral. In the starting cohort of modelled patients, 87% were having haemodialysis and 13% were having peritoneal dialysis. The starting age of the cohort was 66 years. Survival on haemodialysis and peritoneal dialysis was assumed to be equivalent, and patients did not switch between dialysis modes. Fixed proportions of the cohort were on a waiting list for transplant, and waited a median of about 3 years, depending on survival. No transplants were done in patients over 75 years. It was assumed that 17.6% of all inpatient hospitalisations were because of cardiovascular events. Health state utility decrements were applied in the acute period for all hospitalisation events, and ongoing health state utility decrements were also applied after hospitalisation for a cardiovascular event. Effects of bioimpedance monitoring on all-cause mortality were applied for 10 years in the model. Effects of bioimpedance monitoring on cardiovascular-related or all-cause hospitalisation were applied over the lifetime of the cohort. Six base-case scenarios were modelled, each differing in the assumed effects of BCM – Body Composition Monitor-guided monitoring, as described above in table 1. Incremental cost-effectiveness ratios (ICERs) were calculated both with and without dialysis costs (table 3), because including BCM – Body Composition Monitor-guided monitoring in the model prolonged life expectancy, so dialysis was needed over a longer period which increased dialysis costs. Scenario Intervention ICER (cost per QALY gained) with dialysis costs Net monetary benefit with dialysis costs ICER (cost per QALY gained) without dialysis costs Net monetary benefit without dialysis costs Standard assessment BCM Standard assessment BCM Standard assessment BCM Standard assessment BCM Standard assessment BCM Standard assessment BCM Abbreviations: BCM, BCM – Body Composition Monitor; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. Cumulative costs per patient monitored with and without the BCM – Body Composition Monitor device in scenario 3 were calculated. Costs were higher for BCM – Body Composition Monitor-guided monitoring because people on average lived for longer, with dialysis costs making up most (74%) of the increase in cost. ## Analysis of alternative scenarios Several further scenario analyses, based on varying parameters in the base-case scenario 3 model, were done. Results were generally reported without considering the costs of dialysis (unless otherwise stated) and in relation to the ICER produced in base-case scenario 3 when dialysis costs were excluded (£15,636 per quality-adjusted life year gained). The results were as follows: Increasing the frequency of BCM – Body Composition Monitor monitoring to every month (from every 3 months) increased the ICER to £19,818 per QALY gained. Applying the estimated costs associated with monitoring in paediatric centres (which have a lower throughput of patients and so higher estimated costs of bioimpedance monitoring) to the modelled adult population increased the ICER to £20,329 per QALY gained (assuming testing every 3 months). This was increased to £23,647 per QALY gained if testing was assumed to be done every month. Assuming that BCM – Body Composition Monitor-guided fluid management resulted in a 2% improvement in health state utility over a patient's lifetime reduced the ICER to £11,758 per QALY gained (£44,477 if dialysis costs were included). If this improvement was increased to 5%, the ICER reduced further to £8,570 per QALY gained (£32,418 if dialysis costs were included). If BCM – Body Composition Monitor-guided monitoring was assumed to result in a 10% reduction in lifetime dialysis costs, BCM– Body Composition Monitor-guided care dominated standard care (that is, costs less but produces more QALYs). If a 5% reduction in lifetime dialysis costs was assumed, the ICER for BCM – Body Composition Monitor-guided care (including dialysis costs) was £19,759 per QALY gained (compared with £59,144 per QALY gained in the base-case analysis when including dialysis costs). If BCM – Body Composition Monitor-guided monitoring was assumed to have no effect on mortality (that is, the effects were only because of changes in the incidence of non-fatal cardiovascular events), the ICER including the cost of dialysis was £21,327 per QALY gained (compared with £59,144 per QALY gained in base-case analysis). If BCM – Body Composition Monitor-guided monitoring was assumed to have no effect after 3 years, the ICER for BCM – Body Composition Monitor-guided monitoring increased to £18,324 per QALY gained. Further scenario analyses produced little change in the base-case scenario ICERs, with ICER values (not including dialysis costs) of between £9,000 and £19,000 per QALY gained. No clinical-effectiveness data were found for the InBody S10 or MultiScan 5000. These devices were therefore not included in base-case cost-effectiveness modelling. But they were included in scenario analyses which assumed that these devices reduced mortality and non-fatal cardiovascular events to the same extent as the BCM – Body Composition Monitor device in scenario 3 (but with different costs). The ICERs produced for these devices were very similar, being between £15,000 and £16,000 per QALY gained. ## Subgroup analyses Subgroup analysis were also done with the dialysis population grouped by comorbidity status (none or at least 1), dialysis modality (haemodialysis or peritoneal dialysis), starting age of the cohort, whether a person was on a transplant list or not, and whether or not they were chronically overhydrated. No large differences in cost effectiveness by subgroup were identified. ICERs for all subgroups stayed below £16,500 per QALY gained (when dialysis costs were not included), except for people listed for a transplant who had an ICER of £20,297 per QALY gained. ## Sensitivity analyses One-way sensitivity analyses were done on model parameters for base-case scenario 3 (both with and without dialysis costs). When dialysis costs were included, adjusting the hazard ratio for all-cause mortality to 1.00 resulted in the most favourable ICER for BCM – Body Composition Monitor-guided monitoring. This was because these people have the same survival as those having standard monitoring, and therefore do not have higher dialysis costs, but do have the benefit of a reduced cardiovascular hospitalisation rate. When dialysis costs are included, ICERs produced by varying model parameters within their specified ranges generally stayed above £30,000 per QALY gained. When dialysis costs were not included, the ICERs stayed sensitive to varying all-cause mortality. But, in this case, the least favourable ICER occurs when the hazard ratio is equal to 1.00. The EAG did probabilistic sensitivity analyses for base-case scenarios 1, 3 and 4 (both with and without dialysis costs included). Results are shown in table 4. The probabilistic ICERs produced for all 3 base-case scenarios were similar to the deterministic ICERs (shown in table 3 above). If dialysis costs were included, the probability of BCM – Body Composition Monitor-guided monitoring being cost effective at a maximum acceptable ICER of £20,000 per QALY gained was 26% in scenario 1 and less than 6% in scenarios 3 and 4. If dialysis costs were excluded, BCM – Body Composition Monitor-guided monitoring was 67% to 75% likely to be cost effective at this maximum acceptable ICER in the 3 scenarios. The EAG warned that the uncertainty in the parameters produced by linking the effects of monitoring with the BCM – Body Composition Monitor device on arterial stiffness to mortality and non-fatal cardiovascular events (as in base-case scenarios 3 and 4) may not be fully captured in the probabilistic modelling. Scenario Intervention ICER (cost per QALY gained) with dialysis costs Probability of cost effectiveness at £20,000 per QALY gained with dialysis costs ICER (cost per QALY gained) without dialysis costs Probability of cost effectiveness at £20,000 per QALY gained without dialysis costs Standard assessment BCM Standard assessment BCM Standard assessment BCM Abbreviations: BCM, BCM – Body Composition Monitor; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. As noted in the clinical-effectiveness section, removing the Onofriescu et al. (2012) data from meta-analysis reduced the estimated effect of BCM – Body Composition Monitor-guided monitoring on reducing arterial stiffness. Because the pooled estimate of arterial stiffness was used to estimate the relative treatment effects of the BCM – Body Composition Monitor in modelling (in base-case scenarios 2, 3 and 4), a revised cost-effectiveness analyses was done with BCM – Body Composition Monitor-guided modelling assumed to have a smaller and more uncertain effect on hospitalisation for cardiovascular events and mortality. Similar ICERs were produced for revised base-case scenarios 2, 3 and 4 and also for most of the further revised sensitivity, subgroup and scenario analyses. But there was greater uncertainty about the cost-effectiveness results in the revised probabilistic analyses. When dialysis costs were included, the probability of BCM – Body Composition Monitor being cost effective increased from less than 6% to about 13% for scenarios 3 and 4. When dialysis costs were excluded, the probability of BCM – Body Composition Monitor being cost effective decreased for revised scenarios 3 and 4 (from about 72% to about 62%). This reflected the greater uncertainty in the effect of BCM – Body Composition Monitor-guided monitoring on reducing arterial stiffness, and so the linked effect on all-cause mortality and hospitalisation for cardiovascular events.# Committee discussion The committee discussed current practice in the NHS for monitoring the fluid status of people with chronic kidney disease who are having dialysis. It heard from clinical experts that target weights are set to determine how much fluid should be removed during a dialysis session. A person's target weight is usually set and adjusted based on clinical assessment, which takes into account the person's clinical history and any reported symptoms that may suggest fluid overload or dehydration. It heard that there is currently no standardised approach to clinical assessment of fluid status and that there is variation both in how it is done and also the frequency with which it occurs. The committee concluded that current practice for monitoring fluid status in people having dialysis is highly subjective and results in variation in practice both in and between centres. The committee discussed the effect of fluid imbalances on the quality of life of a person having dialysis. It heard from a patient expert that the consequences of fluid overload can include oedema and difficulty breathing. In contrast, removing too much fluid during haemodialysis can lead to painful muscle cramps and hypotension, which can cause a person to faint during or shortly after dialysis sessions. It can also cause more prolonged side effects such as headaches and fatigue after a haemodialysis session. The committee heard from clinical experts that in the shorter term, fluid overload can result in hypertension whereas dehydration can lead to hypotension and decreased blood flow to organs, such as the heart and brain. The longer-term consequences of persistent or intermittent fluid overload and dehydration in adults can include cognitive decline, reduced residual renal function and major adverse cardiovascular events. In children, who often have dialysis as a bridge to a renal transplant, it may contribute to developmental delay and increase their risk of adverse cardiovascular events in later life, particularly if they go on to have dialysis as an adult after transplant failure. The committee concluded that technologies that aim to provide a more objective assessment of fluid status in people having dialysis may be a way of improving the quality of life for this population. # Clinical effectiveness The committee reviewed the available evidence on the clinical effectiveness of using multiple frequency bioimpedance devices to guide fluid management in people with chronic kidney disease having dialysis. It noted that in total, 14 studies were included in the review, 6 of which were randomised controlled trials (RCTs). All of the studies reported data for the BCM – Body Composition Monitor device only, and 5 of the RCTs were noted to be at a high or uncertain risk of bias. No studies reported data for the InBody S10 or MultiScan 5000. The committee heard from clinical experts that the devices use different models to calculate how overhydrated or underhydrated a person is. Also, no data were available to determine the equivalence of fluid overload or target weight calculated by these devices and values calculated by the BCM – Body Composition Monitor; therefore clinical-outcome data from studies with the BCM – Body Composition Monitor could not be considered applicable to the other devices. The committee noted that without device-specific or equivalence data, the InBody S10 or MultiScan 5000 could not be considered further in this assessment. The committee discussed the generalisability of data from the included studies to the NHS. It noted that none of the RCTs and 2 of the non-randomised studies (reported in 3 papers) were done in the UK. The committee heard from clinical experts that current practice varies widely between countries, particularly on whether fluid status is assessed by nursing or medical staff and how frequently assessments are done. It also noted that many of the studies did not give enough details to determine how standard clinical assessment was done, making it difficult to determine whether they were representative of UK practice. The committee therefore concluded that the effect estimates reported by the included studies may not be generalisable to clinical practice in England. The committee discussed the evidence available on the effect of BCM – Body Composition Monitor-guided monitoring on mortality. The committee noted that the pooled-effect estimate (pooled hazard ratio 0.69; 95% confidence interval 0.23 to 2.08; p=0.51) of BCM – Body Composition Monitor-guided monitoring on mortality was not significant. It noted that the total number of mortality events in the 3 included studies was small (42 events) and that the methods used for randomisation were not adequate. It heard from clinical experts that these studies were not powered to show an effect on mortality because this is not the main aim of using the BCM device to guide fluid management. The committee concluded that there is likely to be substantial bias underlying the meta-analysis of mortality data and so there is great uncertainty about the pooled-effect estimate. The committee discussed the effect of BCM – Body Composition Monitor-guided monitoring on intermediate outcomes such as blood pressure control and arterial stiffness. The committee noted that 3 RCTs reported data on arterial stiffness measured by pulse wave velocity and questioned the methods used to get the data. It heard from clinical experts that measurements of pulse wave velocity in these studies were carotid-femoral pulse wave velocity, which is not considered an appropriate surrogate for cardiac morbidity. The committee also noted that 2 of the studies included in the meta-analyses for blood pressure and arterial stiffness (Onofriescu et al. 2012 and 2014) seemed to have overlapping patient populations. When both of these studies are included in the meta-analyses, BCM– Body Composition Monitor-guided monitoring results in a statistically significant improvement in blood pressure (p=0.006) and arterial stiffness (p=0.04). If Onofriescu et al. (2012) is removed the effect is no longer statistically significant. The committee concluded that there was substantial uncertainty around the effect of BCM – Body Composition Monitor-guided monitoring on reducing arterial stiffness and blood pressure, and so on cardiovascular outcomes. The committee considered the data available on the effect of BCM – Body Composition Monitor-guided monitoring on patient-reported adverse effects associated with dialysis. It noted that data from identified studies did not show a clear benefit to using the device. A patient expert commented that since their fluid levels had been monitored using the BCM – Body Composition Monitor device, they had experienced fewer side effects associated with fluid imbalance, and that if they have symptoms possibly related to dialysis a reading with the device can be used to check if they are because of fluid levels. The committee concluded that there is considerable uncertainty about the effect of BCM – Body Composition Monitor-guided monitoring on reducing the number of patient-reported adverse effects associated with fluid imbalance and dialysis. The committee noted that the studies included reported data on the effect of fluid overload, but did not consider the effect of underhydration. It heard from a clinical expert that the BCM – Body Composition Monitor device may identify people, who have previously been identified as normally hydrated by clinical assessment, as underhydrated. Underhydration can lead to clotting in dialysis fistulas, muscle cramps and nausea. It heard that identifying people who are underhydrated, or preventing underhydration, could help to preserve residual renal function in people having dialysis. The committee concluded that more data is needed in this subgroup and noted that this will be collected in the National Institute for Health Research (NIHR) funded BISTRO trial (see section 5.17). The committee discussed the likely effect of BCM – Body Composition Monitor-guided monitoring on peritoneal dialysis. The committee noted that most of the studies included in the clinical-effectiveness analyses reported data for haemodialysis. Only 1 RCT assessed use of the BCM – Body Composition Monitor device in people having peritoneal dialysis, and reported that BCM – Body Composition Monitor-guided monitoring reduced systolic blood pressure (mean difference −6.08 mm Hg; 95% CI −12.57 to 0.41) and absolute overhydration (−0.80 litres; 95% CI −1.32 to −0.28). The committee questioned whether BCM – Body Composition Monitor-guided monitoring could be expected to have a similar effect in both types of dialysis. The committee heard from clinical experts that the effect of BCM – Body Composition Monitor-guided monitoring for people on haemodialysis will not necessarily be the same for people having peritoneal dialysis because the pattern of fluid accumulation which occurs between sessions may be more pronounced with haemodialysis, which is done less often. Also, peritoneal dialysis may preserve residual renal function for longer, so any effect on this outcome could be more pronounced. The committee therefore concluded that there are insufficient data to determine the clinical effectiveness of BCM – Body Composition Monitor-guided monitoring for people having peritoneal dialysis. The committee discussed the clinical effectiveness of BCM – Body Composition Monitor-guided monitoring in people under 18 years (that is, babies, children and young people). It noted that none of the identified studies assessed the use of the device in this group. The committee heard from clinical experts that because of physiological differences, and differences in comorbidities, between adults and babies, young people and children, the available data in adults cannot be considered applicable. It heard from clinical experts that a higher proportion of children who have dialysis have peritoneal dialysis rather than haemodialysis. The committee noted that any benefits or negative effects associated with managing fluids in children could influence outcomes and future treatments when they are adults, and so it is plausible that the effects of the BCM – Body Composition Monitor device may be greater in this population. The committee concluded that more data are needed on the clinical effectiveness of BCM – Body Composition Monitor-guided monitoring for people under 18 years having both haemodialysis and peritoneal dialysis. # Cost effectiveness The committee considered the results of the cost-effectiveness analyses for BCM – Body Composition Monitor-guided fluid monitoring. It noted that several scenarios had been modelled to investigate the uncertainties in estimates of effect on mortality and hospitalisation events that had been identified in the clinical-effectiveness review. The committee heard that the model was based on data from UK and European renal registries, supplemented with data from the clinical-effectiveness review. It heard from clinical experts that the baseline population risk data and clinical-effectiveness data reflected outcomes for adults only and concluded that the results of the cost-effectiveness analyses could not be considered applicable to children. The committee questioned the impact of excluding the effect of prolonged underhydration, and related outcomes, from the model. It heard from the external assessment group that they had not been able to identify appropriate data sources for the prevalence of prolonged underhydration or its effect on mortality and hospitalisation rates. Also, data were not available to include an effect of BCM – Body Composition Monitor-guided monitoring on the incidence of prolonged underhydration or on the maintenance of residual renal function in the model. Clinical experts noted that this could either over- or underestimate the benefits of using the BCM – Body Composition Monitor, depending on whether its use increased or decreased the occurrence of prolonged underhydration. The committee concluded that the effect of BCM – Body Composition Monitor-guided monitoring on the incidence of prolonged underhydration, and associated outcomes such as residual renal function, is likely to be an important factor in assessing the cost effectiveness of the device and that, because of an absence of data, this has not been captured in the analyses. The committee discussed the use of quality-of-life data in the model. It noted that the base-case model did not include an effect of BCM – Body Composition Monitor monitoring on quality of life, beyond its assumed effect on reducing mortality and hospitalisation events. The committee heard from clinical and patient experts that if using the BCM – Body Composition Monitor improved fluid management there would be reductions in dialysis-related side effects and improved recovery after dialysis, which would be of substantial benefit to patients. The committee concluded that, because of an absence of data, the effect of BCM – Body Composition Monitor-guided fluid management on quality of life had not been captured in the analyses. The committee discussed the mortality estimates included in the model. It noted that the pooled-effect estimate from the clinical-effectiveness review showed no significant effect on this outcome (see section 5.5), but that BCM – Body Composition Monitor-guided monitoring was assumed to increase survival in the base-case scenarios. The committee considered that, based on the available evidence, it is uncertain whether BCM – Body Composition Monitor-guided monitoring has any effect on mortality. It also questioned whether this uncertainty had been captured in probabilistic analyses. The committee determined that the most plausible scenario modelled is further scenario 17, which assumes no difference in mortality between BCM – Body Composition Monitor-guided monitoring and clinical assessment alone. This scenario produced an incremental cost-effectiveness ratio (ICER) of about £20,000 per quality-adjusted life year (QALY) gained. The committee noted that this scenario results in very small QALY gains and so its ICER is sensitive to small changes in the non-fatal cardiovascular-event rate. Decreasing the effect of BCM – Body Composition Monitor-guided monitoring on this parameter by a small amount (changing the applied hazard ratio from 0.91 to 0.93) increased the ICER to over £40,000 per QALY. The committee concluded that the results of further scenario analysis 17 were the most plausible, but that there was considerable uncertainty about the results of this analysis, and whether they show that BCM – Body Composition Monitor-guided monitoring is a cost-effective intervention based on a reduction in cardiovascular-event rates alone. The committee discussed the effect of including dialysis costs in the model. It noted that 2 sets of ICERs had been calculated, one with and one without dialysis costs. It noted that when dialysis costs are included, BCM – Body Composition Monitor-guided monitoring is unlikely to be considered cost effective, even if the device is provided at no cost. When dialysis costs are excluded the ICERs generally drop below £20,000 per QALY gained. The committee noted that despite the high costs of dialysis, these results were largely driven by the assumption that BCM – Body Composition Monitor-guided monitoring increases survival and therefore the duration of dialysis treatment. For scenarios which include a survival benefit, the committee concluded that it would be appropriate to exclude costs related to the extended period of survival because dialysis has been generally available in the health service for a long time and it has therefore already been accepted that the benefits gained by providing dialysis outweigh the cost of delivering the intervention. The committee discussed the level of uncertainty in both the clinical- and cost-effectiveness analyses. It noted that there was considerable uncertainty about the effectiveness of BCM – Body Composition Monitor-guided monitoring to reduce the incidence of adverse outcomes, such as cardiovascular events. Also, no data were available for potentially important outcomes, such as residual renal function. Because of this uncertainty in clinical effectiveness, there was insufficient evidence to determine the cost effectiveness of the BCM – Body Composition Monitor at present with any certainty. However, the committee noted that exploratory cost-effectiveness analyses done for the BCM – Body Composition Monitor device suggested that it could be cost effective, although this was sensitive to small changes in the estimated effect of BCM – Body Composition Monitor-guided monitoring. The committee concluded that there was too much uncertainty at present to recommend the BCM – Body Composition Monitor for routine use, but wished to encourage further research (see section 6). # Research considerations The committee considered ongoing research on the clinical effectiveness of multiple frequency bioimpedance devices. It noted that the multi-centre, UK-based BISTRO RCT funded by the NIHR and designed to assess the effectiveness of the BCM – Body Composition Monitor device for monitoring people over 18 years on haemodialysis, will begin recruitment in 2017. The trial is scheduled to report in 2020. The committee heard from clinical experts that the primary outcome will be loss of renal function and noted that the effect of BCM – Body Composition Monitor-guided monitoring on this outcome had not been included in cost-effectiveness analyses because of a lack of data (see section 5.12). The committee concluded that the BISTRO study is highly relevant to this assessment and data from this ongoing study are therefore likely to be important when the guidance is considered for updating in the future. The committee noted that BCM – Body Composition Monitor-guided monitoring is routinely used alongside standard clinical assessment in about 25% of UK dialysis services for people with chronic kidney disease having dialysis. It heard from clinical experts that these centres have developed experience of the benefits and limitations of using the BCM – Body Composition Monitor device to help manage dialysis-related symptoms associated with fluid imbalance. The committee encouraged centres currently using the BCM – Body Composition Monitor device to continue using it and participate in relevant data collection and research. The committee considered the feasibility of further research on the clinical effectiveness of BCM – Body Composition Monitor-guided fluid management in babies, children and young people having dialysis. It heard from clinical experts that this age group makes up less than 1% of the total population of people on dialysis, and that people in this group typically stay on dialysis for a relatively short period of time, until they have a renal transplant. Therefore multi-centre studies are likely to be needed to recruit enough participants to show an effect on clinical outcomes. In the shorter term, the committee wished to encourage paediatric renal services to collect and publish data on cognitive function and quality of life in patients having BCM– Body Composition Monitor-guided fluid management. The committee noted that there were no data to determine the clinical effectiveness of the InBody S10 or MultiScan 5000 devices for guiding fluid management in people with chronic kidney disease who are having dialysis. The committee wished to encourage the companies to collect and publish data on both the validity of their device's underlying fluid model to calculate fluid overload and its associated clinical outcomes. The committee further noted the importance of validating the accuracy of all the multiple frequency bioimpedance devices included in this assessment for people with amputations, people for whom recommended electrode configurations cannot be used and people who are unable to assume recommended positioning for measurements to be made. Also, validation data may be important for people with extremes of body composition, and across different ethnicities, because normal ranges of lean or adipose tissue body composition may differ between ethnicities. It wished to encourage the publication of data on the validity of multiple frequency bioimpedance devices to calculate fluid overload and target weight in these groups.# Recommendations for further research The committee recommended further research into the clinical effectiveness of BCM – Body Composition Monitor-guided fluid management in people with chronic kidney disease having dialysis. It noted that the ongoing BISTRO study will assess the effect of the device in people aged 18 years or over having haemodialysis. Further research should collect clinical-outcome data in the following populations: adults (aged 18 years and over) having peritoneal dialysis babies, children and young people (aged under 18 years) having haemodialysis babies, children and young people (aged under 18 years) having peritoneal dialysis. The committee recommended that data on the effect of BCM – Body Composition Monitor-guided monitoring on health-related quality of life is collected and published. Prospective within-patient studies, which record quality of life and symptoms before and after having BCM – Body Composition Monitor-guided fluid management should be considered.# Review NICE reviews the evidence 3 years after publication to ensure that any relevant new evidence is identified. However, NICE may review and update the guidance at any time if significant new evidence becomes available.Andrew DillonChief ExecutiveJune 2017	{'Recommendations': 'There is currently not enough evidence to recommend the routine adoption of the BCM – Body Composition Monitor to guide fluid management in people with chronic kidney disease having dialysis in the NHS. Further research is recommended to show the effect of using the BCM – Body Composition Monitor on clinical outcomes (see section\xa06.1).Centres that are currently using the BCM – Body Composition Monitor to guide fluid management are encouraged to take part in research and data collection (see section\xa05.18).Centres that do not currently use the BCM – Body Composition Monitor to guide fluid management should only do so as part of a research study, such as the BISTRO trial.NICE will support this guidance through a range of activities to promote the recommendations for further research (see section\xa07).\n\nThere is currently not enough validation or clinical-outcome data to recommend the routine adoption of the InBody\xa0S10 or the MultiScan\xa05000 to guide fluid management in people with chronic kidney disease having dialysis in the NHS.', 'Clinical need and practice': "# The problem addressed\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of using multiple frequency bioimpedance devices to monitor the hydration status of a person with chronic kidney disease who is having either haemodialysis or peritoneal dialysis treatment.\n\nDialysis is used to replace renal function in people with severe chronic kidney disease, including removing excess fluid from the blood. It is important that a correct volume of fluid is removed; removing too little will result in the person becoming overhydrated and may lead to oedema, increased blood pressure and an increased risk of cardiovascular events. Alternatively, if too much fluid is removed during dialysis the person will become underhydrated, which can result in the loss of residual renal function and an increased incidence of symptoms such as cramps, nausea and dizziness.\n\nIn current practice, the fluid status of a person on dialysis is usually determined by clinical assessment, taking into account clinical features and symptoms that suggest overhydration or underhydration. People who are over or underhydrated are often asymptomatic, so clinical assessment may not identify this. Multiple frequency bioimpedance devices give an objective assessment of a person's fluid status which, when used with clinical assessment, may help make decisions about the amount of fluid to remove in dialysis. Using the devices may help reduce the incidence of overhydration or underhydration and their associated clinical consequences.\n\n# The condition\n\n## Chronic kidney disease and dialysis\n\nChronic kidney disease can be categorised into 5 stages of severity, in accordance with NICE's clinical guideline on chronic kidney disease. If chronic kidney disease progresses to the most severe stage (stage\xa05), kidney failure occurs and renal replacement therapy (transplantation or dialysis) is needed for survival.\n\nDialysis replicates many of the functions of a healthy kidney, for example, filtering waste products and excess water from the blood, and is available in 2 types: haemodialysis and peritoneal dialysis. When used as longer-term renal replacement therapy, dialysis can be delivered in an outpatient setting or at home (see NICE's technology appraisal guidance on home compared with hospital haemodialysis for patients with end-stage renal failure).\n\n# The diagnostic and care pathways\n\n## Management of chronic kidney disease\n\nThe management of chronic kidney disease and renal replacement therapy is described in NICE's guidelines on chronic kidney disease, peritoneal dialysis, anaemia management in chronic kidney disease and hyperphosphatemia management in chronic kidney disease.\n\n## Determining fluid volumes to remove by dialysis\n\nOne of the main aims of dialysis is to remove fluid which builds up because of reduced renal function. Determining the volume of fluid to be removed by dialysis involves identifying a target weight for a person. This is often defined as how much a person should weigh at the end of a haemodialysis session or, for people who have peritoneal dialysis, how much they should weigh in the morning. Comparing a person's current and target weight helps to decide the amount of fluid to be removed during dialysis.\n\nAssessing fluid status to set, or adjust, a person's target dialysis weight is usually based on clinical judgement and identifying symptoms of over or underhydration. Clinical parameters assessed include blood pressure, the presence of oedema, weight and any intradialytic or interdialytic symptoms that could suggest overhydration or underhydration (such as cramps, fatigue or nausea). Identification of a person's first target weight often involves gradually reducing a person's post-dialysis weight over successive dialysis sessions until it is as low as can be tolerated.", 'The diagnostic tests': "The assessment compared 3 intervention devices with 1 comparator.\n\n# The interventions\n\nMultiple frequency bioimpedance devices send small, painless electrical signals through the body by way of electrodes. The electrodes also measure the opposition to the flow of the electric current from body tissues (bioimpedance). Each of the devices included in this assessment are portable and could be used by a healthcare professional in either a clinic or the patient's home. Built-in software uses bioimpedance values to calculate parameters relating to hydration, such as volumes of extracellular, intracellular and total body water. Based on these parameters, multiple frequency bioimpedance devices can also produce estimates of a person's target dialysis weight, using models or algorithms that differ between devices. These outputs should be used with clinical assessment to make decisions about the amount of fluid to be removed during dialysis.\n\n## BCM – Body Composition Monitor (Fresenius Medical Care)\n\nThe BCM – Body Composition Monitor uses bioimpedance spectroscopy and measures bioimpedance across 50\xa0frequencies between 5 and 1,000\xa0kilohertz (kHz). The technology includes a BCM – Body Composition Monitor unit with an output display screen. It is connected by cables to disposable electrodes which are attached to the body. A computer software application is provided for further analysis, and external data storage devices (PatientCards) can be used to transfer outputs from the device to a computer using a card reader.\n\nThe device calculates parameters relating to hydration, such as volumes of extracellular, intracellular and total body water, and the ratio of extracellular to intracellular water volumes. It also estimates fluid overload using 2 physiological models adapted from techniques published by Chamney et al. (2007) and Moissl et al. (2006). This is the estimated volume that a person is above, or below, their predicted normally hydrated volume.\n\n## InBody\xa0S10 (InBody)\n\nThe InBody\xa0S10 model is a multifrequency bioimpedance device that measures bioimpedance across 6\xa0different frequencies (1, 5, 50, 250, 500 and 1,000\xa0kHz). The device consists of an InBody\xa0S10 unit which contains a display monitor. The unit is connected by cables to electrodes which are attached to the body. Two types of electrode can be used with this device: disposable adhesive type electrodes and reusable touch type electrodes which can be clipped to a person's hand and foot. As well as whole body measurements, bioimpedance measurements can also be made in 5 areas of the body; right arm, left arm, trunk, right leg, left leg.\n\nThe device calculates hydration-related outputs including water volumes (extracellular water and intracellular water) and ratio of extracellular to total body water. A suggested standard range of values is given, to help identify people who may be overhydrated or underhydrated. Accompanying software can estimate several suggested dry weight values for use, depending on any complications which may alter extracellular fluid volumes, such as diabetes or hypoalbuminaemia.\n\n## MultiScan\xa05000 (Bodystat)\n\nThe MultiScan\xa05000 uses bioimpedance spectroscopy and measures bioimpedance across 50\xa0frequencies between 5 and 1,000\xa0kHz. The system consists of a bioimpedance spectroscopy hardware unit which is connected by leads to disposable electrodes. Outputs are displayed on a colour touchscreen display. Results for up to 1,000\xa0tests can be stored on the device, with additional data storage available through a Wi-Fi or Bluetooth connection to a computer. A calibrator unit and analytical software are also provided. As well as whole body measurements, bioimpedance can also be measured in different body areas by attaching electrodes in different positions on the body.\n\nThe device calculates hydration-related parameters such as the volumes of total body water and intracellular and extracellular water, as well as the ratio of total body to extracellular water volumes. The device also displays an estimate of the volume of fluid excess or deficit in a person, which is reported as the volume of overhydration in litres. This value is estimated using models based on methods set out in published literature (Chamney et al. 2007; Moissl et al. 2006). The device can also do a bioelectrical impedance vector analysis.\n\n# The comparator\n\n## Clinical assessment\n\nThe comparator is clinical assessment to determine fluid status and set, or adjust, target weights for people with chronic kidney disease who are on dialysis. Clinical assessment may include blood pressure measurements, changes in weight, the presence of oedema, assessment of residual renal function, any pre-existing cardiovascular conditions and also any reported symptoms of overhydration or underhydration (such as dizziness or nausea). There is no generally accepted gold standard for identifying a person's target weight for assessing the accuracy of the comparator or interventions.", 'Evidence': "The diagnostics advisory committee (section\xa09) considered evidence on the use of the BCM – Body Composition Monitor, InBody\xa0S10 and MultiScan\xa05000 to guide fluid management in people with chronic kidney disease having dialysis from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nSix randomised controlled trials (RCTs) met the inclusion criteria for the systematic review, all of which assessed use of the BCM – Body Composition Monitor (Huan-Sheng et al. 2016; Hur et al. 2013; Luo et al. 2011; Onofriescu et al. 2012; Onofriescu et al. 2014; Ponce et al. 2014). Two of these trials (Onofriescu et al. 2012 and Onofriescu et al. 2014) may have reported the same trial or outcomes from an overlapping patient population. The possible effect of this was explored by reporting the meta-analyses with and without Onofriescu et al. (2012). The Cochrane risk of bias tool was used to assess the risk of bias in the included RCTs. One of the RCTs was judged to be at low risk of overall bias (Onofriescu et al. 2012) and 1 was at high risk of bias (Luo et al. 2011). The remaining 4 RCTs did not give enough information to make a judgement on the risk of bias.\n\nThe frequency of BCM – Body Composition Monitor use varied between studies, from twice monthly to every 3\xa0months. All of the RCTs were done outside the UK. Only 1 study included people having peritoneal dialysis (Luo et al. 2011); the remaining studies enrolled people having haemodialysis. Five trials included people aged 18 years or over and the remaining trial did not give the age-related exclusion criteria, but the mean age of participants was 52.4\xa0years (standard deviation 13.1\xa0years; Onofriescu et al. 2012). Other groups excluded from some of these studies were people with limb amputations, pregnant women and people with coronary stents, pacemakers or metallic implants. No RCTs were identified for the InBody\xa0S10 or the MultiScan\xa05000.\n\nEight non-randomised cohort studies, reported in 9 papers, were also included in the systematic review (Castellano et al. 2014; Hoppe et al. 2015; Kim et al. 2012; Kim et al. 2015; Oei et al. 2016; O'Lone et al. 2014; Onofriescu et al. 2015; Santhakumaran et al. 2016; Wizemann et al. 2009), all of which assessed the BCM – Body Composition Monitor device. Studies were included if they involved at least 100\xa0participants. Two of these studies may have overlapping patient populations (1 was reported in both O'Lone et al. 2014 and Santhakumaran et al. 2016, and the other was reported in Oei et al. 2016). All participants included in the non-randomised studies had monitoring using the BCM – Body Composition Monitor.\n\nThe frequency of device use varied widely between studies, from just once in the first week of dialysis to 3 assessments per week. Two studies were done in the UK (reported in O'Lone et al. 2014 and Santhakumaran et al. 2016, and Oei et al. 2016) and none of the studies enrolled paediatric patients. Most of the studies included people having haemodialysis (6\xa0studies) rather than peritoneal dialysis (2\xa0studies). The risk of bias in the non-randomised studies was assessed using the Review Body for Interventional Procedures tool. None of the studies included blinded participants or study personnel, and the characteristics of participants who withdrew from the studies were not reported.\n\n## Evidence on clinical outcomes\n\nThree RCTs reported data on mortality (Onofriescu et al. 2014; Ponce et al. 2014; Huan-Sheng et al. 2016). Use of the BCM – Body Composition Monitor device had no significant effect on mortality rates (pooled hazard ratio 0.69; 95% confidence interval [CI] 0.23 to 2.08; p=0.51) and there was moderate statistical heterogeneity between trials.\n\nThree non-randomised studies had results for the effects of hydration status on mortality in subgroups of participants monitored with the BCM – Body Composition Monitor device. Kim et al. (2015) reported a higher incidence of mortality in overhydrated participants (defined by relative hydration state; odds ratio 2.57; 95% CI 1.08 to 6.13; p=0.033). In O'Lone et al. (2014), absolute overhydration had a significant effect on the risk of mortality (hazard ratio 1.10; 95% CI 1.01 to 1.20; p=0.025) and Wizemann et al. (2009) reported that hydration state was an important predictor of mortality in patients having haemodialysis (adjusted hazard ratio 2.10; 90% CI 1.39 to 3.18; p=0.003).\n\nHuan-Sheng et al. (2016) reported significant differences in intradialytic complications between people monitored with and without the BCM – Body Composition Monitor device. But incidences were not consistently higher in 1 group. For people monitored using BCM – Body Composition Monitor, significantly higher incidences of cramping, chest tightness and headaches were reported. However, significantly lower incidences of complications caused by hypotension during dialysis sessions and skin itching were reported. The difference in the number of patient-reported events of intradialytic fatigue in participants monitored with and without the BCM – Body Composition Monitor was not statistically significant (p=0.7).\n\nHur et al. (2013) reported no significant difference in the frequency of intradialytic events between groups monitored with and without the BCM – Body Composition Monitor device at 12\xa0months (66.6 and 63.9 events per 1,000 dialysis sessions respectively; p=0.4). Similarly, Onofriescu et al. (2014) found no significant difference in the incidence of hypotension or cramps (p=0.6). Ponce et al. (2014) reported no significant difference in the incidence of hypotensive events (defined as a drop in systolic blood pressure during dialysis by at least 30\xa0mm of mercury [Hg] or to below 90\xa0mm\xa0Hg) at 12\xa0months.\n\nOne RCT (Huan-Sheng et al. 2016) reported the incidence of cardiovascular-related events, although this was in combination with the incidence of acute fluid overload events. The incidence rate in people monitored with the BCM – Body Composition Monitor device was significantly lower than the control group (incidence rate ratio 0.50 per patient-year; 95% CI 0.26 to 0.94; p=0.03).\n\nThree non-randomised studies gave the incidence of cardiovascular events among subgroups of people monitored using the BCM – Body Composition Monitor device. Kim et al. (2015) reported no statistically significant difference in the number of cardiovascular events per year between overhydrated and non-overhydrated subgroups as determined by the level of relative overhydration (p=0.13). Onofriescu et al. (2015) also found no statistically significant difference in the incidence of coronary heart disease, peripheral vascular disease, heart failure or stroke between subgroups with lower relative fluid overload (less than 17.4%) and higher relative fluid overload (over 17.4%). Hoppe et al. (2015) reported a non-significant difference in the incidence of acute myocardial infarction and stroke between people who had been having dialysis for a shorter length of time (short dialysis vintage) and people who had been having dialysis for a longer length of time (long dialysis vintage).\n\nNo RCTs gave data on residual renal function, although 2 reported urinary output which could be used as a surrogate measure. Hur et al. (2013) found a significant increase in the proportion of patients with anuria, that is when the kidneys no longer produce urine, and a significant decrease in urine output in patients without anuria in a group monitored using the BCM – Body Composition Monitor device. In the corresponding control group, there was no change in the proportion of patients with anuria and the decrease in urine output seen in patients without anuria was not significant. Luo et al. (2011) reported non-significant decreases in urine volume in groups monitored with and without the BCM – Body Composition Monitor device.\n\n## Evidence on intermediate outcomes\n\nAll 6 included RCTs reported systolic blood pressure measurements. Use of the BCM – Body Composition Monitor device was associated with a significantly lower systolic blood pressure in a meta-analysis (pooled mean difference −3.48\xa0mm\xa0Hg; 95% CI −5.96 to −1.00; p=0.006). When data from Onofriescu et al. (2012) was removed from the meta-analysis, the effect size of BCM – Body Composition Monitor-guided monitoring was reduced and was no longer significant (pooled mean difference −2.46 mm Hg; 95% CI −5.07 to 0.15; p=0.06).\n\nThe external assessment group (EAG) also did a subgroup analysis of systolic blood pressure according to the type of dialysis: peritoneal dialysis (1\xa0RCT) or haemodialysis (5\xa0RCTs). In the haemodialysis subgroup, use of the BCM – Body Composition Monitor device was associated with a significant decrease in systolic blood pressure (pooled mean difference −3.09\xa0mm\xa0Hg; 95% CI −5.88 to −0.31; p=0.03). For patients having peritoneal dialysis, Luo et al. (2011) reported a mean decrease in systolic blood pressure of −6.08\xa0mm\xa0Hg (95% CI −12.57 to 0.41) associated with use of the BCM – Body Composition Monitor device.\n\nFour non-randomised studies gave data on blood pressure among subgroups of people monitored using the BCM – Body Composition Monitor device. No statistically significant differences in blood pressure were seen in the following subgroup comparisons: patients in whom the average overhydration decreased within 6\xa0months compared with those in whom it did not decrease (Castellano et al. 2014), patients who had been having dialysis for a short length of time compared with those who had been having it for longer (Hoppe et al. 2015), and patients with a high relative fluid overload (more than 17.4%) compared with those in whom it was low (less than 17.4%; Onofriescu et al. 2015). Kim et al. (2012) reported that systolic blood pressure was higher in hyperhydrated patients when compared with dehydrated patients (significance not stated).\n\nThree RCTs gave data on carotid-femoral pulse wave velocity as a surrogate for arterial stiffness (Hur et al. 2013; Onofriescu et al. 2012; Onofriescu et al. 2014) and were included in a meta-analysis. Arterial stiffness is thought to be associated with an increased risk of cardiovascular events in the longer term. Pulse wave velocity was significantly reduced in patients who were monitored using the BCM – Body Composition Monitor device and standard clinical assessment compared with standard clinical assessment alone (mean difference −1.53 meters per second [m/s]; 95% CI −3.00 to −0.07; p=0.04). There was high statistical heterogeneity between the studies. If data from Onofriescu et al. (2012) were removed from the meta-analysis, the pooled effect was no longer significant (mean difference −1.18 m/s; 95% CI −3.14 to 0.78; p=0.24).\n\nFive RCTs (Huan-Sheng et al. 2016; Hur et al. 2013; Luo et al. 2011; Onofriescu et al. 2012; Ponce et al. 2014) assessed absolute overhydration; that is, the volume of fluid by which the participants were above their target volume (as assessed by the BCM – Body Composition Monitor device). No data on underhydration were available. A meta-analysis of the mean difference in absolute overhydration volumes showed that absolute overhydration was significantly lower in groups monitored with the BCM – Body Composition Monitor device (mean difference = −0.39 litres, 95% CI −0.62 to −0.15, p=0.001).\n\nThe EAG did a subgroup analysis for absolute overhydration, as assessed by the BCM – Body Composition Monitor device, according to type of dialysis. They compared the pooled effect of using the BCM – Body Composition Monitor device on absolute overhydration in the overall group (all 5\xa0studies) and a subgroup of studies on people having haemodialysis (4 of these studies). A difference in effect between the overall and haemodialysis subgroup was seen, but the EAG stated that this was not large enough to suggest a significant dialysis effect.\n\nFour RCTs had results for relative overhydration (Huan-Sheng et al. 2016; Onofriescu et al. 2012; Onofriescu et al. 2014; Ponce et al. 2014); that is, a person's absolute overhydration volume normalised against their total extracellular body water volume (both volumes assessed by the BCM – Body Composition Monitor device). A meta-analysis of the reported mean differences in the relative overhydration between groups monitored with and without the BCM – Body Composition Monitor device showed that relative overhydration was significantly lower when the BCM – Body Composition Monitor device was used (mean difference = −1.54; 95%CI −3.01 to −0.07; p=0.04).\n\nThree RCTs gave data on hospitalisations. Huan-Sheng et al. (2016) reported that the difference in all-cause hospitalisation in patient groups monitored with and without the BCM – Body Composition Monitor device was not significant (hazard ratio 1.19; 95% CI 0.79 to 1.80). Hur et al. (2013) found that the difference in rates of hospitalisation caused by new cardiovascular events in the control and BCM – Body Composition Monitor monitored groups was not statistically significant. In Ponce et al. (2014), 39.6% of participants in the BCM – Body Composition Monitor monitored group and 31.8% of the standard clinical assessment group were hospitalised at least once.\n\nTwo non-randomised studies gave data on hospitalisation. Kim et al. (2015) found no significant differences in the number of hospital days per event between overhydrated and non-overhydrated groups (as determined by the BCM – Body Composition Monitor device). Onofriescu et al. (2015) found a significantly higher all-cause hospitalisation rate for patients classified as overhydrated when a relative overhydration value of 17.4% was used as a cut-off to define people as overhydrated, but not when a value of 15% was used.\n\nMeasures of left ventricular hypertrophy, and surrogates of this, such as left ventricular mass index, may be associated with longer-term cardiac morbidity. Hur et al. (2013) reported that left ventricular hypertrophy was present at 12\xa0months in 44% of participants monitored using the BCM – Body Composition Monitor device and in 50% of participants monitored using standard clinical assessment alone. This was a non-significant reduction from baseline in both groups (67% and 53% respectively). But there was a statistically significant reduction in left ventricular mass index from baseline in the group monitored using the BCM – Body Composition Monitor device (p<0.001), although not in the group monitored using standard clinical assessment (p=0.9).\n\nTwo non-randomised studies gave data on the use of antihypertensive medication in subgroups of people monitored using the BCM – Body Composition Monitor device. In Castellano et al. (2014), consumption of antihypertensive medication was significantly higher in a subgroup of patients who did not have reduced relative overhydration after 6\xa0months of monitoring. Kim et al. (2012) found no significant difference in medication use between people who were dehydrated or hyperhydrated.\n\n## People under 18 years\n\nThree non-randomised studies that enrolled people under 18 years were identified by the EAG (all of which assessed the BCM – Body Composition Monitor). One of these studies (reported in Zaloszyc et al. and Zaloszyc et al. ) investigated the association between relative hydration status (measured using the BCM – Body Composition Monitor device) and blood pressure in children having dialysis. The study authors concluded that hypertension was not always related to overhydration; and that using bioimpedance spectroscopy could prevent incorrect reduction of a child's target weight to try and reduce hypertension, when it is not caused by excess fluid.\n\n## Ongoing trials\n\nFour ongoing trials that will report outcomes which may be relevant to this assessment were identified. One of these trials, the BioImpedance Spectroscopy to maintain Renal Output (the BISTRO trial), will be UK based. This multi-centre study, funded by the National Institute for Health Research, has a primary outcome of time to anuria (loss of urine output). The study will involve random allocation of participants (adults starting haemodialysis because of chronic kidney disease stage 5) for either regular assessment with a bioimpedance device plus standard treatment or standard treatment alone. Secondary outcomes will include the rate of kidney function reduction, vascular access failure, cardiovascular events, hospital admissions, death and patient-reported outcomes, such as quality of life, dialysis symptoms and functional status (measured at baseline, then every 3\xa0months for up to 24\xa0months). The trial is scheduled to start recruiting in March 2017, with a planned publication date of February 2020.\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nThe EAG did a systematic review to identify existing studies on the cost effectiveness of using multiple frequency bioimpedance devices to monitor the fluid status of people with chronic kidney disease who are on dialysis. No studies reporting full economic evaluations relevant to the scope of this assessment were identified.\n\n## Modelling approach\n\nThe EAG developed a de novo economic model to assess the cost effectiveness of using multiple frequency bioimpedance testing to help guide fluid management decisions in people having dialysis for chronic kidney disease. The model took the perspective of NHS and personal social services.\n\nA Markov model was developed to simulate the effects of monitoring the fluid status of cohorts of people on dialysis, using a multiple frequency bioimpedance device with standard assessment or by standard assessment alone. The model was run as a cohort simulation over a 30‑year time horizon for a 66\xa0year old mixed dialysis population in the base-case analyses. All future costs and benefits included in modelling were discounted at a rate of 3.5% per annum.\n\nIn the model, people started in a stable state on either haemodialysis or peritoneal dialysis and over time could either stay in that state or move to others when events (such as a kidney transplant, cardiovascular event or death) happened. These events could occur in each cycle of the model, which was set as 3\xa0months. The characteristics of the cohort of patients modelled (for example, their age, the proportion of people on haemodialysis or peritoneal dialysis, gender, and incidence of comorbidities) were based on the UK Renal Registry Report (2015). Mortality rates and hospitalisation rates were informed by a combination of European (ERA-EDTA Registry Annual Report 2013) and UK Renal Registry data, and other published sources.\n\nThe model also had an option to allow people in the 'stable' and 'post-CV event' dialysis states to be further classified as either severely overhydrated or normohydrated (based on their relative overhydration). This allowed scenarios to be run in the model in which mortality and hospitalisation rates were increased for dialysis patients who were overhydrated. No 'underhydrated' state was included because of a lack of evidence on the prevalence of underhydration in UK dialysis cohorts, the effect of underhydration on the risk of adverse events and quality of life, and the effectiveness of the BCM – Body Composition Monitor device in reducing the incidence of underhydration.\n\nParameter values used in the model were taken from focused reviews of the literature to identify baseline risks for mortality and hospitalisation, and also sources for cost and utility data, and the clinical-effectiveness review. Several possible outcomes that may be affected by using the BCM – Body Composition Monitor device were not included in base-case modelling because of a lack of evidence. These included changes in quality of life (independent of effects of hospitalisation and cardiovascular events), maintenance of residual renal function and effects on dialysis requirements (number and duration of sessions).\n\nThe clinical-effectiveness review only found data on using the BCM – Body Composition Monitor, therefore only this device has been assessed in base-case analyses. Several scenarios were used to model the effect of BCM – Body Composition Monitor-guided fluid management on baseline model parameters. Direct evidence was only available for the effect of BCM – Body Composition Monitor-guided monitoring on all-cause mortality. Several identified trials also reported the effects of BCM – Body Composition Monitor-guided monitoring on surrogate endpoints, such as pulse wave velocity as a measure of arterial stiffness. The EAG did a further literature search to identify evidence that could be used to link changes in these surrogate endpoints to final health outcomes. Using this linked approach, estimated effects of BCM – Body Composition Monitor-guided monitoring on mortality and non-fatal cardiovascular events were calculated. The EAG also modelled an effect of assuming that BCM – Body Composition Monitor-guided monitoring reduced the proportion of people who were seriously overhydrated (with relative overhydration over 15%). This was applied by classifying people in dialysis states in the model as either severely overhydrated or normohydrated, which allowed mortality and hospitalisation rates to be adjusted upwards for proportions of people in the dialysis cohorts who were estimated to be severely overhydrated. Table\xa01 gives a summary of the relative effects applied to different parameters in the base-case scenario analyses.\n\nScenario\n\nRelative effect on all-cause mortality (HR; 95% CI)\n\nRelative effect on hospitalisation for non-fatal CV (HR; 95% CI)\n\nEffect on blood pressure medication costs (£\xa0mean reduction)\n\nProportional reduction in severe overhydration\n\nScenario\xa01\n\n\n\n(0.23 to 2.08)\n\n\n\n\n\n–\n\nScenario\xa02\n\n\n\n(0.23 to 2.08)\n\n\n\n(0.82 to 1.01)\n\n\n\n–\n\nScenario\xa03\n\n\n\n(0.82 to 1.01)\n\n\n\n(0.82 to 1.01)\n\n\n\n–\n\nScenario\xa04\n\n\n\n(0.82 to 1.01)\n\n\n\n(0.82 to 1.01)\n\n−12.98\n\n–\n\nScenario\xa05\n\n–\n\n–\n\n–\n\n\n\nScenario\xa06\n\n–\n\n–\n\n–\n\n\n\nAbbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio.\n\nThe model incorporates health service costs associated with maintenance dialysis, blood pressure medication, erythropoietin stimulating agents, all-cause inpatient hospitalisation, renal transplantation (including work-up, surgery and follow-up), post-transplantation immunosuppression and outpatient visits. Dialysis costs, per session (haemodialysis) or per day (peritoneal dialysis), were taken from NHS reference costs (2014 to 2015). For haemodialysis, the average cost of £154 per haemodialysis session was calculated based on the cost per type of session, at home or at a unit, weighted by relative incidence. For peritoneal dialysis, the average cost per day of £69 was taken from the NHS reference costs.\n\nCosts of bioimpedance monitoring included in modelling were purchase costs for devices (annuitised over 5\xa0years), maintenance costs, staff costs related to using the device, training costs and device consumable costs (such as electrodes). The costs of the bioimpedance devices are shown in table\xa02.\n\nBioimpedance device\n\nCost\n\nExpected service life\n\nMaintenance cost\n\nEstimated annual cost of device consumables\n\nEstimated annual cost per patient per year (assuming a test every 3 months)\n\nBCM – Body Composition Monitor\n\n£5,750\n\nyears\n\n£250\n\n£13.26 (assuming use of patient cards)\n\n£96.50 (including maintenance contract without parts and labour)\n\nInBody S10\n\n£8,100\n\nyears\n\nNo maintenance costs provided\n\n£2.08 (assuming use of reusable electrodes and cost of results sheets)\n\n£93.03\n\nMultiScan 5000\n\n£7,600\n\nyears\n\n£70 (assuming a replacement set of leads annually)\n\n£4.40\n\n£91.22\n\nHealth state utility values for people on dialysis and post-renal transplant were identified through a focused search of the literature. Two systematic reviews were found that published EQ‑5D data for UK patients (Liem et al. 2008; Wyld et al. 2012). Further searches did not identify any other studies reporting EQ‑5D data for UK patients after 2010 (the end date for searches in the most recent systematic review). Short and longer-term utility multipliers associated with cardiovascular events were calculated based on data from the Health Survey for England (2003 and 2006). Decreases in health state utilities resulting from hospitalisations were taken from the NICE guideline on peritoneal dialysis.\n\n## Base-case results\n\nThe following main assumptions were applied in the base-case analysis:\n\nHydration status was assessed with a bioimpedance device every 3\xa0months and, if needed, people had their target weight modified in line with the results.\n\nAny effect of BCM – Body Composition Monitor-guided monitoring on the length and frequency of dialysis sessions was assumed to be cost neutral.\n\nIn the starting cohort of modelled patients, 87% were having haemodialysis and 13% were having peritoneal dialysis.\n\nThe starting age of the cohort was 66\xa0years.\n\nSurvival on haemodialysis and peritoneal dialysis was assumed to be equivalent, and patients did not switch between dialysis modes.\n\nFixed proportions of the cohort were on a waiting list for transplant, and waited a median of about 3\xa0years, depending on survival. No transplants were done in patients over 75\xa0years.\n\nIt was assumed that 17.6% of all inpatient hospitalisations were because of cardiovascular events.\n\nHealth state utility decrements were applied in the acute period for all hospitalisation events, and ongoing health state utility decrements were also applied after hospitalisation for a cardiovascular event.\n\nEffects of bioimpedance monitoring on all-cause mortality were applied for 10\xa0years in the model.\n\nEffects of bioimpedance monitoring on cardiovascular-related or all-cause hospitalisation were applied over the lifetime of the cohort.\n\nSix base-case scenarios were modelled, each differing in the assumed effects of BCM – Body Composition Monitor-guided monitoring, as described above in table\xa01. Incremental cost-effectiveness ratios (ICERs) were calculated both with and without dialysis costs (table\xa03), because including BCM – Body Composition Monitor-guided monitoring in the model prolonged life expectancy, so dialysis was needed over a longer period which increased dialysis costs.\n\nScenario\n\nIntervention\n\nICER (cost per QALY gained) with dialysis costs\n\nNet monetary benefit with dialysis costs\n\nICER (cost per QALY gained) without dialysis costs\n\nNet monetary benefit without dialysis costs\n\n\n\nStandard assessment\n\n–\n\n−£104,097\n\n–\n\n£7,793\n\n\n\nBCM\n\n£62,532\n\n−£128,366\n\n£16,378\n\n£9,859\n\n\n\nStandard assessment\n\n–\n\n−£104,097\n\n–\n\n£7,793\n\n\n\nBCM\n\n£60,855\n\n−£127,786\n\n£15,435\n\n£10,440\n\n\n\nStandard assessment\n\n–\n\n−£104,097\n\n–\n\n£7,793\n\n\n\nBCM\n\n£59,144\n\n−£109,983\n\n£15,636\n\n£8,449\n\n\n\nStandard assessment\n\n–\n\n−£104,097\n\n–\n\n£7,793\n\n\n\nBCM\n\n£58,721\n\n−£109,919\n\n£15,212\n\n£8,513\n\n\n\nStandard assessment\n\n–\n\n−£106,708\n\n–\n\n£8,285\n\n\n\nBCM\n\n£66,013\n\n−£109,858\n\n£21,206\n\n£8,203\n\n\n\nStandard assessment\n\n–\n\n−£106,708\n\n–\n\n£8,285\n\n\n\nBCM\n\n£64,157\n\n−£110,810\n\n£19,350\n\n£8,346\n\nAbbreviations: BCM, BCM – Body Composition Monitor; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.\n\nCumulative costs per patient monitored with and without the BCM – Body Composition Monitor device in scenario\xa03 were calculated. Costs were higher for BCM – Body Composition Monitor-guided monitoring because people on average lived for longer, with dialysis costs making up most (74%) of the increase in cost.\n\n## Analysis of alternative scenarios\n\nSeveral further scenario analyses, based on varying parameters in the base-case scenario 3 model, were done. Results were generally reported without considering the costs of dialysis (unless otherwise stated) and in relation to the ICER produced in base-case scenario 3 when dialysis costs were excluded (£15,636 per quality-adjusted life year [QALY] gained). The results were as follows:\n\nIncreasing the frequency of BCM – Body Composition Monitor monitoring to every month (from every 3\xa0months) increased the ICER to £19,818 per QALY gained.\n\nApplying the estimated costs associated with monitoring in paediatric centres (which have a lower throughput of patients and so higher estimated costs of bioimpedance monitoring) to the modelled adult population increased the ICER to £20,329 per QALY gained (assuming testing every 3\xa0months). This was increased to £23,647 per QALY gained if testing was assumed to be done every month.\n\nAssuming that BCM – Body Composition Monitor-guided fluid management resulted in a 2% improvement in health state utility over a patient's lifetime reduced the ICER to £11,758 per QALY gained (£44,477 if dialysis costs were included). If this improvement was increased to 5%, the ICER reduced further to £8,570 per QALY gained (£32,418 if dialysis costs were included).\n\nIf BCM – Body Composition Monitor-guided monitoring was assumed to result in a 10% reduction in lifetime dialysis costs, BCM– Body Composition Monitor-guided care dominated standard care (that is, costs less but produces more QALYs). If a 5% reduction in lifetime dialysis costs was assumed, the ICER for BCM – Body Composition Monitor-guided care (including dialysis costs) was £19,759 per QALY gained (compared with £59,144 per QALY gained in the base-case analysis when including dialysis costs).\n\nIf BCM – Body Composition Monitor-guided monitoring was assumed to have no effect on mortality (that is, the effects were only because of changes in the incidence of non-fatal cardiovascular events), the ICER including the cost of dialysis was £21,327 per QALY gained (compared with £59,144 per QALY gained in base-case analysis).\n\nIf BCM – Body Composition Monitor-guided monitoring was assumed to have no effect after 3 years, the ICER for BCM – Body Composition Monitor-guided monitoring increased to £18,324 per QALY gained.\n\nFurther scenario analyses produced little change in the base-case scenario ICERs, with ICER values (not including dialysis costs) of between £9,000 and £19,000 per QALY gained.\n\nNo clinical-effectiveness data were found for the InBody\xa0S10 or MultiScan\xa05000. These devices were therefore not included in base-case cost-effectiveness modelling. But they were included in scenario analyses which assumed that these devices reduced mortality and non-fatal cardiovascular events to the same extent as the BCM – Body Composition Monitor device in scenario 3 (but with different costs). The ICERs produced for these devices were very similar, being between £15,000 and £16,000 per QALY gained.\n\n## Subgroup analyses\n\nSubgroup analysis were also done with the dialysis population grouped by comorbidity status (none or at least 1), dialysis modality (haemodialysis or peritoneal dialysis), starting age of the cohort, whether a person was on a transplant list or not, and whether or not they were chronically overhydrated. No large differences in cost effectiveness by subgroup were identified. ICERs for all subgroups stayed below £16,500 per QALY gained (when dialysis costs were not included), except for people listed for a transplant who had an ICER of £20,297 per QALY gained.\n\n## Sensitivity analyses\n\nOne-way sensitivity analyses were done on model parameters for base-case scenario 3 (both with and without dialysis costs). When dialysis costs were included, adjusting the hazard ratio for all-cause mortality to 1.00 resulted in the most favourable ICER for BCM – Body Composition Monitor-guided monitoring. This was because these people have the same survival as those having standard monitoring, and therefore do not have higher dialysis costs, but do have the benefit of a reduced cardiovascular hospitalisation rate. When dialysis costs are included, ICERs produced by varying model parameters within their specified ranges generally stayed above £30,000 per QALY gained.\n\nWhen dialysis costs were not included, the ICERs stayed sensitive to varying all-cause mortality. But, in this case, the least favourable ICER occurs when the hazard ratio is equal to 1.00.\n\nThe EAG did probabilistic sensitivity analyses for base-case scenarios\xa01, 3 and 4 (both with and without dialysis costs included). Results are shown in table\xa04. The probabilistic ICERs produced for all 3 base-case scenarios were similar to the deterministic ICERs (shown in table\xa03 above). If dialysis costs were included, the probability of BCM – Body Composition Monitor-guided monitoring being cost effective at a maximum acceptable ICER of £20,000 per QALY gained was 26% in scenario 1 and less than 6% in scenarios 3 and 4. If dialysis costs were excluded, BCM – Body Composition Monitor-guided monitoring was 67% to 75% likely to be cost effective at this maximum acceptable ICER in the 3 scenarios. The EAG warned that the uncertainty in the parameters produced by linking the effects of monitoring with the BCM – Body Composition Monitor device on arterial stiffness to mortality and non-fatal cardiovascular events (as in base-case scenarios 3 and 4) may not be fully captured in the probabilistic modelling.\n\nScenario\n\nIntervention\n\nICER (cost per QALY gained) with dialysis costs\n\nProbability of cost effectiveness at £20,000 per QALY gained with dialysis costs\n\nICER (cost per QALY gained) without dialysis costs\n\nProbability of cost effectiveness at £20,000 per QALY gained without dialysis costs\n\n\n\nStandard assessment\n\n–\n\n\n\n–\n\n\n\n\n\nBCM\n\n£63,983\n\n\n\n£16,269\n\n\n\n\n\nStandard assessment\n\n–\n\n\n\n–\n\n\n\n\n\nBCM\n\n£58,396\n\n\n\n£15,579\n\n\n\n\n\nStandard assessment\n\n–\n\n\n\n–\n\n\n\n\n\nBCM\n\n£58,011\n\n\n\n£15,015\n\n\n\nAbbreviations: BCM, BCM – Body Composition Monitor; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.\n\nAs noted in the clinical-effectiveness section, removing the Onofriescu et al. (2012) data from meta-analysis reduced the estimated effect of BCM – Body Composition Monitor-guided monitoring on reducing arterial stiffness. Because the pooled estimate of arterial stiffness was used to estimate the relative treatment effects of the BCM – Body Composition Monitor in modelling (in base-case scenarios\xa02, 3 and 4), a revised cost-effectiveness analyses was done with BCM – Body Composition Monitor-guided modelling assumed to have a smaller and more uncertain effect on hospitalisation for cardiovascular events and mortality. Similar ICERs were produced for revised base-case scenarios\xa02, 3 and 4 and also for most of the further revised sensitivity, subgroup and scenario analyses. But there was greater uncertainty about the cost-effectiveness results in the revised probabilistic analyses. When dialysis costs were included, the probability of BCM – Body Composition Monitor being cost effective increased from less than 6% to about 13% for scenarios\xa03 and 4. When dialysis costs were excluded, the probability of BCM – Body Composition Monitor being cost effective decreased for revised scenarios\xa03 and 4 (from about 72% to about 62%). This reflected the greater uncertainty in the effect of BCM – Body Composition Monitor-guided monitoring on reducing arterial stiffness, and so the linked effect on all-cause mortality and hospitalisation for cardiovascular events.", 'Committee discussion': "The committee discussed current practice in the NHS for monitoring the fluid status of people with chronic kidney disease who are having dialysis. It heard from clinical experts that target weights are set to determine how much fluid should be removed during a dialysis session. A person's target weight is usually set and adjusted based on clinical assessment, which takes into account the person's clinical history and any reported symptoms that may suggest fluid overload or dehydration. It heard that there is currently no standardised approach to clinical assessment of fluid status and that there is variation both in how it is done and also the frequency with which it occurs. The committee concluded that current practice for monitoring fluid status in people having dialysis is highly subjective and results in variation in practice both in and between centres.\n\nThe committee discussed the effect of fluid imbalances on the quality of life of a person having dialysis. It heard from a patient expert that the consequences of fluid overload can include oedema and difficulty breathing. In contrast, removing too much fluid during haemodialysis can lead to painful muscle cramps and hypotension, which can cause a person to faint during or shortly after dialysis sessions. It can also cause more prolonged side effects such as headaches and fatigue after a haemodialysis session. The committee heard from clinical experts that in the shorter term, fluid overload can result in hypertension whereas dehydration can lead to hypotension and decreased blood flow to organs, such as the heart and brain. The longer-term consequences of persistent or intermittent fluid overload and dehydration in adults can include cognitive decline, reduced residual renal function and major adverse cardiovascular events. In children, who often have dialysis as a bridge to a renal transplant, it may contribute to developmental delay and increase their risk of adverse cardiovascular events in later life, particularly if they go on to have dialysis as an adult after transplant failure. The committee concluded that technologies that aim to provide a more objective assessment of fluid status in people having dialysis may be a way of improving the quality of life for this population.\n\n# Clinical effectiveness\n\nThe committee reviewed the available evidence on the clinical effectiveness of using multiple frequency bioimpedance devices to guide fluid management in people with chronic kidney disease having dialysis. It noted that in total, 14\xa0studies were included in the review, 6 of which were randomised controlled trials (RCTs). All of the studies reported data for the BCM – Body Composition Monitor device only, and 5 of the RCTs were noted to be at a high or uncertain risk of bias. No studies reported data for the InBody\xa0S10 or MultiScan\xa05000. The committee heard from clinical experts that the devices use different models to calculate how overhydrated or underhydrated a person is. Also, no data were available to determine the equivalence of fluid overload or target weight calculated by these devices and values calculated by the BCM – Body Composition Monitor; therefore clinical-outcome data from studies with the BCM – Body Composition Monitor could not be considered applicable to the other devices. The committee noted that without device-specific or equivalence data, the InBody\xa0S10 or MultiScan\xa05000 could not be considered further in this assessment.\n\nThe committee discussed the generalisability of data from the included studies to the NHS. It noted that none of the RCTs and 2 of the non-randomised studies (reported in 3\xa0papers) were done in the UK. The committee heard from clinical experts that current practice varies widely between countries, particularly on whether fluid status is assessed by nursing or medical staff and how frequently assessments are done. It also noted that many of the studies did not give enough details to determine how standard clinical assessment was done, making it difficult to determine whether they were representative of UK practice. The committee therefore concluded that the effect estimates reported by the included studies may not be generalisable to clinical practice in England.\n\nThe committee discussed the evidence available on the effect of BCM – Body Composition Monitor-guided monitoring on mortality. The committee noted that the pooled-effect estimate (pooled hazard ratio 0.69; 95% confidence interval [CI] 0.23 to 2.08; p=0.51) of BCM – Body Composition Monitor-guided monitoring on mortality was not significant. It noted that the total number of mortality events in the 3 included studies was small (42\xa0events) and that the methods used for randomisation were not adequate. It heard from clinical experts that these studies were not powered to show an effect on mortality because this is not the main aim of using the BCM device to guide fluid management. The committee concluded that there is likely to be substantial bias underlying the meta-analysis of mortality data and so there is great uncertainty about the pooled-effect estimate.\n\nThe committee discussed the effect of BCM – Body Composition Monitor-guided monitoring on intermediate outcomes such as blood pressure control and arterial stiffness. The committee noted that 3\xa0RCTs reported data on arterial stiffness measured by pulse wave velocity and questioned the methods used to get the data. It heard from clinical experts that measurements of pulse wave velocity in these studies were carotid-femoral pulse wave velocity, which is not considered an appropriate surrogate for cardiac morbidity. The committee also noted that 2 of the studies included in the meta-analyses for blood pressure and arterial stiffness (Onofriescu et al. 2012 and 2014) seemed to have overlapping patient populations. When both of these studies are included in the meta-analyses, BCM– Body Composition Monitor-guided monitoring results in a statistically significant improvement in blood pressure (p=0.006) and arterial stiffness (p=0.04). If Onofriescu et al. (2012) is removed the effect is no longer statistically significant. The committee concluded that there was substantial uncertainty around the effect of BCM – Body Composition Monitor-guided monitoring on reducing arterial stiffness and blood pressure, and so on cardiovascular outcomes.\n\nThe committee considered the data available on the effect of BCM – Body Composition Monitor-guided monitoring on patient-reported adverse effects associated with dialysis. It noted that data from identified studies did not show a clear benefit to using the device. A patient expert commented that since their fluid levels had been monitored using the BCM – Body Composition Monitor device, they had experienced fewer side effects associated with fluid imbalance, and that if they have symptoms possibly related to dialysis a reading with the device can be used to check if they are because of fluid levels. The committee concluded that there is considerable uncertainty about the effect of BCM – Body Composition Monitor-guided monitoring on reducing the number of patient-reported adverse effects associated with fluid imbalance and dialysis.\n\nThe committee noted that the studies included reported data on the effect of fluid overload, but did not consider the effect of underhydration. It heard from a clinical expert that the BCM – Body Composition Monitor device may identify people, who have previously been identified as normally hydrated by clinical assessment, as underhydrated. Underhydration can lead to clotting in dialysis fistulas, muscle cramps and nausea. It heard that identifying people who are underhydrated, or preventing underhydration, could help to preserve residual renal function in people having dialysis. The committee concluded that more data is needed in this subgroup and noted that this will be collected in the National Institute for Health Research (NIHR) funded BISTRO trial (see section 5.17).\n\nThe committee discussed the likely effect of BCM – Body Composition Monitor-guided monitoring on peritoneal dialysis. The committee noted that most of the studies included in the clinical-effectiveness analyses reported data for haemodialysis. Only 1\xa0RCT assessed use of the BCM – Body Composition Monitor device in people having peritoneal dialysis, and reported that BCM – Body Composition Monitor-guided monitoring reduced systolic blood pressure (mean difference −6.08\xa0mm\xa0Hg; 95% CI −12.57 to 0.41) and absolute overhydration (−0.80 litres; 95% CI −1.32 to −0.28). The committee questioned whether BCM – Body Composition Monitor-guided monitoring could be expected to have a similar effect in both types of dialysis. The committee heard from clinical experts that the effect of BCM – Body Composition Monitor-guided monitoring for people on haemodialysis will not necessarily be the same for people having peritoneal dialysis because the pattern of fluid accumulation which occurs between sessions may be more pronounced with haemodialysis, which is done less often. Also, peritoneal dialysis may preserve residual renal function for longer, so any effect on this outcome could be more pronounced. The committee therefore concluded that there are insufficient data to determine the clinical effectiveness of BCM – Body Composition Monitor-guided monitoring for people having peritoneal dialysis.\n\nThe committee discussed the clinical effectiveness of BCM – Body Composition Monitor-guided monitoring in people under 18\xa0years (that is, babies, children and young people). It noted that none of the identified studies assessed the use of the device in this group. The committee heard from clinical experts that because of physiological differences, and differences in comorbidities, between adults and babies, young people and children, the available data in adults cannot be considered applicable. It heard from clinical experts that a higher proportion of children who have dialysis have peritoneal dialysis rather than haemodialysis. The committee noted that any benefits or negative effects associated with managing fluids in children could influence outcomes and future treatments when they are adults, and so it is plausible that the effects of the BCM – Body Composition Monitor device may be greater in this population. The committee concluded that more data are needed on the clinical effectiveness of BCM – Body Composition Monitor-guided monitoring for people under 18\xa0years having both haemodialysis and peritoneal dialysis.\n\n# Cost effectiveness\n\nThe committee considered the results of the cost-effectiveness analyses for BCM – Body Composition Monitor-guided fluid monitoring. It noted that several scenarios had been modelled to investigate the uncertainties in estimates of effect on mortality and hospitalisation events that had been identified in the clinical-effectiveness review. The committee heard that the model was based on data from UK and European renal registries, supplemented with data from the clinical-effectiveness review. It heard from clinical experts that the baseline population risk data and clinical-effectiveness data reflected outcomes for adults only and concluded that the results of the cost-effectiveness analyses could not be considered applicable to children.\n\nThe committee questioned the impact of excluding the effect of prolonged underhydration, and related outcomes, from the model. It heard from the external assessment group that they had not been able to identify appropriate data sources for the prevalence of prolonged underhydration or its effect on mortality and hospitalisation rates. Also, data were not available to include an effect of BCM – Body Composition Monitor-guided monitoring on the incidence of prolonged underhydration or on the maintenance of residual renal function in the model. Clinical experts noted that this could either over- or underestimate the benefits of using the BCM – Body Composition Monitor, depending on whether its use increased or decreased the occurrence of prolonged underhydration. The committee concluded that the effect of BCM – Body Composition Monitor-guided monitoring on the incidence of prolonged underhydration, and associated outcomes such as residual renal function, is likely to be an important factor in assessing the cost effectiveness of the device and that, because of an absence of data, this has not been captured in the analyses.\n\nThe committee discussed the use of quality-of-life data in the model. It noted that the base-case model did not include an effect of BCM – Body Composition Monitor monitoring on quality of life, beyond its assumed effect on reducing mortality and hospitalisation events. The committee heard from clinical and patient experts that if using the BCM – Body Composition Monitor improved fluid management there would be reductions in dialysis-related side effects and improved recovery after dialysis, which would be of substantial benefit to patients. The committee concluded that, because of an absence of data, the effect of BCM – Body Composition Monitor-guided fluid management on quality of life had not been captured in the analyses.\n\nThe committee discussed the mortality estimates included in the model. It noted that the pooled-effect estimate from the clinical-effectiveness review showed no significant effect on this outcome (see section 5.5), but that BCM – Body Composition Monitor-guided monitoring was assumed to increase survival in the base-case scenarios. The committee considered that, based on the available evidence, it is uncertain whether BCM – Body Composition Monitor-guided monitoring has any effect on mortality. It also questioned whether this uncertainty had been captured in probabilistic analyses. The committee determined that the most plausible scenario modelled is further scenario 17, which assumes no difference in mortality between BCM – Body Composition Monitor-guided monitoring and clinical assessment alone. This scenario produced an incremental cost-effectiveness ratio (ICER) of about £20,000 per quality-adjusted life year (QALY) gained. The committee noted that this scenario results in very small QALY gains and so its ICER is sensitive to small changes in the non-fatal cardiovascular-event rate. Decreasing the effect of BCM – Body Composition Monitor-guided monitoring on this parameter by a small amount (changing the applied hazard ratio from 0.91 to 0.93) increased the ICER to over £40,000 per QALY. The committee concluded that the results of further scenario analysis 17 were the most plausible, but that there was considerable uncertainty about the results of this analysis, and whether they show that BCM – Body Composition Monitor-guided monitoring is a cost-effective intervention based on a reduction in cardiovascular-event rates alone.\n\nThe committee discussed the effect of including dialysis costs in the model. It noted that 2 sets of ICERs had been calculated, one with and one without dialysis costs. It noted that when dialysis costs are included, BCM – Body Composition Monitor-guided monitoring is unlikely to be considered cost effective, even if the device is provided at no cost. When dialysis costs are excluded the ICERs generally drop below £20,000 per QALY gained. The committee noted that despite the high costs of dialysis, these results were largely driven by the assumption that BCM – Body Composition Monitor-guided monitoring increases survival and therefore the duration of dialysis treatment. For scenarios which include a survival benefit, the committee concluded that it would be appropriate to exclude costs related to the extended period of survival because dialysis has been generally available in the health service for a long time and it has therefore already been accepted that the benefits gained by providing dialysis outweigh the cost of delivering the intervention.\n\nThe committee discussed the level of uncertainty in both the clinical- and cost-effectiveness analyses. It noted that there was considerable uncertainty about the effectiveness of BCM – Body Composition Monitor-guided monitoring to reduce the incidence of adverse outcomes, such as cardiovascular events. Also, no data were available for potentially important outcomes, such as residual renal function. Because of this uncertainty in clinical effectiveness, there was insufficient evidence to determine the cost effectiveness of the BCM – Body Composition Monitor at present with any certainty. However, the committee noted that exploratory cost-effectiveness analyses done for the BCM – Body Composition Monitor device suggested that it could be cost effective, although this was sensitive to small changes in the estimated effect of BCM – Body Composition Monitor-guided monitoring. The committee concluded that there was too much uncertainty at present to recommend the BCM – Body Composition Monitor for routine use, but wished to encourage further research (see section\xa06).\n\n# Research considerations\n\nThe committee considered ongoing research on the clinical effectiveness of multiple frequency bioimpedance devices. It noted that the multi-centre, UK-based BISTRO RCT funded by the NIHR and designed to assess the effectiveness of the BCM – Body Composition Monitor device for monitoring people over 18\xa0years on haemodialysis, will begin recruitment in 2017. The trial is scheduled to report in 2020. The committee heard from clinical experts that the primary outcome will be loss of renal function and noted that the effect of BCM – Body Composition Monitor-guided monitoring on this outcome had not been included in cost-effectiveness analyses because of a lack of data (see section\xa05.12). The committee concluded that the BISTRO study is highly relevant to this assessment and data from this ongoing study are therefore likely to be important when the guidance is considered for updating in the future.\n\nThe committee noted that BCM – Body Composition Monitor-guided monitoring is routinely used alongside standard clinical assessment in about 25% of UK dialysis services for people with chronic kidney disease having dialysis. It heard from clinical experts that these centres have developed experience of the benefits and limitations of using the BCM – Body Composition Monitor device to help manage dialysis-related symptoms associated with fluid imbalance. The committee encouraged centres currently using the BCM – Body Composition Monitor device to continue using it and participate in relevant data collection and research.\n\nThe committee considered the feasibility of further research on the clinical effectiveness of BCM – Body Composition Monitor-guided fluid management in babies, children and young people having dialysis. It heard from clinical experts that this age group makes up less than 1% of the total population of people on dialysis, and that people in this group typically stay on dialysis for a relatively short period of time, until they have a renal transplant. Therefore multi-centre studies are likely to be needed to recruit enough participants to show an effect on clinical outcomes. In the shorter term, the committee wished to encourage paediatric renal services to collect and publish data on cognitive function and quality of life in patients having BCM– Body Composition Monitor-guided fluid management.\n\nThe committee noted that there were no data to determine the clinical effectiveness of the InBody\xa0S10 or MultiScan\xa05000 devices for guiding fluid management in people with chronic kidney disease who are having dialysis. The committee wished to encourage the companies to collect and publish data on both the validity of their device's underlying fluid model to calculate fluid overload and its associated clinical outcomes. The committee further noted the importance of validating the accuracy of all the multiple frequency bioimpedance devices included in this assessment for people with amputations, people for whom recommended electrode configurations cannot be used and people who are unable to assume recommended positioning for measurements to be made. Also, validation data may be important for people with extremes of body composition, and across different ethnicities, because normal ranges of lean or adipose tissue body composition may differ between ethnicities. It wished to encourage the publication of data on the validity of multiple frequency bioimpedance devices to calculate fluid overload and target weight in these groups.", 'Recommendations for further research': 'The committee recommended further research into the clinical effectiveness of BCM – Body Composition Monitor-guided fluid management in people with chronic kidney disease having dialysis. It noted that the ongoing BISTRO study will assess the effect of the device in people aged 18\xa0years or over having haemodialysis. Further research should collect clinical-outcome data in the following populations:\n\nadults (aged 18\xa0years and over) having peritoneal dialysis\n\nbabies, children and young people (aged under 18\xa0years) having haemodialysis\n\nbabies, children and young people (aged under 18\xa0years) having peritoneal dialysis.\n\nThe committee recommended that data on the effect of BCM – Body Composition Monitor-guided monitoring on health-related quality of life is collected and published. Prospective within-patient studies, which record quality of life and symptoms before and after having BCM – Body Composition Monitor-guided fluid management should be considered.', 'Review': 'NICE reviews the evidence 3\xa0years after publication to ensure that any relevant new evidence is identified. However, NICE may review and update the guidance at any time if significant new evidence becomes available.Andrew DillonChief ExecutiveJune 2017'}	https://www.nice.org.uk/guidance/dg29	Evidence-based recommendations on multiple frequency bioimpedance devices to guide fluid management in people with chronic kidney disease having dialysis.
ecd5e8e56a8400e59c041274f2f1f5fb16643688	nice	Obesity: working with local communities	Obesity: working with local communities This guideline covers how local communities, with support from local organisations and networks, can help prevent people from becoming overweight or obese or help them lose weight. It aims to support sustainable and community-wide action to achieve this. # Introduction: scope and purpose of this guidance # What is this guidance about? This guidance aims to support effective, sustainable and community-wide action to prevent overweight and obesity in adults and overweight and obesity in children. It sets out how local communities, with support from local organisations and networks, can achieve this. The recommendations cover: developing a sustainable, community-wide approach to obesity strategic leadership supporting leadership at all levels coordinating local action communication involving the community integrated commissioning involving businesses and social enterprises operating in the local area local authorities and the NHS as exemplars of good practice planning systems for monitoring and evaluation implementing monitoring and evaluation functions cost effectiveness -rganisational development and training scrutiny and accountability. This guidance focuses on the prevention of overweight and obesity. The recommendations may also help people who are already overweight or obese to lose weight, or to prevent them from gaining further weight. It does not cover clinical management for people who are already overweight or obese. A 'sustainable, community-wide approach' to prevent obesity involves a set of integrated services and actions delivered by the many organisations, community services and networks that make up the local system. For the purpose of this guidance, 'local community' refers to a group of people from the same geographic location that is not necessarily related to any official, administrative boundary. The community may be located in a ward, borough, region or city. This guidance does not cover interventions in a particular setting (such as a school or workplace) that do not involve the wider community. The guidance has a strong focus on local partnership working. For the purpose of this guidance, a partner could be a local department, service, organisation, network, community group or individual that could help prevent obesity. # Who is this guidance for? This guidance is for local policy makers, commissioners, managers, practitioners and other professionals working in local authorities, the NHS and the wider public, private, voluntary and community sectors. It is particularly aimed at: local authority chief executive officers executive directors of local authority services (such as directors of children's or adult's services and directors of planning or leisure services) directors of public health, members of health and wellbeing boards elected members (particularly council leaders, including cabinet leads for health) community champions. The recommendations will also be of interest to academic organisations involved in designing and evaluating community-wide interventions to prevent and manage obesity, as well as members of the public. # Why is this guidance being produced? This guidance focuses on an overarching approach to obesity in local communities and the importance of integrating action on obesity in other local agendas (such as initiatives to prevent type 2 diabetes, cardiovascular disease and cancers, or initiatives to improve the environment and promote sustainability). The guidance will support the government's call for action on obesity and the public health outcomes framework. It provides an organisational framework for existing NICE guidance (community-based or individual interventions) that directly or indirectly impacts on obesity prevention or management. The ongoing structural changes to the public sector, particularly local authorities and the NHS, have influenced the direction and tone of the recommendations. This guidance is intended to support organisations that have a role in obesity prevention in the wider public health agenda, including Public Health England, the National Commissioning Board, local authorities, local Healthwatch, local health and wellbeing boards and clinical commissioning groups.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The guidance complements, but does not replace, NICE's other guidance on obesity. The Programme Development Group (PDG) considers that the recommended approaches are cost effective. The evidence statements underpinning the recommendations are listed in appendix C. For the gaps in research, see appendix D. See also the evidence reviews, supporting evidence statements and economic modelling report. # Guiding principles The recommendations should be undertaken in parallel, wherever possible as part of a system-wide approach to preventing obesity. Ideally, to be as cost effective as possible, they should be implemented as part of integrated programmes that address the whole population, but with a scale and intensity that is proportionate to addressing locally identified inequalities in obesity and associated diseases and conditions. The guidance provides a framework for existing NICE guidance (community based or individual interventions) that directly or indirectly impacts on obesity prevention or management. Other NICE guidance can also be used to ensure effective delivery of the recommendations made in this guidance (see below). ## Community engagement The prerequisites for effective community engagement are covered in NICE's guideline on community engagement. ## Behaviour change The prerequisites for effective interventions and programmes aimed at changing behaviour are covered in NICE's guideline on behaviour change: general approaches. In summary, NICE recommends that interventions and programmes should be based on: careful planning, taking into account the local and national context and working in partnership with recipients a sound knowledge of community needs existing skills and resources, by identifying and building on the strengths of individuals and communities and the relationships within communities. In addition, interventions and programmes should be evaluated, either locally or as part of a larger project, and practitioners should be equipped with the necessary competencies and skills to support behaviour change. This includes knowing how to use evidence-based tools. (NICE recommends that courses for practitioners should be based on theoretically informed, evidence-based best practice.) ## Cultural appropriateness The prerequisites for culturally appropriate action are outlined in NICE's guideline on type 2 diabetes prevention: population and community interventions. The guidance emphasises that culturally appropriate action takes account of the community's cultural or religious beliefs and language and literacy skills by: Using community resources to improve awareness of, and increase access to, interventions. For example, they involve community organisations and leaders early on in the development stage, use media, plan events or make use of festivals specific to black and minority ethnic groups. Understanding the target community and the messages that resonate with them. Identifying and addressing barriers to access and participation, for example, by keeping costs low to ensure affordability, and by taking account of different working patterns and education levels. Developing communication strategies that are sensitive to language use and information requirements. For example, they involve staff who can speak the languages used by the community. In addition, they may provide information in different languages and for varying levels of literacy (for example, by using colour-coded visual aids and the spoken rather than the written word). Taking account of cultural or religious values, for example, the need for separate physical activity sessions for men and women, or in relation to body image, or beliefs and practices about hospitality and food. They also take account of religious and cultural practices that may mean certain times of the year, days of the week, settings, or timings are not suitable for community events or interventions. In addition, they provide opportunities to discuss how interventions would work in the context of people's lives. Considering how closely aligned people are to their ethnic group or religion and whether they are exposed to influences from both the mainstream and their community in relation to diet and physical activity. # Whose health will benefit from these recommendations? Everyone in a locally defined community but, in particular, vulnerable groups and communities where there is a high percentage of people who are at risk of excess weight gain or who are already overweight or obese (this includes those from particular ethnic or socioeconomic groups, those who are less likely to access services, people with mental health problems, a learning or physical disability). For more information, see the section on public health need and practice). # Recommendation 1 Developing a sustainable, community-wide approach to obesity ## Who should take action? Council leaders and elected members. Local authority chief executive officers. Health and wellbeing boards. Directors of public health. Executive directors of local authority services. Local NHS trusts. Local Healthwatch. Leaders of local voluntary and community organisations. Clinical commissioning groups. Local education and training boards. ## What action should they take? All of the above should ensure, through the health and wellbeing board, a coherent, community-wide, multi-agency approach is in place to address obesity prevention and management. Activities should be integrated within the joint health and wellbeing strategy and broader regeneration and environmental strategies. Action should also be aligned with other disease-specific prevention and health improvement strategies such as initiatives to prevent type 2 diabetes, cancers and cardiovascular disease, as well as broader initiatives, such as those to promote good maternal and child nutrition or mental health or prevent harmful drinking. (See NICE's guidelines on type 2 diabetes prevention: population and community interventions, cardiovascular disease prevention, maternal and child nutrition, and alcohol use disorders: prevention.) Health and wellbeing boards, supported by directors of public health, should ensure joint strategic needs assessments (JSNAs) address the prevention and management of obesity. They should ensure JSNAs: consider the full range of factors that may influence weight, such as access to food and drinks that contribute to a healthy and balanced diet, or opportunities to use more physically active modes of travel consider inequalities and the social determinants of obesity consider local evidence on obesity (such as data from the National Child Measurement Programme). Health and wellbeing boards should ensure tackling obesity is one of the strategic priorities of the joint health and wellbeing strategy (based on needs identified in JSNAs). Health and wellbeing boards and local authority chief executive officers should encourage partners to provide funding and other resources for activities that make it as easy as possible for people to achieve and maintain a healthy weight. This includes, for example, activities to improve local recreation opportunities, community safety or access to food that can contribute to a healthier diet. Partners should be encouraged to provide funding and resources beyond one financial or political cycle and have clear plans for sustainability. Health and wellbeing boards should work in partnership with local clinical commissioning groups to ensure a coherent approach to tackling obesity that spans both prevention and treatment. Health and wellbeing boards should work with partners to optimise the positive impact (and mitigate any adverse impacts) of local policies on obesity levels. This includes strategies and policies that may have an indirect impact, for example, those favouring car use over other modes of transport, or decisions to remove park wardens, that affect people's use of parks. Health and wellbeing boards, through their performance infrastructure, should regularly (for example, annually) assess local partners' work to tackle obesity (taking account of any relevant evidence from monitoring and evaluation). In particular, they should ensure clinical commissioning group operational plans support the obesity agenda within the health and wellbeing strategy. # Recommendation 2 Strategic leadership ## Who should take action? Directors of public health and public health teams. Chairs of local health and wellbeing boards. Executive directors of local authority services. Council leaders and elected members. Leaders of local voluntary and community organisations. Clinical commissioning group leads for obesity (where they exist). Clinical commissioning representatives on local health and wellbeing boards. Local education and training boards. ## What action should they take? All of the above should provide visible, strategic leadership to tackle obesity at all levels and ensure an effective team is in place. Directors of public health and public health teams should ensure all those responsible for activity that impacts on obesity understand the needs and priorities of the local community, as outlined in JSNAs. They should ensure all partners understand JSNA priorities and be prepared to decommission services, if necessary, to divert resources to priority areas. Local authority chief executive officers and directors of public health should: regularly brief elected members on the local prevalence of obesity, the health risks and the local factors that may have an impact help elected members identify what they can do to ensure obesity prevention is integrated across the breadth of council strategies and plans. Directors of public health should seek to secure high-level commitment to long-term, integrated action on obesity, as part of the joint health and wellbeing strategy. This includes: local indicators and targets being established collaboratively with all partners ensuring the strategy defines long-term goals and also includes short and intermediate measures cross-sector and two-tier (as appropriate) coordination and communication between transport, planning and leisure services at strategic level and better involvement of local communities in each of these policy areas ensuring performance management focuses on processes that support effective partnership working as well as measuring outputs and outcomes ensuring the strategy on obesity is reviewed regularly (for example, every 3 to 5 years), based on needs identified in JSNAs and mapping of local assets. Leaders of local voluntary and community organisations should ensure the local approach to obesity: fully engages and addresses marginalised groups at particular risk of obesity addresses inequalities in obesity and associated diseases. All clinical commissioning groups should be encouraged to identify an obesity or public health lead to work with the public health team on joint approaches to tackling obesity. # Recommendation 3 Supporting leadership at all levels ## Who should take action? Directors of public health and public health teams. Health and wellbeing board chairs. Clinical commissioning groups. Executive directors of local authority services. Council leaders and elected members. Chief executive officer of the local education and training board. ## What action should they take? Public health teams should identify and work with 'champions' who have a particular interest or role in preventing obesity in local authority and NHS strategy groups and public, private, community and voluntary sector bodies. This includes, for example, those involved in planning, transport, education and regeneration. All of the above should work to build and support a network of leaders from all organisations and partnerships that could make a contribution to preventing obesity. This should include relevant local authority and NHS services, voluntary and community organisations and the private sector. Directors of public health should support leaders at all levels (including senior and middle managers and frontline staff) of all the partnerships involved in local action on obesity, to ensure local people and organisations are empowered to take action. This means: providing regular opportunities for partners to meet and share learning in both formal meetings and informal, open environments, as appropriate addressing any overlapping, fragmented or competing agendas among different partners and considering options to enhance cooperation and joint working (options might include workshops or away days) funding small-scale community-led projects such as local gardening, cooking and walking groups; and exploring how such initiatives can contribute to defined long-term goals and can be evaluated in a proportionate way fostering a 'learning culture' by explicitly supporting monitoring and evaluation, especially for innovative interventions, and allowing partnerships to build on effective action and change or discard less effective solutions (see recommendations 10 and 11). # Recommendation 4 Coordinating local action ## Who should take action? Health and wellbeing boards. Executive directors of local authority services. Directors of public health and public health teams. Community-based health workers, volunteers, groups or networks. Community engagement workers such as health trainers. ## What action should they take? Local authority chief executive officers should ensure there is an effective public health team in place to develop a coordinated approach to the prevention of obesity. This should include: a director or lead public health consultant to provide strategic direction a senior coordinator who has dedicated time to support the director or consultant in their work on obesity and oversee the local programme. The coordinator should have: specialist expertise in obesity prevention and community engagement the skills and experience to work across organisational boundaries community 'health champions' (volunteering with community or voluntary organisations) and other people who work directly with the community (such as health trainers and community engagement teams) to encourage local participation and support delivery of the programme. Coordinators should advise commissioners on contracts that support the local obesity agenda to ensure a 'joined-up' approach. They should encourage commissioners to promote better integration between providers through the use of joint contracts and supply chain models that provide a range of local options. The aim is to tackle the wider determinants of obesity and support local people to make changes in their behaviour to prevent obesity. Directors of public health should ensure coordinators engage frontline staff (such as health visitors, environmental health officers and neighbourhood wardens) who can contribute to local action on obesity. Directors of public health should ensure frontline staff set aside dedicated time to deliver specific aspects of the obesity agenda and receive training to improve their understanding of the needs of the local community and improve their practical implementation skills. Coordinators and community engagement workers (such as health trainers and community development teams) should work together to develop and maintain a map of local people and assets that could support a community-wide approach to combating obesity. This includes: community-based health workers such as health visitors, community pharmacists or weight management group leaders existing networks of volunteers and 'champions', health trainers and community organisations such as religious groups, sports clubs, school governors or parent groups people working in the community, such as the police, park wardens, leisure centre staff, active travel coordinators, school crossing patrol officers or school and workplace canteen staff physical activity organisations and networks such as county sport physical activity partnerships unused open spaces or meeting places that could be used for community-based events and courses. Coordinators and community engagement workers should jointly plan how they will work with population groups, or in geographic areas, with high levels of obesity. Plans should consider the motivations and characteristics of the target groups, in relation to obesity. Coordinators should also map where public, private, community and voluntary organisations are already working in partnership to improve health or on other relevant issues. Coordinators, supported by the director of public health, should encourage and support partnership working at both strategic and operational levels. They should ensure partner organisations are clear about their contribution and responsibilities. They should consider asking them to sign an agreement that pledges specific relevant actions in the short and long term. # Recommendation 5 Communication ## Who should take action? Directors of public health and public health teams. Local government and NHS communications leads. ## What action should they take? Directors of public health and local government communications leads should ensure elected members and all management and staff working with local communities, both within and across partner organisations, are aware of the importance of preventing and managing obesity. The commitment of middle managers and those with a strategic role is particularly important. For example, they should: be aware of, and committed to, the obesity agenda in the health and wellbeing strategy be aware of the impact of obesity on other priorities (for example, the rising local incidence of type 2 diabetes, due to obesity). Local government communications leads should ensure obesity prevention programmes are highly visible and easily recognisable. Recognition may be increased – and costs kept to a minimum – by adapting a widely known brand for use locally (such as NHS healthier families). Where appropriate, branding should be agreed by elected members and the health and wellbeing board. Communications leads should ensure partners have shared vision, speak with 'a common voice' and are clearly identifiable to the community. This can be fostered by promoting all relevant activities under the obesity programme 'brand' and using this branding consistently over the long term. Health and wellbeing board chairs and executive directors of local authority services should advocate for action on obesity in any discussions with partners or the local media. Directors of public health and local government communications leads should carefully consider the type of language and media to use to communicate about obesity, tailoring language to the situation or intended audience. Local insight may be particularly important when developing communications to subgroups within a community or specific at-risk groups. For example, in communications to some local communities, it might be better to refer to a 'healthier weight' rather than 'preventing obesity', and to talk more generally about health and wellbeing or specific community issues. Making explicit the relevance of a wide range of initiatives for tackling obesity, for example in annual reports, may be helpful. The local coordinator and public health teams should ensure the results of all monitoring and evaluation are made available to all those who can use them to inform their work, both in the local community and nationally. For example, log evaluation reports in the Obesity Learning Centre or Public Health England's healthy places databases, or the NICE shared learning database. The local coordinator and communications leads should ensure information from monitoring and evaluation is accessible and easy to use by everyone in the community, including those involved with obesity prevention, local groups and networks, the media and the public. This includes presenting information in accessible formats and different languages. # Recommendation 6 Involving the community ## Who should take action? Local Healthwatch. Local authority community involvement teams. Directors of public health and public health teams. Local voluntary and community organisations, champions and networks. Council leaders and elected members. Clinical commissioning groups. ## What action should they take? Local Healthwatch, community involvement and public health teams should engage local people in identifying their priorities in relation to weight issues. For example, residents may feel that issues such as crime, the siting of hot food takeaways or alcohol outlets, the lack of well-maintained green space, pavement parking, speeding, or the lack of a sense of community are their top priorities. Where possible, it should be made explicit that local concerns often can (and do) impact on levels of obesity in the community. Community involvement and public health teams should work with local people, groups and organisations to decide what action to take on obesity. They should recognise local concerns both in terms of the focus of programmes or services and how they might be delivered. This includes involving local groups, networks or social enterprises in any discussions about service redesign and ensuring that they receive feedback about decisions taken. Public health teams should use community engagement and capacity-building methods to identify networks of local people, champions and advocates who have the potential to co-produce action on obesity as part of an integrated health and wellbeing strategy. These networks include: people who are active and trusted in the community people who have the potential to be local health champions people who represent the needs of subgroups within the community (such as people with disabilities or mental health problems) marginalised groups such as asylum seekers or homeless people (where there is no established network or partnership working, additional action may be needed to get them involved) local champions (such as managers of youth or children's centres, school governors or parent groups, or those who organise walking or gardening groups) people who can provide a link to local business or the private or voluntary sector advocates who have a strong voice in the community, who can challenge social norms and beliefs of the community or who can champion obesity prevention and management as part of their usual role (this includes local elected members, GPs, head teachers, pharmacists, local weight management group leaders, health trainers, community leaders and representatives of local voluntary groups) patient or carer groups. Public health teams should ensure those identified are provided with the resources and training they need to take action on obesity. Clinical commissioning groups should make their GP practices aware of local obesity prevention and treatment services. They should encourage GPs to: make all their patients aware of the importance of a healthy diet and physical activity in helping to prevent obesity signpost people to relevant community programmes. Council leaders and elected members should raise the profile of obesity prevention initiatives through informal meetings with local people and groups and at formal ward meetings. # Recommendation 7 Integrated commissioning ## Who should take action? Local authority, NHS and other local commissioners. Directors of public health and public health teams. ## What action should they take? Commissioners and public health teams should foster an integrated approach to local commissioning that supports a long-term (beyond 5 years) system-wide health and wellbeing strategy. Public health teams should ensure commissioners understand the demographics of their local area, and consider local insight on the motivations and characteristics of subgroups within local communities that may impact on obesity levels. Commissioners and public health teams should create an environment that allows the local system to take a truly community-wide approach to obesity. They should consider: which 'packages' of interventions are most effective (including cost effective) the 'intensity' of effective programmes (for example, the number of interventions which make up an effective programme or the percentage of the population that should be reached) synergies between common actions to tackle obesity. Commissioners should focus on all of the following areas (focusing on just one at the expense of others may reduce effectiveness): raising awareness of the health problems caused by obesity and the benefits of being a healthier weight among partners and the public training to meet the needs of staff and volunteers (prioritising those who are working directly with local communities) influencing the wider determinants of health, including, for example, ensuring access to affordable, healthier food and drinks, and green space and built environments that encourage physical activity aiming activities at both adults and children in a broad range of settings providing lifestyle weight management services for adults, children and families providing clinical services for treating obesity. Commissioners should fund both targeted and universal services that can help people achieve or maintain a healthy weight. The specific package of services should be based on local needs, but should include both top-down approaches such as planning cycle routes and food procurement specifications and bottom-up approaches such as running activities in local parks and breastfeeding peer support (as appropriate). They should include interventions that are known to be effective as outlined in existing NICE guidance, including: community engagement and workforce development: NICE's guidelines on behaviour change: general approaches, community engagement and type 2 diabetes prevention: population and community interventions prevention for adults: NICE's guidelines on promoting physical activity in the workplace, alcohol-use disorders: prevention, cardiovascular disease prevention, weight management before, during and after pregnancy, type 2 diabetes prevention: population and community interventions, obesity prevention and physical activity: walking and cycling prevention for children: NICE's guidelines on physical activity and the environment, maternal and child nutrition, physical activity for children and young people, cardiovascular disease prevention and obesity prevention lifestyle weight management: NICE's guidelines on weight management before, during and after pregnancy, and obesity prevention clinical management: NICE's guideline obesity prevention wider local policies: NICE's guidelines on physical activity and the environment, cardiovascular disease prevention, and type 2 diabetes prevention: population and community interventions evaluation and monitoring: NICE's guidelines on cardiovascular disease prevention, type 2 diabetes prevention: population and community interventions, and obesity prevention. Commissioners should allocate some of their budget to help establish and sustain local community engagement activities such as small community projects or local community groups. This can be done by, for example, funding the expenses of the leaders of community walking groups, or providing small grants to hire meeting spaces. Commissioners should allocate some of their budget to innovative approaches to obesity prevention that are based on sound principles, have the support of the local community and are likely to be effective, but for which there is limited evidence. Funds for innovative approaches should be allocated within a framework of action learning and evaluation. All contracts should include requirements for regular monitoring or evaluation (see recommendations 10 and 11). Commissioners should ensure some flexibility in contracts to allow programmes or services to be adapted and improved, based on early or ongoing monitoring. Any changes should be clearly documented and carefully monitored. Clear processes should be put in place for learning and evaluation, especially for new approaches. Commissioners should ensure service specifications and contracts encourage local partnership working and reduce unnecessary duplication and overlap, particularly for local services provided by the voluntary and community sector (for example, by specifying a joint rather than separate approach for physical activity and food and nutrition initiatives). Where possible, commissioners should consider extending effective programmes or services, recommissioning effective small-scale projects and commissioning small-scale projects or prototypes that fill a gap in provision. (Such actions should be based on local experience, monitoring and evaluation.) Commissioners should consider redesigning or decommissioning programmes or services that are identified by local Healthwatch or other local bodies with a scrutiny function (such as health overview and scrutiny committees) as ineffective or not meeting the community's needs. # Recommendation 8 Involving businesses and social enterprises operating in the local area ## Who should take action? Directors of public health and public health teams. Local authority communications leads. Chambers of commerce. Environmental health departments. Council leaders and elected members. ## What action should they take? Public health coordinators, with support from directors of public health, should establish methods for involving business and social enterprises in the implementation of the local obesity strategy. This includes, for example, caterers, leisure providers, weight management groups, the local chamber of commerce, food retailers and workplaces. They should consider developing local activities based on national initiatives to achieve this. Public health teams and local authority communications leads should develop mechanisms of governance for working with business and social enterprises that are in the public interest. For example, they could address issues around appropriate sponsorship or competing priorities, with transparent mechanisms to address real or perceived conflicts of interest. All of the above should encourage all businesses and social enterprises operating in the local area to recognise their corporate social responsibilities in relation to health and wellbeing. This should be in relation to: employees – for example, supporting and encouraging employees (and employee's families) to adopt a healthy diet or developing and implementing active travel plans to encourage walking and cycling products – for example, ensuring the range and content of the food and drinks they sell does not create an incentive to overeat and gives people the opportunity to eat healthily wider social interests – such as actively supporting wider community initiatives on health and wellbeing. See also NICE's guidelines on obesity, physical activity in the workplace, cardiovascular disease prevention, alcohol use disorders: prevention drinking and type 2 diabetes prevention: population and community interventions. # Recommendation 9 Local authorities and the NHS as exemplars of good practice ## Who should take action? Chief executive officers. Executive directors of local authority services. Local authority and NHS commissioners. Directors of public health and public health teams. Council leaders and elected members. ## What action should they take? Public health teams should ensure local authorities and NHS organisations develop internal policies to help staff, service users and the wider community achieve and maintain a healthy weight. Local authorities, NHS executive directors and commissioners should promote healthier food and drink choices (and discourage less healthy choices) in all onsite restaurants, hospitality suites, vending machines, outreach services and shops. They should do this through contracts with caterers, pricing and the positioning of products, information at the point of choice and educational initiatives. See also the recommendation on public sector food provision in NICE's guideline on cardiovascular disease prevention (recommendation 20) and the recommendation on promoting a healthy diet: local action in NICE's guideline on type 2 diabetes prevention: population and community interventions (recommendation 8). Local authorities and NHS organisations should introduce and monitor an organisation-wide programme that encourages and supports staff and, where appropriate, service users, to be physically active. This includes, for example, introducing physically active travel plans for staff to promote walking and cycling to and from work. It also includes considering the design of working environments to increase opportunities for physical activity. See also the recommendation on physical activity in NICE's guideline on cardiovascular disease prevention (recommendation 21); the recommendation on promoting physical activity: local action in NICE's guideline on type 2 diabetes prevention: population and community interventions (recommendation 10); and NICE's guideline on physical activity in the workplace). Local authorities and NHS organisations should offer lifestyle weight management services (in line with best practice outlined in NICE's guideline on weight management: lifestyle services for overweight or obese adults) for overweight or obese staff who would like support to manage their weight. Local authority and NHS commissioners should consider how their decisions impact on obesity in the local community. For example, ensuring the provision of healthier choices is included in food contracts for leisure centres may have a positive impact on the diet of people who visit or work at these centres. # Recommendation 10 Planning systems for monitoring and evaluation ## Who should take action? Directors of public health and public health teams. Local authority, NHS and other local commissioners. Providers of local authority or NHS commissioned services that have a direct or indirect impact on obesity. ## What action should they take? All of the above should ensure sufficient resources are set aside for planning, monitoring and evaluation, and that all partners and providers appreciate the importance of monitoring and evaluation. All of the above should ensure all monitoring and evaluation considers the impact of strategies, policies and activities on inequalities in obesity and related health issues. All of the above should ensure all strategies, policies and activities that may impact on the obesity agenda (whether intended or not) are monitored in a proportionate manner. Monitoring arrangements should be built into all relevant contracts. All of the above should ensure sufficient resources are set aside to thoroughly evaluate new or innovative pieces of work (for example, 10% of project budgets). Local authority, NHS and other commissioners should ensure, when commissioning services, there is an appropriate lead-in time for baseline data collection, and data are stratified so that the impact on inequalities can be considered. All of the above should use simple tests to assess value for money (such as resources saved by working in partnership). All of the above should encourage a reflective learning approach that builds on effective practice and changes or discards practices that are found to be less effective. All of the above should ensure monitoring arrangements address the information needs and expectations of a broad range of groups by: assessing a broad range of process indicators such as the views and experience of people who have participated in the obesity programme, feedback from partner organisations, programme referral rates and impact on community wellbeing ensuring the results of monitoring are fed back to teams delivering projects to improve implementation recognising the input of all organisations involved ensuring positive findings are used to motivate all those involved in the programme (for example, by capturing success stories in media campaigns). # Recommendation 11 Implementing monitoring and evaluation functions ## Who should take action? Public Health England. Directors of public health and public health teams. Academic health networks and other academic institutions. Local authority, NHS and other local commissioners. Provider organisations. ## What action should they take? Public Health England is encouraged to develop a framework for monitoring and evaluating integrated community-wide approaches to obesity to ensure consistency and comparability across all local areas. Directors of public health and public health teams should develop methods to capture changes in know of what it means to be a healthy weight and the benefits of maintaining a healthy weight. Academic health networks and academic institutions should: establish links with local practitioners to help with planning, collecting and analysing data on obesity strategies and interventions identify aspects of partnership working or cooperation that can achieve health benefits at a negligible or lower cost (extensive economic modelling of partnership working is not needed on a routine basis). All of the above should encourage all partners to measure a broad range of outcomes to capture the full benefits of a sustainable, integrated health and wellbeing strategy. Appropriate outcomes include: anthropometric measures such as body mass index (BMI) or waist circumference indicators of dietary intake (for example intake of fruit and vegetables or sugar sweetened drinks), physical activity (for example time spent in moderately vigorous activities such as brisk walking) or sedentary behaviour (for example screen time or car use) prevalence of obesity-related diseases wider health outcomes such as indicators of mental health process outcomes such as service use, engagement of disadvantaged groups, establishment or expansion of community groups indicators of structural changes (such as changes to procurement contracts). # Recommendation 12 Cost effectiveness ## Who should take action? Academic health networks and other academic institutions. Directors of public health and public health teams. Local authority, NHS and other local commissioners. Provider organisations. ## What action should they take? All of the above should use simple tests to assess value for money of local action to tackle obesity. This may include determining whether resources would be saved by working in partnership, or measuring whether benefits in one sector (such as health) are sufficient to offset costs incurred in another (such as transport or leisure services). All of the above should ensure evaluation frameworks assess the value for money of partnership working and collaboration compared with working as separate entities. All of the above should identify aspects of partnership working or cooperation that can achieve health benefits at negligible or low cost (extensive economic modelling is not needed on a routine basis). # Recommendation 13 Organisational development and training ## Who should take action? Health and wellbeing boards. Local education and training boards. Directors of public health and local public health providers. Academic health networks and other academic institutions. Professional bodies providing training in weight management, diet or physical activity. ## What action should they take? Health and wellbeing boards, local education and training boards, and public health teams should ensure partners across the local system have opportunities to increase their awareness and develop their skills to take forward an integrated approach to obesity prevention. Local organisations, decision makers, partners and local champions, including those from public, private, community and voluntary sector bodies working in health, planning, transport, education and regeneration, should receive training to: increase their awareness of the local challenges in relation to public health and preventing obesity (in particular, increasing their awareness of the local JSNAs) understand the local systems and how their own work can contribute to preventing and managing the condition (for example when developing local commissioning plans, local planning frameworks or care provision) develop their community engagement skills to encourage local solutions and ensure co-production of an integrated approach understand the importance of monitoring and evaluation to the approach. Local education and training boards should ensure health promotion, chronic disease prevention and early intervention are part of the basic and post basic education and training for the public health workforce. Local education and training boards and the other groups listed above should ensure health and other relevant professionals are trained to be aware of the health risks of being overweight and obese and the benefits of preventing and managing obesity. This training should include: understanding the wider determinants of obesity (such as the impact of the local environment or socioeconomic status) understanding the local system in relation to the obesity agenda (such as who the key partners are) understanding methods for working with local communities knowing the appropriate language to use (referring to achieving or maintaining a 'healthy weight' may be more acceptable than 'preventing obesity' for some communities) understanding why it can be difficult for some people to avoid weight gain or to achieve and maintain weight loss being aware of strategies people can use to address their weight concerns being aware of local services that are likely to be effective in helping people maintain a healthy weight being aware of local lifestyle weight management services that follow best practice as outlined in NICE's guideline on weight management: lifestyle services for overweight or obese adults. All of the above should ensure training addresses the barriers some professionals may feel they face when initiating conversations about weight issues. For example, they may be overweight themselves, or feel that broaching the subject might damage their relationship with the person they are advising. All of the above should ensure all relevant staff who are not specialists in weight management or behaviour change can give people details of: local services that are likely to be effective in helping people maintain a healthy weight local lifestyle weight management services that meet best practice as outlined in NICE's guideline on weight management: lifestyle services for overweight or obese adults. All of the above should promote, as appropriate, web resources which encourage a community-wide approach to obesity. Resources include: National Heart Forum's healthy weight, healthy lives toolkit for developing local strategies, the Obesity Learning Centre and Public Health England's healthy places resources. # Recommendation 14 Scrutiny and accountability ## Who should take action? Local bodies with a scrutiny function (such as health overview and scrutiny committees). Local Healthwatch. ## What action should they take? Local bodies with a scrutiny function (such as health overview and scrutiny committees) should assess local action on preventing obesity, ensuring that commissioning meets the breadth of the joint health and wellbeing strategy. This includes: the impact of wider policies and strategies -rganisational development and training on obesity to ensure a system-wide approach the extent to which services aimed at tackling obesity are reaching those most in need and addressing inequalities in health. Local bodies with a scrutiny function should be encouraged to include plans of action to prevent obesity within their rolling programme of service reviews. Local Healthwatch should ensure the views of the local community are reflected in the development and delivery of the local approach to obesity. They should also scrutinise the priority given to obesity prevention by local health and wellbeing boards and the implementation of local obesity strategies.# Public health need and practice In England in 2010, just over a quarter of adults (26%) and almost a sixth of children (16%) aged 2 to 15 years were obese (The Health and Social Care Information Centre 2012). By 2050, 60% of adult men, 50% of adult women and 25% of children may be obese (Foresight 2007). Adults with a body mass index (BMI) more than or equal to 30 kg/m2 are classified as obese, as are children with a BMI over the 95th percentile – based on the 1990 UK reference population (The Health and Social Care Information Centre 2012). Differences in measurement methods make comparison with other countries difficult. However, the prevalence of obesity in England is at least as high, if not higher, than in other EU countries. While there is some suggestion that it may be starting to level off among children in England (McPherson et al. 2009; The Health and Social Care Information Centre 2012), prevalence remains very high among this group. Obesity is related to social disadvantage with marked trends, especially in children, by area of residence (The Marmot Review 2010). It is also linked to ethnicity. Obesity is most prevalent among Black Caribbean, Black African and Irish men – and least prevalent among Chinese and Bangladeshi men. Among women, it is more prevalent among those of Black African, Black Caribbean and Pakistani origin – and least prevalent among Chinese women (The Health and Social Care Information Centre 2008). Around 58% of cases of type 2 diabetes, 21% of cases of heart disease and between 8% and 42% of certain cancers (endometrial, breast, and colon) are attributable to excess body fat (Foresight 2007). Obesity reduces life expectancy by an average of 9 years and is responsible for 9000 premature deaths a year in England. In addition, people who are obese can experience stigmatisation and bullying that can lead to depression and low self-esteem (Foresight 2007). It is estimated that overweight and obesity now costs the NHS £5.1 billion per year (Scarborough et al. 2011). However, if current trends continue, these costs will increase by an additional £1.9 billion per year by 2030 (Wang et al. 2011). In 2007, the cost to the wider economy was £16 billion – this is predicted to rise to £50 billion a year (at today's prices) by 2050 if left unchecked (Foresight 2007). The determinants of obesity are complex. Factors include: genetic disposition, early life nutrition and growth, individual lifestyle, psychological issues, the physical and cultural environment, food production and consumption, education, social and economic factors and the influence of the media (Foresight 2007). Existing NICE guidance indicates the type of national and local interventions that can be used to tackle obesity and improve people's diet and physical activity levels. (Existing guidance covers settings such as primary care, schools and workplaces.) However, none of the recommendations have considered the synergy between discrete policies or 'packages' of interventions and the complex organisational issues involved in local delivery. To date, no country has managed to reverse the rising rates of obesity at a population level. The Foresight report (2007) argued that a wide range of partners should work together to develop and implement community-wide approaches to tackle the determinants. More recently, the white paper 'A call to action on obesity in England' has reinforced the importance of synergistic efforts at a range of levels, including local action (DH 2011). However, it remains unclear how such an approach can best be implemented. Community-based programmes are notoriously difficult to evaluate and often do not lend themselves to traditional research designs. Current practice is patchy and is dominated by short-term single interventions, usually developed and implemented through a top-down approach. Integrated, coordinated action that feeds into an overarching, long-term strategy is uncommon. In addition, commissioners often find it difficult to decide whether to allocate funds to prevention or treatment, although it is clear that there is a need for both to operate in tandem (DH 2011).# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations. # Definitions For the purpose of this guidance, 'local community' refers to a group of people from the same geographic location that is not necessarily related to any official, administrative boundary. The community may be located in a ward, borough, region or city. The PDG recognised that 'community' can also refer to groups with an interest, background or issue in common (such as low income and black and minority ethnic groups – see NICE's guideline on type 2 diabetes prevention: population and community interventions). However, while communities of interest are not excluded from this guidance, the primary focus is on those located in specific geographic areas. The Group noted that aiming for a 'healthier weight', rather than focusing on preventing or combating obesity, may be a more acceptable and achievable goal for many people. Members also felt this goal could be accommodated within a general health and wellbeing agenda. The PDG heard that the term 'obesity' may be unhelpful among some communities – while some people may like to 'hear it like it is', others may consider it derogatory. Bearing these differing views in mind, the PDG acknowledged the need to choose the most appropriate language for any given community or situation. # Evidence The scope for this guidance was revised during its development. Originally the aim was to look at a whole-system approach to obesity. Following the revision, the PDG focused more on local, community-wide best practice. Consultation with stakeholders confirmed that the evidence previously considered was still relevant and features of an effective whole-systems approach have been incorporated in the recommendations. There is a lack of evidence on effective community-wide approaches to obesity. The most advanced studies have only started to publish early findings. These include: EPODE in France ('Ensemble prevenons l'obesite des enfants' ) or CO-OPS Collaboration in Australia (the 'Collaboration of community-based obesity prevention sites'). No UK-based studies were identified. The PDG had hoped to gain insight from community-wide approaches to tobacco control, but again there was little UK-based evidence. As a result, the recommendations draw heavily on the experience of local practitioners in England (via expert testimony and commissioned research). They also draw on early learning from ongoing initiatives (such as Healthy Towns, Cycling Demonstration Towns and the work of the Department of Health Child Obesity National Support Team). In recent years, there has been a proliferation of community-based interventions aimed at preventing and managing obesity. These have tended to be one-off, highly controlled explanatory studies, developed and delivered by academic centres. While some studies have been evaluated using the approaches set out in the MRC Framework on complex interventions, system-wide interventions are still being evaluated using randomised trials. The PDG considered that there is a need to develop appropriate methodological models for evaluating system-wide, community-led approaches to obesity prevention and management. Evaluation of local action on obesity is not straightforward, as the full impact may not be seen for a number of years. In particular, there is a lack of evaluation that considers process and economics, as well as health outcomes, over the short, medium and long term. The PDG noted that the recommendations on monitoring and evaluation in NICE's guideline on cardiovascular disease prevention are of relevance. The recommendations synthesise learning from the available evidence and indicate promising areas for future innovation in a culture of ongoing evaluation and action. The evidence does not demonstrate that a particular approach (or established package of interventions) holds the key to tackling obesity in any given community. However, it does provide useful pointers to approaches that may be worth putting into practice and evaluating. # Context There is enormous variation in current practice, both in terms of the types of action taken, local capacity and assets. The PDG recognised that different areas are at different 'starting points'. The recommendations aim to bring all areas up to the standard of the most advanced and to encourage future innovation. Context is vital – and what works in one locality may not always work in another. The PDG considered techniques that could be used to tailor interventions for particular contexts. These included, for example, community engagement techniques and development and good practice in relation to partnerships and commissioning. # Public sector reorganisation Ongoing structural changes to the public sector, particularly local authorities and the NHS, have influenced the direction and tone of the PDG's recommendations. The Group was aware that the timing of the guidance offered an opportunity to stress the importance of a systemic approach to obesity that is integrated with other local agendas. Many of the recommendations are aimed at local authorities and new bodies, particularly health and wellbeing boards. The PDG believes the latter will provide a crucial forum for the NHS, public health and local authority representatives. This includes playing a critical role in developing a long-term obesity strategy. In two-tier areas the involvement of district councils and other tiers of local government in the development and implementation of a long-term obesity strategy will be critical to success. The PDG acknowledges that individual health and wellbeing boards will manage this local engagement differently but advocates that key contributors to obesity prevention such as planning, transport, parks and leisure services must be included in the strategy and are integral to action to prevent obesity. The PDG recognised the importance of informing elected members of the personal, community and wider economic and social costs that will accrue if the prevalence of obesity continues to rise. It also noted the need to provide elected members with tools to take effective action. The PDG acknowledged that national policy can act as a facilitator or barrier to local action on obesity. Analogies were drawn with action on tobacco control and smoking cessation. Here evidence points to the importance of supportive national policies. It also points to the need to 'de-normalise' behaviours that increase the risk of obesity via strong advocacy and market regulation (in this analogy, in relation to tobacco products). The PDG considered that if the findings from recommended local action on monitoring and evaluation were fed back to national or supra-regional policy teams and practitioners, it may foster a wider culture of action learning and aid the development of supportive national policies. # Overarching approach The PDG strongly emphasised the need to take systemic, sustainable action that encompasses the wider determinants of health. Obesity may be the long-term consequence of a passive response to decisions taken elsewhere (for example, in relation to planning, policing or traffic law enforcement). The Group believes single, one-off interventions are likely to have a limited impact – and that multi-sector action is needed across the local system if there are to be appreciable changes in the prevalence of obesity. The recommendations focus on sustained community engagement and the development of effective partnerships involving a broad range of groups. The PDG believes the public health team's role in this is to build an area-wide partnership across sectors to help tackle the wider social, economic and environmental determinants of obesity. The PDG recognised that change will take a long time unless a simultaneous top-down, bottom-up and partnerships (co-production) approach is adopted. This includes action across all local organisations and networks supported by effective policies and delivery systems. The effectiveness of individual interventions was outside the scope of this guidance. However, the PDG recognised that a range of existing NICE guidance provides details on the types of interventions that are likely to be effective. The exact package commissioned will depend on the needs of the local area. However, the PDG felt that it was very important to take a long-term, coherent approach to commissioning – for both obesity prevention and treatment among children and adults. The PDG noted that activities focused on obesity prevention receive greater support, especially among practitioners, when there are clear opportunities for referral into local treatment services. This is also the case when actions to prevent and treat obesity are closely integrated. # Workforce capacity Evidence considered by the PDG suggests managing weight is difficult for many people and health professionals may avoid raising this issue. Moreover, just as someone who smokes may attempt to quit many times before they finally succeed, so it may take many conversations (and attempts) before someone is able to change their behaviour to control their weight. The PDG heard that many public health workers lack confidence in raising the issue of obesity with clients. The Group felt that this was a fundamental issue for local authority and NHS staff. It considered it vital that all staff, but particularly those on the 'frontline', have the skills and confidence to provide basic information about local obesity services. The PDG recognised that success in preventing and managing obesity in local areas can sometimes depend on one or two highly motivated people. While passionate individuals can be a catalyst for change, it leaves sustained action vulnerable to any change in personnel. Accordingly, the PDG has advocated action that is embedded in organisational processes and skill sets. Volunteers have a vital role in driving community-wide action on obesity – from championing community needs and assets to providing peer support. While there may be a high turnover in volunteers, the PDG acknowledged that they free up other resources and provide an essential supporting role. However, members were concerned to ensure volunteers' training needs and other related costs are not ignored. # Health economics Relevant NICE guidance (such as the NICE guidelines on obesity prevention and type 2 diabetes prevention: population and community intervention) demonstrates that individual interventions to prevent or reduce the prevalence of obesity in a particular setting or environment are known to be cost effective. While some interventions or programmes may result in short-term financial benefits, most benefits will be health benefits that will take place over the medium to long term. It is very difficult, if not impossible, to apply the standard techniques of health-economic evaluation to local system-wide approaches to obesity. Economic evaluation of system-wide approaches reduces to determining the cost effectiveness of partnership working. Partnerships are formed in many different ways and circumstances, and this makes economic evaluation very difficult. The depth of involvement of the partners can vary enormously, as can the number of partners. The decision to become involved as a partner will also depend on how long a project will be funded, how assured the funding is, and whether all potential partners have the same assurances on project funding. At low levels of engagement, potential partners may simply wish to share information. Such 'partnerships' are virtually costless and may generate relatively large benefits. They will therefore almost certainly be cost effective when viewed from a societal perspective. Further engagement that is likely to cost little to achieve but which is expected to yield relatively large future health benefits should also be cost effective. The greater the number of partners or the more the level of engagement is increased, the more difficult it will become to decide whether further engagement would be cost effective. There will usually come a time when the addition of more partners or the further increase in the level of engagement will no longer be worth the additional effort. However, in practice it will not be easy to determine when such points are reached, particularly when arrangements are already complex. This guidance concludes that it is more informative to consider the cost effectiveness of each intervention or set of interventions within a complex programme rather than try to consider the cost effectiveness of the programme as a whole. It will be important for potential partners to consider: whether it would be better to work together than to work alone whether to increase the existing level of engagement. Modelling shows that projects with long-term funding are more likely to be cost effective, compared with projects funded on an annual basis.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects. # Who should take action? Research councils, research commissioners, funders. # Recommendation 1 What is the most effective way to monitor and evaluate community-wide approaches to obesity to ensure: evidence of effectiveness is gathered across the breadth of the local system and data are produced to help local communities adapt and improve their approach? An action research approach should be considered (see Waterman et al.'s action research: a systematic review and guidance for assessment). Researchers may also wish to refer to Medical Research Council guidance on developing and evaluating complex interventions and using natural experiments to evaluate population health interventions. # Recommendation 2 What factors are necessary for an effective and cost effective community-wide approach to obesity prevention? In particular: How can learning from systemic approaches to other complex problems be applied to obesity prevention? How does the local context affect local engagement, adherence and effectiveness? This includes local population characteristics (for example, age, ethnicity or deprivation levels). It also includes funding arrangements and features of the local environment (such as transport links, access to green space or food outlets). What components are needed to build and sustain successful local community partnerships? This includes how to identify and get local people and professionals involved; the relative benefits of voluntary versus imposed partnerships; and best practice in forming and sustaining partnerships. At what point is partnership working no longer cost effective? How cost effective and practical is it to extend and expand existing obesity prevention programmes to support a whole community, in terms of: geographic coverage variety of contexts number of participants return on investment? How can strategic approaches to obesity be sustained in terms of: funding partnerships volunteer involvement leadership continuity 'champion' participation? How can change best be achieved using a community development approach? # Recommendation 3 Research that specifically aims to improve understanding of community-wide approaches to prevent obesity should not: be conceived, developed and implemented by academics with limited consultation with local practitioners or the local community be limited in terms of the number of situations where it could be transferred to or implemented focus on interventions in one setting (such as an individual school). See more detail on the gaps in the evidence identified during development of this guidance.# Glossary # Action learning A process by which someone performs an activity and then analyses their actions and gains feedback to improve future performance. # Action research Action research aims to respond to the practical concerns of participants involved in a change process, such as a new approach to obesity prevention. It involves a partnership between researchers and participants in which problem identification, planning, action and evaluation are all interlinked. # Body mass index Body mass index (BMI) is commonly used to indicate whether adults are a healthy weight or underweight, overweight or obese. It is defined as the weight in kilograms divided by the square of the height in metres (kg/m2). # 'Bottom-up' activities or approaches Activity is initiated by the community, or people working directly with the community, rather than being introduced by senior management. # Capacity-building Actions or interventions that improve the ability of an individual, an organisation or a community to identify and address health or other issues on a sustainable basis, for example through skills development, improved networking and communication or shared decision making. # Community A group of people who have common characteristics. Communities can be defined by location, race, ethnicity, age, occupation, a shared interest (such as using the same service), a shared belief (such as religion or faith) or other common bonds. Local community refers to a group of people from the same geographic location that is not necessarily related to any official, administrative boundary. The community may be located in a ward, borough, region or city. # Community assets A community asset (or resource) is anything that can be used to improve the quality of community life. It could be a physical structure or place (such as a recreation centre, library, hospital, meeting place, monument or business). Or it could be a group or an individual, for example, a local community group or a community leader. # Community champions The term 'community champion' covers a range of roles, and includes inspirational figures, community entrepreneurs, mentors or leaders who 'champion' the priorities and needs of their communities and help them build on their existing skills. It also includes those 'on the ground' who drive forward community activities and pass on their expertise to others. They may provide mentoring or a range of other support, for example, by helping people to get appropriate training or by helping to manage small projects. # Community development Community development is about building active and sustainable communities based on social justice, mutual respect, participation, equality, learning and cooperation. It involves changing power structures to remove the barriers that prevent people from participating in the issues that affect their lives. # Community engagement The process of getting communities involved in decisions that affect them. This includes the planning, development and management of services, as well as activities that aim to improve health or reduce health inequalities (Popay 2006). # Community health champions Community health champions are local people who are recruited and trained as volunteers to 'champion' the health priorities and need of their communities. # Co-production For this guidance, co-production means developing and delivering action on obesity in an equal and reciprocal relationship between professionals, the local community, people using local services and their families. # Joint strategic needs assessments Joint strategic needs assessments (JSNAs) identify the current and future health needs of a local population. They are used as the basis for the priorities and targets set by local areas, expressed in local health and wellbeing strategies. They are also used for commissioning to improve health outcomes and reduce health inequalities. # Local system The local system comprises a broad set of interrelated organisations, community services and networks operating at a range of levels and involving a number of delivery processes. # Overweight and obesity: adults For adults, overweight and obesity are assessed by body mass index. The sections on classifying overweight, obesity and central adiposity in adults, and classifying overweight, obesity and central adiposity in children and young people, in NICE's guideline on obesity assessment and management give the cut-off points for healthy weight, overweight and obesity. BMI is a less accurate indicator of adiposity in adults who are highly muscular, so BMI should be interpreted with caution in this group. Some other population groups, such as Asians and older people, have comorbidity risk factors that would be of concern at different BMIs (lower for Asian adults and higher for older people). Healthcare professionals should use clinical judgement when considering risk factors in these groups, even in people not classified as overweight or obese using the classification in the table. Assessment of the health risks of being overweight or obese can also be based on waist circumference. For men, waist circumference of less than 94 cm is low, 94–102 cm is high and more than 102 cm is very high. For women, waist circumference of less than 80 cm is low risk, 80–88 cm is high and more than 88 cm is very high. # Overweight and obesity: children More than one classification system is used in the UK to define 'overweight' and 'obesity' in children. The National Child Measurement Programme (NCMP) for primary care states that body mass index (BMI) should be plotted onto a gender-specific BMI chart for children (UK 1990 chart for children aged over 4 years). Children over the 85th centile, and on or below the 95th centile, are categorised as 'overweight'. Children over the 95th centile are classified as 'obese'. Other surveys, such as the Health Survey for England also use this system. In clinical practice, however, the 91st and 98th centiles may be used to define 'overweight' and 'obesity' respectively. Children on or above the 98th centile may also be described as very overweight. # Partner For the purpose of this guidance, a partner is a local department, service, organisation, network, community group or individual that could help prevent obesity. # 'Top-down' activities or approaches Where an activity is initiated from a senior level in an organisation and cascaded down to those working directly with the local community. # Two-tier Two-tier counties in England consist of an 'upper-tier' county council and various 'lower-tier' city, borough and district councils. # Wider determinants of health The social determinants of health are the circumstances in which people are born, grow up, live, work, and age, as well as the systems put in place to deal with illness. These circumstances are in turn shaped by a wider set of forces: economics, social and political forces.# References Department of Health (2011) Healthy lives, healthy people: a call to action on obesity in England. London: Department of Health Foresight (2007) Tackling obesities: future choices – project report. London: Government Office for Science The Health and Social Care Information Centre (2012) Statistics on obesity, physical activity and diet: England. London: The Health and Social Care Information Centre The Health and Social Care Information Centre (2008) Health Survey for England 2007: Healthy lifestyles: knowledge, attitudes and behaviour. Leeds: The Information Centre for Health and Social Care McPherson K, Brown M, Marsh T et al. (2009) Obesity: recent trends in children aged 2–11y and 12–19y. Analysis from the health survey for England 1993–2007. London: National Heart Forum The Marmot Review (2010) Fair society, healthy lives. Strategic review of health inequalities in England post 2010. London: The Marmot Review Community engagement for health improvement: questions of definition, outcomes and evaluation - a background paper prepared for NICE by Professor Jenny Popay (2006) Scarborough P, Bhatnagar P, Wickramasinghe K et al. (2011) The economic burden of ill health due to diet, physical inactivity, smoking alcohol and obesity in the UK. Journal of Public Health 33: 527–35 Wang YC, McPherson K, Marsh T et al. (2011) Health and economic burden of the projected obesity trends in the USA and the UK. The Lancet 378: 815–25# Appendix B Summary of the methods used to develop this guidance # Introduction The reviews, primary research, commissioned reports and economic modelling include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E. # Key questions The key questions were established as part of the scope. They formed the starting point for consideration of the reviews of evidence and were used by the PDG to help develop the recommendations. The key questions were: What are the essential elements of a local, community-wide approach to preventing obesity that is sustainable, effective and cost effective? What barriers and facilitators may influence the delivery and effectiveness of a local, community-wide approach (including for specific groups)? Who are the key leaders, actors and partners and how do they work with each other? What factors need to be considered to ensure local, community-wide approaches are robust and sustainable? What does effective monitoring and evaluation look like? Can the cost effectiveness of local, community-wide obesity interventions be established and, if so, what is the best method to use? # Reviewing the evidence ## Effectiveness reviews One review of effectiveness was conducted (review 2). A number of databases were searched in July 2010 for interventions published in English from 1990 onwards. See the review for details. General health and topic-specific websites and other sources of grey literature were also searched including: Scrutiny committee reports (searched via an Internet search engine) ZeTOC database (British Library) ISI proceedings (Web of Science) Conference Proceedings Citation Index (Web of Science). Studies were included in the effectiveness review if they: demonstrated core features of a whole-system approach (as identified in review 1) to preventing obesity or smoking covered whole populations or communities and reported on outcome measures or other indicators for an intervention used comparative study designs were published from 1990 onwards in English. Studies were excluded if they: did not report on the outcomes listed -nly presented a single component of an intervention or strategy did not focus on obesity prevention, improving physical activity or diet, or smoking prevention. ## Other reviews One review was undertaken to define a 'whole-system approach' (review 1) and one review of qualitative data was undertaken to consider the barriers and facilitators to such an approach (review 3). For reviews 1 and 3, the databases and websites searched were the same as for the effectiveness review (see above). Studies were included in review 1 if they considered: the theory, key elements and relationships of a whole-system approach a whole-system approach in relation to obesity or smoking prevention. Qualitative studies were included in review 3 if they focused on: any 'whole-community' programme in the UK 'whole-community' obesity and smoking prevention programmes, including those delivered in schools or workplaces in Organisation for Economic Co-operation and Development (OECD) countries. Studies were excluded from review 3 if they focused on: people's opinions about eating and exercise and their understanding of the issues around obesity, for example, food choices community engagement, unless there were elements specific to obesity prevention relationships between members of a single agency (for example, a primary care team) a single setting (even where the intervention was part of a multi-agency initiative) or a single aspect of health (for example, physical activity or diet). ## Quality appraisal For review 1, included papers were assessed according to whether they provided a coherent account of the concepts and approaches taken and their relationship to each other. (Those that provided more information along these lines were considered better 'quality'.) For the effectiveness review (review 2), included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual Methods for the development of NICE public health guidance (see appendix E). Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. − Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. For review 3, the qualitative research studies were assessed using a thirteen-question checklist to determine: the clarity of descriptions the appropriateness of the aims and methods the evidence for the findings logical and theoretical coherence. ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full evidence reviews). The findings from the evidence reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Commissioned report Primary, qualitative research was commissioned (September 2011) to understand how local teams can work together effectively to prevent obesity in local communities. The opinions and experiences of the 93 participants are reported in 'Implementing community-wide action to prevent obesity: opinions and experiences of local public health teams and other relevant parties'. # Cost effectiveness There was a review of economic evaluations and an economic modelling report. ## Review of economic evaluations The obesity-related Reference Manager databases were searched for economic evidence as part of reviews 1 and 2. In addition, selected new searches were undertaken in economic bibliographic databases (NHS EED and EconLit). As a result, four economic evaluations were selected and summarised narratively. The generic tool for economic evaluations (Drummond and Jefferson 1996) was used for quality assessment. ## Economic modelling report An economic logic model was constructed to explore the circumstances in which a collaboration of two or more local organisations could usually be expected to be cost effective. The model aimed to deduce the direction of change of interventions, but not the magnitude of that change. The results are reported in the economic modelling report 'Cost effectiveness analysis in partnership working for reducing obesity and other long-term conditions.' # How the PDG formulated the recommendations At its meetings from July 2011 to February 2012, the Programme Development Group (PDG) considered the evidence, expert reports, primary research and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed draft recommendations through informal consensus, based on the following criteria: strength (type, quality, quantity and consistency) of the evidence the applicability of the evidence to the populations or settings referred to in the scope effect size and potential impact on the target population's health impact on inequalities in health between different groups of the population equality and diversity legislation ethical issues and social value judgements cost effectiveness (for the NHS and other public sector organisations) balance of harms and benefits ease of implementation and any anticipated changes in practice. The PDG noted that effectiveness can vary according to the context. Where evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme. Where possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The draft guidance, including the recommendations, was released for consultation in May 2012. At its meeting in July 2012 the PDG amended the guidance in light of comments from stakeholders. The guidance was signed off by the NICE Guidance Executive in October 2012.# Appendix C The evidence This appendix lists the evidence statements from four evidence reviews and commissioned research provided by external contractors (see appendix A and appendix E) and links them to the relevant recommendations. See appendix B for the meaning of the (++), (+) and (−) quality assessments referred to in the evidence statements. The additional evidence section of this appendix also lists 19 expert papers and their links to the recommendations and sets out a brief summary of findings from the economic modelling. The evidence statements are short summaries of evidence in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letter(s) in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement number 1.1 indicates that the linked statement is numbered 1 in the review 'Identifying the key elements and interactions of a whole system approach to obesity prevention'. Evidence statement 2.1 indicates that the linked statement is numbered 1 in the review 'The effectiveness of whole system approaches to prevent obesity'. Evidence statement 3.1 indicates that the linked statement is numbered 1 in the review 'Barriers and facilitators to effective whole system approaches'. Evidence statement 4.1 indicates that the linked statement is numbered 1 in the review 'Whole system approaches to obesity prevention: review of cost-effectiveness evidence'. Evidence statement CR1 indicates that the linked statement in numbered 1 in the commissioned report 'Implementing community-wide action to prevent obesity: opinions and experiences of local public health teams and other relevant parties'. See the full reviews, commissioned research, expert papers and economic modelling report. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Where the Programme Development Group (PDG) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix. Recommendation 1: evidence statements 1.6, 2.5, 3.1, 3.2, 3.5, CR1; expert papers 2, 3, 5, 6, 7, 9, 12, 14 Recommendation 2: evidence statements 1.2, 1.6, 3.1, 3.2, 3.4, 3.7, 3.8, CR1, CR3; expert papers 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 18 Recommendation 3: evidence statements 1.6, 3.4, 3.5, 3.7, CR1, CR5; expert papers 2, 3, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18 Recommendation 4: evidence statements 1.2, 1.6, 3.2, 3.3, 3.4, 3.5, 3.7, CR2, CR3, CR4; expert papers 1, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16 Recommendation 5: evidence statements 1.6, 3.3, 3.4, CR1, CR2, CR3, CR4; expert papers 2, 3, 5, 6, 8, 9, 11, 12, 14, 15, 16 Recommendation 6: evidence statements 1.2, 1.6, 3.1, 3.2, 3.3, 3.4, 3.7, CR1, CR4, CR5; expert papers 2, 4, 5, 7, 8, 9, 10, 12, 15, 17 Recommendation 7: evidence statements 1.3, 1.4, 1.6, 3.3, 3.6, 3.8, CR3, CR4, CR5; expert papers 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 19 Recommendation 8: evidence statements 1.6, 3.2; expert papers 2, 5, 8, 11, 18; IDE Recommendation 9: evidence statements 3.2, 3.5, CR3; expert papers 2, 5, 11, 18; IDE Recommendation 10: evidence statements 1.4, 1.6, 3.6, 3.8, 4.3, CR4, CR5; expert papers 2, 3, 4, 5, 9, 11, 12, 13, 14, 16, 19 Recommendation 11: evidence statements 1.4, 1.6, 3.6, 3.8, 4.3, CR4, CR5; expert papers 2, 3, 4, 5, 9, 11, 12, 13, 14, 16, 19 Recommendation 12: evidence statements 4.3; CR6; expert papers 5, 9, economic modelling report Recommendation 13: evidence statements 1.6, 3.2, 3.3, 3.6, CR3, CR4; expert papers 2, 5, 7 Recommendation 14: evidence statements 3.7, 3.8, CR1, CR4; IDE # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style. The superscript numbers refer to the studies cited beneath each statement. The full references for those studies can be found in the reviews. ## Evidence statement 1.1: Whole systems theory Authors may interpret what is meant by a whole system in different ways; there is a clear division in views between those advocating 'complexity theory' and those discussing a more mechanistic approach. A whole-system approach to achieving change in organisations, communities or individuals shares conceptual underpinnings with complexity science and complex adaptive systems. Systems continually evolve, with complex outcomes arising from a few simple rules of interaction. Self-regulation occurs within systems, and efforts to contain them may be counterproductive. Systems include formal and informal relationships or networks; these relationships are of great importance. Systems can exist in single or multi-sector organisations. ## Evidence statement 1.2: Implications of whole-system theory for ways of working Whole system theory suggests that organisation or community goals may best be achieved by: Creating more flexible organisational structures. Recognising that relationships are crucial. Understanding how positive and negative feedback loops within a system operate – giving insights into how to increase or sustain positive outcomes. Genuine engagement and discussion about the issues to be addressed – developing shared meaning and purpose – before moving on to 'problem-solving'. This must include a diverse range of actors and community members at all organisational levels. All actors understanding the system in which they operate (and their role within it). Awareness of the divisions between traditional ways of working and whole-system working. The former may involve hierarchical leadership and complex targets and plans while the approach of the latter may be to increase opportunities for natural adaption. ## Evidence statement 1.3: Implications of whole-system theory for those working within the system Individuals participate in their own capacity rather than as a representative of an organisation, community or profession so that they only agree to do what is in their power. Successful and productive communication within or across organisations may require innovative approaches to break down traditional restrictions stemming from hierarchies and differing expectations of organisations, professions and individuals. The personal qualities of individuals working within the system may be important. Personal qualities such as optimism, empathy, humility and tenacity may increase the likelihood of success. A willingness to take the 'long view' rather than go for the 'quick fix' is essential for a systems approach to be effective. ## Evidence statement 1.4: Implications of a whole-system approach for evaluation In a whole-system approach, it is the function rather than the form of activities that is standardised. The change in behaviour of individuals working within the system, through developing relationships and creating robust networks, is central. Evaluating a systems approach is complex. Different techniques for evaluation may be required to assess the added benefit of taking a systems approach. Process outcomes and the robustness of the systems are of particular interest (over and above short term outcomes). Evaluation of a systems approach needs to consider the networks that have been established and the relationships and synergies between and within settings. Evaluation of a systems approach may be time consuming. ## Evidence statement 1.5: Potential challenges of whole-system working Challenging long-standing assumptions can be uncomfortable. Traditional organisational structures are culturally embedded and change may appear chaotic. ## Evidence statement 1.6: The features of a systems approach to tackle health problems Identifying a system: explicit recognition of the public health system with the interacting, self-regulating and evolving elements of a complex adaptive system. Recognise that a wide range of bodies with no overt interest or objectives referring to public health may have a role in the system and therefore that the boundaries of the system may be broad. Capacity building: an explicit goal to support communities and organisations within the system. For example, increasing understanding about obesity in the community and by potential partner organisations or training for those in posts directly or indirectly related to obesity. Creativity and innovation: mechanisms to support and encourage local creativity and/or innovation to address obesity. For example, mechanisms that allow the local community to design locally relevant activities and solutions. Relationships: methods of working and specific activities to develop and maintain effective relationships within and between organisations. For example, establishing and maintaining relationships with organisations without a health remit or an overt focus on obesity. Engagement: clear methods to enhance the ability of people, organisations and sectors to engage community members in programme development and delivery. For example, sufficient time in projects allocated to ensuring that the community can be involved in planning and assessing services. Communication: mechanisms to support communication between actors and organisations within the system. For example, ensuring sufficient face-to-face meeting time for partners, having planned mechanisms for feeding back information about local successes or changes. Embedded action and policies: practices explicitly set out for obesity prevention within organisations within the system. For example, local strategic commitments to obesity, aligning with wider policies and drivers (such as planning or transport policy) and ensuring obesity is an explicit concern for organisations without a health remit. Robust and sustainable: clear strategies to resource existing and new projects and staff. For example, contingency planning to manage risks. Facilitative leadership: strong strategic support and appropriate resourcing developed at all levels. For example, specific methods to facilitate and encourage bottom-up solutions and activities. Monitoring and evaluation: clear methods to provide ongoing feedback into the system, to drive change to enhance effectiveness and acceptability. For example, developing action-learning or continuous-improvement models for service delivery. ## Evidence statement 2.1: paucity of evidence There is a paucity of evidence on the effectiveness of community-wide programmes displaying features of a whole-system approach to prevent obesity. Of the eight community-wide obesity prevention programmes included in this review – two before-and-after (one and one ) three non-randomised control trials (all ) one controlled before-and-after study (+); one longitudinal epidemiological study (+); and one repeated cross-sectional survey (+) – none were undertaken in the UK and all targeted children below 14 years. Although they stated an aim to influence the wider community through the programme, including parents, childcare centre workers, teachers and other members of the community. This evidence is judged to be partially applicable to communities of a similar size in the UK. ## Evidence statement 2.2: Range of whole-system approach (WSA) features in obesity prevention programmes None of the eight obesity prevention programmes included in the review demonstrated evidence of explicit recognition of the public health problem as a system. All programmes demonstrated inconsistent evidence of local creativity. Seven programmes demonstrated more robust evidence of capacity building, robustness and sustainability and community engagement, but this was still inconsistent across the groups and all these features did not appear across the same seven programmes. Five obesity prevention programmes demonstrated inconsistent evidence of a focus on the embeddedness of actions and policies, and of developing working relationships within and between partners. Four of the obesity prevention programmes demonstrated inconsistent evidence of a focus on enhancing communication between actors and organisations within the system, facilitative leadership and the use of well-articulated methods for monitoring and evaluation of activities. ## Evidence statement 2.3: The effectiveness of obesity prevention programmes – anthropometric outcomes Overall, there is evidence from a range of community-wide obesity programmes that they can have a beneficial effect on body mass index (BMI) scores, weight gain or the prevalence of overweight and obesity in children. However, these observed differences tended to be relatively small and were not always significant. There is no clear evidence of a relationship between features of system working and programme effectiveness. Studies reported lower BMI scores (one controlled before-and-after; one non-randomised control trial; and one repeated cross-sectional survey). Lower BMI z scores (and one before-and-after and one non-randomised control trial); weight gain (and one cross-sectional survey in France); increase in waist circumference or the prevalence of overweight or obesity (and one longitudinal study). Only one before-and-after (+) study in New Zealand reported a statistically non-significant increase in the prevalence of overweight or obesity among the intervention group. ## Evidence statement 2.4: The effectiveness of obesity prevention programmes – diet and physical activity outcomes There is some evidence that community-wide obesity programmes can have a beneficial effect on diet or physical activity outcomes in children. However, there is no clear evidence of a relationship between features of a system working and the programme's effectiveness. Studies reported a significant decrease in the number of daily servings of 'less healthy' foods and increased daily servings of vegetables and less TV viewing (one controlled before-and-after study). A statistically significantly higher percentage of children passing a fitness test post intervention (one before-and-after study) and a statistically significant increase in diet and activity 'best practice' at childcare centres (one before-and-after study). One non-randomised control trial study also reported a decrease in the number of children unhappy with their body size post intervention. ## Evidence statement 2.5: Relationship between system working and effectiveness of obesity prevention programmes Due to the degree of variation across studies, the small number of the included studies, and the wide range of outcomes reported, the relationship between the presence of features of system working and the effectiveness of community-based programmes to prevent obesity remains ambiguous. It is therefore not possible to suggest a clear relationship. Two community programmes based in Australia demonstrated the strongest evidence for system working. One controlled before-and-after (+) study describes nine out of the ten features of system working, and demonstrated favourable (though statistically non-significant) between-group differences in anthropometric outcomes. The programme also reported favourable outcomes relating to nutrition (that were statistically significant) and physical activity (that were statistically non-significant). The other study, a (+) non-randomised control trial, shows clear evidence of six out of ten features of a whole system approach, and makes implicit reference to an additional three features. This study reports statistically non-significant between-group decreases in BMI, weight gain and the prevalence of overweight and obesity. Three community programmes in the US showed five to seven features of whole-system working. One (+) study clearly demonstrates the presence of four WSA features and implies another three features. This study reported a non-significant decrease in BMI z scores. Another (+) study describes three WSA features and makes reference to another three features. It reported a statistically significant change in the prevalence of obesity and improvements in fitness among children post-intervention. Another (−) study describes only two WSA features and makes reference to another three features. No anthropometric outcomes were reported, but the authors reported a statistically non-significant post-intervention increase in diet and activity 'best practices' at childcare centres. The remaining three community programmes clearly displayed evidence of four or fewer features of whole-system working. One longitudinal epidemiological (+) study based in France clearly demonstrated evidence of four features, and demonstrated unclear evidence of two additional features. Another, related, repeated cross-sectional (+) survey in France demonstrated unclear evidence of four features. Both studies showed significant pre-/post-reductions in obesity prevalence. One (+) non-randomised control trial from New Zealand provides unclear evidence of two features and reported a between-group statistically significant and favourable change in BMI z scores. ## Evidence statement 3.1: System recognition According to three UK studies (one and two ) and one (−) USA study, it is important to recognise the system in which public health problems such as obesity exist. The importance of collaborative working practices (such as partnership working, using novel networks, or managing meetings in a constructive, non-hierarchical way) was also recognised. ## Evidence statement 3.2: Ownership and involvement According to three studies (one and one based in the UK and one based in the USA), partner organisations need to feel that they are actively involved and have some 'ownership' of a strategy. This can help reduce the strain between partner organisations. It is important to develop shared awareness and perspectives (for example, through pre-engagement work or training), but this may take considerable time (that is, years rather than months). Consultations should be focused to prevent partners becoming disillusioned and community concerns recognised, even if these are at odds with those envisaged in the public health programme. ## Evidence statement 3.3: Capacity building According to three (−) studies – one from the USA, one from the UK and one from New Zealand, adequate time and resources need to be set aside for capacity building. Training and awareness-raising may be particularly important – for example to increase staff evaluation (or other technical) skills or bring health onto the agenda of bodies that do not have public health as a primary concern (for example, city planners), according to four (+) UK studies. ## Evidence statement 3.4: Partnerships According to eight studies (two from the UK; three from the UK; one from the UK; one from the USA; and one from New Zealand) partnerships may encounter problems in establishing consensus on the design, delivery and priorities of a programme. Partnerships need time and space to develop and are likely to be stronger where: there is active involvement from both the community and senior staff in key organisations (with communication downwards and upwards) -rganisations have a positive historical relationship actors form natural communities and share at least some interests or areas of work pre-existing tensions are resolved there is strategic leadership a common language is developed (poor communication can lead to silo working and strained relationships). Studies also found joint working is easier where programme workers have the skills to establish a relationship with the local community and key individuals can act as 'boundary spanners' across organisations, linking their concerns (two UK; six UK; one UK; one New Zealand and one USA). Such individuals can be vital to the success of a programme, but this has implications for sustainability (one UK). ## Evidence statement 3.5: Embeddedness Whole-system working is more likely to become embedded where whole systems principles are integrated into strategy and policy documents (one UK) and actions and policies are present at both strategic and operational levels (one UK). ## Evidence statement 3.6: Sustainability The sustainability of whole-systems approaches may be hindered by traditional organisational structures (one UK) or poor experience from previous projects (one UK). According to seven studies (two UK; one UK; one UK; one USA; one USA; one New Zealand) funding issues impact on the sustainability of a whole-system approach for a range of reasons including: difficulties in making the case for funding for diffuse objectives the lack of continuity and stability inherent in short-term funding for addressing long-term issues inadequate staffing levels. ## Evidence statement 3.7: Leadership According to four UK studies (three and one ) strategic leadership was considered important when implementing a whole-system approach – for example, ensuring focus in programme meetings, providing clarity on staff roles, managing tensions between programme staff, providing active leadership at local level and demonstrating personal commitment. However, implementing formal accountability arrangements in cross-organisation partnerships can be difficult. Leadership may face a range of problems including difficulties in achieving consensus between partners (one UK); tensions between local and national priorities, ensuring the overall strategic direction does not stifle local leadership (one UK) and difficulties ensuring inclusive working with minimal resources. Studies have noted implementation problems related to management decisions taken without staff consultation, autonomy of local staff and clarity of management structures, and local programme staff feeling isolated from a national programme (one UK). ## Evidence statement 3.8: Monitoring and evaluation According to two UK studies (one and one ) the usefulness of evaluation may be limited by a lack of clarity about objectives and a lack of specificity about outcomes to be measured. Six studies (one USA, one UK and two UK) found intermediate or broader outcome measures may be more appropriate for assessing whole-system approaches, at least in the first instance, rather than specific short-term health outcomes. Broader indicators of success may have the added benefit of fostering partnership working. It may be particularly difficult to evaluate non-health outcomes and 'reward' partners who do not have a traditional health role. Problems may arise with data collection where staff responsible for collecting the data are unclear about its usefulness or relevance, partners use different information systems or where organisations struggle to reach a consensus on appropriate outcome measures. Unresolved organisational issues or the promotion of a working culture where partners feel unable to openly discuss problems in implementation may act as a barrier to organisational learning (one UK). There may be an unfounded assumption at national level that local agencies have the capacity to develop and deliver a whole system approach. ## Evidence statement 3.9: National policy and priorities According to two studies (both one USA and one UK) the broader political climate may open a 'national policy window' that facilitates policy change, influencing the ability to take a systems approach. Three UK studies (all ) found this would enable partnerships that focus on addressing health inequalities. Supportive national policy can help foster partnerships and influence the local agenda. However, changes in national policy may create uncertainty (one UK) and reduce the credibility of local programmes. Targets or funding attached to narrowly defined areas of health, and limited timeframes may limit the ability to take a systems approach (one UK). ## Evidence statement 4.1: Quantity and quality of published cost effectiveness and obesity modelling evidence Only four published economic evaluations were found which related to community-wide multi-faceted obesity prevention or smoking prevention programmes. Two of the economic evaluations (a conference poster relating to the 'Be active eat well' programme in Australia, and a 3-page section of a larger evaluation report on the 'Breathing space' smoking prevention intervention in Edinburgh) were not presented in sufficient detail to warrant a full summary or critical appraisal. The other two cost-effectiveness analyses were not comparable because they were: A small pilot-trial based cost-effectiveness analysis of a school-based community-wide child obesity prevention programme (in New Zealand, results presented in $NZ per kg of weight gain prevented after 2 years). A modelling-based study of the cost-effectiveness of two US-based community-wide campaigns to promote physical activity (the 'Stanford five cities project' and 'Wheeling walks' programme for older people – results presented in cost per life-year and cost per quality-adjusted life-year). ## Evidence statement 4.2: Cost-effectiveness findings There is evidence from only one community-wide obesity prevention programme that estimated incremental cost-effectiveness ratios, and can be judged as having used appropriate methods (of the APPLE pilot project in four small towns in New Zealand). However, while having some community-based activities, the APPLE project was judged to only weakly exhibit two of the ten defined features of a whole-system approach. Only four published economic evaluations were identified that were potentially relevant to the scope of this guidance. Two of these studies were so under-reported that their findings cannot be relied upon. The other included cost-effectiveness study was of two community-wide physical activity promotion campaigns in the USA. ## Evidence statement 4.3: Approaches to modelling of obesity and for obesity prevention Simulation modelling of obesity or obesity policies is still at a relatively early stage of development. However, in some cases methods for modelling outcomes in the area of obesity and obesity prevention policies or programmes has already become so complex and advanced that the usefulness (or even feasibility) of attempting to develop credible new models without significant modelling capacity, access to national data, and significant modeller time and other resources is questionable. Instead, with limited resources, any realistic modelling of alternative local community-wide obesity prevention policies should aim to make best use of one of the well-established and tested existing population-level obesity models (such as the National Heart Forum's micro-simulation model, or the ACE Obesity model framework). ## Evidence statement CR1: Establishing a community-wide approach to preventing obesity – key actors and players A genuinely community-wide approach to preventing obesity includes a vast range of actors and agencies. For such a network to be effective, partners must share an overarching vision around obesity prevention, with each organisation 'buying in' and feeling a sense of ownership. At the strategic level, the impetus for a community-wide approach begins with local elected members and senior managers (particularly from the NHS and the local authority). Public health is best placed to provide investment and leadership for the network of partners, aided by the health and wellbeing board that needs to exert its influence on the clinical commissioning group to ensure investment and 'buy in' across community health services. In order to build the network of partners, local communities and services should be viewed from the perspective of individual citizens, to identify the most relevant services regularly used and trusted by key groups such as parents. Once signed up as partners, these services can be leveraged to make every contact count. Information needs to be shared and relationships developed both 'horizontally' across partner organisations, and 'vertically' inside individual organisations. Failure to ensure middle managers and frontline workers share the vision and understand the community-wide approach is perhaps the most common factor limiting the effectiveness of such partnerships. The main delivery organisations (for example, community projects with provider contracts) must have credibility in their local communities. Community engagement is the key activity in building and developing this credibility. ## Evidence statement CR2: Facilitators of an effective community-wide approach Having a central coordination and communications function is considered to be essential and must engage beyond senior management level in the partner organisations, striving to ensure middle managers share the vision, and are well informed about the wider network. Concise briefings on key issues are important for middle managers and frontline staff, to build confidence, capacity and consistency in messaging across the wide range of partners. Partner organisations should be expected to make an explicit commitment of what they will contribute, and this should be publicised across the network. Those making investment decisions should build on proven success by 'backing winners', and concentrate investment where it is most likely to succeed. Strategy should take an iterative approach, reviewing progress regularly. ## Evidence statement CR3: Barriers to an effective community-wide approach Starting conversations about obesity with individual clients and patients is difficult, and there are numerous reasons why staff may not have the confidence or the motivation to do so, even among primary care professionals. It is very important to build confidence and capability among customer-facing staff in both primary care and community settings, as the credibility of messages from the latter will be seriously undermined if inconsistent with messages from the former. In terms of population-wide primary prevention, the term 'obesity' can be off-putting, and engagement with target audiences may be easier if the focus is framed as 'healthy lifestyles'. This more broad-based approach may also be more stable in terms of long-term funding. Financial barriers are significant for many low-income groups, particularly in terms of the cost of transport and accessing services. Cultural minorities and disabled people face additional barriers in accessing information and services, and their specific needs should be considered carefully when assessing needs. A significant contribution can be made by volunteers (health champions and peer mentors), but their effectiveness may be limited by the willingness of health professionals to make referrals to them. The prevention of obesity is a long-term objective, but most project funding is short term. There are complex personal, family and socioeconomic causes applying to many obese and overweight people. Both commissioners and providers would like to be able to commit to longer-term contracts for obesity prevention work, in recognition of the considerable time and resources needed to successfully engage with clients with complex needs, for whom positive short-term outcomes are less likely. ## Evidence statement CR4: Sustainability It is inevitable that funding streams will change over time. By recognising that obesity is an essential concern for many health and social issues, it should be possible to be flexible and creative in justifying ongoing funds for obesity prevention work, despite such changes. The strategy and the wider network of partners must be sustainable. The maintenance and development of the shared vision is fundamental for sustainability, and this requires effective communication to maintain the engagement, particularly with politicians and middle managers. Frontline staff and organisations may see themselves as peripheral to the issue of obesity. Having a strong local brand or identity is important, particularly for workers in the network of organisations, as it is important for them to feel part of a bigger picture. A key message in this communication must be the commitment to evaluation and ongoing service improvement. If pump-priming funds (that is, short-term funds, aimed at stimulating future investment from mainstream sources) are made available to establish the network, plans to transfer responsibilities to mainstream budgets should be built in wherever possible. However, in the context of current public expenditure constraints, mainstream incorporation cannot be guaranteed. The community-wide approach should seek to build on existing community assets. This will build capacity in people and institutions that will continue, even if obesity-specific funding diminishes. Commissioners should also consider that at some point in the future, they may be relying on influence and goodwill rather than contractual obligations. A clear separation of strategic and operational management, using boards and forums with distinctive terms of reference, may be helpful. ## Evidence statement CR5: Evaluation Data collection and monitoring can contribute to project sustainability, project management, keeping all parties focused on goals and service improvement. Evaluation is primarily considered for individual programmes, projects and interventions; a complex, community-wide approach is seldom evaluated. Further consideration needs to be given to the applicability and acceptability of different types of evidence, in the context of the very limited time and resources available at a local level. There is concern that while obesity prevention is a long-term challenge, with long timescales for return on investment, funding is very often short term, with unrealistic outcome expectations. Consideration should be given to the acceptance of intermediate outcomes in commissioning contracts. The example of 'job readiness' in employment-related community work was cited, with the suggestion that 'weight-loss readiness' was a similarly legitimate intermediate outcome. There is a tension between the use of narrow, quantitative outcome criteria (often the focus of commissioners), versus a broader range of outcome measures including qualitative data of community wellbeing (often the focus of providers). Evaluation is often focused on contract performance management. There was little evidence of a systematic approach to building a local evidence base. Project timetables and budgets rarely allow for the establishment of robust baselines on which to base evaluations. Evaluation often ignores clients who had dropped out of the programme or intervention. This would seem to be a significant gap in the development of evidence. Providers express concerns about the burden of data collection and monitoring, particularly those receiving funding from multiple sources. There is frustration at the inconsistency of data required by different funders. Evaluators should properly brief those collecting the data on the rationale and requirements. ## Evidence statement CR6: Cost effectiveness Very little true cost-effectiveness evaluation is undertaken at a local level due to the lack of specialist skills. To commission externally is expensive, and if the skills are available internally it is very time intensive. Thus, cost-effectiveness analysis may be considered not justified on grounds of cost effectiveness. There seems to be relatively little scrutiny of cost effectiveness (as opposed to cost management). Budget holders at a higher level appear to have limited understanding of cost-effectiveness analysis, and as a result, there is little pressure to undertake such work. Some participants expressed concern that public health investment might be disadvantaged by more exposure to cost-effectiveness analysis, due to public health delivering longer-term returns on investment, and the difficulty of attributing cause and effect (relative to clinical treatment). There was also a concern that truly like-for-like comparisons are difficult to achieve in cost-effectiveness analysis. In this view there was a risk of simplistic interpretation, in which differences between programmes and interventions may be caused by underlying socioeconomic factors that were not visible in the calculation. # Additional evidence Expert paper 1: 'Whole systems – adapted and designed' Expert paper 2: 'Lessons from tobacco control' Expert paper 3: 'Systems and system failure' Expert paper 4: 'Whole system approaches to obesity – progress and future plans' Expert paper 5: 'Insight, experiences and evidence of the Childhood Obesity National Support Team' Expert paper 6: 'Cycling cities/cycling demonstration towns initiative' Expert paper 7: 'The contribution of health trainers, community health champions and the general public' Expert paper 8: 'Well London' Expert paper 9: 'Tower Hamlets healthy borough programme' Expert paper 10: 'Healthy places, healthy lives – tackling childhood obesity in Luton case study' Expert paper 11: 'Exeter cycling demonstration town 2005 to 2011' Expert paper 12: 'Commissioning – learning from Sheffield and Rotherham' Expert paper 13: 'Evaluation in Hull' Expert paper 14: 'Working in partnership: An example from a rural area – South Gloucestershire' Expert paper 15: 'Tackling obesity in a rural county' Expert paper 16: 'West and Mid Essex local commissioning experience' Expert paper 17: 'Effective partnership working and stakeholder engagement in the delivery of obesity prevention and treatment programmes in Kirklees' Expert paper 18: 'Short paper on organisational issues' Expert paper 19: 'Evaluating complex community-based interventions (CBIs) for obesity prevention' # Economic modelling report Where two organisations decide to work in partnership to implement an intervention more effectively than they could while working alone and there is a low initial cost, the partnership can usually be considered cost effective. When the partnership is known to lead to cost savings (especially as a result of sharing resources), it will be cost effective provided that the health benefits are not diminished when the organisations work together. In more complex situations, it is unclear whether or not partnerships are cost effective, because conventional cost-effectiveness methods cannot be applied. On funding for projects, a simple model suggests that obesity projects with long-term funding are likely to be more cost effective than equivalent projects with less secure funding. Previous modelling suggests that any public health interventions costing £10 or less per head will be cost effective for all except the smallest weight losses (or weight gains prevented). Engaging with local communities can, for a relatively low cost, ensure aspects of a large project that have not been acceptable to a community may be modified, and result in large community gains that would otherwise have been rejected. The decision to engage will depend on whether the original plans are likely to succeed without engagement, and the likelihood that engagement will succeed in producing a consensus in favour of a modified project.# Appendix D Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence reviews, commissioned primary research and expert testimony. These gaps are set out below. . Community-wide programmes a) Few community-wide obesity programmes have been evaluated (that is, programmes involving multiple actions locally). Those that do exist are mainly school-based, the components are often inadequately described, and the terminology varies from study to study. Follow-up times are too short and clients who dropped out are often ignored. b) There is a lack of evidence on community based obesity prevention programmes for children and adults with disabilities. (Source: review 1 and 2; commissioned report; PDG discussions) . Partnerships There is a lack of evidence on community-wide partnership working. In particular, the following questions need answering: a) What are the most cost-effective components of a partnership? b) How can oversight and management committees or groups effectively manage a partnership? How can the best local representatives for these committees or groups be identified? c) On what basis should a decision be made to form a local partnership – as opposed to working unilaterally? d) Is there a difference between 'adaptive' (that is, voluntary) partnerships that emerge spontaneously and 'mandated' (imposed from above) partnerships in terms of effectiveness? e) What are the best incentives or techniques to encourage partnership working? (Source: PDG discussions) . Complexity of local systems There is a lack of evidence on how complexity theory, management theory, change theory and a whole-systems approach works in practice. Specifically, we need to know: a) What are the synergies between common actions to tackle obesity? b) Where are the greatest opportunities for tackling obesity in any given community? c) How can the local system – and components of the local system – evolve to better tackle obesity? d) Does a local community programme that focuses on prevention tend to work against efforts in the same community to treat people who are already obese (and vice versa)? (Source: PDG discussions) . Health economics There is a lack of evidence on the economics of community-wide partnership working to prevent obesity. This type of activity involves complex interactions and is not amenable to current economic evaluation techniques. (Source: PDG discussions) . Scalability There is a lack of evidence on the practicality and effectiveness of extending or 'scaling up' small obesity prevention programmes. 'Scalability' in this sense means increasing the: geographic coverage number of contexts in which it is offered number of participants. (Source: PDG discussions) . Programme composition There are unresolved questions about the composition of an effective, local community-wide programme aimed at tackling obesity, specifically: a) How can a 'community development' approach best be applied? b) How can learning from other programmes be used (for example, how transferrable is the learning from tobacco or alcohol control programmes)? c) What combination of features ensures a programme is effective – and how do they relate to each other? d) What aspects of a community-wide intervention (or parts of an intervention) need guidance to ensure health and community workers can implement them effectively? e) How 'intense' does a programme need to be, both in terms of the number of interventions (or sub-interventions), and the amount of activities involved in each one? (Source: PDG discussions) . Sustainability There is a lack of evidence on how to ensure programmes can be sustained over the longer term. This includes effective ways of ensuring: continuation of funding, the partnership remains strong, volunteer and 'Please link to glossary participation and long-term leadership. (Source: PDG discussions) . Business There is a lack of evidence on how to get local businesses (in particular, small businesses) and chambers of commerce involved in obesity prevention work. (Source: PDG discussions) . Measurement There is a lack of evidence on effective measurement and segmentation tools that could be used as part of the JSNAs and for programme evaluation. Similarly, there is a lack of research on appropriate benchmarks that could be used. (Source: PDG discussions)# Appendix E Supporting documents Supporting documents include: Evidence reviews: Review 1 'Identifying the key elements and interactions of a whole system approach to obesity prevention' Review 2 'The effectiveness of whole system approaches to prevent obesity' Review 3 'Barriers and facilitators to effective whole system approaches'. Review of economic evaluations: 'Whole system approaches to obesity prevention: Review of cost-effectiveness evidence'. Economic modelling: 'Cost effectiveness analysis in partnership working for reducing obesity and other long-term conditions'. Commissioned report: 'Implementing community-wide action to prevent obesity: opinions and experiences of local public health teams and other relevant parties'. Expert testimony: Expert paper 1: 'Whole systems – adapted and designed' Expert paper 2: 'Lessons from tobacco control' Expert paper 3: 'Systems and system failure' Expert paper 4: 'Whole system approaches to obesity – progress and future plans' Expert paper 5: 'Insight, experiences and evidence of the Childhood Obesity National Support Team' Expert paper 6: 'Cycling cities/cycling demonstration towns initiative' Expert paper 7: 'The contribution of health trainers, community health champions and the general public' Expert paper 8: 'Well London' Expert paper 9: 'Tower Hamlets healthy borough programme' Expert paper 10: 'Healthy places, healthy lives – tackling childhood obesity in Luton case study' Expert paper 11: 'Exeter cycling demonstration town 2005 to 2011' Expert paper 12: 'Commissioning – learning from Sheffield and Rotherham' Expert paper 13: 'Evaluation in Hull' Expert paper 14: 'Working in partnership: An example from a rural area – South Gloucestershire' Expert paper 15: 'Tackling obesity in a rural county' Expert paper 16: 'West and Mid Essex local commissioning experience' Expert paper 17: 'Effective partnership working and stakeholder engagement in the delivery of obesity prevention and treatment programmes in Kirklees' Expert paper 18: 'Short paper on organisational issues' Expert paper 19: 'Evaluating complex community-based interventions (CBIs) for obesity prevention'. # Finding more information To find NICE guidance on related topics, including guidance in development, see the NICE topic page on obesity. For full details of the evidence and the guideline committee's discussions, see the evidence reviews and expert papers. You can also find information about how the guideline was developed. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.	{'Introduction: scope and purpose of this guidance': "# What is this guidance about?\n\nThis guidance aims to support effective, sustainable and community-wide action to prevent overweight and obesity in adults and overweight and obesity in children. It sets out how local communities, with support from local organisations and networks, can achieve this. The recommendations cover:\n\ndeveloping a sustainable, community-wide approach to obesity\n\nstrategic leadership\n\nsupporting leadership at all levels\n\ncoordinating local action\n\ncommunication\n\ninvolving the community\n\nintegrated commissioning\n\ninvolving businesses and social enterprises operating in the local area\n\nlocal authorities and the NHS as exemplars of good practice\n\nplanning systems for monitoring and evaluation\n\nimplementing monitoring and evaluation functions\n\ncost effectiveness\n\norganisational development and training\n\nscrutiny and accountability.\n\nThis guidance focuses on the prevention of overweight and obesity. The recommendations may also help people who are already overweight or obese to lose weight, or to prevent them from gaining further weight. It does not cover clinical management for people who are already overweight or obese.\n\nA 'sustainable, community-wide approach' to prevent obesity involves a set of integrated services and actions delivered by the many organisations, community services and networks that make up the local system.\n\nFor the purpose of this guidance, 'local community' refers to a group of people from the same geographic location that is not necessarily related to any official, administrative boundary. The community may be located in a ward, borough, region or city. This guidance does not cover interventions in a particular setting (such as a school or workplace) that do not involve the wider community.\n\nThe guidance has a strong focus on local partnership working. For the purpose of this guidance, a partner could be a local department, service, organisation, network, community group or individual that could help prevent obesity.\n\n# Who is this guidance for?\n\nThis guidance is for local policy makers, commissioners, managers, practitioners and other professionals working in local authorities, the NHS and the wider public, private, voluntary and community sectors. It is particularly aimed at:\n\nlocal authority chief executive officers\n\nexecutive directors of local authority services (such as directors of children's or adult's services and directors of planning or leisure services)\n\ndirectors of public health, members of health and wellbeing boards\n\nelected members (particularly council leaders, including cabinet leads for health)\n\ncommunity champions.\n\nThe recommendations will also be of interest to academic organisations involved in designing and evaluating community-wide interventions to prevent and manage obesity, as well as members of the public.\n\n# Why is this guidance being produced?\n\nThis guidance focuses on an overarching approach to obesity in local communities and the importance of integrating action on obesity in other local agendas (such as initiatives to prevent type 2 diabetes, cardiovascular disease and cancers, or initiatives to improve the environment and promote sustainability).\n\nThe guidance will support the government's call for action on obesity and the public health outcomes framework. It provides an organisational framework for existing NICE guidance (community-based or individual interventions) that directly or indirectly impacts on obesity prevention or management.\n\nThe ongoing structural changes to the public sector, particularly local authorities and the NHS, have influenced the direction and tone of the recommendations. This guidance is intended to support organisations that have a role in obesity prevention in the wider public health agenda, including Public Health England, the National Commissioning Board, local authorities, local Healthwatch, local health and wellbeing boards and clinical commissioning groups.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe guidance complements, but does not replace, NICE's other guidance on obesity.\n\nThe Programme Development Group (PDG) considers that the recommended approaches are cost effective.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nFor the gaps in research, see appendix D.\n\nSee also the evidence reviews, supporting evidence statements and economic modelling report.\n\n# Guiding principles\n\nThe recommendations should be undertaken in parallel, wherever possible as part of a system-wide approach to preventing obesity. Ideally, to be as cost effective as possible, they should be implemented as part of integrated programmes that address the whole population, but with a scale and intensity that is proportionate to addressing locally identified inequalities in obesity and associated diseases and conditions.\n\nThe guidance provides a framework for existing NICE guidance (community based or individual interventions) that directly or indirectly impacts on obesity prevention or management.\n\nOther NICE guidance can also be used to ensure effective delivery of the recommendations made in this guidance (see below).\n\n## Community engagement\n\nThe prerequisites for effective community engagement are covered in NICE's guideline on community engagement.\n\n## Behaviour change\n\nThe prerequisites for effective interventions and programmes aimed at changing behaviour are covered in NICE's guideline on behaviour change: general approaches. In summary, NICE recommends that interventions and programmes should be based on:\n\ncareful planning, taking into account the local and national context and working in partnership with recipients\n\na sound knowledge of community needs\n\nexisting skills and resources, by identifying and building on the strengths of individuals and communities and the relationships within communities.\n\nIn addition, interventions and programmes should be evaluated, either locally or as part of a larger project, and practitioners should be equipped with the necessary competencies and skills to support behaviour change. This includes knowing how to use evidence-based tools. (NICE recommends that courses for practitioners should be based on theoretically informed, evidence-based best practice.)\n\n## Cultural appropriateness\n\nThe prerequisites for culturally appropriate action are outlined in NICE's guideline on type 2 diabetes prevention: population and community interventions. The guidance emphasises that culturally appropriate action takes account of the community's cultural or religious beliefs and language and literacy skills by:\n\nUsing community resources to improve awareness of, and increase access to, interventions. For example, they involve community organisations and leaders early on in the development stage, use media, plan events or make use of festivals specific to black and minority ethnic groups.\n\nUnderstanding the target community and the messages that resonate with them.\n\nIdentifying and addressing barriers to access and participation, for example, by keeping costs low to ensure affordability, and by taking account of different working patterns and education levels.\n\nDeveloping communication strategies that are sensitive to language use and information requirements. For example, they involve staff who can speak the languages used by the community. In addition, they may provide information in different languages and for varying levels of literacy (for example, by using colour-coded visual aids and the spoken rather than the written word).\n\nTaking account of cultural or religious values, for example, the need for separate physical activity sessions for men and women, or in relation to body image, or beliefs and practices about hospitality and food. They also take account of religious and cultural practices that may mean certain times of the year, days of the week, settings, or timings are not suitable for community events or interventions. In addition, they provide opportunities to discuss how interventions would work in the context of people's lives.\n\nConsidering how closely aligned people are to their ethnic group or religion and whether they are exposed to influences from both the mainstream and their community in relation to diet and physical activity.\n\n# Whose health will benefit from these recommendations?\n\nEveryone in a locally defined community but, in particular, vulnerable groups and communities where there is a high percentage of people who are at risk of excess weight gain or who are already overweight or obese (this includes those from particular ethnic or socioeconomic groups, those who are less likely to access services, people with mental health problems, a learning or physical disability). For more information, see the section on public health need and practice).\n\n# Recommendation 1 Developing a sustainable, community-wide approach to obesity\n\n## Who should take action?\n\nCouncil leaders and elected members.\n\nLocal authority chief executive officers.\n\nHealth and wellbeing boards.\n\nDirectors of public health.\n\nExecutive directors of local authority services.\n\nLocal NHS trusts.\n\nLocal Healthwatch.\n\nLeaders of local voluntary and community organisations.\n\nClinical commissioning groups.\n\nLocal education and training boards.\n\n## What action should they take?\n\nAll of the above should ensure, through the health and wellbeing board, a coherent, community-wide, multi-agency approach is in place to address obesity prevention and management. Activities should be integrated within the joint health and wellbeing strategy and broader regeneration and environmental strategies. Action should also be aligned with other disease-specific prevention and health improvement strategies such as initiatives to prevent type 2 diabetes, cancers and cardiovascular disease, as well as broader initiatives, such as those to promote good maternal and child nutrition or mental health or prevent harmful drinking. (See NICE's guidelines on type 2 diabetes prevention: population and community interventions, cardiovascular disease prevention, maternal and child nutrition, and alcohol use disorders: prevention.)\n\nHealth and wellbeing boards, supported by directors of public health, should ensure joint strategic needs assessments (JSNAs) address the prevention and management of obesity. They should ensure JSNAs:\n\n\n\nconsider the full range of factors that may influence weight, such as access to food and drinks that contribute to a healthy and balanced diet, or opportunities to use more physically active modes of travel\n\nconsider inequalities and the social determinants of obesity\n\nconsider local evidence on obesity (such as data from the National Child Measurement Programme).\n\n\n\nHealth and wellbeing boards should ensure tackling obesity is one of the strategic priorities of the joint health and wellbeing strategy (based on needs identified in JSNAs).\n\nHealth and wellbeing boards and local authority chief executive officers should encourage partners to provide funding and other resources for activities that make it as easy as possible for people to achieve and maintain a healthy weight. This includes, for example, activities to improve local recreation opportunities, community safety or access to food that can contribute to a healthier diet. Partners should be encouraged to provide funding and resources beyond one financial or political cycle and have clear plans for sustainability.\n\nHealth and wellbeing boards should work in partnership with local clinical commissioning groups to ensure a coherent approach to tackling obesity that spans both prevention and treatment.\n\nHealth and wellbeing boards should work with partners to optimise the positive impact (and mitigate any adverse impacts) of local policies on obesity levels. This includes strategies and policies that may have an indirect impact, for example, those favouring car use over other modes of transport, or decisions to remove park wardens, that affect people's use of parks.\n\nHealth and wellbeing boards, through their performance infrastructure, should regularly (for example, annually) assess local partners' work to tackle obesity (taking account of any relevant evidence from monitoring and evaluation). In particular, they should ensure clinical commissioning group operational plans support the obesity agenda within the health and wellbeing strategy.\n\n# Recommendation 2 Strategic leadership\n\n## Who should take action?\n\nDirectors of public health and public health teams.\n\nChairs of local health and wellbeing boards.\n\nExecutive directors of local authority services.\n\nCouncil leaders and elected members.\n\nLeaders of local voluntary and community organisations.\n\nClinical commissioning group leads for obesity (where they exist).\n\nClinical commissioning representatives on local health and wellbeing boards.\n\nLocal education and training boards.\n\n## What action should they take?\n\nAll of the above should provide visible, strategic leadership to tackle obesity at all levels and ensure an effective team is in place.\n\nDirectors of public health and public health teams should ensure all those responsible for activity that impacts on obesity understand the needs and priorities of the local community, as outlined in JSNAs. They should ensure all partners understand JSNA priorities and be prepared to decommission services, if necessary, to divert resources to priority areas.\n\nLocal authority chief executive officers and directors of public health should:\n\n\n\nregularly brief elected members on the local prevalence of obesity, the health risks and the local factors that may have an impact\n\nhelp elected members identify what they can do to ensure obesity prevention is integrated across the breadth of council strategies and plans.\n\n\n\nDirectors of public health should seek to secure high-level commitment to long-term, integrated action on obesity, as part of the joint health and wellbeing strategy. This includes:\n\n\n\nlocal indicators and targets being established collaboratively with all partners\n\nensuring the strategy defines long-term goals and also includes short and intermediate measures\n\ncross-sector and two-tier (as appropriate) coordination and communication between transport, planning and leisure services at strategic level and better involvement of local communities in each of these policy areas\n\nensuring performance management focuses on processes that support effective partnership working as well as measuring outputs and outcomes\n\nensuring the strategy on obesity is reviewed regularly (for example, every 3\xa0to\xa05 years), based on needs identified in JSNAs and mapping of local assets.\n\n\n\nLeaders of local voluntary and community organisations should ensure the local approach to obesity:\n\n\n\nfully engages and addresses marginalised groups at particular risk of obesity\n\naddresses inequalities in obesity and associated diseases.\n\n\n\nAll clinical commissioning groups should be encouraged to identify an obesity or public health lead to work with the public health team on joint approaches to tackling obesity.\n\n# Recommendation 3 Supporting leadership at all levels\n\n## Who should take action?\n\nDirectors of public health and public health teams.\n\nHealth and wellbeing board chairs.\n\nClinical commissioning groups.\n\nExecutive directors of local authority services.\n\nCouncil leaders and elected members.\n\nChief executive officer of the local education and training board.\n\n## What action should they take?\n\nPublic health teams should identify and work with 'champions' who have a particular interest or role in preventing obesity in local authority and NHS strategy groups and public, private, community and voluntary sector bodies. This includes, for example, those involved in planning, transport, education and regeneration.\n\nAll of the above should work to build and support a network of leaders from all organisations and partnerships that could make a contribution to preventing obesity. This should include relevant local authority and NHS services, voluntary and community organisations and the private sector.\n\nDirectors of public health should support leaders at all levels (including senior and middle managers and frontline staff) of all the partnerships involved in local action on obesity, to ensure local people and organisations are empowered to take action. This means:\n\n\n\nproviding regular opportunities for partners to meet and share learning in both formal meetings and informal, open environments, as appropriate\n\naddressing any overlapping, fragmented or competing agendas among different partners and considering options to enhance cooperation and joint working (options might include workshops or away days)\n\nfunding small-scale community-led projects such as local gardening, cooking and walking groups; and exploring how such initiatives can contribute to defined long-term goals and can be evaluated in a proportionate way\n\nfostering a 'learning culture' by explicitly supporting monitoring and evaluation, especially for innovative interventions, and allowing partnerships to build on effective action and change or discard less effective solutions (see recommendations 10 and 11).\n\n\n\n# Recommendation 4 Coordinating local action\n\n## Who should take action?\n\nHealth and wellbeing boards.\n\nExecutive directors of local authority services.\n\nDirectors of public health and public health teams.\n\nCommunity-based health workers, volunteers, groups or networks.\n\nCommunity engagement workers such as health trainers.\n\n## What action should they take?\n\nLocal authority chief executive officers should ensure there is an effective public health team in place to develop a coordinated approach to the prevention of obesity. This should include:\n\n\n\na director or lead public health consultant to provide strategic direction\n\na senior coordinator who has dedicated time to support the director or consultant in their work on obesity and oversee the local programme. The coordinator should have:\n\n\n\nspecialist expertise in obesity prevention and community engagement\n\nthe skills and experience to work across organisational boundaries\n\n\n\ncommunity 'health champions' (volunteering with community or voluntary organisations) and other people who work directly with the community (such as health trainers and community engagement teams) to encourage local participation and support delivery of the programme.\n\n\n\nCoordinators should advise commissioners on contracts that support the local obesity agenda to ensure a 'joined-up' approach. They should encourage commissioners to promote better integration between providers through the use of joint contracts and supply chain models that provide a range of local options. The aim is to tackle the wider determinants of obesity and support local people to make changes in their behaviour to prevent obesity.\n\nDirectors of public health should ensure coordinators engage frontline staff (such as health visitors, environmental health officers and neighbourhood wardens) who can contribute to local action on obesity.\n\nDirectors of public health should ensure frontline staff set aside dedicated time to deliver specific aspects of the obesity agenda and receive training to improve their understanding of the needs of the local community and improve their practical implementation skills.\n\nCoordinators and community engagement workers (such as health trainers and community development teams) should work together to develop and maintain a map of local people and assets that could support a community-wide approach to combating obesity. This includes:\n\n\n\ncommunity-based health workers such as health visitors, community pharmacists or weight management group leaders\n\nexisting networks of volunteers and 'champions', health trainers and community organisations such as religious groups, sports clubs, school governors or parent groups\n\npeople working in the community, such as the police, park wardens, leisure centre staff, active travel coordinators, school crossing patrol officers or school and workplace canteen staff\n\nphysical activity organisations and networks such as county sport physical activity partnerships\n\nunused open spaces or meeting places that could be used for community-based events and courses.\n\n\n\nCoordinators and community engagement workers should jointly plan how they will work with population groups, or in geographic areas, with high levels of obesity. Plans should consider the motivations and characteristics of the target groups, in relation to obesity. Coordinators should also map where public, private, community and voluntary organisations are already working in partnership to improve health or on other relevant issues.\n\nCoordinators, supported by the director of public health, should encourage and support partnership working at both strategic and operational levels. They should ensure partner organisations are clear about their contribution and responsibilities. They should consider asking them to sign an agreement that pledges specific relevant actions in the short and long term.\n\n# Recommendation 5 Communication\n\n## Who should take action?\n\nDirectors of public health and public health teams.\n\nLocal government and NHS communications leads.\n\n## What action should they take?\n\nDirectors of public health and local government communications leads should ensure elected members and all management and staff working with local communities, both within and across partner organisations, are aware of the importance of preventing and managing obesity. The commitment of middle managers and those with a strategic role is particularly important. For example, they should:\n\n\n\nbe aware of, and committed to, the obesity agenda in the health and wellbeing strategy\n\nbe aware of the impact of obesity on other priorities (for example, the rising local incidence of type 2 diabetes, due to obesity).\n\n\n\nLocal government communications leads should ensure obesity prevention programmes are highly visible and easily recognisable. Recognition may be increased – and costs kept to a minimum – by adapting a widely known brand for use locally (such as NHS healthier families). Where appropriate, branding should be agreed by elected members and the health and wellbeing board.\n\nCommunications leads should ensure partners have shared vision, speak with 'a common voice' and are clearly identifiable to the community. This can be fostered by promoting all relevant activities under the obesity programme 'brand' and using this branding consistently over the long term.\n\nHealth and wellbeing board chairs and executive directors of local authority services should advocate for action on obesity in any discussions with partners or the local media.\n\nDirectors of public health and local government communications leads should carefully consider the type of language and media to use to communicate about obesity, tailoring language to the situation or intended audience. Local insight may be particularly important when developing communications to subgroups within a community or specific at-risk groups. For example, in communications to some local communities, it might be better to refer to a 'healthier weight' rather than 'preventing obesity', and to talk more generally about health and wellbeing or specific community issues. Making explicit the relevance of a wide range of initiatives for tackling obesity, for example in annual reports, may be helpful.\n\nThe local coordinator and public health teams should ensure the results of all monitoring and evaluation are made available to all those who can use them to inform their work, both in the local community and nationally. For example, log evaluation reports in the Obesity Learning Centre or Public Health England's healthy places databases, or the NICE shared learning database.\n\nThe local coordinator and communications leads should ensure information from monitoring and evaluation is accessible and easy to use by everyone in the community, including those involved with obesity prevention, local groups and networks, the media and the public. This includes presenting information in accessible formats and different languages.\n\n# Recommendation 6 Involving the community\n\n## Who should take action?\n\nLocal Healthwatch.\n\nLocal authority community involvement teams.\n\nDirectors of public health and public health teams.\n\nLocal voluntary and community organisations, champions and networks.\n\nCouncil leaders and elected members.\n\nClinical commissioning groups.\n\n## What action should they take?\n\nLocal Healthwatch, community involvement and public health teams should engage local people in identifying their priorities in relation to weight issues. For example, residents may feel that issues such as crime, the siting of hot food takeaways or alcohol outlets, the lack of well-maintained green space, pavement parking, speeding, or the lack of a sense of community are their top priorities. Where possible, it should be made explicit that local concerns often can (and do) impact on levels of obesity in the community.\n\nCommunity involvement and public health teams should work with local people, groups and organisations to decide what action to take on obesity. They should recognise local concerns both in terms of the focus of programmes or services and how they might be delivered. This includes involving local groups, networks or social enterprises in any discussions about service redesign and ensuring that they receive feedback about decisions taken.\n\nPublic health teams should use community engagement and capacity-building methods to identify networks of local people, champions and advocates who have the potential to co-produce action on obesity as part of an integrated health and wellbeing strategy. These networks include:\n\n\n\npeople who are active and trusted in the community\n\npeople who have the potential to be local health champions\n\npeople who represent the needs of subgroups within the community (such as people with disabilities or mental health problems)\n\nmarginalised groups such as asylum seekers or homeless people (where there is no established network or partnership working, additional action may be needed to get them involved)\n\nlocal champions (such as managers of youth or children's centres, school governors or parent groups, or those who organise walking or gardening groups)\n\npeople who can provide a link to local business or the private or voluntary sector\n\nadvocates who have a strong voice in the community, who can challenge social norms and beliefs of the community or who can champion obesity prevention and management as part of their usual role (this includes local elected members, GPs, head teachers, pharmacists, local weight management group leaders, health trainers, community leaders and representatives of local voluntary groups)\n\npatient or carer groups.\n\n\n\nPublic health teams should ensure those identified are provided with the resources and training they need to take action on obesity.\n\nClinical commissioning groups should make their GP practices aware of local obesity prevention and treatment services. They should encourage GPs to:\n\n\n\nmake all their patients aware of the importance of a healthy diet and physical activity in helping to prevent obesity\n\nsignpost people to relevant community programmes.\n\n\n\nCouncil leaders and elected members should raise the profile of obesity prevention initiatives through informal meetings with local people and groups and at formal ward meetings.\n\n# Recommendation 7 Integrated commissioning\n\n## Who should take action?\n\nLocal authority, NHS and other local commissioners.\n\nDirectors of public health and public health teams.\n\n## What action should they take?\n\nCommissioners and public health teams should foster an integrated approach to local commissioning that supports a long-term (beyond 5 years) system-wide health and wellbeing strategy.\n\nPublic health teams should ensure commissioners understand the demographics of their local area, and consider local insight on the motivations and characteristics of subgroups within local communities that may impact on obesity levels.\n\nCommissioners and public health teams should create an environment that allows the local system to take a truly community-wide approach to obesity. They should consider:\n\n\n\nwhich 'packages' of interventions are most effective (including cost effective)\n\nthe 'intensity' of effective programmes (for example, the number of interventions which make up an effective programme or the percentage of the population that should be reached)\n\nsynergies between common actions to tackle obesity.\n\n\n\nCommissioners should focus on all of the following areas (focusing on just one at the expense of others may reduce effectiveness):\n\n\n\nraising awareness of the health problems caused by obesity and the benefits of being a healthier weight among partners and the public\n\ntraining to meet the needs of staff and volunteers (prioritising those who are working directly with local communities)\n\ninfluencing the wider determinants of health, including, for example, ensuring access to affordable, healthier food and drinks, and green space and built environments that encourage physical activity\n\naiming activities at both adults and children in a broad range of settings\n\nproviding lifestyle weight management services for adults, children and families\n\nproviding clinical services for treating obesity.\n\n\n\nCommissioners should fund both targeted and universal services that can help people achieve or maintain a healthy weight. The specific package of services should be based on local needs, but should include both top-down approaches such as planning cycle routes and food procurement specifications and bottom-up approaches such as running activities in local parks and breastfeeding peer support (as appropriate). They should include interventions that are known to be effective as outlined in existing NICE guidance, including:\n\n\n\ncommunity engagement and workforce development:\n NICE's guidelines on behaviour change: general approaches, community engagement and type 2 diabetes prevention: population and community interventions\n\nprevention for adults:\n NICE's guidelines on promoting physical activity in the workplace, alcohol-use disorders: prevention, cardiovascular disease prevention, weight management before, during and after pregnancy, type 2 diabetes prevention: population and community interventions, obesity prevention and physical activity: walking and cycling\n\nprevention for children:\n NICE's guidelines on physical activity and the environment, maternal and child nutrition, physical activity for children and young people, cardiovascular disease prevention and obesity prevention\n\nlifestyle weight management:\n NICE's guidelines on weight management before, during and after pregnancy, and obesity prevention\n\nclinical management:\n NICE's guideline obesity prevention\n\nwider local policies:\n NICE's guidelines on physical activity and the environment, cardiovascular disease prevention, and type 2 diabetes prevention: population and community interventions\n\nevaluation and monitoring:\n NICE's guidelines on cardiovascular disease prevention, type 2 diabetes prevention: population and community interventions, and obesity prevention.\n\n\n\nCommissioners should allocate some of their budget to help establish and sustain local community engagement activities such as small community projects or local community groups. This can be done by, for example, funding the expenses of the leaders of community walking groups, or providing small grants to hire meeting spaces.\n\nCommissioners should allocate some of their budget to innovative approaches to obesity prevention that are based on sound principles, have the support of the local community and are likely to be effective, but for which there is limited evidence. Funds for innovative approaches should be allocated within a framework of action learning and evaluation.\n\nAll contracts should include requirements for regular monitoring or evaluation (see recommendations 10 and 11). Commissioners should ensure some flexibility in contracts to allow programmes or services to be adapted and improved, based on early or ongoing monitoring. Any changes should be clearly documented and carefully monitored. Clear processes should be put in place for learning and evaluation, especially for new approaches.\n\nCommissioners should ensure service specifications and contracts encourage local partnership working and reduce unnecessary duplication and overlap, particularly for local services provided by the voluntary and community sector (for example, by specifying a joint rather than separate approach for physical activity and food and nutrition initiatives).\n\nWhere possible, commissioners should consider extending effective programmes or services, recommissioning effective small-scale projects and commissioning small-scale projects or prototypes that fill a gap in provision. (Such actions should be based on local experience, monitoring and evaluation.)\n\nCommissioners should consider redesigning or decommissioning programmes or services that are identified by local Healthwatch or other local bodies with a scrutiny function (such as health overview and scrutiny committees) as ineffective or not meeting the community's needs.\n\n# Recommendation 8 Involving businesses and social enterprises operating in the local area\n\n## Who should take action?\n\nDirectors of public health and public health teams.\n\nLocal authority communications leads.\n\nChambers of commerce.\n\nEnvironmental health departments.\n\nCouncil leaders and elected members.\n\n## What action should they take?\n\nPublic health coordinators, with support from directors of public health, should establish methods for involving business and social enterprises in the implementation of the local obesity strategy. This includes, for example, caterers, leisure providers, weight management groups, the local chamber of commerce, food retailers and workplaces. They should consider developing local activities based on national initiatives to achieve this.\n\nPublic health teams and local authority communications leads should develop mechanisms of governance for working with business and social enterprises that are in the public interest. For example, they could address issues around appropriate sponsorship or competing priorities, with transparent mechanisms to address real or perceived conflicts of interest.\n\nAll of the above should encourage all businesses and social enterprises operating in the local area to recognise their corporate social responsibilities in relation to health and wellbeing. This should be in relation to:\n\n\n\nemployees – for example, supporting and encouraging employees (and employee's families) to adopt a healthy diet or developing and implementing active travel plans to encourage walking and cycling\n\nproducts – for example, ensuring the range and content of the food and drinks they sell does not create an incentive to overeat and gives people the opportunity to eat healthily\n\nwider social interests – such as actively supporting wider community initiatives on health and wellbeing.\n\n\n\nSee also NICE's guidelines on obesity, physical activity in the workplace, cardiovascular disease prevention, alcohol use disorders: prevention drinking and type 2 diabetes prevention: population and community interventions.\n\n# Recommendation 9 Local authorities and the NHS as exemplars of good practice\n\n## Who should take action?\n\nChief executive officers.\n\nExecutive directors of local authority services.\n\nLocal authority and NHS commissioners.\n\nDirectors of public health and public health teams.\n\nCouncil leaders and elected members.\n\n## What action should they take?\n\nPublic health teams should ensure local authorities and NHS organisations develop internal policies to help staff, service users and the wider community achieve and maintain a healthy weight.\n\nLocal authorities, NHS executive directors and commissioners should promote healthier food and drink choices (and discourage less healthy choices) in all onsite restaurants, hospitality suites, vending machines, outreach services and shops. They should do this through contracts with caterers, pricing and the positioning of products, information at the point of choice and educational initiatives. See also the recommendation on public sector food provision in NICE's guideline on cardiovascular disease prevention (recommendation 20) and the recommendation on promoting a healthy diet: local action in NICE's guideline on type 2 diabetes prevention: population and community interventions (recommendation 8).\n\nLocal authorities and NHS organisations should introduce and monitor an organisation-wide programme that encourages and supports staff and, where appropriate, service users, to be physically active. This includes, for example, introducing physically active travel plans for staff to promote walking and cycling to and from work. It also includes considering the design of working environments to increase opportunities for physical activity. See also the recommendation on physical activity in NICE's guideline on cardiovascular disease prevention (recommendation 21); the recommendation on promoting physical activity: local action in NICE's guideline on type 2 diabetes prevention: population and community interventions (recommendation 10); and NICE's guideline on physical activity in the workplace).\n\nLocal authorities and NHS organisations should offer lifestyle weight management services (in line with best practice outlined in NICE's guideline on weight management: lifestyle services for overweight or obese adults) for overweight or obese staff who would like support to manage their weight.\n\nLocal authority and NHS commissioners should consider how their decisions impact on obesity in the local community. For example, ensuring the provision of healthier choices is included in food contracts for leisure centres may have a positive impact on the diet of people who visit or work at these centres.\n\n# Recommendation 10 Planning systems for monitoring and evaluation\n\n## Who should take action?\n\nDirectors of public health and public health teams.\n\nLocal authority, NHS and other local commissioners.\n\nProviders of local authority or NHS commissioned services that have a direct or indirect impact on obesity.\n\n## What action should they take?\n\nAll of the above should ensure sufficient resources are set aside for planning, monitoring and evaluation, and that all partners and providers appreciate the importance of monitoring and evaluation.\n\nAll of the above should ensure all monitoring and evaluation considers the impact of strategies, policies and activities on inequalities in obesity and related health issues.\n\nAll of the above should ensure all strategies, policies and activities that may impact on the obesity agenda (whether intended or not) are monitored in a proportionate manner. Monitoring arrangements should be built into all relevant contracts.\n\nAll of the above should ensure sufficient resources are set aside to thoroughly evaluate new or innovative pieces of work (for example, 10% of project budgets).\n\nLocal authority, NHS and other commissioners should ensure, when commissioning services, there is an appropriate lead-in time for baseline data collection, and data are stratified so that the impact on inequalities can be considered.\n\nAll of the above should use simple tests to assess value for money (such as resources saved by working in partnership).\n\nAll of the above should encourage a reflective learning approach that builds on effective practice and changes or discards practices that are found to be less effective.\n\nAll of the above should ensure monitoring arrangements address the information needs and expectations of a broad range of groups by:\n\n\n\nassessing a broad range of process indicators such as the views and experience of people who have participated in the obesity programme, feedback from partner organisations, programme referral rates and impact on community wellbeing\n\nensuring the results of monitoring are fed back to teams delivering projects to improve implementation\n\nrecognising the input of all organisations involved\n\nensuring positive findings are used to motivate all those involved in the programme (for example, by capturing success stories in media campaigns).\n\n\n\n# Recommendation 11 Implementing monitoring and evaluation functions\n\n## Who should take action?\n\nPublic Health England.\n\nDirectors of public health and public health teams.\n\nAcademic health networks and other academic institutions.\n\nLocal authority, NHS and other local commissioners.\n\nProvider organisations.\n\n## What action should they take?\n\nPublic Health England is encouraged to develop a framework for monitoring and evaluating integrated community-wide approaches to obesity to ensure consistency and comparability across all local areas.\n\nDirectors of public health and public health teams should develop methods to capture changes in know of what it means to be a healthy weight and the benefits of maintaining a healthy weight.\n\nAcademic health networks and academic institutions should:\n\n\n\nestablish links with local practitioners to help with planning, collecting and analysing data on obesity strategies and interventions\n\nidentify aspects of partnership working or cooperation that can achieve health benefits at a negligible or lower cost (extensive economic modelling of partnership working is not needed on a routine basis).\n\n\n\nAll of the above should encourage all partners to measure a broad range of outcomes to capture the full benefits of a sustainable, integrated health and wellbeing strategy. Appropriate outcomes include:\n\n\n\nanthropometric measures such as body mass index (BMI) or waist circumference\n\nindicators of dietary intake (for example intake of fruit and vegetables or sugar sweetened drinks), physical activity (for example time spent in moderately vigorous activities such as brisk walking) or sedentary behaviour (for example screen time or car use)\n\nprevalence of obesity-related diseases\n\nwider health outcomes such as indicators of mental health\n\nprocess outcomes such as service use, engagement of disadvantaged groups, establishment or expansion of community groups\n\nindicators of structural changes (such as changes to procurement contracts).\n\n\n\n# Recommendation 12 Cost effectiveness\n\n## Who should take action?\n\nAcademic health networks and other academic institutions.\n\nDirectors of public health and public health teams.\n\nLocal authority, NHS and other local commissioners.\n\nProvider organisations.\n\n## What action should they take?\n\nAll of the above should use simple tests to assess value for money of local action to tackle obesity. This may include determining whether resources would be saved by working in partnership, or measuring whether benefits in one sector (such as health) are sufficient to offset costs incurred in another (such as transport or leisure services).\n\nAll of the above should ensure evaluation frameworks assess the value for money of partnership working and collaboration compared with working as separate entities.\n\nAll of the above should identify aspects of partnership working or cooperation that can achieve health benefits at negligible or low cost (extensive economic modelling is not needed on a routine basis).\n\n# Recommendation 13 Organisational development and training\n\n## Who should take action?\n\nHealth and wellbeing boards.\n\nLocal education and training boards.\n\nDirectors of public health and local public health providers.\n\nAcademic health networks and other academic institutions.\n\nProfessional bodies providing training in weight management, diet or physical activity.\n\n## What action should they take?\n\nHealth and wellbeing boards, local education and training boards, and public health teams should ensure partners across the local system have opportunities to increase their awareness and develop their skills to take forward an integrated approach to obesity prevention. Local organisations, decision makers, partners and local champions, including those from public, private, community and voluntary sector bodies working in health, planning, transport, education and regeneration, should receive training to:\n\n\n\nincrease their awareness of the local challenges in relation to public health and preventing obesity (in particular, increasing their awareness of the local JSNAs)\n\nunderstand the local systems and how their own work can contribute to preventing and managing the condition (for example when developing local commissioning plans, local planning frameworks or care provision)\n\ndevelop their community engagement skills to encourage local solutions and ensure co-production of an integrated approach\n\nunderstand the importance of monitoring and evaluation to the approach.\n\n\n\nLocal education and training boards should ensure health promotion, chronic disease prevention and early intervention are part of the basic and post basic education and training for the public health workforce.\n\nLocal education and training boards and the other groups listed above should ensure health and other relevant professionals are trained to be aware of the health risks of being overweight and obese and the benefits of preventing and managing obesity. This training should include:\n\n\n\nunderstanding the wider determinants of obesity (such as the impact of the local environment or socioeconomic status)\n\nunderstanding the local system in relation to the obesity agenda (such as who the key partners are)\n\nunderstanding methods for working with local communities\n\nknowing the appropriate language to use (referring to achieving or maintaining a 'healthy weight' may be more acceptable than 'preventing obesity' for some communities)\n\nunderstanding why it can be difficult for some people to avoid weight gain or to achieve and maintain weight loss\n\nbeing aware of strategies people can use to address their weight concerns\n\nbeing aware of local services that are likely to be effective in helping people maintain a healthy weight\n\nbeing aware of local lifestyle weight management services that follow best practice as outlined in NICE's guideline on weight management: lifestyle services for overweight or obese adults.\n\n\n\nAll of the above should ensure training addresses the barriers some professionals may feel they face when initiating conversations about weight issues. For example, they may be overweight themselves, or feel that broaching the subject might damage their relationship with the person they are advising.\n\nAll of the above should ensure all relevant staff who are not specialists in weight management or behaviour change can give people details of:\n\n\n\nlocal services that are likely to be effective in helping people maintain a healthy weight\n\nlocal lifestyle weight management services that meet best practice as outlined in NICE's guideline on weight management: lifestyle services for overweight or obese adults.\n\n\n\nAll of the above should promote, as appropriate, web resources which encourage a community-wide approach to obesity. Resources include: National Heart Forum's healthy weight, healthy lives toolkit for developing local strategies, the Obesity Learning Centre and Public Health England's healthy places resources.\n\n# Recommendation 14 Scrutiny and accountability\n\n## Who should take action?\n\nLocal bodies with a scrutiny function (such as health overview and scrutiny committees).\n\nLocal Healthwatch.\n\n## What action should they take?\n\nLocal bodies with a scrutiny function (such as health overview and scrutiny committees) should assess local action on preventing obesity, ensuring that commissioning meets the breadth of the joint health and wellbeing strategy. This includes:\n\n\n\nthe impact of wider policies and strategies\n\norganisational development and training on obesity to ensure a system-wide approach\n\nthe extent to which services aimed at tackling obesity are reaching those most in need and addressing inequalities in health.\n\n\n\nLocal bodies with a scrutiny function should be encouraged to include plans of action to prevent obesity within their rolling programme of service reviews.\n\nLocal Healthwatch should ensure the views of the local community are reflected in the development and delivery of the local approach to obesity. They should also scrutinise the priority given to obesity prevention by local health and wellbeing boards and the implementation of local obesity strategies.", 'Public health need and practice': "In England in 2010, just over a quarter of adults (26%) and almost a sixth of children (16%) aged 2 to 15 years were obese (The Health and Social Care Information Centre 2012). By 2050, 60% of adult men, 50% of adult women and 25% of children may be obese (Foresight 2007). Adults with a body mass index (BMI) more than or equal to 30 kg/m2 are classified as obese, as are children with a BMI over the 95th percentile – based on the 1990 UK reference population (The Health and Social Care Information Centre 2012).\n\nDifferences in measurement methods make comparison with other countries difficult. However, the prevalence of obesity in England is at least as high, if not higher, than in other EU countries. While there is some suggestion that it may be starting to level off among children in England (McPherson et al. 2009; The Health and Social Care Information Centre 2012), prevalence remains very high among this group.\n\nObesity is related to social disadvantage with marked trends, especially in children, by area of residence (The Marmot Review 2010). It is also linked to ethnicity. Obesity is most prevalent among Black Caribbean, Black African and Irish men – and least prevalent among Chinese and Bangladeshi men. Among women, it is more prevalent among those of Black African, Black Caribbean and Pakistani origin – and least prevalent among Chinese women (The Health and Social Care Information Centre 2008).\n\nAround 58% of cases of type 2 diabetes, 21% of cases of heart disease and between 8% and 42% of certain cancers (endometrial, breast, and colon) are attributable to excess body fat (Foresight 2007).\n\nObesity reduces life expectancy by an average of 9 years and is responsible for 9000 premature deaths a year in England. In addition, people who are obese can experience stigmatisation and bullying that can lead to depression and low self-esteem (Foresight 2007).\n\nIt is estimated that overweight and obesity now costs the NHS £5.1 billion per year (Scarborough et al. 2011). However, if current trends continue, these costs will increase by an additional £1.9 billion per year by 2030 (Wang et al. 2011). In 2007, the cost to the wider economy was £16 billion – this is predicted to rise to £50 billion a year (at today's prices) by 2050 if left unchecked (Foresight 2007).\n\nThe determinants of obesity are complex. Factors include: genetic disposition, early life nutrition and growth, individual lifestyle, psychological issues, the physical and cultural environment, food production and consumption, education, social and economic factors and the influence of the media (Foresight 2007).\n\nExisting NICE guidance indicates the type of national and local interventions that can be used to tackle obesity and improve people's diet and physical activity levels. (Existing guidance covers settings such as primary care, schools and workplaces.) However, none of the recommendations have considered the synergy between discrete policies or 'packages' of interventions and the complex organisational issues involved in local delivery.\n\nTo date, no country has managed to reverse the rising rates of obesity at a population level. The Foresight report (2007) argued that a wide range of partners should work together to develop and implement community-wide approaches to tackle the determinants. More recently, the white paper 'A call to action on obesity in England' has reinforced the importance of synergistic efforts at a range of levels, including local action (DH 2011).\n\nHowever, it remains unclear how such an approach can best be implemented. Community-based programmes are notoriously difficult to evaluate and often do not lend themselves to traditional research designs. Current practice is patchy and is dominated by short-term single interventions, usually developed and implemented through a top-down approach. Integrated, coordinated action that feeds into an overarching, long-term strategy is uncommon.\n\nIn addition, commissioners often find it difficult to decide whether to allocate funds to prevention or treatment, although it is clear that there is a need for both to operate in tandem (DH 2011).", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# Definitions\n\nFor the purpose of this guidance, 'local community' refers to a group of people from the same geographic location that is not necessarily related to any official, administrative boundary. The community may be located in a ward, borough, region or city. The PDG recognised that 'community' can also refer to groups with an interest, background or issue in common (such as low income and black and minority ethnic groups – see NICE's guideline on type 2 diabetes prevention: population and community interventions). However, while communities of interest are not excluded from this guidance, the primary focus is on those located in specific geographic areas.\n\nThe Group noted that aiming for a 'healthier weight', rather than focusing on preventing or combating obesity, may be a more acceptable and achievable goal for many people. Members also felt this goal could be accommodated within a general health and wellbeing agenda. The PDG heard that the term 'obesity' may be unhelpful among some communities – while some people may like to 'hear it like it is', others may consider it derogatory. Bearing these differing views in mind, the PDG acknowledged the need to choose the most appropriate language for any given community or situation.\n\n# Evidence\n\nThe scope for this guidance was revised during its development. Originally the aim was to look at a whole-system approach to obesity. Following the revision, the PDG focused more on local, community-wide best practice. Consultation with stakeholders confirmed that the evidence previously considered was still relevant and features of an effective whole-systems approach have been incorporated in the recommendations.\n\nThere is a lack of evidence on effective community-wide approaches to obesity. The most advanced studies have only started to publish early findings. These include: EPODE in France ('Ensemble prevenons l'obesite des enfants' ['Together let's prevent childhood obesity']) or CO-OPS Collaboration in Australia (the 'Collaboration of community-based obesity prevention sites'). No UK-based studies were identified. The PDG had hoped to gain insight from community-wide approaches to tobacco control, but again there was little UK-based evidence. As a result, the recommendations draw heavily on the experience of local practitioners in England (via expert testimony and commissioned research). They also draw on early learning from ongoing initiatives (such as Healthy Towns, Cycling Demonstration Towns and the work of the Department of Health Child Obesity National Support Team).\n\nIn recent years, there has been a proliferation of community-based interventions aimed at preventing and managing obesity. These have tended to be one-off, highly controlled explanatory studies, developed and delivered by academic centres. While some studies have been evaluated using the approaches set out in the MRC Framework on complex interventions, system-wide interventions are still being evaluated using randomised trials. The PDG considered that there is a need to develop appropriate methodological models for evaluating system-wide, community-led approaches to obesity prevention and management.\n\nEvaluation of local action on obesity is not straightforward, as the full impact may not be seen for a number of years. In particular, there is a lack of evaluation that considers process and economics, as well as health outcomes, over the short, medium and long term. The PDG noted that the recommendations on monitoring and evaluation in NICE's guideline on cardiovascular disease prevention are of relevance.\n\nThe recommendations synthesise learning from the available evidence and indicate promising areas for future innovation in a culture of ongoing evaluation and action. The evidence does not demonstrate that a particular approach (or established package of interventions) holds the key to tackling obesity in any given community. However, it does provide useful pointers to approaches that may be worth putting into practice and evaluating.\n\n# Context\n\nThere is enormous variation in current practice, both in terms of the types of action taken, local capacity and assets. The PDG recognised that different areas are at different 'starting points'. The recommendations aim to bring all areas up to the standard of the most advanced and to encourage future innovation.\n\nContext is vital – and what works in one locality may not always work in another. The PDG considered techniques that could be used to tailor interventions for particular contexts. These included, for example, community engagement techniques and development and good practice in relation to partnerships and commissioning.\n\n# Public sector reorganisation\n\nOngoing structural changes to the public sector, particularly local authorities and the NHS, have influenced the direction and tone of the PDG's recommendations. The Group was aware that the timing of the guidance offered an opportunity to stress the importance of a systemic approach to obesity that is integrated with other local agendas.\n\nMany of the recommendations are aimed at local authorities and new bodies, particularly health and wellbeing boards. The PDG believes the latter will provide a crucial forum for the NHS, public health and local authority representatives. This includes playing a critical role in developing a long-term obesity strategy.\n\nIn two-tier areas the involvement of district councils and other tiers of local government in the development and implementation of a long-term obesity strategy will be critical to success. The PDG acknowledges that individual health and wellbeing boards will manage this local engagement differently but advocates that key contributors to obesity prevention such as planning, transport, parks and leisure services must be included in the strategy and are integral to action to prevent obesity.\n\nThe PDG recognised the importance of informing elected members of the personal, community and wider economic and social costs that will accrue if the prevalence of obesity continues to rise. It also noted the need to provide elected members with tools to take effective action.\n\nThe PDG acknowledged that national policy can act as a facilitator or barrier to local action on obesity. Analogies were drawn with action on tobacco control and smoking cessation. Here evidence points to the importance of supportive national policies. It also points to the need to 'de-normalise' behaviours that increase the risk of obesity via strong advocacy and market regulation (in this analogy, in relation to tobacco products).\n\nThe PDG considered that if the findings from recommended local action on monitoring and evaluation were fed back to national or supra-regional policy teams and practitioners, it may foster a wider culture of action learning and aid the development of supportive national policies.\n\n# Overarching approach\n\nThe PDG strongly emphasised the need to take systemic, sustainable action that encompasses the wider determinants of health. Obesity may be the long-term consequence of a passive response to decisions taken elsewhere (for example, in relation to planning, policing or traffic law enforcement). The Group believes single, one-off interventions are likely to have a limited impact – and that multi-sector action is needed across the local system if there are to be appreciable changes in the prevalence of obesity.\n\nThe recommendations focus on sustained community engagement and the development of effective partnerships involving a broad range of groups. The PDG believes the public health team's role in this is to build an area-wide partnership across sectors to help tackle the wider social, economic and environmental determinants of obesity.\n\nThe PDG recognised that change will take a long time unless a simultaneous top-down, bottom-up and partnerships (co-production) approach is adopted. This includes action across all local organisations and networks supported by effective policies and delivery systems.\n\nThe effectiveness of individual interventions was outside the scope of this guidance. However, the PDG recognised that a range of existing NICE guidance provides details on the types of interventions that are likely to be effective. The exact package commissioned will depend on the needs of the local area. However, the PDG felt that it was very important to take a long-term, coherent approach to commissioning – for both obesity prevention and treatment among children and adults.\n\nThe PDG noted that activities focused on obesity prevention receive greater support, especially among practitioners, when there are clear opportunities for referral into local treatment services. This is also the case when actions to prevent and treat obesity are closely integrated.\n\n# Workforce capacity\n\nEvidence considered by the PDG suggests managing weight is difficult for many people and health professionals may avoid raising this issue. Moreover, just as someone who smokes may attempt to quit many times before they finally succeed, so it may take many conversations (and attempts) before someone is able to change their behaviour to control their weight. The PDG heard that many public health workers lack confidence in raising the issue of obesity with clients. The Group felt that this was a fundamental issue for local authority and NHS staff. It considered it vital that all staff, but particularly those on the 'frontline', have the skills and confidence to provide basic information about local obesity services.\n\nThe PDG recognised that success in preventing and managing obesity in local areas can sometimes depend on one or two highly motivated people. While passionate individuals can be a catalyst for change, it leaves sustained action vulnerable to any change in personnel. Accordingly, the PDG has advocated action that is embedded in organisational processes and skill sets.\n\nVolunteers have a vital role in driving community-wide action on obesity – from championing community needs and assets to providing peer support. While there may be a high turnover in volunteers, the PDG acknowledged that they free up other resources and provide an essential supporting role. However, members were concerned to ensure volunteers' training needs and other related costs are not ignored.\n\n# Health economics\n\nRelevant NICE guidance (such as the NICE guidelines on obesity prevention and type 2 diabetes prevention: population and community intervention) demonstrates that individual interventions to prevent or reduce the prevalence of obesity in a particular setting or environment are known to be cost effective. While some interventions or programmes may result in short-term financial benefits, most benefits will be health benefits that will take place over the medium to long term.\n\nIt is very difficult, if not impossible, to apply the standard techniques of health-economic evaluation to local system-wide approaches to obesity. Economic evaluation of system-wide approaches reduces to determining the cost effectiveness of partnership working. Partnerships are formed in many different ways and circumstances, and this makes economic evaluation very difficult. The depth of involvement of the partners can vary enormously, as can the number of partners. The decision to become involved as a partner will also depend on how long a project will be funded, how assured the funding is, and whether all potential partners have the same assurances on project funding.\n\nAt low levels of engagement, potential partners may simply wish to share information. Such 'partnerships' are virtually costless and may generate relatively large benefits. They will therefore almost certainly be cost effective when viewed from a societal perspective. Further engagement that is likely to cost little to achieve but which is expected to yield relatively large future health benefits should also be cost effective. The greater the number of partners or the more the level of engagement is increased, the more difficult it will become to decide whether further engagement would be cost effective. There will usually come a time when the addition of more partners or the further increase in the level of engagement will no longer be worth the additional effort. However, in practice it will not be easy to determine when such points are reached, particularly when arrangements are already complex.\n\nThis guidance concludes that it is more informative to consider the cost effectiveness of each intervention or set of interventions within a complex programme rather than try to consider the cost effectiveness of the programme as a whole. It will be important for potential partners to consider:\n\nwhether it would be better to work together than to work alone\n\nwhether to increase the existing level of engagement.\n\nModelling shows that projects with long-term funding are more likely to be cost effective, compared with projects funded on an annual basis.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\n# Who should take action?\n\nResearch councils, research commissioners, funders.\n\n# Recommendation 1\n\nWhat is the most effective way to monitor and evaluate community-wide approaches to obesity to ensure:\n\nevidence of effectiveness is gathered across the breadth of the local system and\n\ndata are produced to help local communities adapt and improve their approach?\n\nAn action research approach should be considered (see Waterman et al.'s action research: a systematic review and guidance for assessment). Researchers may also wish to refer to Medical Research Council guidance on developing and evaluating complex interventions and using natural experiments to evaluate population health interventions.\n\n# Recommendation 2\n\nWhat factors are necessary for an effective and cost effective community-wide approach to obesity prevention? In particular:\n\nHow can learning from systemic approaches to other complex problems be applied to obesity prevention?\n\nHow does the local context affect local engagement, adherence and effectiveness? This includes local population characteristics (for example, age, ethnicity or deprivation levels). It also includes funding arrangements and features of the local environment (such as transport links, access to green space or food outlets).\n\nWhat components are needed to build and sustain successful local community partnerships? This includes how to identify and get local people and professionals involved; the relative benefits of voluntary versus imposed partnerships; and best practice in forming and sustaining partnerships.\n\nAt what point is partnership working no longer cost effective?\n\nHow cost effective and practical is it to extend and expand existing obesity prevention programmes to support a whole community, in terms of:\n\n\n\ngeographic coverage\n\nvariety of contexts\n\nnumber of participants\n\nreturn on investment?\n\n\n\nHow can strategic approaches to obesity be sustained in terms of:\n\n\n\nfunding\n\npartnerships\n\nvolunteer involvement\n\nleadership continuity\n\n'champion' participation?\n\n\n\nHow can change best be achieved using a community development approach?\n\n# Recommendation 3\n\nResearch that specifically aims to improve understanding of community-wide approaches to prevent obesity should not:\n\nbe conceived, developed and implemented by academics with\n\nlimited consultation with local practitioners or the local community\n\nbe limited in terms of the number of situations where it could be transferred to or implemented\n\nfocus on interventions in one setting (such as an individual school).\n\nSee more detail on the gaps in the evidence identified during development of this guidance.", 'Glossary': "# Action learning\n\nA process by which someone performs an activity and then analyses their actions and gains feedback to improve future performance.\n\n# Action research\n\nAction research aims to respond to the practical concerns of participants involved in a change process, such as a new approach to obesity prevention. It involves a partnership between researchers and participants in which problem identification, planning, action and evaluation are all interlinked.\n\n# Body mass index\n\nBody mass index (BMI) is commonly used to indicate whether adults are a healthy weight or underweight, overweight or obese. It is defined as the weight in kilograms divided by the square of the height in metres (kg/m2).\n\n# 'Bottom-up' activities or approaches\n\nActivity is initiated by the community, or people working directly with the community, rather than being introduced by senior management.\n\n# Capacity-building\n\nActions or interventions that improve the ability of an individual, an organisation or a community to identify and address health or other issues on a sustainable basis, for example through skills development, improved networking and communication or shared decision making.\n\n# Community\n\nA group of people who have common characteristics. Communities can be defined by location, race, ethnicity, age, occupation, a shared interest (such as using the same service), a shared belief (such as religion or faith) or other common bonds.\n\nLocal community refers to a group of people from the same geographic location that is not necessarily related to any official, administrative boundary. The community may be located in a ward, borough, region or city.\n\n# Community assets\n\nA community asset (or resource) is anything that can be used to improve the quality of community life. It could be a physical structure or place (such as a recreation centre, library, hospital, meeting place, monument or business). Or it could be a group or an individual, for example, a local community group or a community leader.\n\n# Community champions\n\nThe term 'community champion' covers a range of roles, and includes inspirational figures, community entrepreneurs, mentors or leaders who 'champion' the priorities and needs of their communities and help them build on their existing skills. It also includes those 'on the ground' who drive forward community activities and pass on their expertise to others. They may provide mentoring or a range of other support, for example, by helping people to get appropriate training or by helping to manage small projects.\n\n# Community development\n\nCommunity development is about building active and sustainable communities based on social justice, mutual respect, participation, equality, learning and cooperation. It involves changing power structures to remove the barriers that prevent people from participating in the issues that affect their lives.\n\n# Community engagement\n\nThe process of getting communities involved in decisions that affect them. This includes the planning, development and management of services, as well as activities that aim to improve health or reduce health inequalities (Popay 2006).\n\n# Community health champions\n\nCommunity health champions are local people who are recruited and trained as volunteers to 'champion' the health priorities and need of their communities.\n\n# Co-production\n\nFor this guidance, co-production means developing and delivering action on obesity in an equal and reciprocal relationship between professionals, the local community, people using local services and their families.\n\n# Joint strategic needs assessments\n\nJoint strategic needs assessments (JSNAs) identify the current and future health needs of a local population. They are used as the basis for the priorities and targets set by local areas, expressed in local health and wellbeing strategies. They are also used for commissioning to improve health outcomes and reduce health inequalities.\n\n# Local system\n\nThe local system comprises a broad set of interrelated organisations, community services and networks operating at a range of levels and involving a number of delivery processes.\n\n# Overweight and obesity: adults\n\nFor adults, overweight and obesity are assessed by body mass index. The sections on classifying overweight, obesity and central adiposity in adults, and classifying overweight, obesity and central adiposity in children and young people, in NICE's guideline on obesity assessment and management give the cut-off points for healthy weight, overweight and obesity.\n\nBMI is a less accurate indicator of adiposity in adults who are highly muscular, so BMI should be interpreted with caution in this group. Some other population groups, such as Asians and older people, have comorbidity risk factors that would be of concern at different BMIs (lower for Asian adults and higher for older people). Healthcare professionals should use clinical judgement when considering risk factors in these groups, even in people not classified as overweight or obese using the classification in the table.\n\nAssessment of the health risks of being overweight or obese can also be based on waist circumference. For men, waist circumference of less than 94\xa0cm is low, 94–102\xa0cm is high and more than 102\xa0cm is very high. For women, waist circumference of less than 80\xa0cm is low risk, 80–88\xa0cm is high and more than 88\xa0cm is very high.\n\n# Overweight and obesity: children\n\nMore than one classification system is used in the UK to define 'overweight' and 'obesity' in children. The National Child Measurement Programme (NCMP) for primary care states that body mass index (BMI) should be plotted onto a gender-specific BMI chart for children (UK 1990 chart for children aged over 4\xa0years). Children over the 85th centile, and on or below the 95th centile, are categorised as 'overweight'. Children over the 95th centile are classified as 'obese'. Other surveys, such as the Health Survey for England also use this system. In clinical practice, however, the 91st and 98th centiles may be used to define 'overweight' and 'obesity' respectively. Children on or above the 98th centile may also be described as very overweight.\n\n# Partner\n\nFor the purpose of this guidance, a partner is a local department, service, organisation, network, community group or individual that could help prevent obesity.\n\n# 'Top-down' activities or approaches\n\nWhere an activity is initiated from a senior level in an organisation and cascaded down to those working directly with the local community.\n\n# Two-tier\n\nTwo-tier counties in England consist of an 'upper-tier' county council and various 'lower-tier' city, borough and district councils.\n\n# Wider determinants of health\n\nThe social determinants of health are the circumstances in which people are born, grow up, live, work, and age, as well as the systems put in place to deal with illness. These circumstances are in turn shaped by a wider set of forces: economics, social and political forces.", 'References': 'Department of Health (2011) Healthy lives, healthy people: a call to action on obesity in England. London: Department of Health\n\nForesight (2007) Tackling obesities: future choices – project report. London: Government Office for Science\n\nThe Health and Social Care Information Centre (2012) Statistics on obesity, physical activity and diet: England. London: The Health and Social Care Information Centre\n\nThe Health and Social Care Information Centre (2008) Health Survey for England 2007: Healthy lifestyles: knowledge, attitudes and behaviour. Leeds: The Information Centre for Health and Social Care\n\nMcPherson K, Brown M, Marsh T et al. (2009) Obesity: recent trends in children aged 2–11y and 12–19y. Analysis from the health survey for England 1993–2007. London: National Heart Forum\n\nThe Marmot Review (2010) Fair society, healthy lives. Strategic review of health inequalities in England post 2010. London: The Marmot Review\n\nCommunity engagement for health improvement: questions of definition, outcomes and evaluation - a background paper prepared for NICE by Professor Jenny Popay (2006)\n\nScarborough P, Bhatnagar P, Wickramasinghe K et al. (2011) The economic burden of ill health due to diet, physical inactivity, smoking alcohol and obesity in the UK. Journal of Public Health 33: 527–35\n\nWang YC, McPherson K, Marsh T et al. (2011) Health and economic burden of the projected obesity trends in the USA and the UK. The Lancet 378: 815–25', 'Appendix B Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, primary research, commissioned reports and economic modelling include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for consideration of the reviews of evidence and were used by the PDG to help develop the recommendations. The key questions were:\n\nWhat are the essential elements of a local, community-wide approach to preventing obesity that is sustainable, effective and cost effective?\n\nWhat barriers and facilitators may influence the delivery and effectiveness of a local, community-wide approach (including for specific groups)?\n\nWho are the key leaders, actors and partners and how do they work with each other?\n\nWhat factors need to be considered to ensure local, community-wide approaches are robust and sustainable?\n\nWhat does effective monitoring and evaluation look like?\n\nCan the cost effectiveness of local, community-wide obesity interventions be established and, if so, what is the best method to use?\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nOne review of effectiveness was conducted (review 2).\n\nA number of databases were searched in July 2010 for interventions published in English from 1990 onwards. See the review for details.\n\nGeneral health and topic-specific websites and other sources of grey literature were also searched including:\n\nScrutiny committee reports (searched via an Internet search engine)\n\nZeTOC database (British Library)\n\nISI proceedings (Web of Science)\n\nConference Proceedings Citation Index (Web of Science).\n\nStudies were included in the effectiveness review if they:\n\ndemonstrated core features of a whole-system approach (as identified in review 1) to preventing obesity or smoking\n\ncovered whole populations or communities and reported on outcome measures or other indicators for an intervention\n\nused comparative study designs\n\nwere published from 1990 onwards in English.\n\nStudies were excluded if they:\n\ndid not report on the outcomes listed\n\nonly presented a single component of an intervention or strategy\n\ndid not focus on obesity prevention, improving physical activity or diet, or smoking prevention.\n\n## Other reviews\n\nOne review was undertaken to define a 'whole-system approach' (review 1) and one review of qualitative data was undertaken to consider the barriers and facilitators to such an approach (review 3).\n\nFor reviews 1 and 3, the databases and websites searched were the same as for the effectiveness review (see above).\n\nStudies were included in review 1 if they considered:\n\nthe theory, key elements and relationships of a whole-system approach\n\na whole-system approach in relation to obesity or smoking prevention.\n\nQualitative studies were included in review 3 if they focused on:\n\nany 'whole-community' programme in the UK\n\n'whole-community' obesity and smoking prevention programmes, including those delivered in schools or workplaces in Organisation for Economic Co-operation and Development (OECD) countries.\n\nStudies were excluded from review 3 if they focused on:\n\npeople's opinions about eating and exercise and their understanding of the issues around obesity, for example, food choices\n\ncommunity engagement, unless there were elements specific to obesity prevention\n\nrelationships between members of a single agency (for example, a primary care team)\n\na single setting (even where the intervention was part of a multi-agency initiative) or a single aspect of health (for example, physical activity or diet).\n\n## Quality appraisal\n\nFor review 1, included papers were assessed according to whether they provided a coherent account of the concepts and approaches taken and their relationship to each other. (Those that provided more information along these lines were considered better 'quality'.)\n\nFor the effectiveness review (review 2), included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual Methods for the development of NICE public health guidance (see appendix E). Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nFor review 3, the qualitative research studies were assessed using a thirteen-question checklist to determine:\n\nthe clarity of descriptions\n\nthe appropriateness of the aims and methods\n\nthe evidence for the findings\n\nlogical and theoretical coherence.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full evidence reviews).\n\nThe findings from the evidence reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Commissioned report\n\nPrimary, qualitative research was commissioned (September 2011) to understand how local teams can work together effectively to prevent obesity in local communities. The opinions and experiences of the 93 participants are reported in 'Implementing community-wide action to prevent obesity: opinions and experiences of local public health teams and other relevant parties'.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling report.\n\n## Review of economic evaluations\n\nThe obesity-related Reference Manager databases were searched for economic evidence as part of reviews 1 and 2. In addition, selected new searches were undertaken in economic bibliographic databases (NHS EED and EconLit). As a result, four economic evaluations were selected and summarised narratively.\n\nThe generic tool for economic evaluations (Drummond and Jefferson 1996) was used for quality assessment.\n\n## Economic modelling report\n\nAn economic logic model was constructed to explore the circumstances in which a collaboration of two or more local organisations could usually be expected to be cost effective. The model aimed to deduce the direction of change of interventions, but not the magnitude of that change.\n\nThe results are reported in the economic modelling report 'Cost effectiveness analysis in partnership working for reducing obesity and other long-term conditions.'\n\n# How the PDG formulated the recommendations\n\nAt its meetings from July 2011 to February 2012, the Programme Development Group (PDG) considered the evidence, expert reports, primary research and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nstrength (type, quality, quantity and consistency) of the evidence\n\nthe applicability of the evidence to the populations or settings referred to in the scope\n\neffect size and potential impact on the target population's health\n\nimpact on inequalities in health between different groups of the population\n\nequality and diversity legislation\n\nethical issues and social value judgements\n\ncost effectiveness (for the NHS and other public sector organisations)\n\nbalance of harms and benefits\n\nease of implementation and any anticipated changes in practice.\n\nThe PDG noted that effectiveness can vary according to the context.\n\nWhere evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in May 2012. At its meeting in July 2012 the PDG amended the guidance in light of comments from stakeholders. The guidance was signed off by the NICE Guidance Executive in October 2012.", 'Appendix C The evidence': "This appendix lists the evidence statements from four evidence reviews and commissioned research provided by external contractors (see appendix A and appendix E) and links them to the relevant recommendations. See appendix B for the meaning of the (++), (+) and (−) quality assessments referred to in the evidence statements.\n\nThe additional evidence section of this appendix also lists 19 expert papers and their links to the recommendations and sets out a brief summary of findings from the economic modelling.\n\nThe evidence statements are short summaries of evidence in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letter(s) in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement number 1.1 indicates that the linked statement is numbered 1 in the review 'Identifying the key elements and interactions of a whole system approach to obesity prevention'. Evidence statement 2.1 indicates that the linked statement is numbered 1 in the review 'The effectiveness of whole system approaches to prevent obesity'. Evidence statement 3.1 indicates that the linked statement is numbered 1 in the review 'Barriers and facilitators to effective whole system approaches'. Evidence statement 4.1 indicates that the linked statement is numbered 1 in the review 'Whole system approaches to obesity prevention: review of cost-effectiveness evidence'. Evidence statement CR1 indicates that the linked statement in numbered 1 in the commissioned report 'Implementing community-wide action to prevent obesity: opinions and experiences of local public health teams and other relevant parties'.\n\nSee the full reviews, commissioned research, expert papers and economic modelling report. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nWhere the Programme Development Group (PDG) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.\n\nRecommendation 1: evidence statements 1.6, 2.5, 3.1, 3.2, 3.5, CR1; expert papers 2, 3, 5, 6, 7, 9, 12, 14\n\nRecommendation 2: evidence statements 1.2, 1.6, 3.1, 3.2, 3.4, 3.7, 3.8, CR1, CR3; expert papers 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 18\n\nRecommendation 3: evidence statements 1.6, 3.4, 3.5, 3.7, CR1, CR5; expert papers 2, 3, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18\n\nRecommendation 4: evidence statements 1.2, 1.6, 3.2, 3.3, 3.4, 3.5, 3.7, CR2, CR3, CR4; expert papers 1, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16\n\nRecommendation 5: evidence statements 1.6, 3.3, 3.4, CR1, CR2, CR3, CR4; expert papers 2, 3, 5, 6, 8, 9, 11, 12, 14, 15, 16\n\nRecommendation 6: evidence statements 1.2, 1.6, 3.1, 3.2, 3.3, 3.4, 3.7, CR1, CR4, CR5; expert papers 2, 4, 5, 7, 8, 9, 10, 12, 15, 17\n\nRecommendation 7: evidence statements 1.3, 1.4, 1.6, 3.3, 3.6, 3.8, CR3, CR4, CR5; expert papers 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 19\n\nRecommendation 8: evidence statements 1.6, 3.2; expert papers 2, 5, 8, 11, 18; IDE\n\nRecommendation 9: evidence statements 3.2, 3.5, CR3; expert papers 2, 5, 11, 18; IDE\n\nRecommendation 10: evidence statements 1.4, 1.6, 3.6, 3.8, 4.3, CR4, CR5; expert papers 2, 3, 4, 5, 9, 11, 12, 13, 14, 16, 19\n\nRecommendation 11: evidence statements 1.4, 1.6, 3.6, 3.8, 4.3, CR4, CR5; expert papers 2, 3, 4, 5, 9, 11, 12, 13, 14, 16, 19\n\nRecommendation 12: evidence statements 4.3; CR6; expert papers 5, 9, economic modelling report\n\nRecommendation 13: evidence statements 1.6, 3.2, 3.3, 3.6, CR3, CR4; expert papers 2, 5, 7\n\nRecommendation 14: evidence statements 3.7, 3.8, CR1, CR4; IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style. The superscript numbers refer to the studies cited beneath each statement. The full references for those studies can be found in the reviews.\n\n## Evidence statement 1.1: Whole systems theory\n\nAuthors may interpret what is meant by a whole system in different ways; there is a clear division in views between those advocating 'complexity theory' and those discussing a more mechanistic approach.\n\nA whole-system approach to achieving change in organisations, communities or individuals shares conceptual underpinnings with complexity science and complex adaptive systems. Systems continually evolve, with complex outcomes arising from a few simple rules of interaction. Self-regulation occurs within systems, and efforts to contain them may be counterproductive. Systems include formal and informal relationships or networks; these relationships are of great importance. Systems can exist in single or multi-sector organisations.\n\n## Evidence statement 1.2: Implications of whole-system theory for ways of working\n\nWhole system theory suggests that organisation or community goals may best be achieved by:\n\nCreating more flexible organisational structures.\n\nRecognising that relationships are crucial.\n\nUnderstanding how positive and negative feedback loops within a system operate – giving insights into how to increase or sustain positive outcomes.\n\nGenuine engagement and discussion about the issues to be addressed – developing shared meaning and purpose – before moving on to 'problem-solving'. This must include a diverse range of actors and community members at all organisational levels.\n\nAll actors understanding the system in which they operate (and their role within it).\n\nAwareness of the divisions between traditional ways of working and whole-system working. The former may involve hierarchical leadership and complex targets and plans while the approach of the latter may be to increase opportunities for natural adaption.\n\n## Evidence statement 1.3: Implications of whole-system theory for those working within the system\n\nIndividuals participate in their own capacity rather than as a representative of an organisation, community or profession so that they only agree to do what is in their power.\n\nSuccessful and productive communication within or across organisations may require innovative approaches to break down traditional restrictions stemming from hierarchies and differing expectations of organisations, professions and individuals.\n\nThe personal qualities of individuals working within the system may be important. Personal qualities such as optimism, empathy, humility and tenacity may increase the likelihood of success.\n\nA willingness to take the 'long view' rather than go for the 'quick fix' is essential for a systems approach to be effective.\n\n## Evidence statement 1.4: Implications of a whole-system approach for evaluation\n\nIn a whole-system approach, it is the function rather than the form of activities that is standardised.\n\nThe change in behaviour of individuals working within the system, through developing relationships and creating robust networks, is central.\n\nEvaluating a systems approach is complex. Different techniques for evaluation may be required to assess the added benefit of taking a systems approach. Process outcomes and the robustness of the systems are of particular interest (over and above short term outcomes).\n\nEvaluation of a systems approach needs to consider the networks that have been established and the relationships and synergies between and within settings.\n\nEvaluation of a systems approach may be time consuming.\n\n## Evidence statement 1.5: Potential challenges of whole-system working\n\nChallenging long-standing assumptions can be uncomfortable. Traditional organisational structures are culturally embedded and change may appear chaotic.\n\n## Evidence statement 1.6: The features of a systems approach to tackle health problems\n\nIdentifying a system: explicit recognition of the public health system with the interacting, self-regulating and evolving elements of a complex adaptive system. Recognise that a wide range of bodies with no overt interest or objectives referring to public health may have a role in the system and therefore that the boundaries of the system may be broad.\n\nCapacity building: an explicit goal to support communities and organisations within the system. For example, increasing understanding about obesity in the community and by potential partner organisations or training for those in posts directly or indirectly related to obesity.\n\nCreativity and innovation: mechanisms to support and encourage local creativity and/or innovation to address obesity. For example, mechanisms that allow the local community to design locally relevant activities and solutions.\n\nRelationships: methods of working and specific activities to develop and maintain effective relationships within and between organisations. For example, establishing and maintaining relationships with organisations without a health remit or an overt focus on obesity.\n\nEngagement: clear methods to enhance the ability of people, organisations and sectors to engage community members in programme development and delivery. For example, sufficient time in projects allocated to ensuring that the community can be involved in planning and assessing services.\n\nCommunication: mechanisms to support communication between actors and organisations within the system. For example, ensuring sufficient face-to-face meeting time for partners, having planned mechanisms for feeding back information about local successes or changes.\n\nEmbedded action and policies: practices explicitly set out for obesity prevention within organisations within the system. For example, local strategic commitments to obesity, aligning with wider policies and drivers (such as planning or transport policy) and ensuring obesity is an explicit concern for organisations without a health remit.\n\nRobust and sustainable: clear strategies to resource existing and new projects and staff. For example, contingency planning to manage risks.\n\nFacilitative leadership: strong strategic support and appropriate resourcing developed at all levels. For example, specific methods to facilitate and encourage bottom-up solutions and activities.\n\nMonitoring and evaluation: clear methods to provide ongoing feedback into the system, to drive change to enhance effectiveness and acceptability. For example, developing action-learning or continuous-improvement models for service delivery.\n\n## Evidence statement 2.1: paucity of evidence\n\nThere is a paucity of evidence on the effectiveness of community-wide programmes displaying features of a whole-system approach to prevent obesity. Of the eight community-wide obesity prevention programmes included in this review – two before-and-after (one [−] and one [+]) three non-randomised control trials (all [+]) one controlled before-and-after study (+); one longitudinal epidemiological study (+); and one repeated cross-sectional survey (+) – none were undertaken in the UK and all targeted children below 14 years. Although they stated an aim to influence the wider community through the programme, including parents, childcare centre workers, teachers and other members of the community. This evidence is judged to be partially applicable to communities of a similar size in the UK.\n\n## Evidence statement 2.2: Range of whole-system approach (WSA) features in obesity prevention programmes\n\nNone of the eight obesity prevention programmes included in the review demonstrated evidence of explicit recognition of the public health problem as a system. All programmes demonstrated inconsistent evidence of local creativity. Seven programmes demonstrated more robust evidence of capacity building, robustness and sustainability and community engagement, but this was still inconsistent across the groups and all these features did not appear across the same seven programmes. Five obesity prevention programmes demonstrated inconsistent evidence of a focus on the embeddedness of actions and policies, and of developing working relationships within and between partners. Four of the obesity prevention programmes demonstrated inconsistent evidence of a focus on enhancing communication between actors and organisations within the system, facilitative leadership and the use of well-articulated methods for monitoring and evaluation of activities.\n\n## Evidence statement 2.3: The effectiveness of obesity prevention programmes – anthropometric outcomes\n\nOverall, there is evidence from a range of community-wide obesity programmes that they can have a beneficial effect on body mass index (BMI) scores, weight gain or the prevalence of overweight and obesity in children. However, these observed differences tended to be relatively small and were not always significant. There is no clear evidence of a relationship between features of system working and programme effectiveness. Studies reported lower BMI scores (one [+] controlled before-and-after; one non-randomised control trial; and one [+] repeated cross-sectional survey). Lower BMI z scores (and one [+] before-and-after and one [+] non-randomised control trial); weight gain (and one cross-sectional [+] survey in France); increase in waist circumference or the prevalence of overweight or obesity (and one [+] longitudinal study). Only one before-and-after (+) study in New Zealand reported a statistically non-significant increase in the prevalence of overweight or obesity among the intervention group.\n\n## Evidence statement 2.4: The effectiveness of obesity prevention programmes – diet and physical activity outcomes\n\nThere is some evidence that community-wide obesity programmes can have a beneficial effect on diet or physical activity outcomes in children. However, there is no clear evidence of a relationship between features of a system working and the programme's effectiveness. Studies reported a significant decrease in the number of daily servings of 'less healthy' foods and increased daily servings of vegetables and less TV viewing (one controlled before-and-after [+] study). A statistically significantly higher percentage of children passing a fitness test post intervention (one before-and-after [+] study) and a statistically significant increase in diet and activity 'best practice' at childcare centres (one before-and-after [−] study). One non-randomised control trial study also reported a decrease in the number of children unhappy with their body size post intervention.\n\n## Evidence statement 2.5: Relationship between system working and effectiveness of obesity prevention programmes\n\nDue to the degree of variation across studies, the small number of the included studies, and the wide range of outcomes reported, the relationship between the presence of features of system working and the effectiveness of community-based programmes to prevent obesity remains ambiguous. It is therefore not possible to suggest a clear relationship.\n\nTwo community programmes based in Australia demonstrated the strongest evidence for system working. One controlled before-and-after (+) study describes nine out of the ten features of system working, and demonstrated favourable (though statistically non-significant) between-group differences in anthropometric outcomes. The programme also reported favourable outcomes relating to nutrition (that were statistically significant) and physical activity (that were statistically non-significant). The other study, a (+) non-randomised control trial, shows clear evidence of six out of ten features of a whole system approach, and makes implicit reference to an additional three features. This study reports statistically non-significant between-group decreases in BMI, weight gain and the prevalence of overweight and obesity.\n\nThree community programmes in the US showed five to seven features of whole-system working. One (+) study clearly demonstrates the presence of four WSA features and implies another three features. This study reported a non-significant decrease in BMI z scores. Another (+) study describes three WSA features and makes reference to another three features. It reported a statistically significant change in the prevalence of obesity and improvements in fitness among children post-intervention. Another (−) study describes only two WSA features and makes reference to another three features. No anthropometric outcomes were reported, but the authors reported a statistically non-significant post-intervention increase in diet and activity 'best practices' at childcare centres.\n\nThe remaining three community programmes clearly displayed evidence of four or fewer features of whole-system working.\n\nOne longitudinal epidemiological (+) study based in France clearly demonstrated evidence of four features, and demonstrated unclear evidence of two additional features. Another, related, repeated cross-sectional (+) survey in France demonstrated unclear evidence of four features. Both studies showed significant pre-/post-reductions in obesity prevalence. One (+) non-randomised control trial from New Zealand provides unclear evidence of two features and reported a between-group statistically significant and favourable change in BMI z scores.\n\n## Evidence statement 3.1: System recognition\n\nAccording to three UK studies (one [−] and two [+]) and one (−) USA study, it is important to recognise the system in which public health problems such as obesity exist. The importance of collaborative working practices (such as partnership working, using novel networks, or managing meetings in a constructive, non-hierarchical way) was also recognised.\n\n## Evidence statement 3.2: Ownership and involvement\n\nAccording to three studies (one [+] and one [++] based in the UK and one [−] based in the USA), partner organisations need to feel that they are actively involved and have some 'ownership' of a strategy. This can help reduce the strain between partner organisations. It is important to develop shared awareness and perspectives (for example, through pre-engagement work or training), but this may take considerable time (that is, years rather than months). Consultations should be focused to prevent partners becoming disillusioned and community concerns recognised, even if these are at odds with those envisaged in the public health programme.\n\n## Evidence statement 3.3: Capacity building\n\nAccording to three (−) studies – one from the USA, one from the UK and one from New Zealand, adequate time and resources need to be set aside for capacity building. Training and awareness-raising may be particularly important – for example to increase staff evaluation (or other technical) skills or bring health onto the agenda of bodies that do not have public health as a primary concern (for example, city planners), according to four (+) UK studies.\n\n## Evidence statement 3.4: Partnerships\n\nAccording to eight studies (two [−] from the UK; three [+] from the UK; one [++] from the UK; one [+] from the USA; and one [−] from New Zealand) partnerships may encounter problems in establishing consensus on the design, delivery and priorities of a programme. Partnerships need time and space to develop and are likely to be stronger where:\n\nthere is active involvement from both the community and senior staff in key organisations (with communication downwards and upwards)\n\norganisations have a positive historical relationship\n\nactors form natural communities and share at least some interests or areas of work\n\npre-existing tensions are resolved\n\nthere is strategic leadership\n\na common language is developed (poor communication can lead to silo working and strained relationships).\n\nStudies also found joint working is easier where programme workers have the skills to establish a relationship with the local community and key individuals can act as 'boundary spanners' across organisations, linking their concerns (two [−] UK; six [+] UK; one [++] UK; one [−] New Zealand and one [−] USA).\n\nSuch individuals can be vital to the success of a programme, but this has implications for sustainability (one [+] UK).\n\n## Evidence statement 3.5: Embeddedness\n\nWhole-system working is more likely to become embedded where whole systems principles are integrated into strategy and policy documents (one [+] UK) and actions and policies are present at both strategic and operational levels (one [−] UK).\n\n## Evidence statement 3.6: Sustainability\n\nThe sustainability of whole-systems approaches may be hindered by traditional organisational structures (one [++] UK) or poor experience from previous projects (one [+] UK).\n\nAccording to seven studies (two [−] UK; one [+] UK; one [++] UK; one [−] USA; one [+] USA; one [−] New Zealand) funding issues impact on the sustainability of a whole-system approach for a range of reasons including:\n\ndifficulties in making the case for funding for diffuse objectives\n\nthe lack of continuity and stability inherent in short-term funding for addressing long-term issues\n\ninadequate staffing levels.\n\n## Evidence statement 3.7: Leadership\n\nAccording to four UK studies (three [+] and one [++]) strategic leadership was considered important when implementing a whole-system approach – for example, ensuring focus in programme meetings, providing clarity on staff roles, managing tensions between programme staff, providing active leadership at local level and demonstrating personal commitment. However, implementing formal accountability arrangements in cross-organisation partnerships can be difficult. Leadership may face a range of problems including difficulties in achieving consensus between partners (one [+] UK); tensions between local and national priorities, ensuring the overall strategic direction does not stifle local leadership (one [+] UK) and difficulties ensuring inclusive working with minimal resources. Studies have noted implementation problems related to management decisions taken without staff consultation, autonomy of local staff and clarity of management structures, and local programme staff feeling isolated from a national programme (one [−] UK).\n\n## Evidence statement 3.8: Monitoring and evaluation\n\nAccording to two UK studies (one [−] and one [+]) the usefulness of evaluation may be limited by a lack of clarity about objectives and a lack of specificity about outcomes to be measured. Six studies (one [+] USA, one [++] UK and two [−] UK) found intermediate or broader outcome measures may be more appropriate for assessing whole-system approaches, at least in the first instance, rather than specific short-term health outcomes. Broader indicators of success may have the added benefit of fostering partnership working.\n\nIt may be particularly difficult to evaluate non-health outcomes and 'reward' partners who do not have a traditional health role. Problems may arise with data collection where staff responsible for collecting the data are unclear about its usefulness or relevance, partners use different information systems or where organisations struggle to reach a consensus on appropriate outcome measures. Unresolved organisational issues or the promotion of a working culture where partners feel unable to openly discuss problems in implementation may act as a barrier to organisational learning (one [+] UK). There may be an unfounded assumption at national level that local agencies have the capacity to develop and deliver a whole system approach.\n\n## Evidence statement 3.9: National policy and priorities\n\nAccording to two studies (both [+] one USA and one UK) the broader political climate may open a 'national policy window' that facilitates policy change, influencing the ability to take a systems approach. Three UK studies (all [+]) found this would enable partnerships that focus on addressing health inequalities. Supportive national policy can help foster partnerships and influence the local agenda. However, changes in national policy may create uncertainty (one [−] UK) and reduce the credibility of local programmes. Targets or funding attached to narrowly defined areas of health, and limited timeframes may limit the ability to take a systems approach (one [−] UK).\n\n## Evidence statement 4.1: Quantity and quality of published cost effectiveness and obesity modelling evidence\n\nOnly four published economic evaluations were found which related to community-wide multi-faceted obesity prevention or smoking prevention programmes. Two of the economic evaluations (a conference poster relating to the 'Be active eat well' programme in Australia, and a 3-page section of a larger evaluation report on the 'Breathing space' smoking prevention intervention in Edinburgh) were not presented in sufficient detail to warrant a full summary or critical appraisal. The other two cost-effectiveness analyses were not comparable because they were:\n\nA small pilot-trial based cost-effectiveness analysis of a school-based community-wide child obesity prevention programme (in New Zealand, results presented in $NZ per kg of weight gain prevented after 2 years).\n\nA modelling-based study of the cost-effectiveness of two US-based community-wide campaigns to promote physical activity (the 'Stanford five cities project' and 'Wheeling walks' programme for older people – results presented in cost per life-year and cost per quality-adjusted life-year).\n\n## Evidence statement 4.2: Cost-effectiveness findings\n\nThere is evidence from only one community-wide obesity prevention programme that estimated incremental cost-effectiveness ratios, and can be judged as having used appropriate methods (of the APPLE pilot project in four small towns in New Zealand). However, while having some community-based activities, the APPLE project was judged to only weakly exhibit two of the ten defined features of a whole-system approach. Only four published economic evaluations were identified that were potentially relevant to the scope of this guidance. Two of these studies were so under-reported that their findings cannot be relied upon. The other included cost-effectiveness study was of two community-wide physical activity promotion campaigns in the USA.\n\n## Evidence statement 4.3: Approaches to modelling of obesity and for obesity prevention\n\nSimulation modelling of obesity or obesity policies is still at a relatively early stage of development. However, in some cases methods for modelling outcomes in the area of obesity and obesity prevention policies or programmes has already become so complex and advanced that the usefulness (or even feasibility) of attempting to develop credible new models without significant modelling capacity, access to national data, and significant modeller time and other resources is questionable. Instead, with limited resources, any realistic modelling of alternative local community-wide obesity prevention policies should aim to make best use of one of the well-established and tested existing population-level obesity models (such as the National Heart Forum's micro-simulation model, or the ACE Obesity model framework).\n\n## Evidence statement CR1: Establishing a community-wide approach to preventing obesity – key actors and players\n\nA genuinely community-wide approach to preventing obesity includes a vast range of actors and agencies. For such a network to be effective, partners must share an overarching vision around obesity prevention, with each organisation 'buying in' and feeling a sense of ownership.\n\nAt the strategic level, the impetus for a community-wide approach begins with local elected members and senior managers (particularly from the NHS and the local authority). Public health is best placed to provide investment and leadership for the network of partners, aided by the health and wellbeing board that needs to exert its influence on the clinical commissioning group to ensure investment and 'buy in' across community health services.\n\nIn order to build the network of partners, local communities and services should be viewed from the perspective of individual citizens, to identify the most relevant services regularly used and trusted by key groups such as parents. Once signed up as partners, these services can be leveraged to make every contact count.\n\nInformation needs to be shared and relationships developed both 'horizontally' across partner organisations, and 'vertically' inside individual organisations. Failure to ensure middle managers and frontline workers share the vision and understand the community-wide approach is perhaps the most common factor limiting the effectiveness of such partnerships.\n\nThe main delivery organisations (for example, community projects with provider contracts) must have credibility in their local communities. Community engagement is the key activity in building and developing this credibility.\n\n## Evidence statement CR2: Facilitators of an effective community-wide approach\n\nHaving a central coordination and communications function is considered to be essential and must engage beyond senior management level in the partner organisations, striving to ensure middle managers share the vision, and are well informed about the wider network. Concise briefings on key issues are important for middle managers and frontline staff, to build confidence, capacity and consistency in messaging across the wide range of partners.\n\nPartner organisations should be expected to make an explicit commitment of what they will contribute, and this should be publicised across the network. Those making investment decisions should build on proven success by 'backing winners', and concentrate investment where it is most likely to succeed.\n\nStrategy should take an iterative approach, reviewing progress regularly.\n\n## Evidence statement CR3: Barriers to an effective community-wide approach\n\nStarting conversations about obesity with individual clients and patients is difficult, and there are numerous reasons why staff may not have the confidence or the motivation to do so, even among primary care professionals. It is very important to build confidence and capability among customer-facing staff in both primary care and community settings, as the credibility of messages from the latter will be seriously undermined if inconsistent with messages from the former.\n\nIn terms of population-wide primary prevention, the term 'obesity' can be off-putting, and engagement with target audiences may be easier if the focus is framed as 'healthy lifestyles'. This more broad-based approach may also be more stable in terms of long-term funding.\n\nFinancial barriers are significant for many low-income groups, particularly in terms of the cost of transport and accessing services. Cultural minorities and disabled people face additional barriers in accessing information and services, and their specific needs should be considered carefully when assessing needs.\n\nA significant contribution can be made by volunteers (health champions and peer mentors), but their effectiveness may be limited by the willingness of health professionals to make referrals to them.\n\nThe prevention of obesity is a long-term objective, but most project funding is short term. There are complex personal, family and socioeconomic causes applying to many obese and overweight people. Both commissioners and providers would like to be able to commit to longer-term contracts for obesity prevention work, in recognition of the considerable time and resources needed to successfully engage with clients with complex needs, for whom positive short-term outcomes are less likely.\n\n## Evidence statement CR4: Sustainability\n\nIt is inevitable that funding streams will change over time. By recognising that obesity is an essential concern for many health and social issues, it should be possible to be flexible and creative in justifying ongoing funds for obesity prevention work, despite such changes.\n\nThe strategy and the wider network of partners must be sustainable. The maintenance and development of the shared vision is fundamental for sustainability, and this requires effective communication to maintain the engagement, particularly with politicians and middle managers. Frontline staff and organisations may see themselves as peripheral to the issue of obesity. Having a strong local brand or identity is important, particularly for workers in the network of organisations, as it is important for them to feel part of a bigger picture.\n\nA key message in this communication must be the commitment to evaluation and ongoing service improvement. If pump-priming funds (that is, short-term funds, aimed at stimulating future investment from mainstream sources) are made available to establish the network, plans to transfer responsibilities to mainstream budgets should be built in wherever possible. However, in the context of current public expenditure constraints, mainstream incorporation cannot be guaranteed.\n\nThe community-wide approach should seek to build on existing community assets. This will build capacity in people and institutions that will continue, even if obesity-specific funding diminishes. Commissioners should also consider that at some point in the future, they may be relying on influence and goodwill rather than contractual obligations.\n\nA clear separation of strategic and operational management, using boards and forums with distinctive terms of reference, may be helpful.\n\n## Evidence statement CR5: Evaluation\n\nData collection and monitoring can contribute to project sustainability, project management, keeping all parties focused on goals and service improvement. Evaluation is primarily considered for individual programmes, projects and interventions; a complex, community-wide approach is seldom evaluated.\n\nFurther consideration needs to be given to the applicability and acceptability of different types of evidence, in the context of the very limited time and resources available at a local level. There is concern that while obesity prevention is a long-term challenge, with long timescales for return on investment, funding is very often short term, with unrealistic outcome expectations. Consideration should be given to the acceptance of intermediate outcomes in commissioning contracts. The example of 'job readiness' in employment-related community work was cited, with the suggestion that 'weight-loss readiness' was a similarly legitimate intermediate outcome. There is a tension between the use of narrow, quantitative outcome criteria (often the focus of commissioners), versus a broader range of outcome measures including qualitative data of community wellbeing (often the focus of providers).\n\nEvaluation is often focused on contract performance management. There was little evidence of a systematic approach to building a local evidence base. Project timetables and budgets rarely allow for the establishment of robust baselines on which to base evaluations. Evaluation often ignores clients who had dropped out of the programme or intervention. This would seem to be a significant gap in the development of evidence.\n\nProviders express concerns about the burden of data collection and monitoring, particularly those receiving funding from multiple sources. There is frustration at the inconsistency of data required by different funders. Evaluators should properly brief those collecting the data on the rationale and requirements.\n\n## Evidence statement CR6: Cost effectiveness\n\nVery little true cost-effectiveness evaluation is undertaken at a local level due to the lack of specialist skills. To commission externally is expensive, and if the skills are available internally it is very time intensive. Thus, cost-effectiveness analysis may be considered not justified on grounds of cost effectiveness.\n\nThere seems to be relatively little scrutiny of cost effectiveness (as opposed to cost management). Budget holders at a higher level appear to have limited understanding of cost-effectiveness analysis, and as a result, there is little pressure to undertake such work.\n\nSome participants expressed concern that public health investment might be disadvantaged by more exposure to cost-effectiveness analysis, due to public health delivering longer-term returns on investment, and the difficulty of attributing cause and effect (relative to clinical treatment). There was also a concern that truly like-for-like comparisons are difficult to achieve in cost-effectiveness analysis. In this view there was a risk of simplistic interpretation, in which differences between programmes and interventions may be caused by underlying socioeconomic factors that were not visible in the calculation.\n\n# Additional evidence\n\nExpert paper 1: 'Whole systems – adapted and designed'\n\nExpert paper 2: 'Lessons from tobacco control'\n\nExpert paper 3: 'Systems and system failure'\n\nExpert paper 4: 'Whole system approaches to obesity – progress and future plans'\n\nExpert paper 5: 'Insight, experiences and evidence of the Childhood Obesity National Support Team'\n\nExpert paper 6: 'Cycling cities/cycling demonstration towns initiative'\n\nExpert paper 7: 'The contribution of health trainers, community health champions and the general public'\n\nExpert paper 8: 'Well London'\n\nExpert paper 9: 'Tower Hamlets healthy borough programme'\n\nExpert paper 10: 'Healthy places, healthy lives – tackling childhood obesity in Luton case study'\n\nExpert paper 11: 'Exeter cycling demonstration town 2005 to 2011'\n\nExpert paper 12: 'Commissioning – learning from Sheffield and Rotherham'\n\nExpert paper 13: 'Evaluation in Hull'\n\nExpert paper 14: 'Working in partnership: An example from a rural area – South Gloucestershire'\n\nExpert paper 15: 'Tackling obesity in a rural county'\n\nExpert paper 16: 'West and Mid Essex local commissioning experience'\n\nExpert paper 17: 'Effective partnership working and stakeholder engagement in the delivery of obesity prevention and treatment programmes in Kirklees'\n\nExpert paper 18: 'Short paper on organisational issues'\n\nExpert paper 19: 'Evaluating complex community-based interventions (CBIs) for obesity prevention'\n\n# Economic modelling report\n\nWhere two organisations decide to work in partnership to implement an intervention more effectively than they could while working alone and there is a low initial cost, the partnership can usually be considered cost effective. When the partnership is known to lead to cost savings (especially as a result of sharing resources), it will be cost effective provided that the health benefits are not diminished when the organisations work together. In more complex situations, it is unclear whether or not partnerships are cost effective, because conventional cost-effectiveness methods cannot be applied.\n\nOn funding for projects, a simple model suggests that obesity projects with long-term funding are likely to be more cost effective than equivalent projects with less secure funding.\n\nPrevious modelling suggests that any public health interventions costing £10 or less per head will be cost effective for all except the smallest weight losses (or weight gains prevented).\n\nEngaging with local communities can, for a relatively low cost, ensure aspects of a large project that have not been acceptable to a community may be modified, and result in large community gains that would otherwise have been rejected. The decision to engage will depend on whether the original plans are likely to succeed without engagement, and the likelihood that engagement will succeed in producing a consensus in favour of a modified project.", 'Appendix D Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence reviews, commissioned primary research and expert testimony. These gaps are set out below.\n\n. Community-wide programmes\n\na) Few community-wide obesity programmes have been evaluated (that is, programmes involving multiple actions locally). Those that do exist are mainly school-based, the components are often inadequately described, and the terminology varies from study to study. Follow-up times are too short and clients who dropped out are often ignored.\n\nb) There is a lack of evidence on community based obesity prevention programmes for children and adults with disabilities.\n\n(Source: review 1 and 2; commissioned report; PDG discussions)\n\n. Partnerships\n\nThere is a lack of evidence on community-wide partnership working. In particular, the following questions need answering:\n\na) What are the most cost-effective components of a partnership?\n\nb) How can oversight and management committees or groups effectively manage a partnership? How can the best local representatives for these committees or groups be identified?\n\nc) On what basis should a decision be made to form a local partnership – as opposed to working unilaterally?\n\nd) Is there a difference between 'adaptive' (that is, voluntary) partnerships that emerge spontaneously and 'mandated' (imposed from above) partnerships in terms of effectiveness?\n\ne) What are the best incentives or techniques to encourage partnership working?\n\n(Source: PDG discussions)\n\n. Complexity of local systems\n\nThere is a lack of evidence on how complexity theory, management theory, change theory and a whole-systems approach works in practice. Specifically, we need to know:\n\na) What are the synergies between common actions to tackle obesity?\n\nb) Where are the greatest opportunities for tackling obesity in any given community?\n\nc) How can the local system – and components of the local system – evolve to better tackle obesity?\n\nd) Does a local community programme that focuses on prevention tend to work against efforts in the same community to treat people who are already obese (and vice versa)?\n\n(Source: PDG discussions)\n\n. Health economics\n\nThere is a lack of evidence on the economics of community-wide partnership working to prevent obesity. This type of activity involves complex interactions and is not amenable to current economic evaluation techniques.\n\n(Source: PDG discussions)\n\n. Scalability\n\nThere is a lack of evidence on the practicality and effectiveness of extending or 'scaling up' small obesity prevention programmes. 'Scalability' in this sense means increasing the:\n\ngeographic coverage\n\nnumber of contexts in which it is offered\n\nnumber of participants.\n\n(Source: PDG discussions)\n\n. Programme composition\n\nThere are unresolved questions about the composition of an effective, local community-wide programme aimed at tackling obesity, specifically:\n\na) How can a 'community development' approach best be applied?\n\nb) How can learning from other programmes be used (for example, how transferrable is the learning from tobacco or alcohol control programmes)?\n\nc) What combination of features ensures a programme is effective – and how do they relate to each other?\n\nd) What aspects of a community-wide intervention (or parts of an intervention) need guidance to ensure health and community workers can implement them effectively?\n\ne) How 'intense' does a programme need to be, both in terms of the number of interventions (or sub-interventions), and the amount of activities involved in each one?\n\n(Source: PDG discussions)\n\n. Sustainability\n\nThere is a lack of evidence on how to ensure programmes can be sustained over the longer term. This includes effective ways of ensuring: continuation of funding, the partnership remains strong, volunteer and 'Please link to glossary participation and long-term leadership.\n\n(Source: PDG discussions)\n\n. Business\n\nThere is a lack of evidence on how to get local businesses (in particular, small businesses) and chambers of commerce involved in obesity prevention work.\n\n(Source: PDG discussions)\n\n. Measurement\n\nThere is a lack of evidence on effective measurement and segmentation tools that could be used as part of the JSNAs and for programme evaluation. Similarly, there is a lack of research on appropriate benchmarks that could be used.\n\n(Source: PDG discussions)", 'Appendix E Supporting documents': "Supporting documents include:\n\nEvidence reviews:\n\n\n\nReview 1 'Identifying the key elements and interactions of a whole system approach to obesity prevention'\n\nReview 2 'The effectiveness of whole system approaches to prevent obesity'\n\nReview 3 'Barriers and facilitators to effective whole system approaches'.\n\n\n\nReview of economic evaluations:\n\n\n\n'Whole system approaches to obesity prevention: Review of cost-effectiveness evidence'.\n\n\n\nEconomic modelling:\n\n\n\n'Cost effectiveness analysis in partnership working for reducing obesity and other long-term conditions'.\n\n\n\nCommissioned report:\n\n\n\n'Implementing community-wide action to prevent obesity: opinions and experiences of local public health teams and other relevant parties'.\n\n\n\nExpert testimony:\n\n\n\nExpert paper 1: 'Whole systems – adapted and designed'\n\nExpert paper 2: 'Lessons from tobacco control'\n\nExpert paper 3: 'Systems and system failure'\n\nExpert paper 4: 'Whole system approaches to obesity – progress and future plans'\n\nExpert paper 5: 'Insight, experiences and evidence of the Childhood Obesity National Support Team'\n\nExpert paper 6: 'Cycling cities/cycling demonstration towns initiative'\n\nExpert paper 7: 'The contribution of health trainers, community health champions and the general public'\n\nExpert paper 8: 'Well London'\n\nExpert paper 9: 'Tower Hamlets healthy borough programme'\n\nExpert paper 10: 'Healthy places, healthy lives – tackling childhood obesity in Luton case study'\n\nExpert paper 11: 'Exeter cycling demonstration town 2005 to 2011'\n\nExpert paper 12: 'Commissioning – learning from Sheffield and Rotherham'\n\nExpert paper 13: 'Evaluation in Hull'\n\nExpert paper 14: 'Working in partnership: An example from a rural area – South Gloucestershire'\n\nExpert paper 15: 'Tackling obesity in a rural county'\n\nExpert paper 16: 'West and Mid Essex local commissioning experience'\n\nExpert paper 17: 'Effective partnership working and stakeholder engagement in the delivery of obesity prevention and treatment programmes in Kirklees'\n\nExpert paper 18: 'Short paper on organisational issues'\n\nExpert paper 19: 'Evaluating complex community-based interventions (CBIs) for obesity prevention'.\n\n", 'Finding more information': "To find NICE guidance on related topics, including guidance in development, see the NICE topic page on obesity.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews and expert papers. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice."}	https://www.nice.org.uk/guidance/ph42	This guideline covers how local communities, with support from local organisations and networks, can help prevent people from becoming overweight or obese or help them lose weight. It aims to support sustainable and community-wide action to achieve this.
323c5e201c326a8415844efd9394076bb0ed095f	nice	Spondyloarthritis in over 16s: diagnosis and management	Spondyloarthritis in over 16s: diagnosis and management This guideline covers diagnosing and managing spondyloarthritis that is suspected or confirmed in adults who are 16 years or older. It aims to raise awareness of the features of spondyloarthritis and provide clear advice on what action to take when people with signs and symptoms first present in healthcare settings. It also provides advice on the range of treatments available. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Spondyloarthritis is a group of inflammatory conditions that have a range of manifestations. Spondyloarthritis may be predominantly: axial: radiographic axial spondyloarthritis (ankylosing spondylitis) non-radiographic axial spondyloarthritis or peripheral: psoriatic arthritis reactive arthritis enteropathic spondyloarthritis. People with predominantly axial spondyloarthritis may have additional peripheral symptoms, and vice versa. Axial presentations of spondyloarthritis are often misdiagnosed as mechanical low back pain, leading to delays in access to effective treatments. Peripheral presentations are often seen as unrelated joint or tendon problems, and can be misdiagnosed because problems can move around between joints. # Recognition and referral in non-specialist care settings Do not rule out the possibility that a person has spondyloarthritis solely on the presence or absence of any individual sign, symptom or test result. ## Suspecting spondyloarthritis Recognise that spondyloarthritis can have diverse symptoms and be difficult to identify, which can lead to delayed or missed diagnoses. Signs and symptoms may be musculoskeletal (for example, inflammatory back pain, enthesitis and dactylitis) or extra-articular (for example, uveitis and psoriasis ). Risk factors include recent genitourinary infection and a family history of spondyloarthritis or psoriasis. Be aware that axial and peripheral spondyloarthritis may be missed, even if the onset is associated with established comorbidities (for example, uveitis, psoriasis, inflammatory bowel disease , or a gastrointestinal or genitourinary infection). Be aware that axial spondyloarthritis: affects a similar number of women as men can occur in people who are human leukocyte antigen B27 (HLA‑B27) negative may be present despite no evidence of sacroiliitis on a plain film X‑ray. ## Referral for suspected axial spondyloarthritis If a person has low back pain that started before the age of 45 years and has lasted for longer than 3 months, refer the person to a rheumatologist for a spondyloarthritis assessment if 4 or more of the following additional criteria are also present: low back pain that started before the age of 35 years (this further increases the likelihood that back pain is due to spondyloarthritis compared with low back pain that started between 35 and 44 years) waking during the second half of the night because of symptoms buttock pain improvement with movement improvement within 48 hours of taking non-steroidal anti-inflammatory drugs (NSAIDs) a first-degree relative with spondyloarthritis current or past arthritis current or past enthesitis current or past psoriasis.If exactly 3 of the additional criteria are present, perform an HLA‑B27 test. If the test is positive, refer the person to a rheumatologist for a spondyloarthritis assessment. If the person does not meet the criteria in recommendation 1.1.5 but clinical suspicion of axial spondyloarthritis remains, advise the person to seek repeat assessment if new signs, symptoms or risk factors listed in recommendation 1.1.5 develop. This may be especially appropriate if the person has current or past inflammatory bowel disease (Crohn's disease or ulcerative colitis), psoriasis or uveitis (see recommendation 1.1.12 for guidance on referral for immediate ophthalmological assessment for people with acute anterior uveitis). ## Referral for suspected psoriatic arthritis and other peripheral spondyloarthritides For guidance on identifying spondyloarthritis in people with an existing diagnosis of psoriasis, see assessment and referral for psoriatic arthritis in the NICE guideline on psoriasis. Urgently refer people with suspected new‑onset inflammatory arthritis to a rheumatologist for a spondyloarthritis assessment, unless rheumatoid arthritis, gout or acute calcium pyrophosphate (CPP) arthritis ('pseudogout') is suspected. If rheumatoid arthritis is suspected, see referral for specialist treatment in the NICE guideline on rheumatoid arthritis in adults. Refer people with dactylitis to a rheumatologist for a spondyloarthritis assessment. Refer people with enthesitis without apparent mechanical cause to a rheumatologist for a spondyloarthritis assessment if: it is persistent or it is in multiple sites or any of the following are also present: back pain without apparent mechanical cause current or past uveitis (see recommendation 1.1.12 for guidance on immediate ophthalmological assessment for people with acute anterior uveitis) current or past psoriasis gastrointestinal or genitourinary infection inflammatory bowel disease (Crohn's disease or ulcerative colitis) a first-degree relative with spondyloarthritis or psoriasis. ## Recognising psoriasis If a person with suspected spondyloarthritis has signs or symptoms of undiagnosed psoriasis, follow the recommendations in the NICE guideline on psoriasis. ## Referral for suspected acute anterior uveitis Refer people for an immediate (same‑day) ophthalmological assessment if they have symptoms of acute anterior uveitis (for example, eye pain, eye redness, sensitivity to light or blurred vision). ## Case-finding in people with acute anterior uveitis Ophthalmologists should ask people with acute anterior uveitis whether they have: consulted their GP about joint pains or experienced low back pain that started before the age of 45 years and has lasted for longer than 3 months. If the person meets either of the criteria in recommendation 1.1.13, establish whether they have psoriasis or skin complaints that appear psoriatic on physical examination. If they do, refer the person to a rheumatologist for a spondyloarthritis assessment. If they do not, perform an HLA‑B27 test. If the test is positive, refer the person to a rheumatologist for a spondyloarthritis assessment. # Diagnosing spondyloarthritis in specialist care settings ## Diagnostic criteria for suspected spondyloarthritis In specialist care settings, consider using validated spondyloarthritis criteria to guide clinical judgement when diagnosing spondyloarthritis. Examples include: general spondyloarthritis criteria: Amor European Spondyloarthropathy Study Group (ESSG) axial spondyloarthritis criteria: Assessment of Spondyloarthritis International Society (ASAS; axial) Berlin Rome modified New York peripheral spondyloarthritis criteria: ASAS (peripheral) Classification of Psoriatic Arthritis (CASPAR) French Society of Rheumatology (reactive arthritis). Do not rule out a diagnosis of spondyloarthritis solely on the basis of a negative HLA‑B27 result. Do not rule out a diagnosis of spondyloarthritis if a person's C‑reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are normal. ## Imaging for suspected axial spondyloarthritis Offer plain film X‑ray of the sacroiliac joints for people with suspected axial spondyloarthritis, unless the person is likely to have an immature skeleton. Diagnose radiographic axial spondyloarthritis (ankylosing spondylitis) if the plain film X‑ray shows sacroiliitis meeting the modified New York criteria (bilateral grade 2–4 or unilateral grade 3–4 sacroiliitis). If the plain film X‑ray does not show sacroiliitis meeting modified New York criteria (bilateral grade 2–4 or unilateral grade 3–4 sacroiliitis), or an X‑ray is not appropriate because the person's skeleton is not fully mature, request unenhanced MRI using an inflammatory back pain protocol. Radiologists receiving a request for an inflammatory back pain MRI should perform short T1 inversion recovery (STIR) and T1 weighted sequences of the whole spine (sagittal view), and sacroiliac joints (coronal oblique view). Use the ASAS/Outcome Measures in Rheumatology (OMERACT) MRI criteria to interpret the MRI as follows: If the MRI meets the ASAS/OMERACT MRI criteria: diagnose non-radiographic axial spondyloarthritis. If the MRI does not meet the ASAS/OMERACT MRI criteria: do not exclude the possibility of axial spondyloarthritis consider specialist musculoskeletal radiology review if there is disparity between the clinical suspicion and imaging findings, particularly in people with an immature skeleton -ffer an HLA‑B27 test if it has not already been done. If positive, base the diagnosis of non-radiographic axial spondyloarthritis on clinical features, for example, using the clinical 'arm' of the ASAS axial classification criteria. If a diagnosis of axial spondyloarthritis cannot be confirmed and clinical suspicion remains high, consider a follow‑up MRI. Do not offer scintigraphy for people with suspected axial spondyloarthritis. ## Imaging for suspected psoriatic arthritis and other peripheral spondyloarthritides Offer plain film X‑ray of symptomatic hands and feet for people with suspected peripheral spondyloarthritis in these areas. If a diagnosis cannot be made from the plain film X‑ray, consider ultrasound of: the hands and feet to assess for joint involvement suspected enthesitis sites. Consider plain film X‑rays, ultrasound and/or MRI of other peripheral and axial symptomatic sites. Interpret a positive HLA‑B27 result as increasing the likelihood of peripheral spondyloarthritis. If a diagnosis of peripheral spondyloarthritis is confirmed, offer plain film X‑ray of the sacroiliac joints to assess for axial involvement, even if the person does not have any symptoms. ## Antibody testing for suspected reactive arthritis Do not routinely test for infective antibody status to diagnose reactive arthritis in people with a history of gastrointestinal infection. # Information and support ## Information about spondyloarthritis Provide people with spondyloarthritis, and their family members or carers (as appropriate), with information that is: available on an ongoing basis relevant to the stage of the person's condition tailored to the person's needs.For more guidance on providing information to people and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services. Provide explanations and information about spondyloarthritis, for example: what spondyloarthritis is diagnosis and prognosis treatment options (pharmacological and non-pharmacological), including possible side effects likely symptoms and how they can be managed flare episodes and extra-articular symptoms self-help options -pportunities for people with spondyloarthritis to be involved in research which healthcare professionals will be involved with the person's care and how to get in touch with them information about employment rights and ability to work local support groups, online forums and national charities, and how to get in touch with them. ## Information about disease flares Advise people with spondyloarthritis about the possibility of experiencing flare episodes and extra-articular symptoms. Consider developing a flare management plan that is tailored to the person's individual needs, preferences and circumstances. When discussing any flare management plan, provide information on: access to care during flares (including details of a named person to contact ) self-care (for example, exercises, stretching and joint protection) pain and fatigue management potential changes to medicines managing the impact on daily life and ability to work. # Pharmacological management of spondyloarthritis ## Axial spondyloarthritis Offer NSAIDs at the lowest effective dose to people with pain associated with axial spondyloarthritis, and think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment. If an NSAID taken at the maximum tolerated dose for 2–4 weeks does not provide adequate pain relief, consider switching to another NSAID. Adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are recommended, within their marketing authorisations, as options for treating severe active ankylosing spondylitis in adults whose disease has responded inadequately to, or who cannot tolerate, NSAIDs. Infliximab is recommended only if treatment is started with the least expensive infliximab product. People currently receiving infliximab should be able to continue treatment with the same infliximab product until they and their NHS clinician consider it appropriate to stop. Adalimumab, certolizumab pegol and etanercept are recommended, within their marketing authorisations, as options for treating severe non-radiographic axial spondyloarthritis in adults whose disease has responded inadequately to, or who cannot tolerate, NSAIDs. The choice of treatment should be made after discussion between the clinician and the patient about the advantages and disadvantages of the treatments available. This may include considering associated conditions such as extra-articular manifestations. If more than 1 treatment is suitable, the least expensive (taking into account administration costs and patient access schemes) should be chosen. The response to adalimumab, certolizumab pegol, etanercept, golimumab or infliximab treatment should be assessed 12 weeks after the start of treatment. Treatment should only be continued if there is clear evidence of response, defined as: a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more. Treatment with another tumour necrosis factor (TNF)‑alpha inhibitor is recommended for people who cannot tolerate, or whose disease has not responded to, treatment with the first TNF‑alpha inhibitor, or whose disease has stopped responding after an initial response. When using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate. Secukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis in adults whose disease has responded inadequately to conventional therapy (NSAIDs or TNF‑alpha inhibitors). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme. Assess the response to secukinumab after 16 weeks of treatment and only continue if there is clear evidence of response, defined as: a reduction in the BASDAI score to 50% of the pre-treatment value or by 2 or more units and a reduction in the spinal pain VAS by 2 cm or more. When using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate. ## Psoriatic arthritis and other peripheral spondyloarthritides Consider local corticosteroid injections as monotherapy for non-progressive monoarthritis. Offer standard disease-modifying anti-rheumatic drugs (DMARDs) to people with: peripheral polyarthritis -ligoarthritis persistent or progressive monoarthritis associated with peripheral spondyloarthritis. When deciding which standard DMARD to offer, take into account: the person's needs, preferences and circumstances (such as pregnancy planning and alcohol consumption) comorbidities such as uveitis, psoriasis and inflammatory bowel disease disease characteristics potential side effects. If a standard DMARD taken at the maximum tolerated dose for at least 3 months does not provide adequate relief from symptoms, consider switching to or adding another standard DMARD. Consider NSAIDs as an adjunct to standard DMARDs or biological DMARDs to manage symptoms. Use oral NSAIDs at the lowest effective dose for the shortest possible period of time, and think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment. If NSAIDs do not provide adequate relief from symptoms, consider steroid injections (local or intramuscular) or short-term oral steroid therapy as an adjunct to standard DMARDs or biological DMARDs to manage symptoms. If extra-articular disease is adequately controlled by an existing standard DMARD but peripheral spondyloarthritis is not, consider adding another standard DMARD. For guidance on treating psoriatic arthritis with apremilast, see NICE's technology appraisal guidance on apremilast for treating active psoriatic arthritis. Etanercept, infliximab and adalimumab are recommended for the treatment of adults with active and progressive psoriatic arthritis when the following criteria are met. The person has peripheral arthritis with 3 or more tender joints and 3 or more swollen joints, and The psoriatic arthritis has not responded to adequate trials of at least 2 standard DMARDs, administered either individually or in combination. Treatment as described in 1.4.20 should normally be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individual patients because of differences in the method of administration and treatment schedules. Etanercept, adalimumab or infliximab treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. An adequate response is defined as an improvement in at least 2 of the 4 PsARC criteria (1 of which has to be joint tenderness or swelling score) with no worsening in any of the 4 criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks but whose PsARC response does not justify continuation of treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis , infliximab for the treatment of adults with psoriasis and adalimumab for the treatment of adults with psoriasis for guidance on the use of TNF inhibitors in psoriasis). When using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. Golimumab is recommended as an option for the treatment of active and progressive psoriatic arthritis in adults only if: it is used as described for other TNF‑inhibitor treatments in NICE technology appraisal guidance etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (see recommendations 1.4.20–1.4.23 in this guideline) and the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose. When using the PsARC (as set out in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (see recommendations 1.4.20–1.4.23 in this guideline), healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. Ustekinumab is recommended as an option, alone or in combination with methotrexate, for treating active psoriatic arthritis in adults only when: treatment with TNF‑alpha inhibitors is contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis , and golimumab for the treatment of psoriatic arthritis ) or the person has had treatment with 1 or more TNF‑alpha inhibitors.Ustekinumab is recommended only if the company provides the 90 mg dose of ustekinumab for people who weigh more than 100 kg at the same cost as the 45 mg dose, as agreed in the patient access scheme. Ustekinumab treatment should be stopped if the person's psoriatic arthritis has not shown an adequate response using the PsARC at 24 weeks. An adequate response is defined as an improvement in at least 2 of the 4 criteria (1 of which must be joint tenderness or swelling score), with no worsening in any of the 4 criteria. As recommended in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (see recommendations 1.4.20–1.4.23 in this guideline), people whose disease has a PASI 75 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see NICE technology appraisal guidance on ustekinumab for the treatment of adults with moderate to severe psoriasis). When using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. People whose treatment with ustekinumab is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue ustekinumab until they and their NHS clinician consider it appropriate to stop. ## Reactive arthritis After treating the initial infection, do not offer long-term (4 weeks or longer) treatment with antibiotics solely to manage reactive arthritis caused by a gastrointestinal or genitourinary infection. # Non-pharmacological management of spondyloarthritis Refer people with axial spondyloarthritis to a specialist physiotherapist to start an individualised, structured exercise programme, which should include: stretching, strengthening and postural exercises deep breathing spinal extension range of motion exercises for the lumbar, thoracic and cervical sections of the spine aerobic exercise. Consider hydrotherapy as an adjunctive therapy to manage pain and maintain or improve function for people with axial spondyloarthritis. Consider a referral to a specialist therapist (such as a physiotherapist, occupational therapist, hand therapist, orthotist or podiatrist) for people with spondyloarthritis who have difficulties with any of their everyday activities. The specialist therapist should: assess people's needs provide advice about physical aids arrange periodic reviews to assess people's changing needs. # Surgery for spondyloarthritis Do not refer people with axial spondyloarthritis to a complex spinal surgery service to be assessed for spinal deformity correction unless the spinal deformity is: significantly affecting their quality of life and severe or progressing despite optimal non-surgical management (including physiotherapy). If a person with axial spondyloarthritis presents with a suspected spinal fracture, refer them to a specialist to confirm the spinal fracture and carry out a stability assessment. After the stability assessment, the specialist should refer people with a potentially unstable spinal fracture to a spinal surgeon. # Managing flares Manage flares in either specialist care or primary care depending on the person's needs. When managing flares in primary care, seek advice from specialist care as needed, particularly for people who: have recurrent or persistent flares are taking biological DMARDs have comorbidities that may affect treatment or management of flares. Be aware that uveitis can occur during flare episodes. See recommendation 1.1.12 for guidance on immediate (same‑day) ophthalmological assessment for people with acute anterior uveitis. # Long-term complications For guidance on monitoring long-term pharmacological treatments, see the NICE guideline on medicines optimisation. Take into account the adverse effects associated with NSAIDs, standard DMARDs and biological DMARDs when monitoring spondyloarthritis in primary care. Advise people that there may be a greater risk of skin cancer in people treated with TNF‑alpha inhibitors. Discuss risk factors for cardiovascular comorbidities with all people with spondyloarthritis. Consider regular osteoporosis assessments (every 2 years) for people with axial spondyloarthritis. Be aware that bone mineral density measures may be elevated on spinal dual‑energy X‑ray absorptiometry (DEXA) due to the presence of syndesmophytes and ligamentous calcification, whereas hip measurements may be more reliable. Advise people with axial spondyloarthritis that they may be prone to fractures, and should consult a healthcare professional following falls or physical trauma, particularly in the event of increased musculoskeletal pain. # Organisation of care ## Coordinating care across settings Commissioners should ensure that local arrangements are in place to coordinate care for people across primary and secondary (specialist) care. These should cover: prescribing NSAIDs and standard DMARDs monitoring NSAIDs, standard DMARDs and biological DMARDs managing flares ensuring prompt access to specialist rheumatology care when needed ensuring prompt access to other specialist services to manage comorbidities and extra-articular symptoms. Ensure that people with spondyloarthritis have access to specialist care in primary or secondary care settings throughout the disease course to ensure optimal long-term spondyloarthritis management (see section 1.7 for arrangements for managing flares). Ensure that there is effective communication and coordination between all healthcare professionals involved in the person's care, particularly if the person has comorbidities or extra-articular symptoms. Ensure that there is communication and coordination between rheumatology and other relevant specialities (such as dermatology, gastroenterology and ophthalmology). This is particularly important for people who: are already receiving standard DMARDs or biological DMARDs for another condition need to start taking standard DMARDs or biological DMARDs for another condition. For guidance on managing the transition of young people with juvenile idiopathic arthritis to adult services, see the NICE guideline on transition from children's to adults' services for young people using health or social care services.# Context Spondyloarthritis encompasses a group of inflammatory conditions with some shared features, including extra-articular manifestations. Both peripheral and axial joints can be affected. The spondyloarthritides are distinct from rheumatoid arthritis but are as important to recognise and manage early in their presentation to improve health outcomes. Most people with these conditions have either psoriatic arthritis or axial spondyloarthritis, which includes ankylosing spondylitis. Ankylosing spondylitis and non-radiographic axial spondyloarthritis primarily affect the spine, in particular the sacroiliac joint. Both conditions present in similar ways; the primary classification difference is whether sacroiliitis is detectable on X‑ray. Psoriatic arthritis may manifest in a number of different patterns. These include predominant involvement of small joints in the hands and feet, predominant large joint involvement, particularly in the knees, or combinations of these. Psoriatic arthritis may also involve the axial joints, and inflammation of the entheses and/or finger and toe joints. Skin and nail involvement may not be present at diagnosis and in its absence, a family history of psoriasis is required to meet the diagnostic criteria. Less common subgroups are enteropathic spondyloarthritis, which is associated with inflammatory bowel disease (Crohn's disease and ulcerative colitis), and reactive arthritis, which can occur in people after gastrointestinal or genitourinary infections. The final subgroup is people who have undifferentiated spondyloarthritis. These people generally have an asymmetrical oligoarticular (fewer than 5 involved joints) arthritis, often involving the knees. They do not meet the diagnostic criteria of the other subgroups at presentation but their disease may evolve to do so at a later stage. This guideline also includes people who are 16 years or older with axial or peripheral symptoms who have previously been diagnosed with juvenile idiopathic arthritis. Healthcare professionals in non-specialist settings do not always recognise the signs and symptoms of spondyloarthritis, particularly spinal symptoms, which may be mistakenly attributed to other causes of low back pain. This can lead to substantial delays in diagnosis and treatment with consequent disease progression and disability. This guideline seeks to raise awareness of the features of spondyloarthritis and provide clear advice on what action to take when people with signs and symptoms first present in healthcare settings. This guideline also provides advice on the interventions available to people with spondyloarthritis. These include pharmacological and non-pharmacological treatments, and surgery. The guidance also provides advice on how care for people with spondyloarthritis should be organised across healthcare settings, and what information and support should be provided.# Recommendations for research The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline. # Referral criteria for people with suspected axial spondyloarthritis What are the optimal referral criteria for people with suspected axial spondyloarthritis? ## Why this is important The Dutch CaFaSpA study (van Hoeven et al. 2014, 2015) should be repeated in a UK population. This would involve examining GP databases to identify a cohort of people who have a diagnosis of non-specific back pain who first consulted their GP for back symptoms under the age of 45. These people would be invited for a full rheumatological assessment (including identifying signs and symptoms relevant to axial spondyloarthritis, X‑ray, MRI and HLA‑B27 test). All participants would be given a reference-standard diagnosis of axial spondyloarthritis or not (ideally using expert clinician opinion, or if this is not possible, using the ASAS classification criteria). The cohort would be split into a development and validation set, to derive and validate optimal rules for case-finding from the available data, with each candidate strategy judged according to expected cost per quality-adjusted life year (QALY) gained (the NICE economic model developed for this guideline could easily be used to estimate these). As a result of the large number of permutations of possible referral strategies, it is impractical to run separate validation studies for all referral criteria that are developed. Therefore, a single large, representative cohort study would, provided it measured the predictor variables for all reasonable referral strategies, provide the ability to develop and validate any number of possible referral strategies. The study would need to be large enough that sufficient data are available to derive new referral rules and to validate those rules in a separate, independent subset of the data. A UK‑specific dataset would provide more relevant data to do this than is currently available from the Dutch CaFaSpA study. For example, that study found an HLA‑B27 prevalence of 20% in people with axial spondyloarthritis and 2% in people without; much lower than the estimates found elsewhere (75% and 20% respectively). This lowers the validity of extrapolating any results found to the UK, and reinforces the need for UK‑specific data to address this question. # Long-term complications of spondyloarthritis What is the incidence of long-term complications, in particular osteoporosis, cardiovascular disease (CVD) and metabolic syndrome, in people with spondyloarthritis, and how does this compare with the general population? Are any specific spondyloarthritis features or risk factors associated with the incidence and outcomes of these complications? ## Why this is important Spondyloarthritides are a group of systemic inflammatory conditions, and as such it is thought that people with these conditions may have an elevated risk of CVD, particularly if their disease is not adequately controlled. This may have direct vascular effects as well as precluding maintenance of a good level of cardiovascular fitness. There is also clinical uncertainty around the long-term use of non-steroidal anti-inflammatory drugs (NSAIDs): whether the long-term CVD risks associated with this class of drugs are observed in this population, or whether the suppression of inflammation with these drugs mitigates some of the CVD risks associated with these conditions. In addition, risks of osteoporosis and fracture are known to be higher in people with axial spondyloarthritis than the general population, and the prevalence of axial manifestations in people diagnosed with peripheral disease implies the risks may also be high in peripheral spondyloarthritis. The longer-term complication rates in the spondyloarthritides need to be established, as well as whether standard biological disease-modifying anti-rheumatic drug (DMARD) therapies and biological DMARDs influence these outcomes. Research that evaluates incidence of osteoporosis, CVD and metabolic syndrome in people with either axial or peripheral spondyloarthritis compared with the general population would therefore be of value. This research should take into account disease stage, personal activity levels and medicine use, and look to address how frequently it is appropriate to monitor people with spondyloarthritis for long-term complications. # Educational intervention to improve healthcare professionals' awareness of spondyloarthritis What is the effectiveness and cost effectiveness of educational interventions for healthcare professionals in order to increase the number of prompt diagnoses of spondyloarthritis? ## Why this is important One of the major reasons for the delays in diagnosing spondyloarthritis is a lack of awareness of the condition by healthcare professionals. This can take many forms, such as a lack of awareness of different spondyloarthritis subtypes, lack of knowledge about associated clinical features (for example, the differences between inflammatory and mechanical back pain) or characteristics of the patient populations (for example, that spondyloarthritis affects similar numbers of men and women, or that a substantial proportion of people with spondyloarthritis are HLA‑B27 negative). Educational interventions to improve the level of awareness may therefore lead to reductions in diagnosis delays, but there is a lack of evidence as to the efficacy of these interventions. Randomised controlled trials of structured educational interventions are therefore needed to assess both whether they reduce the length of time it takes for people to be correctly diagnosed, and whether they represent a cost-effective use of NHS resources. # Pharmacological management of peripheral spondyloarthritis What is the comparative effectiveness and cost effectiveness of standard DMARDs for managing peripheral spondyloarthritis, and is this effectiveness affected by differences in dose escalation protocols? ## Why this is important The committee noted that, although there are a number of randomised controlled trials comparing standard DMARDs with placebo for managing peripheral spondyloarthritis, there is a lack of evidence comparing individual standard DMARDs to other standard DMARDs. This lack of evidence makes it difficult to optimise initial therapy, either by specifying specific drugs within the class or optimising dose, administration and monitoring protocols. There is therefore the need for randomised controlled trials looking at alternative drug, dosing and administration route alternatives for the administration of standard DMARDs for managing peripheral spondyloarthritis. These trials should ensure NSAIDs and steroids are available to participants as needed, and should include (as outcome measures) both health-related quality of life (measured using the EQ‑5D) and health service resource use, to enable the results to be used to assess the cost effectiveness of the interventions. # Biological therapies for peripheral spondyloarthritis What is the effectiveness and cost effectiveness of biological DMARDs in people with persistent peripheral spondyloarthritis (excluding psoriatic arthritis) or undifferentiated spondyloarthritis? ## Why this is important Although there have been trials conducted of biological therapies for psoriatic arthritis, which have led to positive recommendations in NICE technology appraisals, no such good-quality evidence exists in enteropathic arthritis, reactive arthritis or undifferentiated spondyloarthritis. The substantial side effects possible with biological therapies, and their significant cost, means it is difficult to justify offering them to these groups without good evidence of efficacy. There is therefore the need for randomised controlled trials, with a sufficient sample size to identify possible benefits, in these 3 populations. If trials were to recruit participants from multiple spondyloarthritis subpopulations, results should be clearly stratified by diagnosis to enable any differences in benefits or harms between the groups to be identified. These trials should include (as outcome measures) both health-related quality of life (measured using the EQ‑5D) and health service resource use, to enable the results to be used to assess the cost effectiveness of the interventions.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nSpondyloarthritis is a group of inflammatory conditions that have a range of manifestations. Spondyloarthritis may be predominantly:\n\naxial:\n\n\n\nradiographic axial spondyloarthritis (ankylosing spondylitis)\n\nnon-radiographic axial spondyloarthritis or\n\n\n\nperipheral:\n\n\n\npsoriatic arthritis\n\nreactive arthritis\n\nenteropathic spondyloarthritis.\n\n\n\nPeople with predominantly axial spondyloarthritis may have additional peripheral symptoms, and vice versa.\n\nAxial presentations of spondyloarthritis are often misdiagnosed as mechanical low back pain, leading to delays in access to effective treatments. Peripheral presentations are often seen as unrelated joint or tendon problems, and can be misdiagnosed because problems can move around between joints.\n\n# Recognition and referral in non-specialist care settings\n\nDo not rule out the possibility that a person has spondyloarthritis solely on the presence or absence of any individual sign, symptom or test result.\n\n## Suspecting spondyloarthritis\n\nRecognise that spondyloarthritis can have diverse symptoms and be difficult to identify, which can lead to delayed or missed diagnoses. Signs and symptoms may be musculoskeletal (for example, inflammatory back pain, enthesitis and dactylitis) or extra-articular (for example, uveitis and psoriasis [including psoriatic nail symptoms]). Risk factors include recent genitourinary infection and a family history of spondyloarthritis or psoriasis.\n\nBe aware that axial and peripheral spondyloarthritis may be missed, even if the onset is associated with established comorbidities (for example, uveitis, psoriasis, inflammatory bowel disease [Crohn's disease or ulcerative colitis], or a gastrointestinal or genitourinary infection).\n\nBe aware that axial spondyloarthritis:\n\naffects a similar number of women as men\n\ncan occur in people who are human leukocyte antigen\xa0B27 (HLA‑B27) negative\n\nmay be present despite no evidence of sacroiliitis on a plain film X‑ray.\n\n## Referral for suspected axial spondyloarthritis\n\nIf a person has low back pain that started before the age of 45\xa0years and has lasted for longer than 3\xa0months, refer the person to a rheumatologist for a spondyloarthritis assessment if 4\xa0or more of the following additional criteria are also present:\n\nlow back pain that started before the age of 35\xa0years (this further increases the likelihood that back pain is due to spondyloarthritis compared with low back pain that started between 35\xa0and 44\xa0years)\n\nwaking during the second half of the night because of symptoms\n\nbuttock pain\n\nimprovement with movement\n\nimprovement within 48\xa0hours of taking non-steroidal anti-inflammatory drugs (NSAIDs)\n\na first-degree relative with spondyloarthritis\n\ncurrent or past arthritis\n\ncurrent or past enthesitis\n\ncurrent or past psoriasis.If exactly 3 of the additional criteria are present, perform an HLA‑B27 test. If the test is positive, refer the person to a rheumatologist for a spondyloarthritis assessment.\n\nIf the person does not meet the criteria in recommendation\xa01.1.5 but clinical suspicion of axial spondyloarthritis remains, advise the person to seek repeat assessment if new signs, symptoms or risk factors listed in recommendation\xa01.1.5 develop. This may be especially appropriate if the person has current or past inflammatory bowel disease (Crohn's disease or ulcerative colitis), psoriasis or uveitis (see recommendation\xa01.1.12 for guidance on referral for immediate [same‑day] ophthalmological assessment for people with acute anterior uveitis).\n\n## Referral for suspected psoriatic arthritis and other peripheral spondyloarthritides\n\nFor guidance on identifying spondyloarthritis in people with an existing diagnosis of psoriasis, see assessment and referral for psoriatic arthritis in the NICE guideline on psoriasis.\n\nUrgently refer people with suspected new‑onset inflammatory arthritis to a rheumatologist for a spondyloarthritis assessment, unless rheumatoid arthritis, gout or acute calcium pyrophosphate (CPP) arthritis ('pseudogout') is suspected. If rheumatoid arthritis is suspected, see referral for specialist treatment in the NICE guideline on rheumatoid arthritis in adults.\n\nRefer people with dactylitis to a rheumatologist for a spondyloarthritis assessment.\n\nRefer people with enthesitis without apparent mechanical cause to a rheumatologist for a spondyloarthritis assessment if:\n\nit is persistent or\n\nit is in multiple sites or\n\nany of the following are also present:\n\n\n\nback pain without apparent mechanical cause\n\ncurrent or past uveitis (see recommendation\xa01.1.12 for guidance on immediate [same‑day] ophthalmological assessment for people with acute anterior uveitis)\n\ncurrent or past psoriasis\n\ngastrointestinal or genitourinary infection\n\ninflammatory bowel disease (Crohn's disease or ulcerative colitis)\n\n\n\na first-degree relative with spondyloarthritis or psoriasis.\n\n## Recognising psoriasis\n\nIf a person with suspected spondyloarthritis has signs or symptoms of undiagnosed psoriasis, follow the recommendations in the NICE guideline on psoriasis.\n\n## Referral for suspected acute anterior uveitis\n\nRefer people for an immediate (same‑day) ophthalmological assessment if they have symptoms of acute anterior uveitis (for example, eye pain, eye redness, sensitivity to light or blurred vision).\n\n## Case-finding in people with acute anterior uveitis\n\nOphthalmologists should ask people with acute anterior uveitis whether they have:\n\nconsulted their GP about joint pains or\n\nexperienced low back pain that started before the age of 45\xa0years and has lasted for longer than 3\xa0months.\n\nIf the person meets either of the criteria in recommendation\xa01.1.13, establish whether they have psoriasis or skin complaints that appear psoriatic on physical examination.\n\nIf they do, refer the person to a rheumatologist for a spondyloarthritis assessment.\n\nIf they do not, perform an HLA‑B27 test. If the test is positive, refer the person to a rheumatologist for a spondyloarthritis assessment.\n\n# Diagnosing spondyloarthritis in specialist care settings\n\n## Diagnostic criteria for suspected spondyloarthritis\n\nIn specialist care settings, consider using validated spondyloarthritis criteria to guide clinical judgement when diagnosing spondyloarthritis. Examples include:\n\ngeneral spondyloarthritis criteria:\n\n\n\nAmor\n\nEuropean Spondyloarthropathy Study Group (ESSG)\n\n\n\naxial spondyloarthritis criteria:\n\n\n\nAssessment of Spondyloarthritis International Society (ASAS; axial)\n\nBerlin\n\nRome\n\nmodified New York\n\n\n\nperipheral spondyloarthritis criteria:\n\n\n\nASAS (peripheral)\n\nClassification of Psoriatic Arthritis (CASPAR)\n\n\n\nFrench Society of Rheumatology (reactive arthritis).\n\nDo not rule out a diagnosis of spondyloarthritis solely on the basis of a negative HLA‑B27 result.\n\nDo not rule out a diagnosis of spondyloarthritis if a person's C‑reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are normal.\n\n## Imaging for suspected axial spondyloarthritis\n\nOffer plain film X‑ray of the sacroiliac joints for people with suspected axial spondyloarthritis, unless the person is likely to have an immature skeleton.\n\nDiagnose radiographic axial spondyloarthritis (ankylosing spondylitis) if the plain film X‑ray shows sacroiliitis meeting the modified New York criteria (bilateral grade\xa02–4 or unilateral grade\xa03–4 sacroiliitis).\n\nIf the plain film X‑ray does not show sacroiliitis meeting modified New York criteria (bilateral grade\xa02–4 or unilateral grade\xa03–4 sacroiliitis), or an X‑ray is not appropriate because the person's skeleton is not fully mature, request unenhanced MRI using an inflammatory back pain protocol.\n\nRadiologists receiving a request for an inflammatory back pain MRI should perform short T1 inversion recovery (STIR) and T1 weighted sequences of the whole spine (sagittal view), and sacroiliac joints (coronal oblique view).\n\nUse the ASAS/Outcome Measures in Rheumatology (OMERACT) MRI criteria to interpret the MRI as follows:\n\nIf the MRI meets the ASAS/OMERACT MRI criteria:\n\n\n\ndiagnose non-radiographic axial spondyloarthritis.\n\n\n\nIf the MRI does not meet the ASAS/OMERACT MRI criteria:\n\n\n\ndo not exclude the possibility of axial spondyloarthritis\n\nconsider specialist musculoskeletal radiology review if there is disparity between the clinical suspicion and imaging findings, particularly in people with an immature skeleton\n\noffer an HLA‑B27 test if it has not already been done. If positive, base the diagnosis of non-radiographic axial spondyloarthritis on clinical features, for example, using the clinical 'arm' of the ASAS axial classification criteria.\n\n\n\nIf a diagnosis of axial spondyloarthritis cannot be confirmed and clinical suspicion remains high, consider a follow‑up MRI.\n\nDo not offer scintigraphy for people with suspected axial spondyloarthritis.\n\n## Imaging for suspected psoriatic arthritis and other peripheral spondyloarthritides\n\nOffer plain film X‑ray of symptomatic hands and feet for people with suspected peripheral spondyloarthritis in these areas.\n\nIf a diagnosis cannot be made from the plain film X‑ray, consider ultrasound of:\n\nthe hands and feet to assess for joint involvement\n\nsuspected enthesitis sites.\n\nConsider plain film X‑rays, ultrasound and/or MRI of other peripheral and axial symptomatic sites.\n\nInterpret a positive HLA‑B27 result as increasing the likelihood of peripheral spondyloarthritis.\n\nIf a diagnosis of peripheral spondyloarthritis is confirmed, offer plain film X‑ray of the sacroiliac joints to assess for axial involvement, even if the person does not have any symptoms.\n\n## Antibody testing for suspected reactive arthritis\n\nDo not routinely test for infective antibody status to diagnose reactive arthritis in people with a history of gastrointestinal infection.\n\n# Information and support\n\n## Information about spondyloarthritis\n\nProvide people with spondyloarthritis, and their family members or carers (as appropriate), with information that is:\n\navailable on an ongoing basis\n\nrelevant to the stage of the person's condition\n\ntailored to the person's needs.For more guidance on providing information to people and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services.\n\nProvide explanations and information about spondyloarthritis, for example:\n\nwhat spondyloarthritis is\n\ndiagnosis and prognosis\n\ntreatment options (pharmacological and non-pharmacological), including possible side effects\n\nlikely symptoms and how they can be managed\n\nflare episodes and extra-articular symptoms\n\nself-help options\n\nopportunities for people with spondyloarthritis to be involved in research\n\nwhich healthcare professionals will be involved with the person's care and how to get in touch with them\n\ninformation about employment rights and ability to work\n\nlocal support groups, online forums and national charities, and how to get in touch with them.\n\n## Information about disease flares\n\nAdvise people with spondyloarthritis about the possibility of experiencing flare episodes and extra-articular symptoms.\n\nConsider developing a flare management plan that is tailored to the person's individual needs, preferences and circumstances.\n\nWhen discussing any flare management plan, provide information on:\n\naccess to care during flares (including details of a named person to contact [for example, a specialist rheumatology nurse])\n\nself-care (for example, exercises, stretching and joint protection)\n\npain and fatigue management\n\npotential changes to medicines\n\nmanaging the impact on daily life and ability to work.\n\n# Pharmacological management of spondyloarthritis\n\n## Axial spondyloarthritis\n\nOffer NSAIDs at the lowest effective dose to people with pain associated with axial spondyloarthritis, and think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment.\n\nIf an NSAID taken at the maximum tolerated dose for 2–4\xa0weeks does not provide adequate pain relief, consider switching to another NSAID.\n\nAdalimumab, certolizumab pegol, etanercept, golimumab and infliximab are recommended, within their marketing authorisations, as options for treating severe active ankylosing spondylitis in adults whose disease has responded inadequately to, or who cannot tolerate, NSAIDs. Infliximab is recommended only if treatment is started with the least expensive infliximab product. People currently receiving infliximab should be able to continue treatment with the same infliximab product until they and their NHS clinician consider it appropriate to stop. [This recommendation is from NICE's technology appraisal guidance on TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis.]\n\nAdalimumab, certolizumab pegol and etanercept are recommended, within their marketing authorisations, as options for treating severe non-radiographic axial spondyloarthritis in adults whose disease has responded inadequately to, or who cannot tolerate, NSAIDs. [This recommendation is from NICE's technology appraisal guidance on TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis.]\n\nThe choice of treatment should be made after discussion between the clinician and the patient about the advantages and disadvantages of the treatments available. This may include considering associated conditions such as extra-articular manifestations. If more than 1\xa0treatment is suitable, the least expensive (taking into account administration costs and patient access schemes) should be chosen. [This recommendation is from NICE's technology appraisal guidance on TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis.]\n\nThe response to adalimumab, certolizumab pegol, etanercept, golimumab or infliximab treatment should be assessed 12\xa0weeks after the start of treatment. Treatment should only be continued if there is clear evidence of response, defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2\xa0or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more. [This recommendation is from NICE's technology appraisal guidance on TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis.]\n\nTreatment with another tumour necrosis factor (TNF)‑alpha inhibitor is recommended for people who cannot tolerate, or whose disease has not responded to, treatment with the first TNF‑alpha inhibitor, or whose disease has stopped responding after an initial response. [This recommendation is from NICE's technology appraisal guidance on TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis.]\n\nWhen using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate. [This recommendation is from NICE's technology appraisal guidance on TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis.]\n\nSecukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis in adults whose disease has responded inadequately to conventional therapy (NSAIDs or TNF‑alpha inhibitors). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme. [This recommendation is from NICE's technology appraisal guidance on secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF-alpha inhibitors.]\n\nAssess the response to secukinumab after 16\xa0weeks of treatment and only continue if there is clear evidence of response, defined as:\n\na reduction in the BASDAI score to 50% of the pre-treatment value or by 2 or more units and\n\na reduction in the spinal pain VAS by 2\xa0cm or more. [This recommendation is from NICE's technology appraisal guidance on secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF-alpha inhibitors.]\n\nWhen using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.[This recommendation is from NICE's technology appraisal guidance on secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF-alpha inhibitors.]\n\n## Psoriatic arthritis and other peripheral spondyloarthritides\n\nConsider local corticosteroid injections as monotherapy for non-progressive monoarthritis.\n\nOffer standard disease-modifying anti-rheumatic drugs (DMARDs) to people with:\n\nperipheral polyarthritis\n\noligoarthritis\n\npersistent or progressive monoarthritis associated with peripheral spondyloarthritis.\n\nWhen deciding which standard DMARD to offer, take into account:\n\nthe person's needs, preferences and circumstances (such as pregnancy planning and alcohol consumption)\n\ncomorbidities such as uveitis, psoriasis and inflammatory bowel disease\n\ndisease characteristics\n\npotential side effects.\n\nIf a standard DMARD taken at the maximum tolerated dose for at least 3\xa0months does not provide adequate relief from symptoms, consider switching to or adding another standard DMARD.\n\nConsider NSAIDs as an adjunct to standard DMARDs or biological DMARDs to manage symptoms. Use oral NSAIDs at the lowest effective dose for the shortest possible period of time, and think about appropriate clinical assessment, ongoing monitoring of risk factors, and the use of gastroprotective treatment.\n\nIf NSAIDs do not provide adequate relief from symptoms, consider steroid injections (local or intramuscular) or short-term oral steroid therapy as an adjunct to standard DMARDs or biological DMARDs to manage symptoms.\n\nIf extra-articular disease is adequately controlled by an existing standard DMARD but peripheral spondyloarthritis is not, consider adding another standard DMARD.\n\nFor guidance on treating psoriatic arthritis with apremilast, see NICE's technology appraisal guidance on apremilast for treating active psoriatic arthritis.\n\nEtanercept, infliximab and adalimumab are recommended for the treatment of adults with active and progressive psoriatic arthritis when the following criteria are met.\n\nThe person has peripheral arthritis with 3\xa0or more tender joints and 3\xa0or more swollen joints, and\n\nThe psoriatic arthritis has not responded to adequate trials of at least 2\xa0standard DMARDs, administered either individually or in combination. [This recommendation is from NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.]\n\nTreatment as described in 1.4.20 should normally be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individual patients because of differences in the method of administration and treatment schedules. [This recommendation is from NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.]\n\nEtanercept, adalimumab or infliximab treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 12\xa0weeks. An adequate response is defined as an improvement in at least 2\xa0of the 4\xa0PsARC criteria (1\xa0of which has to be joint tenderness or swelling score) with no worsening in any of the 4\xa0criteria. People whose disease has a Psoriasis Area and Severity Index (PASI)\xa075 response at 12\xa0weeks but whose PsARC response does not justify continuation of treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis [TA103], infliximab for the treatment of adults with psoriasis [TA134] and adalimumab for the treatment of adults with psoriasis [TA146] for guidance on the use of TNF inhibitors in psoriasis). [This recommendation is from NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.]\n\nWhen using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. [This recommendation is from NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.]\n\nGolimumab is recommended as an option for the treatment of active and progressive psoriatic arthritis in adults only if:\n\nit is used as described for other TNF‑inhibitor treatments in NICE technology appraisal guidance etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis [TA199] (see recommendations 1.4.20–1.4.23 in this guideline) and\n\nthe manufacturer provides the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose. [This recommendation is from NICE's technology appraisal guidance on golimumab for the treatment of psoriatic arthritis.]\n\nWhen using the PsARC (as set out in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis [TA199] (see recommendations 1.4.20–1.4.23 in this guideline), healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. [This recommendation is from NICE's technology appraisal guidance on golimumab for the treatment of psoriatic arthritis.]\n\nUstekinumab is recommended as an option, alone or in combination with methotrexate, for treating active psoriatic arthritis in adults only when:\n\ntreatment with TNF‑alpha inhibitors is contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis [TA199] [see recommendations 1.4.20 to 1.4.23 in this guideline], and golimumab for the treatment of psoriatic arthritis [TA220] [see recommendations 1.4.24 and 1.4.25 in this guideline]) or\n\nthe person has had treatment with 1\xa0or more TNF‑alpha inhibitors.Ustekinumab is recommended only if the company provides the 90\xa0mg dose of ustekinumab for people who weigh more than 100\xa0kg at the same cost as the 45\xa0mg dose, as agreed in the patient access scheme. [This recommendation is from NICE's technology appraisal guidance on ustekinumab for treating active psoriatic arthritis.]\n\nUstekinumab treatment should be stopped if the person's psoriatic arthritis has not shown an adequate response using the PsARC at 24\xa0weeks. An adequate response is defined as an improvement in at least 2\xa0of the 4\xa0criteria (1\xa0of which must be joint tenderness or swelling score), with no worsening in any of the 4\xa0criteria. As recommended in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (see recommendations 1.4.20–1.4.23 in this guideline), people whose disease has a PASI\xa075 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see NICE technology appraisal guidance on ustekinumab for the treatment of adults with moderate to severe psoriasis). [This recommendation is from NICE's technology appraisal guidance on ustekinumab for treating active psoriatic arthritis.]\n\nWhen using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. [This recommendation is from NICE's technology appraisal guidance on ustekinumab for treating active psoriatic arthritis.]\n\nPeople whose treatment with ustekinumab is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue ustekinumab until they and their NHS clinician consider it appropriate to stop. [This recommendation is from NICE's technology appraisal guidance on ustekinumab for treating active psoriatic arthritis.]\n\n## Reactive arthritis\n\nAfter treating the initial infection, do not offer long-term (4\xa0weeks or longer) treatment with antibiotics solely to manage reactive arthritis caused by a gastrointestinal or genitourinary infection.\n\n# Non-pharmacological management of spondyloarthritis\n\nRefer people with axial spondyloarthritis to a specialist physiotherapist to start an individualised, structured exercise programme, which should include:\n\nstretching, strengthening and postural exercises\n\ndeep breathing\n\nspinal extension\n\nrange of motion exercises for the lumbar, thoracic and cervical sections of the spine\n\naerobic exercise.\n\nConsider hydrotherapy as an adjunctive therapy to manage pain and maintain or improve function for people with axial spondyloarthritis.\n\nConsider a referral to a specialist therapist (such as a physiotherapist, occupational therapist, hand therapist, orthotist or podiatrist) for people with spondyloarthritis who have difficulties with any of their everyday activities. The specialist therapist should:\n\nassess people's needs\n\nprovide advice about physical aids\n\narrange periodic reviews to assess people's changing needs.\n\n# Surgery for spondyloarthritis\n\nDo not refer people with axial spondyloarthritis to a complex spinal surgery service to be assessed for spinal deformity correction unless the spinal deformity is:\n\nsignificantly affecting their quality of life and\n\nsevere or progressing despite optimal non-surgical management (including physiotherapy).\n\nIf a person with axial spondyloarthritis presents with a suspected spinal fracture, refer them to a specialist to confirm the spinal fracture and carry out a stability assessment. After the stability assessment, the specialist should refer people with a potentially unstable spinal fracture to a spinal surgeon.\n\n# Managing flares\n\nManage flares in either specialist care or primary care depending on the person's needs.\n\nWhen managing flares in primary care, seek advice from specialist care as needed, particularly for people who:\n\nhave recurrent or persistent flares\n\nare taking biological DMARDs\n\nhave comorbidities that may affect treatment or management of flares.\n\nBe aware that uveitis can occur during flare episodes. See recommendation\xa01.1.12 for guidance on immediate (same‑day) ophthalmological assessment for people with acute anterior uveitis.\n\n# Long-term complications\n\nFor guidance on monitoring long-term pharmacological treatments, see the NICE guideline on medicines optimisation.\n\nTake into account the adverse effects associated with NSAIDs, standard DMARDs and biological DMARDs when monitoring spondyloarthritis in primary care.\n\nAdvise people that there may be a greater risk of skin cancer in people treated with TNF‑alpha inhibitors.\n\nDiscuss risk factors for cardiovascular comorbidities with all people with spondyloarthritis.\n\nConsider regular osteoporosis assessments (every 2\xa0years) for people with axial spondyloarthritis. Be aware that bone mineral density measures may be elevated on spinal dual‑energy X‑ray absorptiometry (DEXA) due to the presence of syndesmophytes and ligamentous calcification, whereas hip measurements may be more reliable.\n\nAdvise people with axial spondyloarthritis that they may be prone to fractures, and should consult a healthcare professional following falls or physical trauma, particularly in the event of increased musculoskeletal pain.\n\n# Organisation of care\n\n## Coordinating care across settings\n\nCommissioners should ensure that local arrangements are in place to coordinate care for people across primary and secondary (specialist) care. These should cover:\n\nprescribing NSAIDs and standard DMARDs\n\nmonitoring NSAIDs, standard DMARDs and biological DMARDs\n\nmanaging flares\n\nensuring prompt access to specialist rheumatology care when needed\n\nensuring prompt access to other specialist services to manage comorbidities and extra-articular symptoms.\n\nEnsure that people with spondyloarthritis have access to specialist care in primary or secondary care settings throughout the disease course to ensure optimal long-term spondyloarthritis management (see section 1.7 for arrangements for managing flares).\n\nEnsure that there is effective communication and coordination between all healthcare professionals involved in the person's care, particularly if the person has comorbidities or extra-articular symptoms.\n\nEnsure that there is communication and coordination between rheumatology and other relevant specialities (such as dermatology, gastroenterology and ophthalmology). This is particularly important for people who:\n\nare already receiving standard DMARDs or biological DMARDs for another condition\n\nneed to start taking standard DMARDs or biological DMARDs for another condition.\n\nFor guidance on managing the transition of young people with juvenile idiopathic arthritis to adult services, see the NICE guideline on transition from children's to adults' services for young people using health or social care services.", 'Context': "Spondyloarthritis encompasses a group of inflammatory conditions with some shared features, including extra-articular manifestations. Both peripheral and axial joints can be affected. The spondyloarthritides are distinct from rheumatoid arthritis but are as important to recognise and manage early in their presentation to improve health outcomes.\n\nMost people with these conditions have either psoriatic arthritis or axial spondyloarthritis, which includes ankylosing spondylitis. Ankylosing spondylitis and non-radiographic axial spondyloarthritis primarily affect the spine, in particular the sacroiliac joint. Both conditions present in similar ways; the primary classification difference is whether sacroiliitis is detectable on X‑ray.\n\nPsoriatic arthritis may manifest in a number of different patterns. These include predominant involvement of small joints in the hands and feet, predominant large joint involvement, particularly in the knees, or combinations of these. Psoriatic arthritis may also involve the axial joints, and inflammation of the entheses and/or finger and toe joints. Skin and nail involvement may not be present at diagnosis and in its absence, a family history of psoriasis is required to meet the diagnostic criteria.\n\nLess common subgroups are enteropathic spondyloarthritis, which is associated with inflammatory bowel disease (Crohn's disease and ulcerative colitis), and reactive arthritis, which can occur in people after gastrointestinal or genitourinary infections.\n\nThe final subgroup is people who have undifferentiated spondyloarthritis. These people generally have an asymmetrical oligoarticular (fewer than 5 involved joints) arthritis, often involving the knees. They do not meet the diagnostic criteria of the other subgroups at presentation but their disease may evolve to do so at a later stage.\n\nThis guideline also includes people who are 16\xa0years or older with axial or peripheral symptoms who have previously been diagnosed with juvenile idiopathic arthritis.\n\nHealthcare professionals in non-specialist settings do not always recognise the signs and symptoms of spondyloarthritis, particularly spinal symptoms, which may be mistakenly attributed to other causes of low back pain. This can lead to substantial delays in diagnosis and treatment with consequent disease progression and disability. This guideline seeks to raise awareness of the features of spondyloarthritis and provide clear advice on what action to take when people with signs and symptoms first present in healthcare settings.\n\nThis guideline also provides advice on the interventions available to people with spondyloarthritis. These include pharmacological and non-pharmacological treatments, and surgery. The guidance also provides advice on how care for people with spondyloarthritis should be organised across healthcare settings, and what information and support should be provided.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Referral criteria for people with suspected axial spondyloarthritis\n\nWhat are the optimal referral criteria for people with suspected axial spondyloarthritis?\n\n## Why this is important\n\nThe Dutch CaFaSpA study (van Hoeven et al. 2014, 2015) should be repeated in a UK population. This would involve examining GP databases to identify a cohort of people who have a diagnosis of non-specific back pain who first consulted their GP for back symptoms under the age of 45. These people would be invited for a full rheumatological assessment (including identifying signs and symptoms relevant to axial spondyloarthritis, X‑ray, MRI and HLA‑B27 test). All participants would be given a reference-standard diagnosis of axial spondyloarthritis or not (ideally using expert clinician opinion, or if this is not possible, using the ASAS [Assessment of Spondyloarthritis International Society] classification criteria). The cohort would be split into a development and validation set, to derive and validate optimal rules for case-finding from the available data, with each candidate strategy judged according to expected cost per quality-adjusted life year (QALY) gained (the NICE economic model developed for this guideline could easily be used to estimate these).\n\nAs a result of the large number of permutations of possible referral strategies, it is impractical to run separate validation studies for all referral criteria that are developed. Therefore, a single large, representative cohort study would, provided it measured the predictor variables for all reasonable referral strategies, provide the ability to develop and validate any number of possible referral strategies. The study would need to be large enough that sufficient data are available to derive new referral rules and to validate those rules in a separate, independent subset of the data. A UK‑specific dataset would provide more relevant data to do this than is currently available from the Dutch CaFaSpA study. For example, that study found an HLA‑B27 prevalence of 20% in people with axial spondyloarthritis and 2% in people without; much lower than the estimates found elsewhere (75% and 20% respectively). This lowers the validity of extrapolating any results found to the UK, and reinforces the need for UK‑specific data to address this question.\n\n# Long-term complications of spondyloarthritis\n\nWhat is the incidence of long-term complications, in particular osteoporosis, cardiovascular disease (CVD) and metabolic syndrome, in people with spondyloarthritis, and how does this compare with the general population? Are any specific spondyloarthritis features or risk factors associated with the incidence and outcomes of these complications?\n\n## Why this is important\n\nSpondyloarthritides are a group of systemic inflammatory conditions, and as such it is thought that people with these conditions may have an elevated risk of CVD, particularly if their disease is not adequately controlled. This may have direct vascular effects as well as precluding maintenance of a good level of cardiovascular fitness.\n\nThere is also clinical uncertainty around the long-term use of non-steroidal anti-inflammatory drugs (NSAIDs): whether the long-term CVD risks associated with this class of drugs are observed in this population, or whether the suppression of inflammation with these drugs mitigates some of the CVD risks associated with these conditions. In addition, risks of osteoporosis and fracture are known to be higher in people with axial spondyloarthritis than the general population, and the prevalence of axial manifestations in people diagnosed with peripheral disease implies the risks may also be high in peripheral spondyloarthritis.\n\nThe longer-term complication rates in the spondyloarthritides need to be established, as well as whether standard biological disease-modifying anti-rheumatic drug (DMARD) therapies and biological DMARDs influence these outcomes. Research that evaluates incidence of osteoporosis, CVD and metabolic syndrome in people with either axial or peripheral spondyloarthritis compared with the general population would therefore be of value. This research should take into account disease stage, personal activity levels and medicine use, and look to address how frequently it is appropriate to monitor people with spondyloarthritis for long-term complications.\n\n# Educational intervention to improve healthcare professionals' awareness of spondyloarthritis\n\nWhat is the effectiveness and cost effectiveness of educational interventions for healthcare professionals in order to increase the number of prompt diagnoses of spondyloarthritis?\n\n## Why this is important\n\nOne of the major reasons for the delays in diagnosing spondyloarthritis is a lack of awareness of the condition by healthcare professionals. This can take many forms, such as a lack of awareness of different spondyloarthritis subtypes, lack of knowledge about associated clinical features (for example, the differences between inflammatory and mechanical back pain) or characteristics of the patient populations (for example, that spondyloarthritis affects similar numbers of men and women, or that a substantial proportion of people with spondyloarthritis are HLA‑B27 negative). Educational interventions to improve the level of awareness may therefore lead to reductions in diagnosis delays, but there is a lack of evidence as to the efficacy of these interventions. Randomised controlled trials of structured educational interventions are therefore needed to assess both whether they reduce the length of time it takes for people to be correctly diagnosed, and whether they represent a cost-effective use of NHS resources.\n\n# Pharmacological management of peripheral spondyloarthritis\n\nWhat is the comparative effectiveness and cost effectiveness of standard DMARDs for managing peripheral spondyloarthritis, and is this effectiveness affected by differences in dose escalation protocols?\n\n## Why this is important\n\nThe committee noted that, although there are a number of randomised controlled trials comparing standard DMARDs with placebo for managing peripheral spondyloarthritis, there is a lack of evidence comparing individual standard DMARDs to other standard DMARDs. This lack of evidence makes it difficult to optimise initial therapy, either by specifying specific drugs within the class or optimising dose, administration and monitoring protocols. There is therefore the need for randomised controlled trials looking at alternative drug, dosing and administration route alternatives for the administration of standard DMARDs for managing peripheral spondyloarthritis. These trials should ensure NSAIDs and steroids are available to participants as needed, and should include (as outcome measures) both health-related quality of life (measured using the EQ‑5D) and health service resource use, to enable the results to be used to assess the cost effectiveness of the interventions.\n\n# Biological therapies for peripheral spondyloarthritis\n\nWhat is the effectiveness and cost effectiveness of biological DMARDs in people with persistent peripheral spondyloarthritis (excluding psoriatic arthritis) or undifferentiated spondyloarthritis?\n\n## Why this is important\n\nAlthough there have been trials conducted of biological therapies for psoriatic arthritis, which have led to positive recommendations in NICE technology appraisals, no such good-quality evidence exists in enteropathic arthritis, reactive arthritis or undifferentiated spondyloarthritis. The substantial side effects possible with biological therapies, and their significant cost, means it is difficult to justify offering them to these groups without good evidence of efficacy. There is therefore the need for randomised controlled trials, with a sufficient sample size to identify possible benefits, in these 3 populations. If trials were to recruit participants from multiple spondyloarthritis subpopulations, results should be clearly stratified by diagnosis to enable any differences in benefits or harms between the groups to be identified. These trials should include (as outcome measures) both health-related quality of life (measured using the EQ‑5D) and health service resource use, to enable the results to be used to assess the cost effectiveness of the interventions."}	https://www.nice.org.uk/guidance/ng65	This guideline covers diagnosing and managing spondyloarthritis that is suspected or confirmed in adults who are 16 years or older. It aims to raise awareness of the features of spondyloarthritis and provide clear advice on what action to take when people with signs and symptoms first present in healthcare settings. It also provides advice on the range of treatments available.
f3dc3cc65a26a3d2561a769e3262de7fa3a1d455	nice	Endoscopic full thickness removal of non-lifting colonic polyps	Endoscopic full thickness removal of non-lifting colonic polyps Evidence-based recommendations on endoscopic full thickness removal of non-lifting colonic polyps. This involves using a special device to remove the polyp and seal the bowel wall closed afterwards. # Recommendations The evidence on endoscopic full thickness removal of non-lifting colonic polyps raises some major safety concerns. Current evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research. Clinicians wishing to do endoscopic full thickness removal of non-lifting colonic polyps should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having endoscopic full thickness removal of non-lifting colonic polyps (see section 6.1). Patient selection should be done by a polyp and early colorectal cancer multidisciplinary team. Only clinicians with specific training should do this procedure. NICE encourages further research and data collection on endoscopic full thickness removal of non-lifting colonic polyps and may update the guidance on publication of further evidence. This should include safety and efficacy outcomes such as perforation, bleeding, the need for immediate re‑intervention, inadequate resection and longer-term follow‑up of patients found to have malignant disease.# Indications and current treatments Colonic polyps are mucosal lesions that project into the lumen of the large bowel. Most colonic polyps cause no symptoms, but they may cause rectal bleeding, mucus in stools, abdominal pain and, rarely, diarrhoea or constipation. There is a significant risk that, after several years, polyps may develop into bowel cancer if left untreated. Benign polyps and those with very early signs of malignancy can often be successfully removed by endoscopic polypectomy, or endoscopic mucosal or submucosal resection. However, polyps that are non-lifting usually involve deeper layers of the bowel wall because of either invasion by malignant cells or scarring from previous attempts at removal. Trying to remove these polyps by standard techniques risks incomplete resection of invasive disease and bowel perforation.# The procedure Full thickness endoscopic bowel excision uses a full thickness resection device. This comprises a modified snare to remove the polyp and deeper layers of the bowel wall, and a clasp device that closes the full thickness of the bowel wall to prevent perforation. The device is attached to the end of a standard endoscope and advanced through the colon until the polyp is identified. The polyp is grasped at its centre and slowly pulled into the cap of the device. An 'over-the-scope' clip is released, closing the site of a potential defect in the bowel wall. A snare is simultaneously placed around the polyp, which is retrieved for histological analysis after the clip is deployed. After removal of the polyp, the colonoscope is re‑inserted and the surgical site is examined for signs of haemorrhage and to check that the clip has closed the bowel wall. The procedure is usually done with the patient under sedation but sometimes general anaesthesia is needed.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a case series of 25 patients treated by endoscopic full thickness removal (EFTR) for colonic polyps, there was technical success in 83% (20/24). In a case series of 17 patients (10 with colonic lesions) treated by EFTR, there was technical success in 90% (9/10). In the case series of 25 patients, there was complete resection (no microscopic residual tumour) in 75% (18/24). In the same study, residual polyps were present in 16% (4/25) of patients. In the case series of 17 patients, there was complete resection in 100% (9/9) of those with colonic lesions. In the case series of 25 patients, there was full thickness resection of the lesion in 88% (21/24). In the case series of 17 patients, there was full thickness resection in 100% (9/9) of those with colonic lesions. In the case series of 25 patients, local recurrence of the lesion at follow‑up was reported in 4% (1/25). The specialist advisers listed the following efficacy outcomes: histological confirmation of complete removal of the lesion, successful full thickness resection, avoidance of surgery, standardised reporting of lesion histology and documented audit of complications.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Minor bleeding was reported in 4% (1/25) of patients treated by endoscopic full thickness resection (EFTR) for colonic polyps in a case series of 25 patients. Bleeding was reported in 3% (5/180) of patients treated by EFTR in an unpublished case series of 180 patients with low gastrointestinal tract polyps. Bleeding was reported in 5% (4/87) of patients treated by EFTR whose data was recorded in an unpublished registry of 87 patients with gastrointestinal polyps. Bowel perforation was reported in 3% (5/180) of patients in the unpublished case series of 180 patients. Perforation was reported in 6% (5/87) of patients and anastomotic leak needing surgery was reported in 1% (1/87) of patients in the unpublished registry of 87 patients. In the case series of 25 patients, 8% (2/24) of patients had subsequent surgical resection after the diagnosis of high-risk adenocarcinoma. However, histology of the surgical specimen revealed EFTR had completely removed the tumour in the initial resection. Further surgery after EFTR of lesions in the lower gastrointestinal tract was done in 7% (13/180) of patients in the unpublished case series of 180 patients. The reasons for surgery included the presence of high-risk T1‑carcinoma in 5% (9/180) of patients, incomplete resection in less than 1% (1/180), perforation in 1% (2/180]) and appendicitis in less than 1% (1/180). Postpolypectomy syndrome was reported in 8% (2/25) of patients in the case series of 25 patients. Postpolypectomy syndrome was reported in 2% (4/180) of patients in the unpublished case series of 180 patients. Infection was reported in 8% (2/25) of patients in the case series of 25 patients. Appendicitis was reported in 1% (2/180) of patients in the unpublished case series of 180 patients. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: inability to capture the polyp in the snare at resection (necessitating the use of a standard snare). They did not identify any theoretical adverse events that had not previously been reported.# Further information This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). Patient commentary was sought but none was received. For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2499-8	{'Recommendations': "The evidence on endoscopic full thickness removal of non-lifting colonic polyps raises some major safety concerns. Current evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research.\n\nClinicians wishing to do endoscopic full thickness removal of non-lifting colonic polyps should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having endoscopic full thickness removal of non-lifting colonic polyps (see section\xa06.1).\n\nPatient selection should be done by a polyp and early colorectal cancer multidisciplinary team. Only clinicians with specific training should do this procedure.\n\nNICE encourages further research and data collection on endoscopic full thickness removal of non-lifting colonic polyps and may update the guidance on publication of further evidence. This should include safety and efficacy outcomes such as perforation, bleeding, the need for immediate re‑intervention, inadequate resection and longer-term follow‑up of patients found to have malignant disease.", 'Indications and current treatments': 'Colonic polyps are mucosal lesions that project into the lumen of the large bowel. Most colonic polyps cause no symptoms, but they may cause rectal bleeding, mucus in stools, abdominal pain and, rarely, diarrhoea or constipation. There is a significant risk that, after several years, polyps may develop into bowel cancer if left untreated.\n\nBenign polyps and those with very early signs of malignancy can often be successfully removed by endoscopic polypectomy, or endoscopic mucosal or submucosal resection. However, polyps that are non-lifting usually involve deeper layers of the bowel wall because of either invasion by malignant cells or scarring from previous attempts at removal. Trying to remove these polyps by standard techniques risks incomplete resection of invasive disease and bowel perforation.', 'The procedure': "Full thickness endoscopic bowel excision uses a full thickness resection device. This comprises a modified snare to remove the polyp and deeper layers of the bowel wall, and a clasp device that closes the full thickness of the bowel wall to prevent perforation. The device is attached to the end of a standard endoscope and advanced through the colon until the polyp is identified. The polyp is grasped at its centre and slowly pulled into the cap of the device. An 'over-the-scope' clip is released, closing the site of a potential defect in the bowel wall. A snare is simultaneously placed around the polyp, which is retrieved for histological analysis after the clip is deployed. After removal of the polyp, the colonoscope is re‑inserted and the surgical site is examined for signs of haemorrhage and to check that the clip has closed the bowel wall.\n\nThe procedure is usually done with the patient under sedation but sometimes general anaesthesia is needed.", 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a case series of 25\xa0patients treated by endoscopic full thickness removal (EFTR) for colonic polyps, there was technical success in 83% (20/24). In a case series of 17\xa0patients (10\xa0with colonic lesions) treated by EFTR, there was technical success in 90% (9/10).\n\nIn the case series of 25\xa0patients, there was complete resection (no microscopic residual tumour) in 75% (18/24). In the same study, residual polyps were present in 16% (4/25) of patients. In the case series of 17\xa0patients, there was complete resection in 100% (9/9) of those with colonic lesions.\n\nIn the case series of 25\xa0patients, there was full thickness resection of the lesion in 88% (21/24). In the case series of 17\xa0patients, there was full thickness resection in 100% (9/9) of those with colonic lesions.\n\nIn the case series of 25\xa0patients, local recurrence of the lesion at follow‑up was reported in 4% (1/25).\n\nThe specialist advisers listed the following efficacy outcomes: histological confirmation of complete removal of the lesion, successful full thickness resection, avoidance of surgery, standardised reporting of lesion histology and documented audit of complications.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nMinor bleeding was reported in 4% (1/25) of patients treated by endoscopic full thickness resection (EFTR) for colonic polyps in a case series of 25\xa0patients. Bleeding was reported in 3% (5/180) of patients treated by EFTR in an unpublished case series of 180\xa0patients with low gastrointestinal tract polyps. Bleeding was reported in 5% (4/87) of patients treated by EFTR whose data was recorded in an unpublished registry of 87\xa0patients with gastrointestinal polyps.\n\nBowel perforation was reported in 3% (5/180) of patients in the unpublished case series of 180\xa0patients. Perforation was reported in 6% (5/87) of patients and anastomotic leak needing surgery was reported in 1% (1/87) of patients in the unpublished registry of 87\xa0patients.\n\nIn the case series of 25\xa0patients, 8% (2/24) of patients had subsequent surgical resection after the diagnosis of high-risk adenocarcinoma. However, histology of the surgical specimen revealed EFTR had completely removed the tumour in the initial resection. Further surgery after EFTR of lesions in the lower gastrointestinal tract was done in 7% (13/180) of patients in the unpublished case series of 180\xa0patients. The reasons for surgery included the presence of high-risk T1‑carcinoma in 5% (9/180) of patients, incomplete resection in less than 1% (1/180), perforation in 1% (2/180]) and appendicitis in less than 1% (1/180).\n\nPostpolypectomy syndrome was reported in 8% (2/25) of patients in the case series of 25\xa0patients. Postpolypectomy syndrome was reported in 2% (4/180) of patients in the unpublished case series of 180\xa0patients.\n\nInfection was reported in 8% (2/25) of patients in the case series of 25\xa0patients. Appendicitis was reported in 1% (2/180) of patients in the unpublished case series of 180\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: inability to capture the polyp in the snare at resection (necessitating the use of a standard snare). They did not identify any theoretical adverse events that had not previously been reported.', 'Further information': 'This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nPatient commentary was sought but none was received.\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2499-8'}	https://www.nice.org.uk/guidance/ipg580	Evidence-based recommendations on endoscopic full thickness removal of non-lifting colonic polyps. This involves using a special device to remove the polyp and seal the bowel wall closed afterwards.
99c16e3b4314108e0676bf5e11117ce643372b7b	nice	Afatinib for treating advanced squamous non-small-cell lung cancer after platinum-based chemotherapy (terminated appraisal)	Afatinib for treating advanced squamous non-small-cell lung cancer after platinum-based chemotherapy (terminated appraisal) NICE is unable to make a recommendation about the use in the NHS of afatinib for treating locally advanced or metastatic squamous non-small-cell lung cancer after platinum-based chemotherapy because no evidence submission was received from Boehringer Ingelheim. We will review this decision if the company decides to make a submission. # Background Boehringer Ingelheim was invited to submit evidence for this single technology appraisal for afatinib in November 2016. The company's main clinical trial (LUX-LUNG 8) to support the appraisal compared afatinib with erlotinib for treating locally advanced or metastatic squamous non-small-cell lung cancer progressing on or after platinum-based chemotherapy, irrespective of epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation status. At the time the trial was carried out, NICE recommended erlotinib for this patient population. NICE then updated the erlotinib guidance, recommending erlotinib after platinum-based chemotherapy only for a small group of patients with EGFR-TK mutation-positive non-small-cell lung cancer. Because the NICE recommendation for erlotinib has changed, and given the resources and time involved in a NICE technology appraisal, the company felt that it would not be of value to submit evidence for this appraisal. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of afatinib for treating locally advanced or metastatic squamous non-small-cell lung cancer after platinum-based chemotherapy. If, after doing this, organisations still wish to consider afatinib for treating locally advanced or metastatic squamous non-small-cell lung cancer after platinum-based chemotherapy, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable. NICE will review the position if the company decides that it wants to make a full submission. ISBN: 978-1-4731-2510-0	{'Background': "Boehringer Ingelheim was invited to submit evidence for this single technology appraisal for afatinib in November 2016.\n\nThe company's main clinical trial (LUX-LUNG\xa08) to support the appraisal compared afatinib with erlotinib for treating locally advanced or metastatic squamous non-small-cell lung cancer progressing on or after platinum-based chemotherapy, irrespective of epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation status. At the time the trial was carried out, NICE recommended erlotinib for this patient population. NICE then updated the erlotinib guidance, recommending erlotinib after platinum-based chemotherapy only for a small group of patients with EGFR-TK mutation-positive non-small-cell lung cancer.\n\nBecause the NICE recommendation for erlotinib has changed, and given the resources and time involved in a NICE technology appraisal, the company felt that it would not be of value to submit evidence for this appraisal.\n\nNICE has therefore terminated this single technology appraisal.", 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of afatinib for treating locally advanced or metastatic squamous non-small-cell lung cancer after platinum-based chemotherapy. If, after doing this, organisations still wish to consider afatinib for treating locally advanced or metastatic squamous non-small-cell lung cancer after platinum-based chemotherapy, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable.\n\nNICE will review the position if the company decides that it wants to make a full submission.\n\nISBN: 978-1-4731-2510-0'}	https://www.nice.org.uk/guidance/ta444	NICE is unable to make a recommendation about the use in the NHS of afatinib for treating locally advanced or metastatic squamous non-small-cell lung cancer after platinum-based chemotherapy because no evidence submission was received from Boehringer Ingelheim. We will review this decision if the company decides to make a submission.
4f262e19e6d1058d49174495a45e883d8fdf0219	nice	Certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs	Certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs Evidence-based recommendations on certolizumab pegol (Cimzia) and secukinumab (Cosentyx) for treating active psoriatic arthritis in adults. # Recommendations Certolizumab pegol alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if: it is used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.1 and 1.2) or the person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has stopped responding after the first 12 weeks.Certolizumab pegol is only recommended if the company provides it as agreed in the patient access scheme. Secukinumab alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if: it is used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.1 and 1.2) or the person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12 weeks or has stopped responding after 12 weeks or TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Secukinumab is only recommended if the company provides it as agreed in the patient access scheme. Assess the response to certolizumab pegol and secukinumab after 12 weeks and 16 weeks of treatment respectively. Only continue treatment if there is clear evidence of response, defined as an improvement in at least 2 of the 4 Psoriatic Arthritis Response Criteria (PsARC), 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist, to determine whether continuing treatment is appropriate based on skin response (as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, recommendation 1.3). When using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. This guidance is not intended to affect the position of patients whose treatment with certolizumab pegol and secukinumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technologies Description of the technology Certolizumab pegol (Cimzia, UCB Pharma) is a biological therapy (a recombinant humanised antibody Fab' fragment against tumour necrosis factor ‑alpha) and is conjugated to polyethylene glycol. Secukinumab (Cosentyx, Novartis) is a biological therapy (a fully human monoclonal antibody that selectively neutralises interleukin 17A ). Marketing authorisation Certolizumab pegol has a marketing authorisation in the UK for treating active psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug (DMARD) therapy has been inadequate, either: in combination with methotrexate or as monotherapy, if methotrexate cannot be tolerated or when continued treatment with methotrexate is inappropriate. Secukinumab has a marketing authorisation in the UK for treating active psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate, either: in combination with methotrexate or as monotherapy. Adverse reactions The most common treatment-related adverse events associated with certolizumab pegol and secukinumab include upper respiratory tract infections and nasopharyngitis. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Certolizumab pegol is given subcutaneously: as a loading dose of 400 mg at weeks 0, 2 and 4 at a recommended maintenance dose of 200 mg every 2 weeks, after the loading dose. Once clinical response is confirmed, an alternative maintenance dosing of 400 mg every 4 weeks can be considered. Methotrexate should be continued during treatment where appropriate. Clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients whose disease has shown no evidence of therapeutic benefit within the first 12 weeks of treatment. Secukinumab is given subcutaneously: For patients with concomitant moderate to severe plaque psoriasis or patients whose disease has responded inadequately to TNF‑alpha inhibitors, the initial recommended dose is 300 mg at weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at week 4. Each 300 mg dose is given as 2 injections of 150 mg each. For other patients, the recommended initial dose is 150 mg at weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at week 4. Consideration should be given to stopping treatment in patients whose disease has shown no response by 16 weeks of treatment. Some patients whose disease has shown an initial partial response may subsequently improve with continued treatment beyond 16 weeks. Price Certolizumab pegol costs £357.50 per 200-mg prefilled pen or prefilled syringe. The company has agreed a patient access scheme with the Department of Health. The first 12 weeks of therapy with certolizumab pegol will be free of charge. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Secukinumab costs £1,218.78 per 2 × 150-mg prefilled pen or syringe. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of secukinumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence from a number of sources. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of certolizumab pegol and secukinumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of certolizumab pegol and secukinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical need and practice The committee heard from the patient experts about the nature of psoriatic arthritis and their experiences of treatment. It heard that psoriatic arthritis is a lifelong condition that has a serious effect on people's quality of life. It can develop at a young age, and affects all aspects of a person's life including education, career aspirations and family life. The committee heard from the patient experts that symptoms such as fatigue, pain and other associated comorbidities can have a major psychological impact. The committee heard from the clinical experts that psoriatic arthritis not only affects joints and tendons but can also be associated with other debilitating conditions of the skin, bowel and eye and with metabolic syndrome. The committee recognised the importance to patients and clinical experts of addressing these associated comorbidities, which are not always captured in current research. The committee heard from the clinical and patient experts that the psoriatic arthritis population is heterogeneous. Some people's disease responds to the first disease-modifying antirheumatic drug (DMARD), whereas others' disease may respond to a second or a third DMARD. Some people's disease may not respond at all. It heard from the clinical experts that in current UK clinical practice, people usually have 2 DMARDs before progressing to biological therapies (in line with guidelines from the British Society for Rheumatology and with NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis). For people whose disease has poor prognostic markers, 2 or more DMARDs may be given at the same time to progress to biological therapies quicker. The committee was also aware that the British Society for Rheumatology guidelines state that when 1 DMARD has not worked, biological therapies (that is, tumour necrosis factor ‑alpha inhibitors) can be considered for people with specific prognostic factors (including 5 or more swollen joints together with elevated C-reactive protein persisting for more than 3 months, or structural joint damage caused by the disease). However, the committee was not convinced that this is established clinical practice in the NHS. The committee heard from clinical experts that TNF‑alpha inhibitors result in similar joint responses but different responses in comorbid illnesses, especially related to the skin. It also heard that people's disease may not respond to 1 TNF‑alpha inhibitor but may respond to another, and that although TNF‑alpha inhibitors have similar safety profiles, people can have different adverse events. The clinical experts commented that certolizumab pegol targets TNF‑alpha, and that secukinumab has a different mechanism of action, targeting interleukin 17A (IL‑17A), which could potentially benefit people in whom TNF‑alpha inhibitors are contraindicated or not tolerated. The committee recalled that TNF-alpha inhibitors are the preferred first-line biological therapies. The committee heard from the clinical experts that both certolizumab pegol and secukinumab are effective therapies, and that secukinumab 300 mg is particularly effective in severe psoriasis (secukinumab 300 mg is licensed for psoriatic arthritis with concomitant moderate to severe psoriasis or whose disease has not responded to TNF-alpha inhibitors, but secukinumab 150 mg is licensed for psoriatic arthritis with no concomitant psoriasis and mild psoriasis). The committee concluded that patients and clinicians consider certolizumab pegol and secukinumab to be important therapy options for people with active psoriatic arthritis whose disease has responded inadequately to previous DMARDs. # Clinical effectiveness Nineteen randomised controlled trials were identified by the assessment group as meeting the criteria for inclusion in the systematic review of short-term efficacy: trials compared a biological therapy (and apremilast) with placebo, including RAPID-PsA (certolizumab pegol) and FUTURE 2 (secukinumab), which comprise the main clinical evidence were head-to-head comparisons comparing 1 biological therapy with another biological therapy. The committee noted that many of the trials included in the systematic review were of good quality, and had a reasonably low risk of bias. The key outcomes of interest were the American College of Rheumatology response criteria, Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), health assessment questionnaire, and health assessment questionnaire conditional on PsARC data. The committee concluded that the trials were of good quality and the outcomes were appropriate. ## Companies' clinical effectiveness evidence The committee mainly considered the clinical effectiveness evidence from the trials identified for certolizumab pegol (RAPID-PsA) and secukinumab (FUTURE 2). It noted that patients whose disease did not respond to a TNF‑alpha inhibitor in the first 12 weeks of treatment (primary treatment failure) were excluded from RAPID-PsA. It noted that both biological therapies showed short-term efficacy in treating psoriatic arthritis. When considering the full trial population, certolizumab pegol and secukinumab were associated with statistically significant improvements in all key outcomes. When the trial population was split into subpopulations based on previous biological therapy experience, the committee acknowledged that the results became difficult to compare. The committee noted that the comparison of RAPID‑PsA and FUTURE 2 with clinical trials for other biological therapies (and apremilast) was not straightforward. Firstly, the committee noted that populations recruited in clinical trials have changed over time, with earlier trials excluding patients who had previously had biological therapies, and later trials including them. There is variation across trials in the exclusion criteria for the biological-experienced subpopulation. The RAPID‑PsA trial is more selective than the FUTURE 2 (secukinumab), PSUMMIT2 (ustekinumab) and PALACE (apremilast) trials in recruiting biological-experienced patients, because it excluded patients whose disease had not responded to a TNF‑alpha inhibitor in the first 12 weeks of treatment (see section 4.5). Secondly, the committee noted that placebo response rates have increased markedly over time across the trials. The committee concluded that because these issues had either not been accounted for (secukinumab), or because it was unclear how they had been accounted for (certolizumab pegol) in the company submissions, it was not possible to make reliable conclusions about the difference in the efficacy of certolizumab pegol and secukinumab using the companies' analyses. The committee noted that treatment with certolizumab pegol and secukinumab resulted in statistically significant improvements in health-related quality-of-life measures and in improvements in extra-articular manifestations such as dactylitis (that is, inflammation of the fingers or toes) and enthesitis (that is, inflammation of tendons or ligaments). The committee noted that the company (UCB Pharma) submitted evidence on the impact of certolizumab pegol on pain and fatigue measured by the SF‑36 and FASCA (Fatigue Assessment Scale) questionnaires; the company believed that these outcomes may not have been captured in the assessment group's model, which is based on a mapping from the health assessment questionnaire and PASI to a utility score. The committee noted that the company provided values, but it was unable to determine the impact of any potential adjustment on the quality-adjusted life year (QALY) gained. The committee was satisfied that both certolizumab pegol and secukinumab resulted in significantly statistically improvements in health-related quality of life. ## Assessment group's network meta-analysis The committee discussed the results of the network meta-analysis done by the assessment group. It noted that separate analyses were done for each outcome for patients who had had biological therapy, and for patients who had not had biological therapy, to acknowledge the difference in efficacy response in both subpopulations. It also noted that, because of the lack of data, the biological-naive subpopulation (that is, patients who have not had biological therapy before) comprised those patients whose disease had not responded to 1 or more DMARDs. Although it was unclear how many DMARDs patients in the biological-naive subpopulation had previously had, the committee was aware from clinical experts that the efficacy of a biological therapy was not expected to differ between a patient who has had 1 previous DMARD and a patient who has had 2 previous DMARDs. The committee concluded that the biological-naive subpopulation in the network meta-analysis matched the subpopulation specified in the final NICE scope and it was therefore appropriate to use their data in the cost-effectiveness analysis. The committee noted that the assessment group developed several models for use in the cost-effectiveness analysis. These included a model adjusted for placebo response rate (see section 4.6) and exploring the possibility of class effects (adjusted model), as well as a model without any adjustment (independent model). The committee heard from the assessment group and the companies that the adjustment for placebo response rate had been seen in other clinical areas. The committee acknowledged that there was no conclusion on why this occurred. The committee heard from the clinical expert that although ustekinumab (targets IL‑12 and IL‑23) and secukinumab (targets IL‑17A) had a similar clinical pathway, they behaved differently in terms of efficacy and safety and therefore should not be grouped in the same class. The committee heard from the assessment group that adjustment by class reflected any differences in treatment effect within a class. The committee concluded it was reasonable to take into account the adjustment for both placebo response rate and class effect in the analyses. The committee noted that the assessment group excluded certolizumab pegol (RAPID‑PsA) treatment data from the biological-experienced population network meta-analysis because of the differences in trial eligibility based on the definition of treatment-experienced in PSUMMIT2 (ustekinumab) and FUTURE 2 (secukinumab). In RAPID-PsA, patients whose disease had not responded to a TNF‑alpha inhibitor in the first 12 weeks of treatment (see section 4.5) were excluded and only patients whose disease did not respond after 12 weeks, or initially responded but failed to respond thereafter (secondary treatment failure) were included in the biological-experienced subpopulation. In PSUMMIT2 and FUTURE 2, a mix of patients with early or late primary treatment failure or with secondary treatment failure of a previous TNF‑alpha inhibitor were included. The clinical experts agreed that patients with primary treatment failure would respond differently to a subsequent second biological therapy (that is, TNF‑alpha inhibitors) than patients who had not previously experienced primary failure. The committee concluded that patients whose disease did not initially respond to a first biological therapy represent a separate subgroup within the overall biological-experienced subpopulation. The committee concluded that it was reasonable for the assessment group to have excluded certolizumab pegol (RAPID‑PsA) treatment data from the biological-experienced population network meta-analysis. The committee noted that certolizumab pegol and secukinumab showed short-term efficacy in treating psoriatic arthritis compared with placebo. In the biological-naive population, all outcomes showed that certolizumab pegol and secukinumab were effective, but their relative effectiveness compared with etanercept, adalimumab, golimumab and infliximab and with each other, was uncertain, with different treatments being more effective depending on the outcome and analysis (independent and adjusted model). Both certolizumab pegol and secukinumab were consistently more effective than apremilast. The committee noted that the results appeared to show that secukinumab and infliximab are the most effective in terms of PASI response, but this difference was not statistically significant when adjusting for placebo response. In the biological-experienced subpopulation, when only secukinumab 300 mg and ustekinumab were included in the analyses, the results showed that across all outcomes analysed, both secukinumab 300 mg and ustekinumab were statistically significantly more effective than placebo. Most of the outcomes suggested that secukinumab 300 mg may be more efficacious than ustekinumab. However, the patient numbers in the biological-experienced subpopulation were quite low; the results were therefore uncertain (with wide overlapping credible intervals). The clinical experts stated that they could not distinguish between the TNF‑alpha inhibitors in improving joint symptoms in clinical practice, and therefore their choice of therapy would be based on its availability and the patient's comorbidities. The committee concluded that although there were limitations in the analyses, it considered that certolizumab pegol and secukinumab are similar to the other biological therapies in improving joint symptoms in both biological-naive and experienced subpopulations. ## Safety profile The committee heard from the clinical experts that there is no concern about additional adverse events for certolizumab pegol and secukinumab compared with other TNF-alpha inhibitors. The committee concluded that the safety profiles of certolizumab pegol and secukinumab were comparable to other TNF-alpha inhibitors. # Cost effectiveness The committee considered the economic models from the companies and the assessment group. The committee noted that the assessment group updated the York economic model submitted for the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis. The update: allowed some subgroups to have another active treatment before reverting to best supporting care included patients who had initially responded to TNF‑alpha inhibitors but whose disease failed to respond thereafter (see section 4.10) modelled all subpopulations specified in the NICE scope, as well as patients for whom TNF‑alpha inhibitors are contraindicated (subpopulation 4) took into account heterogeneity in terms of baseline PASI with results for 3 subgroups within each subpopulation (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis, with concomitant moderate to severe psoriasis).The committee concluded that the assessment group's economic model was the most relevant to use for decision-making given its appropriate updates. ## Disease management The committee noted that the assessment group used the same source for disease management costs (specifically health assessment questionnaire costs) as the previous York model (Kobelt et al. 2002) in its base-case analysis. The costs from Kobelt et al. addressed only the arthritis component of psoriatic arthritis, so additional costs were needed to capture the psoriasis element of the disease. The committee noted that another source (Poole et al. 2010) was also considered by the assessment group. Poole et al. reported health assessment questionnaire estimates derived from a sample of patients with psoriatic arthritis, rather than those with rheumatoid arthritis (Kobelt et al.). However the committee noted potential limitations of the study including limited clarity on how costs were estimated in the model and uncertainty around model estimates. The use of estimates from Poole et al. was therefore explored as a separate scenario. The committee noted that using the costs from Poole et al. significantly reduces the incremental cost-effectiveness ratios (ICERs) for all treatments relative to best supportive care, although the optimal treatment remained consistent with the base-case analysis across all scenarios. The committee concluded that using the same source as the previous York model was an appropriate choice and its use is consistent across the separate NICE technology appraisals on golimumab and ustekinumab for treating active psoriatic arthritis. The committee considered the results of the assessment group's base-case model for 4 subpopulations in line with the proposed positions of certolizumab pegol and secukinumab in the treatment pathway and 3 subgroups according to severity of psoriasis. The committee noted that the assessment group took into consideration the different marketing authorisations of secukinumab 150 mg and 300 mg according to psoriasis severity (secukinumab 150 mg is licensed for psoriatic arthritis with no concomitant psoriasis and mild psoriasis, secukinumab 300 mg is licensed for psoriatic arthritis with concomitant moderate to severe psoriasis or whose disease has not responded adequately to TNF-alpha inhibitors). Best supportive care is defined as a mix of DMARDs and palliative care. ## Subpopulation 1: 1 previous DMARD but no biological therapy In response to the first appraisal consultation document, Novartis provided additional clinical evidence from FUTURE 2 for subpopulation 1 (people with psoriatic arthritis whose disease had not responded adequately to 1 DMARD). The committee noted that Novartis put the additional clinical evidence into the assessment group's model and generated ICERs comparing secukinumab with best supportive care in all 3 psoriasis subgroups (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis, with concomitant moderate to severe psoriasis). Although the committee acknowledged that the ICERs were below £20,000 per QALY gained when taking into account the patient access scheme for secukinumab, it identified a number of concerns. The committee was aware that the comparators in the assessment group's model, and in the additional analysis done by Novartis, were included to ensure consistency with the NICE scope. The committee noted that when the scope was written it reflected current treatment at that time (use of biological therapy after 2 DMARDs), but clinical practice may have moved on and the use of biological therapy after 1 DMARD may be becoming more common. The committee heard from the assessment group that the analysis done by Novartis only included secukinumab and best supportive care. It was therefore lacking the full range of comparators for subpopulation 1, in particular the other biological treatments (etanercept, infliximab, adalimumab and golimumab), which according to their licences could be used in this subpopulation. However, the committee was not convinced that the use of biological therapy after 1 DMARD is established clinical practice in the NHS (see section 4.2) and, if it is, in which specific group of people it is used. The committee also recognised that the full sequence of treatments (that is, the treatments a patient has after the first-line treatment) should have been modelled to better capture all the incremental cost and effectiveness differences between the technologies. Without the adequate inclusion of subsequent treatments, the analyses could misrepresent the true ICER. The committee agreed that because of these issues, it was not possible to reach a conclusion on the true cost effectiveness of certolizumab pegol and secukinumab in subpopulation 1. The committee was aware of the significant impact on clinical practice that a potential change in the use of biological therapy for psoriatic arthritis would have if it were to recommend secukinumab and certolizumab pegol in this population; particularly given that these are new technologies, one of which has a different mechanism of action (see section 4.2). Therefore, given the risk to the NHS of making an incorrect decision, it needed to be very certain about the cost effectiveness of certolizumab pegol and secukinumab in subpopulation 1. Taking into account all of these concerns, the committee concluded that it was unable to recommend certolizumab pegol and secukinumab as treatment options for people with psoriatic arthritis whose disease had not responded adequately to 1 DMARD. ## Subpopulation 2: at least 2 previous DMARDs and no biological therapy The committee considered that in all psoriasis subgroups, certolizumab pegol and secukinumab 150 mg and 300 mg were cost effective compared with best supportive care, when taking into account the patient access scheme for both therapies. ICERs for both strengths of secukinumab were less than £20,000 per QALY gained compared with best supportive care. For certolizumab pegol, the ICERs were close to, or less than £20,000 per QALY gained compared with best supportive care. The committee considered that the cost effectiveness for certolizumab pegol and secukinumab was acceptable when the criteria in etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis are met; that is, the person has peripheral arthritis with at least 3 tender joints and at least 3 swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least 2 standard DMARDs, given either individually or in combination. The committee therefore concluded that certolizumab pegol and secukinumab could be recommended as treatment options for people with psoriatic arthritis if used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis. ## Subpopulation 3: patients who have had TNF-alpha inhibitors The committee noted that secukinumab 300 mg was considered as a relevant intervention, alongside ustekinumab and best supportive care, in patients who have had biological therapy. Certolizumab pegol was not included in subpopulation 3 because only patients whose disease had initially responded to a biological treatment and stopped responding thereafter were included in the RAPID-PsA trial (see section 4.10). The committee considered that secukinumab 300 mg was cost effective in patients who had had biological therapy (including primary and secondary treatment failures) with ICER values below, or close to, £20,000 per QALY gained compared with best supportive care, when taking into account the patient access scheme for secukinumab 300 mg. The committee concluded that secukinumab 300 mg could be recommended as a treatment option for people with psoriatic arthritis whose disease has not responded adequately to 2 DMARDs and has not responded to a TNF-alpha inhibitor within the first 12 weeks or has stopped responding after 12 weeks and only when taking into account the patient access scheme for secukinumab 300 mg. The committee noted the assessment group did a separate cost-effectiveness analysis (as part of the scenario analysis) for patients whose disease has stopped responding to a TNF-alpha inhibitor after the first 12 weeks. It was aware that, in the absence of data for other comparators for this subgroup, the comparison is restricted to certolizumab pegol and best supportive care. The committee noted that for certolizumab pegol compared with best supportive care, the ICERs were below, or very close to, £20,000 per QALY gained, when taking into account the patient access scheme for certolizumab pegol. The committee therefore concluded that certolizumab pegol could be recommended as a treatment option for people with psoriatic arthritis whose disease has not responded adequately to 2 DMARDs and whose disease has stopped responding to a TNF-alpha inhibitor after the first 12 weeks, and only when taking into account the patient access scheme. ## Subpopulation 4: patients in whom TNF‑alpha inhibitors are contraindicated The committee noted that secukinumab was compared with ustekinumab and best supportive care. It noted that certolizumab pegol was not included because it was assumed that other TNF‑alpha inhibitors including certolizumab pegol would be contraindicated in these patients. In the absence of effectiveness data for these patients, the analysis was done using data from the biological-naive populations from the secukinumab and ustekinumab trial. The committee heard from clinical experts that this was considered a reasonable approach. The committee noted that the assessment group considered the different licensed strengths of secukinumab 150 mg and 300 mg according to psoriasis severity (see section 4.16). The committee noted that secukinumab 150 mg and 300 mg compared with best supportive care resulted in ICERs below £20,000 per QALY gained in patients without concomitant psoriasis, with mild to moderate psoriasis and with moderate to severe psoriasis, when taking into account the patient access scheme for secukinumab. The committee therefore concluded that secukinumab could be recommended as a treatment option for people with psoriatic arthritis in whom TNF‑alpha inhibitors are contraindicated but would otherwise be considered, and only when taking into account the patient access scheme for secukinumab. The committee noted that the economic analyses (in all populations) were based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 12 weeks and 16 weeks stop treatment with certolizumab pegol and secukinumab, respectively. The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as defined in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for certolizumab pegol and secukinumab (assessed at 12 weeks and 16 weeks respectively). It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. # Innovation The committee noted the convenience of self-administration. It concluded that secukinumab and certolizumab pegol are important treatments and represent additional options for patients with active psoriatic arthritis that has not responded to prior DMARDs. It was aware of its earlier conclusion that although UCB Pharma provided evidence of certolizumab pegol's effect on pain and fatigue, it was not possible to determine the impact of any potential adjustment on the QALY calculations because the assessment group's modelling involved mapping from the health assessment questionnaire and PASI to a utility score (see section 4.7). It noted that if health benefits have been missed, this would apply across all the interventions and comparators. Therefore the committee concluded that there are no other significant health benefits that have not been captured in the cost-effectiveness model. # Summary of appraisal committee's key conclusions TA445 Appraisal title: Certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs Section Key conclusion Certolizumab pegol alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if: it is used as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.1 and 1.2) or the person has had a TNF-alpha inhibitor but their disease has stopped responding after the first 12 weeks. Certolizumab pegol is only recommended if the company provides it as agreed in the patient access scheme. Secukinumab alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if: it is used as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.1 and 1.2) or the person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12 weeks or has stopped responding after 12 weeks or TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis). Secukinumab is only recommended if the company provides it as agreed in the patient access scheme. For subpopulation 1 (1 previous disease-modifying antirheumatic drug but no biological therapy), the committee was aware that the comparators in the assessment group's analysis, and in the additional analysis done by Novartis, were included to ensure consistency with the NICE scope. It noted that when the scope was written it reflected current treatment at the time (use of biological therapy after 2 DMARDs), but clinical practice may have moved on and the use of biological therapy after 1 DMARD may be becoming more common. The committee heard from the assessment group that the analysis done by Novartis only included secukinumab and best supportive care and therefore was lacking the full range of comparators for subpopulation 1. The committee also recognised that the full sequence of treatments should have been modelled to better capture all the incremental cost and effectiveness differences between the technologies. Additionally, the committee was mindful of the significant impact on clinical practice that a potential shift in the use of biological therapy for psoriatic arthritis would have if it were to recommend secukinumab and certolizumab pegol in this population. Therefore, given the risk to the NHS of making an incorrect decision, it needed to be very certain about the cost effectiveness of certolizumab pegol and secukinumab in subpopulation 1. Taking into account all of these concerns, the committee concluded that it was unable to recommend certolizumab pegol and secukinumab as treatment options for people with psoriatic arthritis whose disease had not responded adequately to 1 DMARD. For subpopulation 2 (at least 2 previous DMARDs and no biological therapy) the committee noted that, in all psoriasis subgroups, certolizumab pegol and secukinumab 150 mg and 300 mg were cost effective compared with best supportive care, when taking into account the patient access scheme for both therapies. ICERs for both strengths of secukinumab were less than £20,000 per quality-adjusted life year (QALY) gained compared with best supportive care. For certolizumab pegol the ICERs were close to, or less than, £20,000 per QALY gained compared with best supportive care. The committee therefore concluded that certolizumab pegol and secukinumab could be recommended as treatment options for people with psoriatic arthritis if used as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis. For subpopulation 3 (patients who have had TNF-alpha inhibitors), the committee reviewed 2 subgroups: People with psoriatic arthritis whose disease has not responded adequately to 2 DMARDs, and has not responded to TNF-alpha inhibitors within the first 12 weeks or has stopped responding after 12 weeks; the committee noted that secukinumab 300 mg was cost effective compared with best supportive care. ICERs were below, or close to, £20,000 per QALY gained, when taking into account the patient access scheme for secukinumab 300 mg. The committee concluded that secukinumab 300 mg could be recommended as a treatment option in this patient population only when taking into account the patient access scheme for secukinumab 300 mg. People with psoriatic arthritis whose disease has not responded adequately to 2 DMARDs and has stopped responding to TNF-alpha inhibitors after the first 12 weeks; the committee noted that certolizumab pegol was cost effective compared with best supportive care with ICERs below or very close to £20,000 per QALY gained, when taking into account the patient access scheme for certolizumab pegol. For subpopulation 4 (patients in whom TNF‑alpha inhibitors are contraindicated), the committee noted that secukinumab 150 mg and 300 mg compared with best supportive care resulted in ICERs below £20,000 per QALY gained in all psoriasis subgroups, when taking into account the patient access scheme for secukinumab. The committee concluded that secukinumab could be recommended as a treatment option for people with psoriatic arthritis in whom TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis), and only when taking into account the patient access scheme for secukinumab. Current practice Clinical need of patients, including the availability of alternative treatments The committee recognised the importance to patients and clinical experts of addressing the associated comorbidities, which are not always captured in current research. It also heard that response to treatment is heterogeneous in terms of efficacy and safety. Therefore there is a clinical need for alternative therapies in the treatment pathway to offer more options, particularly in people with active psoriatic arthritis whose disease has responded inadequately to previous DMARD therapies. The technologies Proposed benefits of the technology/ies How innovative is the technology/are the technologies in its/their potential to make a significant and substantial impact on health-related benefits? The committee heard from the clinical experts that secukinumab has a different mechanism of action, which could potentially benefit people in whom TNF-alpha inhibitors are contraindicated or not tolerated. The committee noted the convenience of self-administration for certolizumab pegol and secukinumab. It concluded that there are no other significant health benefits that have not been captured in the cost-effectiveness model. What is the position of the treatments in the pathway of care for the condition? The treatments are for: people whose disease has responded inadequately to at least 2 DMARDs, in line with guidelines from the British Society for Rheumatology and NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis secukinumab is for people with psoriatic arthritis that has not responded adequately to at least 2 DMARDs, and to TNF‑alpha inhibitors within the first 12 weeks or has stopped responding after 12 weeks, and also for people in whom TNF‑alpha inhibitors are contraindicated certolizumab pegol is for people with psoriatic arthritis that has not responded to at least 2 DMARDs and has stopped responding to TNF‑alpha inhibitor after the first 12 weeks. Adverse reactions The committee heard from the clinical experts that there is no concern about additional adverse events for certolizumab pegol and secukinumab compared with other TNF-alpha inhibitors. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee mainly considered the clinical effectiveness evidence from the trials identified for certolizumab pegol (RAPID-PsA) and secukinumab (FUTURE 2). The committee considered the results of the network meta-analysis done by the assessment group. It noted that separate analyses were done for each outcome for patients who had had biological therapy, and for patients who had not had biological therapy to acknowledge the difference in efficacy response in both subpopulations. Relevance to general clinical practice in the NHS There were no direct head-to-head trials with treatments currently used in the NHS. The committee concluded that the biological-naive subpopulation in the network meta-analysis matched the subpopulation specified in the final NICE scope and it was therefore appropriate to use their data in the cost-effectiveness analysis. In RAPID‑PsA, patients whose disease had not responded to a TNF‑alpha inhibitor in the first 12 weeks of treatment were excluded and only patients whose disease did not respond after 12 weeks, or initially responded but failed to respond thereafter (secondary treatment failure) were included in the biological-experienced subpopulation. The committee concluded that patients whose disease did not initially respond to a first biological therapy represent a separate subgroup within the overall biologic-experienced subpopulation. The committee concluded that it was reasonable for the assessment group to have excluded certolizumab pegol (RAPID‑PsA) treatment data from the biological-experienced population network meta-analysis. The committee noted that populations recruited in clinical trials have changed over time, with earlier trials excluding patients who had previously had biological therapies and later trials including such patients. Uncertainties generated by the evidence Placebo response rates have increased markedly over time across the trials. The committee concluded it was reasonable to take into account the adjustment for both placebo response rates and class effect. The committee concluded that because these issues had either not been accounted for (secukinumab) or because it was unclear how they had been accounted for (certolizumab pegol) in the company submissions, it was not possible to make reliable conclusions about the difference in the efficacy of certolizumab pegol and secukinumab using the companies' analyses. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? See 'What is the position of the treatments in the pathway of care for the condition?' Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that although there were limitations in the analyses, it considered that certolizumab pegol and secukinumab were similar to TNF-alpha inhibitors in improving joint symptoms in both biological-naive and biological-experienced subpopulations. The committee noted that treatment with certolizumab pegol and secukinumab resulted in statistically significant improvements in health-related quality-of-life measures and in improvements in extra-articular manifestations such dactylitis (that is, inflammation of the fingers or toes) and enthesitis (that is, inflammation of tendons or ligaments). Evidence for cost effectiveness Availability and nature of evidence The committee was aware that the comparators in the assessment group's analysis, and in the additional analysis done by Novartis, were included to ensure consistency with the NICE scope. It noted that when the scope was written it reflected current treatment at the time (use of biological therapy after 2 DMARDs), but clinical practice may have moved on and the use of biological therapy after 1 DMARD may be becoming more common. The committee heard from the assessment group that the analysis done by Novartis only included secukinumab and best supportive care and therefore was lacking the full range of comparators for subpopulation 1. The committee also recognised that the full sequence of treatments should have been modelled to better capture all the incremental cost and effectiveness differences between the technologies. Additionally, the committee was mindful of the significant impact on clinical practice that a potential shift in the use of biological therapy for psoriatic arthritis would have if it were to recommend secukinumab and certolizumab pegol in this population. Therefore, given the risk to the NHS of making an incorrect decision, it needed to be very certain about the cost effectiveness of certolizumab pegol and secukinumab in subpopulation 1. Taking into account all of these concerns, the committee concluded that it was unable to recommend certolizumab pegol and secukinumab as treatment options for people with psoriatic arthritis whose disease had not responded adequately to 1 DMARD. The committee concluded that the biological-naive subpopulation in the network meta-analysis matched the subpopulation specified in the final NICE scope and it was therefore appropriate to use their data in the cost-effectiveness analysis. Uncertainties around and plausibility of assumptions and inputs in the economic model Although the committee acknowledged that the ICERs were below £20,000 per QALY gained when taking into account the patient access scheme for secukinumab, it identified a number of concerns. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? No other health-related benefits have been identified that have not been captured in the QALY calculation. Are there specific groups of people for whom the technology/ies is/are particularly cost effective? The committee considered the results of the assessment group's base-case model for 4 subpopulations in line with the proposed positions of certolizumab pegol and secukinumab in the treatment pathway and 3 subgroups according to severity of psoriasis. What are the key drivers of cost effectiveness? The committee noted that the use of a different source of disease management costs impacted significantly on the ICERs for all treatments relative to best supportive care, although the optimal treatment remained consistent with the base-case analysis across all scenarios. Most likely cost-effectiveness estimate (given as an ICER) The committee concluded that certolizumab pegol is cost effective in 2 subpopulations (patients who had at least 2 previous DMARDs and no biological therapy, and patients who have had TNF‑alpha inhibitors whose disease has stopped responding to TNF‑alpha inhibitor after the first 12 weeks) with ICERs below, or close to, £20,000 per QALY gained when taking into account the patient access scheme for certolizumab pegol. The committee concluded that secukinumab is cost effective in 3 subpopulations (patients who had at least 2 previous DMARDs and no biological therapy, and patients who have had TNF‑alpha inhibitors whose disease has not responded to TNF‑alpha inhibitors within the first 12 weeks or has stopped responding after 12 weeks, and patients in whom TNF‑alpha inhibitors are contraindicated) with ICERs below, or close to, £20,000 per QALY gained only when taking into account the patient access scheme for secukinumab. Additional factors taken into account Patient access schemes (PPRS) Patient access schemes were taken into account for certolizumab pegol, golimumab, ustekinumab and secukinumab. End-of-life considerations Not applicable. Equalities considerations and social value judgements The committee noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the Psoriatic Arthritis Response Criteria (PsARC), and concluded that healthcare professionals should take this into account when using the PsARC.	{'Recommendations': "Certolizumab pegol alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if:\n\nit is used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations\xa01.1 and\xa01.2) or\n\nthe person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has stopped responding after the first 12\xa0weeks.Certolizumab pegol is only recommended if the company provides it as agreed in the patient access scheme.\n\nSecukinumab alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if:\n\nit is used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations\xa01.1 and\xa01.2) or\n\nthe person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12\xa0weeks or has stopped responding after 12\xa0weeks or\n\nTNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Secukinumab is only recommended if the company provides it as agreed in the patient access scheme.\n\nAssess the response to certolizumab pegol and secukinumab after 12\xa0weeks and 16\xa0weeks of treatment respectively. Only continue treatment if there is clear evidence of response, defined as an improvement in at least 2\xa0of the 4\xa0Psoriatic Arthritis Response Criteria (PsARC), 1\xa0of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist, to determine whether continuing treatment is appropriate based on skin response (as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, recommendation\xa01.3).\n\nWhen using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.\n\nThis guidance is not intended to affect the position of patients whose treatment with certolizumab pegol and secukinumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.", 'The technologies': "Description of the technology\n\nCertolizumab pegol (Cimzia, UCB Pharma) is a biological therapy (a recombinant humanised antibody Fab' fragment against tumour necrosis factor [TNF]‑alpha) and is conjugated to polyethylene glycol.\n\nSecukinumab (Cosentyx, Novartis) is a biological therapy (a fully human monoclonal antibody that selectively neutralises interleukin 17A [IL-17A]).\n\nMarketing authorisation\n\nCertolizumab pegol has a marketing authorisation in the UK for treating active psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug (DMARD) therapy has been inadequate, either:\n\nin combination with methotrexate or\n\nas monotherapy, if methotrexate cannot be tolerated or when continued treatment with methotrexate is inappropriate.\n\nSecukinumab has a marketing authorisation in the UK for treating active psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate, either:\n\nin combination with methotrexate or\n\nas monotherapy.\n\nAdverse reactions\n\nThe most common treatment-related adverse events associated with certolizumab pegol and secukinumab include upper respiratory tract infections and nasopharyngitis. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nCertolizumab pegol is given subcutaneously:\n\nas a loading dose of 400\xa0mg at weeks 0, 2 and 4\n\nat a recommended maintenance dose of 200\xa0mg every 2\xa0weeks, after the loading dose. Once clinical response is confirmed, an alternative maintenance dosing of 400\xa0mg every 4\xa0weeks can be considered. Methotrexate should be continued during treatment where appropriate.\n\nClinical response is usually achieved within 12\xa0weeks of treatment. Continued therapy should be carefully reconsidered in patients whose disease has shown no evidence of therapeutic benefit within the first 12\xa0weeks of treatment.\n\nSecukinumab is given subcutaneously:\n\nFor patients with concomitant moderate to severe plaque psoriasis or patients whose disease has responded inadequately to TNF‑alpha inhibitors, the initial recommended dose is 300\xa0mg at weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at week\xa04. Each 300\xa0mg dose is given as 2\xa0injections of 150\xa0mg each.\n\nFor other patients, the recommended initial dose is 150\xa0mg at weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at week\xa04.\n\nConsideration should be given to stopping treatment in patients whose disease has shown no response by 16\xa0weeks of treatment. Some patients whose disease has shown an initial partial response may subsequently improve with continued treatment beyond 16\xa0weeks.\n\nPrice\n\nCertolizumab pegol costs £357.50 per 200-mg prefilled pen or prefilled syringe. The company has agreed a patient access scheme with the Department of Health. The first 12\xa0weeks of therapy with certolizumab pegol will be free of charge. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\nSecukinumab costs £1,218.78 per 2\xa0×\xa0150-mg prefilled pen or syringe. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of secukinumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence from a number of sources. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of certolizumab pegol and secukinumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of certolizumab pegol and secukinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and practice\n\nThe committee heard from the patient experts about the nature of psoriatic arthritis and their experiences of treatment. It heard that psoriatic arthritis is a lifelong condition that has a serious effect on people's quality of life. It can develop at a young age, and affects all aspects of a person's life including education, career aspirations and family life. The committee heard from the patient experts that symptoms such as fatigue, pain and other associated comorbidities can have a major psychological impact. The committee heard from the clinical experts that psoriatic arthritis not only affects joints and tendons but can also be associated with other debilitating conditions of the skin, bowel and eye and with metabolic syndrome. The committee recognised the importance to patients and clinical experts of addressing these associated comorbidities, which are not always captured in current research.\n\nThe committee heard from the clinical and patient experts that the psoriatic arthritis population is heterogeneous. Some people's disease responds to the first disease-modifying antirheumatic drug (DMARD), whereas others' disease may respond to a second or a third DMARD. Some people's disease may not respond at all. It heard from the clinical experts that in current UK clinical practice, people usually have 2\xa0DMARDs before progressing to biological therapies (in line with guidelines from the British Society for Rheumatology and with NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis). For people whose disease has poor prognostic markers, 2 or more DMARDs may be given at the same time to progress to biological therapies quicker. The committee was also aware that the British Society for Rheumatology guidelines state that when 1\xa0DMARD has not worked, biological therapies (that is, tumour necrosis factor [TNF]‑alpha inhibitors) can be considered for people with specific prognostic factors (including 5 or more swollen joints together with elevated C-reactive protein persisting for more than 3\xa0months, or structural joint damage caused by the disease). However, the committee was not convinced that this is established clinical practice in the NHS.\n\nThe committee heard from clinical experts that TNF‑alpha inhibitors result in similar joint responses but different responses in comorbid illnesses, especially related to the skin. It also heard that people's disease may not respond to 1\xa0TNF‑alpha inhibitor but may respond to another, and that although TNF‑alpha inhibitors have similar safety profiles, people can have different adverse events. The clinical experts commented that certolizumab pegol targets TNF‑alpha, and that secukinumab has a different mechanism of action, targeting interleukin 17A (IL‑17A), which could potentially benefit people in whom TNF‑alpha inhibitors are contraindicated or not tolerated. The committee recalled that TNF-alpha inhibitors are the preferred first-line biological therapies. The committee heard from the clinical experts that both certolizumab pegol and secukinumab are effective therapies, and that secukinumab 300\xa0mg is particularly effective in severe psoriasis (secukinumab 300\xa0mg is licensed for psoriatic arthritis with concomitant moderate to severe psoriasis or whose disease has not responded to TNF-alpha inhibitors, but secukinumab 150\xa0mg is licensed for psoriatic arthritis with no concomitant psoriasis and mild psoriasis). The committee concluded that patients and clinicians consider certolizumab pegol and secukinumab to be important therapy options for people with active psoriatic arthritis whose disease has responded inadequately to previous DMARDs.\n\n# Clinical effectiveness\n\nNineteen randomised controlled trials were identified by the assessment group as meeting the criteria for inclusion in the systematic review of short-term efficacy:\n\ntrials compared a biological therapy (and apremilast) with placebo, including RAPID-PsA (certolizumab pegol) and FUTURE\xa02 (secukinumab), which comprise the main clinical evidence\n\nwere head-to-head comparisons comparing 1\xa0biological therapy with another biological therapy.\n\nThe committee noted that many of the trials included in the systematic review were of good quality, and had a reasonably low risk of bias. The key outcomes of interest were the American College of Rheumatology response criteria, Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), health assessment questionnaire, and health assessment questionnaire conditional on PsARC data. The committee concluded that the trials were of good quality and the outcomes were appropriate.\n\n## Companies' clinical effectiveness evidence\n\nThe committee mainly considered the clinical effectiveness evidence from the trials identified for certolizumab pegol (RAPID-PsA) and secukinumab (FUTURE\xa02). It noted that patients whose disease did not respond to a TNF‑alpha inhibitor in the first 12\xa0weeks of treatment (primary treatment failure) were excluded from RAPID-PsA. It noted that both biological therapies showed short-term efficacy in treating psoriatic arthritis. When considering the full trial population, certolizumab pegol and secukinumab were associated with statistically significant improvements in all key outcomes. When the trial population was split into subpopulations based on previous biological therapy experience, the committee acknowledged that the results became difficult to compare. The committee noted that the comparison of RAPID‑PsA and FUTURE\xa02 with clinical trials for other biological therapies (and apremilast) was not straightforward. Firstly, the committee noted that populations recruited in clinical trials have changed over time, with earlier trials excluding patients who had previously had biological therapies, and later trials including them. There is variation across trials in the exclusion criteria for the biological-experienced subpopulation. The RAPID‑PsA trial is more selective than the FUTURE\xa02 (secukinumab), PSUMMIT2 (ustekinumab) and PALACE (apremilast) trials in recruiting biological-experienced patients, because it excluded patients whose disease had not responded to a TNF‑alpha inhibitor in the first 12\xa0weeks of treatment (see section\xa04.5). Secondly, the committee noted that placebo response rates have increased markedly over time across the trials. The committee concluded that because these issues had either not been accounted for (secukinumab), or because it was unclear how they had been accounted for (certolizumab pegol) in the company submissions, it was not possible to make reliable conclusions about the difference in the efficacy of certolizumab pegol and secukinumab using the companies' analyses.\n\nThe committee noted that treatment with certolizumab pegol and secukinumab resulted in statistically significant improvements in health-related quality-of-life measures and in improvements in extra-articular manifestations such as dactylitis (that is, inflammation of the fingers or toes) and enthesitis (that is, inflammation of tendons or ligaments). The committee noted that the company (UCB Pharma) submitted evidence on the impact of certolizumab pegol on pain and fatigue measured by the SF‑36 and FASCA (Fatigue Assessment Scale) questionnaires; the company believed that these outcomes may not have been captured in the assessment group's model, which is based on a mapping from the health assessment questionnaire and PASI to a utility score. The committee noted that the company provided values, but it was unable to determine the impact of any potential adjustment on the quality-adjusted life year (QALY) gained. The committee was satisfied that both certolizumab pegol and secukinumab resulted in significantly statistically improvements in health-related quality of life.\n\n## Assessment group's network meta-analysis\n\nThe committee discussed the results of the network meta-analysis done by the assessment group. It noted that separate analyses were done for each outcome for patients who had had biological therapy, and for patients who had not had biological therapy, to acknowledge the difference in efficacy response in both subpopulations. It also noted that, because of the lack of data, the biological-naive subpopulation (that is, patients who have not had biological therapy before) comprised those patients whose disease had not responded to 1\xa0or more DMARDs. Although it was unclear how many DMARDs patients in the biological-naive subpopulation had previously had, the committee was aware from clinical experts that the efficacy of a biological therapy was not expected to differ between a patient who has had 1\xa0previous DMARD and a patient who has had 2\xa0previous DMARDs. The committee concluded that the biological-naive subpopulation in the network meta-analysis matched the subpopulation specified in the final NICE scope and it was therefore appropriate to use their data in the cost-effectiveness analysis.\n\nThe committee noted that the assessment group developed several models for use in the cost-effectiveness analysis. These included a model adjusted for placebo response rate (see section\xa04.6) and exploring the possibility of class effects (adjusted model), as well as a model without any adjustment (independent model). The committee heard from the assessment group and the companies that the adjustment for placebo response rate had been seen in other clinical areas. The committee acknowledged that there was no conclusion on why this occurred. The committee heard from the clinical expert that although ustekinumab (targets IL‑12 and IL‑23) and secukinumab (targets IL‑17A) had a similar clinical pathway, they behaved differently in terms of efficacy and safety and therefore should not be grouped in the same class. The committee heard from the assessment group that adjustment by class reflected any differences in treatment effect within a class. The committee concluded it was reasonable to take into account the adjustment for both placebo response rate and class effect in the analyses.\n\nThe committee noted that the assessment group excluded certolizumab pegol (RAPID‑PsA) treatment data from the biological-experienced population network meta-analysis because of the differences in trial eligibility based on the definition of treatment-experienced in PSUMMIT2 (ustekinumab) and FUTURE\xa02 (secukinumab). In RAPID-PsA, patients whose disease had not responded to a TNF‑alpha inhibitor in the first 12\xa0weeks of treatment (see section\xa04.5) were excluded and only patients whose disease did not respond after 12\xa0weeks, or initially responded but failed to respond thereafter (secondary treatment failure) were included in the biological-experienced subpopulation. In PSUMMIT2 and FUTURE\xa02, a mix of patients with early or late primary treatment failure or with secondary treatment failure of a previous TNF‑alpha inhibitor were included. The clinical experts agreed that patients with primary treatment failure would respond differently to a subsequent second biological therapy (that is, TNF‑alpha inhibitors) than patients who had not previously experienced primary failure. The committee concluded that patients whose disease did not initially respond to a first biological therapy represent a separate subgroup within the overall biological-experienced subpopulation. The committee concluded that it was reasonable for the assessment group to have excluded certolizumab pegol (RAPID‑PsA) treatment data from the biological-experienced population network meta-analysis.\n\nThe committee noted that certolizumab pegol and secukinumab showed short-term efficacy in treating psoriatic arthritis compared with placebo. In the biological-naive population, all outcomes showed that certolizumab pegol and secukinumab were effective, but their relative effectiveness compared with etanercept, adalimumab, golimumab and infliximab and with each other, was uncertain, with different treatments being more effective depending on the outcome and analysis (independent and adjusted model). Both certolizumab pegol and secukinumab were consistently more effective than apremilast. The committee noted that the results appeared to show that secukinumab and infliximab are the most effective in terms of PASI response, but this difference was not statistically significant when adjusting for placebo response. In the biological-experienced subpopulation, when only secukinumab 300\xa0mg and ustekinumab were included in the analyses, the results showed that across all outcomes analysed, both secukinumab 300\xa0mg and ustekinumab were statistically significantly more effective than placebo. Most of the outcomes suggested that secukinumab 300\xa0mg may be more efficacious than ustekinumab. However, the patient numbers in the biological-experienced subpopulation were quite low; the results were therefore uncertain (with wide overlapping credible intervals). The clinical experts stated that they could not distinguish between the TNF‑alpha inhibitors in improving joint symptoms in clinical practice, and therefore their choice of therapy would be based on its availability and the patient's comorbidities. The committee concluded that although there were limitations in the analyses, it considered that certolizumab pegol and secukinumab are similar to the other biological therapies in improving joint symptoms in both biological-naive and experienced subpopulations.\n\n## Safety profile\n\nThe committee heard from the clinical experts that there is no concern about additional adverse events for certolizumab pegol and secukinumab compared with other TNF-alpha inhibitors. The committee concluded that the safety profiles of certolizumab pegol and secukinumab were comparable to other TNF-alpha inhibitors.\n\n# Cost effectiveness\n\nThe committee considered the economic models from the companies and the assessment group. The committee noted that the assessment group updated the York economic model submitted for the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis. The update:\n\nallowed some subgroups to have another active treatment before reverting to best supporting care\n\nincluded patients who had initially responded to TNF‑alpha inhibitors but whose disease failed to respond thereafter (see section\xa04.10)\n\nmodelled all subpopulations specified in the NICE scope, as well as patients for whom TNF‑alpha inhibitors are contraindicated (subpopulation\xa04)\n\ntook into account heterogeneity in terms of baseline PASI with results for 3\xa0subgroups within each subpopulation (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis, with concomitant moderate to severe psoriasis).The committee concluded that the assessment group's economic model was the most relevant to use for decision-making given its appropriate updates.\n\n## Disease management\n\nThe committee noted that the assessment group used the same source for disease management costs (specifically health assessment questionnaire costs) as the previous York model (Kobelt et al. 2002) in its base-case analysis. The costs from Kobelt et al. addressed only the arthritis component of psoriatic arthritis, so additional costs were needed to capture the psoriasis element of the disease. The committee noted that another source (Poole et al. 2010) was also considered by the assessment group. Poole et al. reported health assessment questionnaire estimates derived from a sample of patients with psoriatic arthritis, rather than those with rheumatoid arthritis (Kobelt et al.). However the committee noted potential limitations of the study including limited clarity on how costs were estimated in the model and uncertainty around model estimates. The use of estimates from Poole et al. was therefore explored as a separate scenario. The committee noted that using the costs from Poole et al. significantly reduces the incremental cost-effectiveness ratios (ICERs) for all treatments relative to best supportive care, although the optimal treatment remained consistent with the base-case analysis across all scenarios. The committee concluded that using the same source as the previous York model was an appropriate choice and its use is consistent across the separate NICE technology appraisals on golimumab and ustekinumab for treating active psoriatic arthritis.\n\nThe committee considered the results of the assessment group's base-case model for 4\xa0subpopulations in line with the proposed positions of certolizumab pegol and secukinumab in the treatment pathway and 3\xa0subgroups according to severity of psoriasis. The committee noted that the assessment group took into consideration the different marketing authorisations of secukinumab 150\xa0mg and 300\xa0mg according to psoriasis severity (secukinumab 150\xa0mg is licensed for psoriatic arthritis with no concomitant psoriasis and mild psoriasis, secukinumab 300\xa0mg is licensed for psoriatic arthritis with concomitant moderate to severe psoriasis or whose disease has not responded adequately to TNF-alpha inhibitors). Best supportive care is defined as a mix of DMARDs and palliative care.\n\n## Subpopulation 1: 1\xa0previous DMARD but no biological therapy\n\nIn response to the first appraisal consultation document, Novartis provided additional clinical evidence from FUTURE\xa02 for subpopulation\xa01 (people with psoriatic arthritis whose disease had not responded adequately to 1\xa0DMARD). The committee noted that Novartis put the additional clinical evidence into the assessment group's model and generated ICERs comparing secukinumab with best supportive care in all 3\xa0psoriasis subgroups (psoriatic arthritis without concomitant psoriasis, with concomitant mild to moderate psoriasis, with concomitant moderate to severe psoriasis). Although the committee acknowledged that the ICERs were below £20,000 per QALY gained when taking into account the patient access scheme for secukinumab, it identified a number of concerns. The committee was aware that the comparators in the assessment group's model, and in the additional analysis done by Novartis, were included to ensure consistency with the NICE scope. The committee noted that when the scope was written it reflected current treatment at that time (use of biological therapy after 2\xa0DMARDs), but clinical practice may have moved on and the use of biological therapy after 1\xa0DMARD may be becoming more common. The committee heard from the assessment group that the analysis done by Novartis only included secukinumab and best supportive care. It was therefore lacking the full range of comparators for subpopulation\xa01, in particular the other biological treatments (etanercept, infliximab, adalimumab and golimumab), which according to their licences could be used in this subpopulation.\n\nHowever, the committee was not convinced that the use of biological therapy after 1\xa0DMARD is established clinical practice in the NHS (see section\xa04.2) and, if it is, in which specific group of people it is used. The committee also recognised that the full sequence of treatments (that is, the treatments a patient has after the first-line treatment) should have been modelled to better capture all the incremental cost and effectiveness differences between the technologies. Without the adequate inclusion of subsequent treatments, the analyses could misrepresent the true ICER. The committee agreed that because of these issues, it was not possible to reach a conclusion on the true cost effectiveness of certolizumab pegol and secukinumab in subpopulation\xa01. The committee was aware of the significant impact on clinical practice that a potential change in the use of biological therapy for psoriatic arthritis would have if it were to recommend secukinumab and certolizumab pegol in this population; particularly given that these are new technologies, one of which has a different mechanism of action (see section\xa04.2). Therefore, given the risk to the NHS of making an incorrect decision, it needed to be very certain about the cost effectiveness of certolizumab pegol and secukinumab in subpopulation\xa01. Taking into account all of these concerns, the committee concluded that it was unable to recommend certolizumab pegol and secukinumab as treatment options for people with psoriatic arthritis whose disease had not responded adequately to 1\xa0DMARD.\n\n## Subpopulation\xa02: at least 2\xa0previous DMARDs and no biological therapy\n\nThe committee considered that in all psoriasis subgroups, certolizumab pegol and secukinumab 150\xa0mg and 300\xa0mg were cost effective compared with best supportive care, when taking into account the patient access scheme for both therapies. ICERs for both strengths of secukinumab were less than £20,000 per QALY gained compared with best supportive care. For certolizumab pegol, the ICERs were close to, or less than £20,000 per QALY gained compared with best supportive care. The committee considered that the cost effectiveness for certolizumab pegol and secukinumab was acceptable when the criteria in etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis are met; that is, the person has peripheral arthritis with at least 3\xa0tender joints and at least 3\xa0swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least 2\xa0standard DMARDs, given either individually or in combination. The committee therefore concluded that certolizumab pegol and secukinumab could be recommended as treatment options for people with psoriatic arthritis if used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.\n\n## Subpopulation\xa03: patients who have had TNF-alpha inhibitors\n\nThe committee noted that secukinumab 300\xa0mg was considered as a relevant intervention, alongside ustekinumab and best supportive care, in patients who have had biological therapy. Certolizumab pegol was not included in subpopulation\xa03 because only patients whose disease had initially responded to a biological treatment and stopped responding thereafter were included in the RAPID-PsA trial (see section\xa04.10). The committee considered that secukinumab 300\xa0mg was cost effective in patients who had had biological therapy (including primary and secondary treatment failures) with ICER values below, or close to, £20,000 per QALY gained compared with best supportive care, when taking into account the patient access scheme for secukinumab 300\xa0mg. The committee concluded that secukinumab 300\xa0mg could be recommended as a treatment option for people with psoriatic arthritis whose disease has not responded adequately to 2\xa0DMARDs and has not responded to a TNF-alpha inhibitor within the first 12\xa0weeks or has stopped responding after 12\xa0weeks and only when taking into account the patient access scheme for secukinumab 300\xa0mg.\n\nThe committee noted the assessment group did a separate cost-effectiveness analysis (as part of the scenario analysis) for patients whose disease has stopped responding to a TNF-alpha inhibitor after the first 12\xa0weeks. It was aware that, in the absence of data for other comparators for this subgroup, the comparison is restricted to certolizumab pegol and best supportive care. The committee noted that for certolizumab pegol compared with best supportive care, the ICERs were below, or very close to, £20,000 per QALY gained, when taking into account the patient access scheme for certolizumab pegol. The committee therefore concluded that certolizumab pegol could be recommended as a treatment option for people with psoriatic arthritis whose disease has not responded adequately to 2\xa0DMARDs and whose disease has stopped responding to a TNF-alpha inhibitor after the first 12\xa0weeks, and only when taking into account the patient access scheme.\n\n## Subpopulation\xa04: patients in whom TNF‑alpha inhibitors are contraindicated\n\nThe committee noted that secukinumab was compared with ustekinumab and best supportive care. It noted that certolizumab pegol was not included because it was assumed that other TNF‑alpha inhibitors including certolizumab pegol would be contraindicated in these patients. In the absence of effectiveness data for these patients, the analysis was done using data from the biological-naive populations from the secukinumab and ustekinumab trial. The committee heard from clinical experts that this was considered a reasonable approach. The committee noted that the assessment group considered the different licensed strengths of secukinumab 150\xa0mg and 300\xa0mg according to psoriasis severity (see section\xa04.16). The committee noted that secukinumab 150\xa0mg and 300\xa0mg compared with best supportive care resulted in ICERs below £20,000 per QALY gained in patients without concomitant psoriasis, with mild to moderate psoriasis and with moderate to severe psoriasis, when taking into account the patient access scheme for secukinumab. The committee therefore concluded that secukinumab could be recommended as a treatment option for people with psoriatic arthritis in whom TNF‑alpha inhibitors are contraindicated but would otherwise be considered, and only when taking into account the patient access scheme for secukinumab.\n\nThe committee noted that the economic analyses (in all populations) were based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 12\xa0weeks and 16\xa0weeks stop treatment with certolizumab pegol and secukinumab, respectively. The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as defined in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for certolizumab pegol and secukinumab (assessed at 12\xa0weeks and 16\xa0weeks respectively). It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC.\n\n# Innovation\n\nThe committee noted the convenience of self-administration. It concluded that secukinumab and certolizumab pegol are important treatments and represent additional options for patients with active psoriatic arthritis that has not responded to prior DMARDs. It was aware of its earlier conclusion that although UCB Pharma provided evidence of certolizumab pegol's effect on pain and fatigue, it was not possible to determine the impact of any potential adjustment on the QALY calculations because the assessment group's modelling involved mapping from the health assessment questionnaire and PASI to a utility score (see section\xa04.7). It noted that if health benefits have been missed, this would apply across all the interventions and comparators. Therefore the committee concluded that there are no other significant health benefits that have not been captured in the cost-effectiveness model.\n\n# Summary of appraisal committee's key conclusions\n\nTA445\n\nAppraisal title: Certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs\n\nSection\n\nKey conclusion\n\nCertolizumab pegol alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if:\n\nit is used as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations\xa01.1 and\xa01.2) or\n\nthe person has had a TNF-alpha inhibitor but their disease has stopped responding after the first 12\xa0weeks.\n\nCertolizumab pegol is only recommended if the company provides it as agreed in the patient access scheme.\n\nSecukinumab alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if:\n\nit is used as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations\xa01.1 and\xa01.2) or\n\nthe person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12\xa0weeks or has stopped responding after 12\xa0weeks or\n\nTNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).\n\nSecukinumab is only recommended if the company provides it as agreed in the patient access scheme.\n\nFor subpopulation\xa01 (1\xa0previous disease-modifying antirheumatic drug [DMARD] but no biological therapy), the committee was aware that the comparators in the assessment group's analysis, and in the additional analysis done by Novartis, were included to ensure consistency with the NICE scope. It noted that when the scope was written it reflected current treatment at the time (use of biological therapy after 2\xa0DMARDs), but clinical practice may have moved on and the use of biological therapy after 1\xa0DMARD may be becoming more common. The committee heard from the assessment group that the analysis done by Novartis only included secukinumab and best supportive care and therefore was lacking the full range of comparators for subpopulation\xa01. The committee also recognised that the full sequence of treatments should have been modelled to better capture all the incremental cost and effectiveness differences between the technologies. Additionally, the committee was mindful of the significant impact on clinical practice that a potential shift in the use of biological therapy for psoriatic arthritis would have if it were to recommend secukinumab and certolizumab pegol in this population. Therefore, given the risk to the NHS of making an incorrect decision, it needed to be very certain about the cost effectiveness of certolizumab pegol and secukinumab in subpopulation\xa01. Taking into account all of these concerns, the committee concluded that it was unable to recommend certolizumab pegol and secukinumab as treatment options for people with psoriatic arthritis whose disease had not responded adequately to 1\xa0DMARD.\n\nFor subpopulation\xa02 (at least 2\xa0previous DMARDs and no biological therapy) the committee noted that, in all psoriasis subgroups, certolizumab pegol and secukinumab 150\xa0mg and 300\xa0mg were cost effective compared with best supportive care, when taking into account the patient access scheme for both therapies. ICERs for both strengths of secukinumab were less than £20,000 per quality-adjusted life year (QALY) gained compared with best supportive care. For certolizumab pegol the ICERs were close to, or less than, £20,000 per QALY gained compared with best supportive care. The committee therefore concluded that certolizumab pegol and secukinumab could be recommended as treatment options for people with psoriatic arthritis if used as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.\n\nFor subpopulation\xa03 (patients who have had TNF-alpha inhibitors), the committee reviewed 2\xa0subgroups:\n\nPeople with psoriatic arthritis whose disease has not responded adequately to 2 DMARDs, and has not responded to TNF-alpha inhibitors within the first 12\xa0weeks or has stopped responding after 12\xa0weeks; the committee noted that secukinumab 300\xa0mg was cost effective compared with best supportive care. ICERs were below, or close to, £20,000 per QALY gained, when taking into account the patient access scheme for secukinumab 300\xa0mg. The committee concluded that secukinumab 300\xa0mg could be recommended as a treatment option in this patient population only when taking into account the patient access scheme for secukinumab 300\xa0mg.\n\nPeople with psoriatic arthritis whose disease has not responded adequately to 2\xa0DMARDs and has stopped responding to TNF-alpha inhibitors after the first 12\xa0weeks; the committee noted that certolizumab pegol was cost effective compared with best supportive care with ICERs below or very close to £20,000 per QALY gained, when taking into account the patient access scheme for certolizumab pegol.\n\nFor subpopulation\xa04 (patients in whom TNF‑alpha inhibitors are contraindicated), the committee noted that secukinumab 150\xa0mg and 300\xa0mg compared with best supportive care resulted in ICERs below £20,000 per QALY gained in all psoriasis subgroups, when taking into account the patient access scheme for secukinumab. The committee concluded that secukinumab could be recommended as a treatment option for people with psoriatic arthritis in whom TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis), and only when taking into account the patient access scheme for secukinumab.\n\n, 1.2, 4.16, 4.17, 4.18, 4.19, 4.20, 4.20\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee recognised the importance to patients and clinical experts of addressing the associated comorbidities, which are not always captured in current research. It also heard that response to treatment is heterogeneous in terms of efficacy and safety. Therefore there is a clinical need for alternative therapies in the treatment pathway to offer more options, particularly in people with active psoriatic arthritis whose disease has responded inadequately to previous DMARD therapies.\n\n, 4.2\n\nThe technologies\n\nProposed benefits of the technology/ies\n\nHow innovative is the technology/are the technologies in its/their potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard from the clinical experts that secukinumab has a different mechanism of action, which could potentially benefit people in whom TNF-alpha inhibitors are contraindicated or not tolerated. The committee noted the convenience of self-administration for certolizumab pegol and secukinumab. It concluded that there are no other significant health benefits that have not been captured in the cost-effectiveness model.\n\n, 4.22\n\nWhat is the position of the treatments in the pathway of care for the condition?\n\nThe treatments are for:\n\npeople whose disease has responded inadequately to at least 2\xa0DMARDs, in line with guidelines from the British Society for Rheumatology and NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis\n\nsecukinumab is for people with psoriatic arthritis that has not responded adequately to at least 2\xa0DMARDs, and to TNF‑alpha inhibitors within the first 12\xa0weeks or has stopped responding after 12\xa0weeks, and also for people in whom TNF‑alpha inhibitors are contraindicated\n\ncertolizumab pegol is for people with psoriatic arthritis that has not responded to at least 2\xa0DMARDs and has stopped responding to TNF‑alpha inhibitor after the first 12\xa0weeks.\n\n, 4.19, 4.21, 4.20\n\nAdverse reactions\n\nThe committee heard from the clinical experts that there is no concern about additional adverse events for certolizumab pegol and secukinumab compared with other TNF-alpha inhibitors.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee mainly considered the clinical effectiveness evidence from the trials identified for certolizumab pegol (RAPID-PsA) and secukinumab (FUTURE\xa02).\n\nThe committee considered the results of the network meta-analysis done by the assessment group. It noted that separate analyses were done for each outcome for patients who had had biological therapy, and for patients who had not had biological therapy to acknowledge the difference in efficacy response in both subpopulations.\n\n, 4.8\n\nRelevance to general clinical practice in the NHS\n\nThere were no direct head-to-head trials with treatments currently used in the NHS.\n\nThe committee concluded that the biological-naive subpopulation in the network meta-analysis matched the subpopulation specified in the final NICE scope and it was therefore appropriate to use their data in the cost-effectiveness analysis.\n\nIn RAPID‑PsA, patients whose disease had not responded to a TNF‑alpha inhibitor in the first 12\xa0weeks of treatment were excluded and only patients whose disease did not respond after 12\xa0weeks, or initially responded but failed to respond thereafter (secondary treatment failure) were included in the biological-experienced subpopulation. The committee concluded that patients whose disease did not initially respond to a first biological therapy represent a separate subgroup within the overall biologic-experienced subpopulation. The committee concluded that it was reasonable for the assessment group to have excluded certolizumab pegol (RAPID‑PsA) treatment data from the biological-experienced population network meta-analysis.\n\nThe committee noted that populations recruited in clinical trials have changed over time, with earlier trials excluding patients who had previously had biological therapies and later trials including such patients.\n\n, 4.10, 4.6\n\nUncertainties generated by the evidence\n\nPlacebo response rates have increased markedly over time across the trials. The committee concluded it was reasonable to take into account the adjustment for both placebo response rates and class effect.\n\nThe committee concluded that because these issues had either not been accounted for (secukinumab) or because it was unclear how they had been accounted for (certolizumab pegol) in the company submissions, it was not possible to make reliable conclusions about the difference in the efficacy of certolizumab pegol and secukinumab using the companies' analyses.\n\n, 4.9, 4.6\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nSee 'What is the position of the treatments in the pathway of care for the condition?'\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that although there were limitations in the analyses, it considered that certolizumab pegol and secukinumab were similar to TNF-alpha inhibitors in improving joint symptoms in both biological-naive and biological-experienced subpopulations.\n\nThe committee noted that treatment with certolizumab pegol and secukinumab resulted in statistically significant improvements in health-related quality-of-life measures and in improvements in extra-articular manifestations such dactylitis (that is, inflammation of the fingers or toes) and enthesitis (that is, inflammation of tendons or ligaments).\n\n, 4.7\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee was aware that the comparators in the assessment group's analysis, and in the additional analysis done by Novartis, were included to ensure consistency with the NICE scope. It noted that when the scope was written it reflected current treatment at the time (use of biological therapy after 2\xa0DMARDs), but clinical practice may have moved on and the use of biological therapy after 1\xa0DMARD may be becoming more common. The committee heard from the assessment group that the analysis done by Novartis only included secukinumab and best supportive care and therefore was lacking the full range of comparators for subpopulation\xa01. The committee also recognised that the full sequence of treatments should have been modelled to better capture all the incremental cost and effectiveness differences between the technologies. Additionally, the committee was mindful of the significant impact on clinical practice that a potential shift in the use of biological therapy for psoriatic arthritis would have if it were to recommend secukinumab and certolizumab pegol in this population. Therefore, given the risk to the NHS of making an incorrect decision, it needed to be very certain about the cost effectiveness of certolizumab pegol and secukinumab in subpopulation\xa01. Taking into account all of these concerns, the committee concluded that it was unable to recommend certolizumab pegol and secukinumab as treatment options for people with psoriatic arthritis whose disease had not responded adequately to 1\xa0DMARD.\n\nThe committee concluded that the biological-naive subpopulation in the network meta-analysis matched the subpopulation specified in the final NICE scope and it was therefore appropriate to use their data in the cost-effectiveness analysis.\n\n, 4.8\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nAlthough the committee acknowledged that the ICERs were below £20,000 per QALY gained when taking into account the patient access scheme for secukinumab, it identified a number of concerns.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo other health-related benefits have been identified that have not been captured in the QALY calculation.\n\n\n\nAre there specific groups of people for whom the technology/ies is/are particularly cost effective?\n\nThe committee considered the results of the assessment group's base-case model for 4\xa0subpopulations in line with the proposed positions of certolizumab pegol and secukinumab in the treatment pathway and 3\xa0subgroups according to severity of psoriasis.\n\n–4.21\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee noted that the use of a different source of disease management costs impacted significantly on the ICERs for all treatments relative to best supportive care, although the optimal treatment remained consistent with the base-case analysis across all scenarios.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that certolizumab pegol is cost effective in 2\xa0subpopulations (patients who had at least 2\xa0previous DMARDs and no biological therapy, and patients who have had TNF‑alpha inhibitors whose disease has stopped responding to TNF‑alpha inhibitor after the first 12\xa0weeks) with ICERs below, or close to, £20,000 per QALY gained when taking into account the patient access scheme for certolizumab pegol.\n\nThe committee concluded that secukinumab is cost effective in 3\xa0subpopulations (patients who had at least 2\xa0previous DMARDs and no biological therapy, and patients who have had TNF‑alpha inhibitors whose disease has not responded to TNF‑alpha inhibitors within the first 12\xa0weeks or has stopped responding after 12\xa0weeks, and patients in whom TNF‑alpha inhibitors are contraindicated) with ICERs below, or close to, £20,000 per QALY gained only when taking into account the patient access scheme for secukinumab.\n\n, 4.19, 4.20, 4.18, 4.19, 4.21\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nPatient access schemes were taken into account for certolizumab pegol, golimumab, ustekinumab and secukinumab.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the Psoriatic Arthritis Response Criteria (PsARC), and concluded that healthcare professionals should take this into account when using the PsARC.\n\n"}	https://www.nice.org.uk/guidance/ta445	Evidence-based recommendations on certolizumab pegol (Cimzia) and secukinumab (Cosentyx) for treating active psoriatic arthritis in adults.
bbe67ca8c32cdd9927125f4a2ad5f61191b27f06	nice	Idiopathic pulmonary fibrosis in adults: diagnosis and management	Idiopathic pulmonary fibrosis in adults: diagnosis and management This guideline covers diagnosing and managing idiopathic pulmonary fibrosis in people aged 18 and over. It aims to improve the quality of life for people with idiopathic pulmonary fibrosis by helping healthcare professionals to diagnose the condition and provide effective symptom management. # Introduction Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic interstitial lung disease of unknown origin. It is a difficult disease to diagnose and often requires the collaborative expertise of a consultant respiratory physician, radiologist and histopathologist to reach a consensus diagnosis. Most people with idiopathic pulmonary fibrosis experience symptoms of breathlessness, which may initially be only on exertion. Cough, with or without sputum, is a common symptom. Over time, these symptoms are associated with a decline in lung function, reduced quality of life and ultimately death. The median survival for people with idiopathic pulmonary fibrosis in the UK is approximately 3 years from the time of diagnosis. However, about 20% of people with the disease survive for more than 5 years. The rate of disease progression can vary greatly. A person's prognosis is difficult to estimate at the time of diagnosis and may only become apparent after a period of careful follow-up. This guideline contains recommendations on the diagnosis of idiopathic pulmonary fibrosis and delivery of care to people with idiopathic pulmonary fibrosis, from initial suspicion of the disease and referral to a consultant respiratory physician, to best supportive care and disease-modifying treatments. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients. This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are noted in the recommendations.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Awareness of clinical features of idiopathic pulmonary fibrosis Be aware of idiopathic pulmonary fibrosis when assessing a patient with the clinical features listed below and when considering requesting a chest X‑ray or referring to a specialist: age over 45 years persistent breathlessness on exertion persistent cough bilateral inspiratory crackles when listening to the chest clubbing of the fingers normal spirometry or impaired spirometry usually with a restrictive pattern but sometimes with an obstructive pattern. # Diagnosis Assess everyone with suspected idiopathic pulmonary fibrosis by: taking a detailed history, carrying out a clinical examination (see recommendation 1.1.1 for clinical features) and performing blood tests to help exclude alternative diagnoses, including lung diseases associated with environmental and occupational exposure, with connective tissue diseases and with drugs and performing lung function testing (spirometry and gas transfer) and reviewing results of chest X‑ray and performing CT of the thorax (including high-resolution images). Diagnose idiopathic pulmonary fibrosis only with the consensus of the multidisciplinary team (listed in table 1), based on: the clinical features, lung function and radiological findings (see recommendation 1.2.1) pathology when indicated (see recommendation 1.2.4). At each stage of the diagnostic care pathway the multidisciplinary team should consist of a minimum of the healthcare professionals listed in table 1, all of whom should have expertise in interstitial lung disease. Stage of diagnostic care pathway Multidisciplinary team composition (all healthcare professionals should have expertise in interstitial lung disease) After clinical evaluation, baseline lung function and CT Consultant respiratory physician Consultant radiologist Interstitial lung disease specialist nurse Multidisciplinary team coordinator When considering performing bronchoalveolar lavage, and/or transbronchial biopsy or surgical lung biopsy Only some patients will have bronchoalveolar lavage or transbronchial biopsy but they may be being considered for surgical lung biopsy Consultant respiratory physician Consultant radiologist Consultant histopathologist Thoracic surgeon as appropriate Interstitial lung disease specialist nurse Multidisciplinary team coordinator When considering results of bronchoalveolar lavage, transbronchial biopsy or surgical lung biopsy Consultant respiratory physician Consultant radiologist Consultant histopathologist Interstitial lung disease specialist nurse Multidisciplinary team coordinator See the full guideline for more information on the expertise of the multidisciplinary team. ## If a confident diagnosis cannot be made If the multidisciplinary team cannot make a confident diagnosis from clinical features, lung function and radiological findings, consider: bronchoalveolar lavage or transbronchial biopsy and/or surgical lung biopsy, with the agreement of the thoracic surgeon. Discuss with the person who may have idiopathic pulmonary fibrosis: the potential benefits of having a confident diagnosis compared with the uncertainty of not having a confident diagnosis and the increased likelihood of obtaining a confident diagnosis with surgical biopsy compared with bronchoalveolar lavage or transbronchial biopsy and the increased risks of surgical biopsy compared with bronchoalveolar lavage or transbronchial biopsy. When considering bronchoalveolar lavage, transbronchial biopsy or surgical lung biopsy take into account: the likely differential diagnoses and the person's clinical condition, including any comorbidities. If a confident diagnosis cannot be made continue to review the person under specialist care. # Information and support The consultant respiratory physician or interstitial lung disease specialist nurse should provide accurate and clear information (verbal and written) to people with idiopathic pulmonary fibrosis, and their families and carers with the person's consent. This should include information about investigations, diagnosis and management. NICE has produced guidance on the components of good patient experience in adult NHS services. Follow the recommendations in NICE's guideline on patient experience in adult NHS services. An interstitial lung disease specialist nurse should be available at all stages of the care pathway to provide information and support to people with idiopathic pulmonary fibrosis and their families and carers with the person's consent. Offer advice, support and treatment to aid smoking cessation to all people with idiopathic pulmonary fibrosis who also smoke, in line with NICE's guideline on tobacco. # Prognosis Measure the initial rate of decline in the person's condition, which may predict subsequent prognosis, by using lung function test results (spirometry and gas transfer) at: diagnosis and months and 12 months after diagnosis. Repeat the lung function tests at shorter intervals if there is concern that the person's condition is deteriorating rapidly. Discuss prognosis with people with idiopathic pulmonary fibrosis in a sensitive manner and include information on: the severity of the person's disease and average life expectancy the varying courses of disease and range of survival management options available. Do not use the 6‑minute walk distance at diagnosis to estimate prognosis. (The 6‑minute walk test may be useful for other purposes, see recommendation 1.5.1.) # Management ## Pulmonary rehabilitation Assess people with idiopathic pulmonary fibrosis for pulmonary rehabilitation at the time of diagnosis. Assessment may include a 6-minute walk test (distance walked and oxygen saturation measured by pulse oximetry) and a quality-of-life assessment.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. Repeat the assessment for pulmonary rehabilitation for people with idiopathic pulmonary fibrosis at 6‑month or 12‑month intervals. If appropriate after each assessment, offer pulmonary rehabilitation including exercise and educational components tailored to the needs of people with idiopathic pulmonary fibrosis in general. Pulmonary rehabilitation should be tailored to the individual needs of each person with idiopathic pulmonary fibrosis. Sessions should be held somewhere that is easy for people with idiopathic pulmonary fibrosis to get to and has good access for people with disabilities. ## Best supportive care Offer best supportive care to people with idiopathic pulmonary fibrosis from the point of diagnosis. Best supportive care should be tailored to disease severity, rate of progression, and the person's preference, and should include if appropriate: information and support (see recommendation 1.3.1 in the section on information and support) symptom relief management of comorbidities withdrawal of therapies suspected to be ineffective or causing harm end of life care. If the person is breathless on exertion consider assessment for: the causes of breathlessness and degree of hypoxia and ambulatory oxygen therapy and long-term oxygen therapy and/or pulmonary rehabilitation. If the person is breathless at rest consider: assessment for the causes of breathlessness and degree of hypoxia and assessment for additional ambulatory oxygen therapy and long-term oxygen therapy and the person's psychosocial needs and offering referral to relevant services such as palliative care services and pharmacological symptom relief with benzodiazepines and/or opioids. Assess the oxygen needs of people who have been hospitalised with idiopathic pulmonary fibrosis before they are discharged. If the person has a cough consider: treatment for causes other than idiopathic pulmonary fibrosis (such as gastro-oesophageal reflux disease, post-nasal drip) treating with opioids if the cough is debilitating discussing treatment with thalidomide with a consultant respiratory physician with expertise in interstitial lung disease if the cough is intractable.At the time of publication (June 2013), thalidomide did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Ensure people with idiopathic pulmonary fibrosis, and their families and carers, have access to the full range of services offered by palliative care teams. Ensure there is collaboration between the healthcare professionals involved in the person's care, community services and the palliative care team. ## Disease-modifying pharmacological interventions There is no conclusive evidence to support the use of any drugs to increase the survival of people with idiopathic pulmonary fibrosis. For recommendations on pirfenidone, see NICE's technology appraisal guidance on pirfenidone for the treatment of idiopathic pulmonary fibrosis. For recommendations on nintedanib, see NICE's technology appraisal guidance on nintedanib for the treatment of idiopathic pulmonary fibrosis. Do not use any of the drugs below, either alone or in combination, to modify disease progression in idiopathic pulmonary fibrosis: ambrisentan azathioprine bosentan co-trimoxazole mycophenolate mofetil prednisolone sildenafil warfarin. Advise the person that oral N‑acetylcysteine is used for managing idiopathic pulmonary fibrosis, but its benefits are uncertain.At the time of publication (June 2013), N‑acetylcysteine did not have a UK marketing authorisation. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. If people with idiopathic pulmonary fibrosis are already using prednisolone or azathioprine, discuss the potential risks and benefits of discontinuing, continuing or altering therapy. Manage any comorbidities according to best practice. For gastro-oesophageal reflux disease, see NICE's guideline on gastro-oesophageal reflux disease and dyspepsia in adults. ## Lung transplantation Discuss lung transplantation as a treatment option for people with idiopathic pulmonary fibrosis who do not have absolute contraindications. Discussions should: take place between 3 and 6 months after diagnosis or sooner if clinically indicated be supported by an interstitial lung disease specialist nurse include the risks and benefits of lung transplantation involve the person's family and carers with the person's consent. (See the recommendations in the section on best supportive care.) Refer people with idiopathic pulmonary fibrosis for lung transplantation assessment if they wish to explore lung transplantation and if there are no absolute contraindications. Ask the transplant centre for an initial response within 4 weeks. ## Ventilation A respiratory physician or specialist nurse with an interest in interstitial lung disease should discuss the poor outcomes associated with mechanical ventilation (including non-invasive mechanical ventilation) for respiratory failure with people with idiopathic pulmonary fibrosis. These discussions should ideally take place between 3 to 6 months after diagnosis or sooner if clinically indicated. (See the recommendations in the section on best supportive care.) Do not routinely offer mechanical ventilation (including non-invasive mechanical ventilation) to people with idiopathic pulmonary fibrosis who develop life-threatening respiratory failure. # Review and follow-up In follow-up appointments for people with idiopathic pulmonary fibrosis: assess lung function assess for oxygen therapy assess for pulmonary rehabilitation -ffer smoking cessation advice, in line with NICE's guideline on tobacco identify exacerbations and previous respiratory hospital admissions consider referral for assessment for lung transplantation in people who do not have absolute contraindications (see the recommendations in the section on lung transplantation) consider psychosocial needs and referral to relevant services as appropriate consider referral to palliative care services assess for comorbidities (which may include anxiety, bronchiectasis, depression, diabetes, dyspepsia, ischaemic heart disease, lung cancer and pulmonary hypertension). Consider follow-up of people with idiopathic pulmonary fibrosis: every 3 months or sooner if they are showing rapid disease progression or rapid deterioration of symptoms or every 6 months or sooner if they have steadily progressing disease or initially every 6 months if they have stable disease and then annually if they have stable disease after 1 year.# Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline. # Pulmonary rehabilitation to improve outcomes in people with idiopathic pulmonary fibrosis Does pulmonary rehabilitation improve outcomes for people with idiopathic pulmonary fibrosis? ## Why this is important There is evidence that people with idiopathic pulmonary fibrosis may benefit from pulmonary rehabilitation. However this evidence is mostly derived from programmes designed principally for people with chronic obstructive pulmonary disease. It is likely that the needs of people with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease differ. Randomised controlled trials should be carried out to determine the effects of pulmonary rehabilitation programmes tailored to idiopathic pulmonary fibrosis, compared with currently offered pulmonary rehabilitation programmes, on quality of life, walking distance and lung function with analysis adjusting for confounding factors appropriately. Trials should analyse benefits of the different aspects of pulmonary rehabilitation including the components, setting and location of the programme, and healthcare resources involved. End points may include: 6‑minute walk distance; breathlessness score; a measure of health-related quality of life (ideally employing a tool validated in people with idiopathic pulmonary fibrosis); mortality (all-cause and idiopathic pulmonary fibrosis-related); hospitalisation (all-cause, non-elective and idiopathic pulmonary fibrosis -related); lung function (vital capacity and diffusion capacity for carbon monoxide). Studies should be of sufficient power and duration and include a health economic evaluation. # Ambulatory oxygen to improve outcomes in idiopathic pulmonary fibrosis Does ambulatory oxygen improve outcomes in idiopathic pulmonary fibrosis? ## Why this is important People with idiopathic pulmonary fibrosis frequently demonstrate a fall in oxygen saturation during exercise even though they are not hypoxic at rest. In such people, ambulatory oxygen is often provided to improve exercise capacity, enhance mobility and enable activities of daily living in order to improve quality of life. However, there are no randomised controlled trials to demonstrate that ambulatory oxygen therapy is effective in achieving these aims in patients with idiopathic pulmonary fibrosis. A randomised controlled trial should be conducted to determine the effects of ambulatory oxygen on quality of life in people with idiopathic pulmonary fibrosis and consideration given to the use of a placebo arm. This should include a standardised protocol for assessing exercise such as the 6-minute walk test. The end points may include 6‑minute walk distance; breathlessness score; a measure of health-related quality of life (ideally employing a tool validated in idiopathic pulmonary fibrosis patients). Phase III trials should have a duration of greater than 12 months and include a health economic evaluation. # Anti-reflux therapy as a treatment for idiopathic pulmonary fibrosis Is anti-reflux therapy an effective treatment for idiopathic pulmonary fibrosis? ## Why this is important There is evidence from observational studies, and uncontrolled interventional trials, that microaspiration of gastric/oesophageal contents contribute to disease progression, and perhaps even cause idiopathic pulmonary fibrosis. There have been no randomised controlled trials of anti-reflux therapy in idiopathic pulmonary fibrosis but proton-pump inhibitors are often prescribed for symptoms of acid-reflux. A randomised, placebo-controlled trial of adequate power and duration of greater than 12 months should be undertaken to determine the benefits and side effects of anti-reflux therapy, including proton pump inhibition in people with a confirmed diagnosis of idiopathic pulmonary fibrosis. Appropriate end points may include mortality (all-cause and idiopathic pulmonary fibrosis-related); hospitalisation (all-cause, non-elective and idiopathic pulmonary fibrosis-related); lung function (vital capacity and diffusion capacity for carbon monoxide); 6‑minute walk distance; breathlessness score; a measure of health-related quality of life (ideally employing a tool validated in idiopathic pulmonary fibrosis patients). Phase III trials should include a health economic evaluation.	{'Introduction': "Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic interstitial lung disease of unknown origin. It is a difficult disease to diagnose and often requires the collaborative expertise of a consultant respiratory physician, radiologist and histopathologist to reach a consensus diagnosis. Most people with idiopathic pulmonary fibrosis experience symptoms of breathlessness, which may initially be only on exertion. Cough, with or without sputum, is a common symptom. Over time, these symptoms are associated with a decline in lung function, reduced quality of life and ultimately death.\n\nThe median survival for people with idiopathic pulmonary fibrosis in the UK is approximately 3\xa0years from the time of diagnosis. However, about 20% of people with the disease survive for more than 5\xa0years. The rate of disease progression can vary greatly. A person's prognosis is difficult to estimate at the time of diagnosis and may only become apparent after a period of careful follow-up.\n\nThis guideline contains recommendations on the diagnosis of idiopathic pulmonary fibrosis and delivery of care to people with idiopathic pulmonary fibrosis, from initial suspicion of the disease and referral to a consultant respiratory physician, to best supportive care and disease-modifying treatments.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are noted in the recommendations.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Awareness of clinical features of idiopathic pulmonary fibrosis\n\nBe aware of idiopathic pulmonary fibrosis when assessing a patient with the clinical features listed below and when considering requesting a chest X‑ray or referring to a specialist:\n\nage over 45\xa0years\n\npersistent breathlessness on exertion\n\npersistent cough\n\nbilateral inspiratory crackles when listening to the chest\n\nclubbing of the fingers\n\nnormal spirometry or impaired spirometry usually with a restrictive pattern but sometimes with an obstructive pattern.\n\n# Diagnosis\n\nAssess everyone with suspected idiopathic pulmonary fibrosis by:\n\ntaking a detailed history, carrying out a clinical examination (see recommendation\xa01.1.1 for clinical features) and performing blood tests to help exclude alternative diagnoses, including lung diseases associated with environmental and occupational exposure, with connective tissue diseases and with drugs and\n\nperforming lung function testing (spirometry and gas transfer) and\n\nreviewing results of chest X‑ray and\n\nperforming CT of the thorax (including high-resolution images).\n\nDiagnose idiopathic pulmonary fibrosis only with the consensus of the multidisciplinary team (listed in table\xa01), based on:\n\nthe clinical features, lung function and radiological findings (see recommendation\xa01.2.1)\n\npathology when indicated (see recommendation\xa01.2.4).\n\nAt each stage of the diagnostic care pathway the multidisciplinary team should consist of a minimum of the healthcare professionals listed in table\xa01, all of whom should have expertise in interstitial lung disease.\n\nStage of diagnostic care pathway\n\nMultidisciplinary team composition (all healthcare professionals should have expertise in interstitial lung disease)\n\nAfter clinical evaluation, baseline lung function and CT\n\nConsultant respiratory physician\n\nConsultant radiologist\n\nInterstitial lung disease specialist nurse\n\nMultidisciplinary team coordinator\n\nWhen considering performing bronchoalveolar lavage, and/or transbronchial biopsy or surgical lung biopsy\n\nOnly some patients will have bronchoalveolar lavage or transbronchial biopsy but they may be being considered for surgical lung biopsy\n\nConsultant respiratory physician\n\nConsultant radiologist\n\nConsultant histopathologist\n\nThoracic surgeon as appropriate\n\nInterstitial lung disease specialist nurse\n\nMultidisciplinary team coordinator\n\nWhen considering results of bronchoalveolar lavage, transbronchial biopsy or surgical lung biopsy\n\nConsultant respiratory physician\n\nConsultant radiologist\n\nConsultant histopathologist\n\nInterstitial lung disease specialist nurse\n\nMultidisciplinary team coordinator\n\nSee the full guideline for more information on the expertise of the multidisciplinary team.\n\n## If a confident diagnosis cannot be made\n\nIf the multidisciplinary team cannot make a confident diagnosis from clinical features, lung function and radiological findings, consider:\n\nbronchoalveolar lavage or transbronchial biopsy and/or\n\nsurgical lung biopsy, with the agreement of the thoracic surgeon.\n\nDiscuss with the person who may have idiopathic pulmonary fibrosis:\n\nthe potential benefits of having a confident diagnosis compared with the uncertainty of not having a confident diagnosis and\n\nthe increased likelihood of obtaining a confident diagnosis with surgical biopsy compared with bronchoalveolar lavage or transbronchial biopsy and\n\nthe increased risks of surgical biopsy compared with bronchoalveolar lavage or transbronchial biopsy.\n\nWhen considering bronchoalveolar lavage, transbronchial biopsy or surgical lung biopsy take into account:\n\nthe likely differential diagnoses and\n\nthe person's clinical condition, including any comorbidities.\n\nIf a confident diagnosis cannot be made continue to review the person under specialist care.\n\n# Information and support\n\nThe consultant respiratory physician or interstitial lung disease specialist nurse should provide accurate and clear information (verbal and written) to people with idiopathic pulmonary fibrosis, and their families and carers with the person's consent. This should include information about investigations, diagnosis and management.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. Follow the recommendations in NICE's guideline on patient experience in adult NHS services.\n\nAn interstitial lung disease specialist nurse should be available at all stages of the care pathway to provide information and support to people with idiopathic pulmonary fibrosis and their families and carers with the person's consent.\n\nOffer advice, support and treatment to aid smoking cessation to all people with idiopathic pulmonary fibrosis who also smoke, in line with NICE's guideline on tobacco.\n\n# Prognosis\n\nMeasure the initial rate of decline in the person's condition, which may predict subsequent prognosis, by using lung function test results (spirometry and gas transfer) at:\n\ndiagnosis and\n\nmonths and 12\xa0months after diagnosis. Repeat the lung function tests at shorter intervals if there is concern that the person's condition is deteriorating rapidly.\n\nDiscuss prognosis with people with idiopathic pulmonary fibrosis in a sensitive manner and include information on:\n\nthe severity of the person's disease and average life expectancy\n\nthe varying courses of disease and range of survival\n\nmanagement options available.\n\nDo not use the 6‑minute walk distance at diagnosis to estimate prognosis. (The 6‑minute walk test may be useful for other purposes, see recommendation\xa01.5.1.)\n\n# Management\n\n## Pulmonary rehabilitation\n\nAssess people with idiopathic pulmonary fibrosis for pulmonary rehabilitation at the time of diagnosis. Assessment may include a 6-minute walk test (distance walked and oxygen saturation measured by pulse oximetry) and a quality-of-life assessment.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nRepeat the assessment for pulmonary rehabilitation for people with idiopathic pulmonary fibrosis at 6‑month or 12‑month intervals.\n\nIf appropriate after each assessment, offer pulmonary rehabilitation including exercise and educational components tailored to the needs of people with idiopathic pulmonary fibrosis in general.\n\nPulmonary rehabilitation should be tailored to the individual needs of each person with idiopathic pulmonary fibrosis. Sessions should be held somewhere that is easy for people with idiopathic pulmonary fibrosis to get to and has good access for people with disabilities.\n\n## Best supportive care\n\nOffer best supportive care to people with idiopathic pulmonary fibrosis from the point of diagnosis. Best supportive care should be tailored to disease severity, rate of progression, and the person's preference, and should include if appropriate:\n\ninformation and support (see recommendation\xa01.3.1 in the section on information and support)\n\nsymptom relief\n\nmanagement of comorbidities\n\nwithdrawal of therapies suspected to be ineffective or causing harm\n\nend of life care.\n\nIf the person is breathless on exertion consider assessment for:\n\nthe causes of breathlessness and degree of hypoxia and\n\nambulatory oxygen therapy and long-term oxygen therapy and/or\n\npulmonary rehabilitation.\n\nIf the person is breathless at rest consider:\n\nassessment for the causes of breathlessness and degree of hypoxia and\n\nassessment for additional ambulatory oxygen therapy and long-term oxygen therapy and\n\nthe person's psychosocial needs and offering referral to relevant services such as palliative care services and\n\npharmacological symptom relief with benzodiazepines and/or\xa0opioids.\n\nAssess the oxygen needs of people who have been hospitalised with idiopathic pulmonary fibrosis before they are discharged.\n\nIf the person has a cough consider:\n\ntreatment for causes other than idiopathic pulmonary fibrosis (such as gastro-oesophageal reflux disease, post-nasal drip)\n\ntreating with opioids if the cough is debilitating\n\ndiscussing treatment with thalidomide with a consultant respiratory physician with expertise in interstitial lung disease if the cough is intractable.At the time of publication (June 2013), thalidomide did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.\n\nEnsure people with idiopathic pulmonary fibrosis, and their families and carers, have access to the full range of services offered by palliative care teams. Ensure there is collaboration between the healthcare professionals involved in the person's care, community services and the palliative care team.\n\n## Disease-modifying pharmacological interventions\n\nThere is no conclusive evidence to support the use of any drugs to increase the survival of people with idiopathic pulmonary fibrosis.\n\nFor recommendations on pirfenidone, see NICE's technology appraisal guidance on pirfenidone for the treatment of idiopathic pulmonary fibrosis. For recommendations on nintedanib, see NICE's technology appraisal guidance on nintedanib for the treatment of idiopathic pulmonary fibrosis.\n\nDo not use any of the drugs below, either alone or in combination, to modify disease progression in idiopathic pulmonary fibrosis:\n\nambrisentan\n\nazathioprine\n\nbosentan\n\nco-trimoxazole\n\nmycophenolate mofetil\n\nprednisolone\n\nsildenafil\n\nwarfarin.\n\nAdvise the person that oral N‑acetylcysteine is used for managing idiopathic pulmonary fibrosis, but its benefits are uncertain.At the time of publication (June 2013), N‑acetylcysteine did not have a UK marketing authorisation. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.\n\nIf people with idiopathic pulmonary fibrosis are already using prednisolone or azathioprine, discuss the potential risks and benefits of discontinuing, continuing or altering therapy.\n\nManage any comorbidities according to best practice. For gastro-oesophageal reflux disease, see NICE's guideline on gastro-oesophageal reflux disease and dyspepsia in adults.\n\n## Lung transplantation\n\nDiscuss lung transplantation as a treatment option for people with idiopathic pulmonary fibrosis who do not have absolute contraindications. Discussions should:\n\ntake place between 3 and 6\xa0months after diagnosis or sooner if clinically indicated\n\nbe supported by an interstitial lung disease specialist nurse\n\ninclude the risks and benefits of lung transplantation\n\ninvolve the person's family and carers with the person's consent. (See the recommendations in the section on best supportive care.)\n\nRefer people with idiopathic pulmonary fibrosis for lung transplantation assessment if they wish to explore lung transplantation and if there are no absolute contraindications. Ask the transplant centre for an initial response within 4\xa0weeks.\n\n## Ventilation\n\nA respiratory physician or specialist nurse with an interest in interstitial lung disease should discuss the poor outcomes associated with mechanical ventilation (including non-invasive mechanical ventilation) for respiratory failure with people with idiopathic pulmonary fibrosis. These discussions should ideally take place between 3 to 6\xa0months after diagnosis or sooner if clinically indicated. (See the recommendations in the section on best supportive care.)\n\nDo not routinely offer mechanical ventilation (including non-invasive mechanical ventilation) to people with idiopathic pulmonary fibrosis who develop life-threatening respiratory failure.\n\n# Review and follow-up\n\nIn follow-up appointments for people with idiopathic pulmonary fibrosis:\n\nassess lung function\n\nassess for oxygen therapy\n\nassess for pulmonary rehabilitation\n\noffer smoking cessation advice, in line with NICE's guideline on tobacco\n\nidentify exacerbations and previous respiratory hospital admissions\n\nconsider referral for assessment for lung transplantation in people who do not have absolute contraindications (see the recommendations in the section on lung transplantation)\n\nconsider psychosocial needs and referral to relevant services as appropriate\n\nconsider referral to palliative care services\n\nassess for comorbidities (which may include anxiety, bronchiectasis, depression, diabetes, dyspepsia, ischaemic heart disease, lung cancer and pulmonary hypertension).\n\nConsider follow-up of people with idiopathic pulmonary fibrosis:\n\nevery 3\xa0months or sooner if they are showing rapid disease progression or rapid deterioration of symptoms or\n\nevery 6\xa0months or sooner if they have steadily progressing disease or\n\ninitially every 6\xa0months if they have stable disease and then annually if they have stable disease after 1\xa0year.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.\n\n# Pulmonary rehabilitation to improve outcomes in people with idiopathic pulmonary fibrosis\n\nDoes pulmonary rehabilitation improve outcomes for people with idiopathic pulmonary fibrosis?\n\n## Why this is important\n\nThere is evidence that people with idiopathic pulmonary fibrosis may benefit from pulmonary rehabilitation. However this evidence is mostly derived from programmes designed principally for people with chronic obstructive pulmonary disease. It is likely that the needs of people with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease differ. Randomised controlled trials should be carried out to determine the effects of pulmonary rehabilitation programmes tailored to idiopathic pulmonary fibrosis, compared with currently offered pulmonary rehabilitation programmes, on quality of life, walking distance and lung function with analysis adjusting for confounding factors appropriately. Trials should analyse benefits of the different aspects of pulmonary rehabilitation including the components, setting and location of the programme, and healthcare resources involved. End points may include: 6‑minute walk distance; breathlessness score; a measure of health-related quality of life (ideally employing a tool validated in people with idiopathic pulmonary fibrosis); mortality (all-cause and idiopathic pulmonary fibrosis-related); hospitalisation (all-cause, non-elective and idiopathic pulmonary fibrosis -related); lung function (vital capacity and diffusion capacity for carbon monoxide). Studies should be of sufficient power and duration and include a health economic evaluation.\n\n# Ambulatory oxygen to improve outcomes in idiopathic pulmonary fibrosis\n\nDoes ambulatory oxygen improve outcomes in idiopathic pulmonary fibrosis?\n\n## Why this is important\n\nPeople with idiopathic pulmonary fibrosis frequently demonstrate a fall in oxygen saturation during exercise even though they are not hypoxic at rest. In such people, ambulatory oxygen is often provided to improve exercise capacity, enhance mobility and enable activities of daily living in order to improve quality of life. However, there are no randomised controlled trials to demonstrate that ambulatory oxygen therapy is effective in achieving these aims in patients with idiopathic pulmonary fibrosis. A randomised controlled trial should be conducted to determine the effects of ambulatory oxygen on quality of life in people with idiopathic pulmonary fibrosis and consideration given to the use of a placebo arm. This should include a standardised protocol for assessing exercise such as the 6-minute walk test. The end points may include 6‑minute walk distance; breathlessness score; a measure of health-related quality of life (ideally employing a tool validated in idiopathic pulmonary fibrosis patients). Phase\xa0III trials should have a duration of greater than 12\xa0months and include a health economic evaluation.\n\n# Anti-reflux therapy as a treatment for idiopathic pulmonary fibrosis\n\nIs anti-reflux therapy an effective treatment for idiopathic pulmonary fibrosis?\n\n## Why this is important\n\nThere is evidence from observational studies, and uncontrolled interventional trials, that microaspiration of gastric/oesophageal contents contribute to disease progression, and perhaps even cause idiopathic pulmonary fibrosis. There have been no randomised controlled trials of anti-reflux therapy in idiopathic pulmonary fibrosis but proton-pump inhibitors are often prescribed for symptoms of acid-reflux. A randomised, placebo-controlled trial of adequate power and duration of greater than 12\xa0months should be undertaken to determine the benefits and side effects of anti-reflux therapy, including proton pump inhibition in people with a confirmed diagnosis of idiopathic pulmonary fibrosis. Appropriate end points may include mortality (all-cause and idiopathic pulmonary fibrosis-related); hospitalisation (all-cause, non-elective and idiopathic pulmonary fibrosis-related); lung function (vital capacity and diffusion capacity for carbon monoxide); 6‑minute walk distance; breathlessness score; a measure of health-related quality of life (ideally employing a tool validated in idiopathic pulmonary fibrosis patients). Phase\xa0III trials should include a health economic evaluation."}	https://www.nice.org.uk/guidance/cg163	This guideline covers diagnosing and managing idiopathic pulmonary fibrosis in people aged 18 and over. It aims to improve the quality of life for people with idiopathic pulmonary fibrosis by helping healthcare professionals to diagnose the condition and provide effective symptom management.
752a3dc6d5f06347ce2e4550d1232bbf5e1fa246	nice	Virtual chromoendoscopy to assess colorectal polyps during colonoscopy	Virtual chromoendoscopy to assess colorectal polyps during colonoscopy Evidence-based recommendations on virtual chromoendoscopy (VCE) using NBI, FICE or i-scan to assess colorectal polyps of 5 mm or less during colonoscopy. # Recommendation Virtual chromoendoscopy using NBI, FICE or i‑scan is recommended to assess polyps of 5 mm or less during colonoscopy, instead of histopathology, to determine whether they are adenomatous or hyperplastic, only if: high-definition enabled virtual chromoendoscopy equipment is used the endoscopist has been trained to use virtual chromoendoscopy, and accredited to use the technique under a national accreditation scheme the endoscopy service includes systems to audit endoscopists and provide ongoing feedback on their performance (see section 6.1) and the assessment is made with high confidence.# Clinical need and practice # The problem addressed Colorectal polyps are small growths on the inner lining of the colon. Polyps are not usually cancerous; most are hyperplastic polyps with a low risk of cancer; but some (known as adenomatous polyps) will eventually turn into cancer if left untreated. Detecting and removing adenomas during colonoscopy has been shown to decrease the later development of colorectal cancers. However, removal of any polyps by polypectomy may have adverse effects such as bleeding and perforation of the bowel. Also, as imaging technologies improve, more polyps may be found, which may in turn increase the number of polyps removed from a person and affect the workload of gastroenterologists and histopathologists. It can take 3 weeks for a person to get the examination results for polyps that were removed during colonoscopy, and they may feel anxious during this waiting period. Virtual chromoendoscopy technologies (Narrow Band Imaging , flexible spectral imaging colour enhancement and i‑scan), are intended to allow colour-enhanced visualisation of blood vessels and surface pattern compared with conventional colonoscopy, without using dyes. Using virtual chromoendoscopy technologies may allow real-time differentiation of adenomas and hyperplastic colorectal polyps during colonoscopy, which could lead to: fewer resections of low‑risk hyperplastic polyps (resulting in a reduction in complications); quicker results and management decisions; and reduced resource use through fewer histopathology examinations. The purpose of this assessment is to evaluate the clinical and cost effectiveness of virtual chromoendoscopy (NBI, FICE and i‑scan) for assessing diminutive (5 mm or less) colorectal polyps during colonoscopy to determine whether they are adenomatous or hyperplastic. # The condition ## Colorectal polyps and colorectal cancer Colorectal polyps are common, affecting 15% to 20% of the UK population. Most polyps produce no symptoms, but some larger polyps can cause a small amount of rectal bleeding, diarrhoea, constipation or abdominal pain. Colorectal cancer is one of the most common cancers in the UK and is the second most common cause of cancer death. About 40,000 new cases are registered each year. Colorectal cancer is strongly related to age, with almost three‑quarters of cases occurring in people aged 65 or over. # The diagnostic and care pathways ## Diagnosis Colonoscopy examinations may be done for several clinical reasons, including: further investigation of symptoms suggestive of colorectal cancer further investigation of a positive faecal occult blood test as part of the NHS bowel cancer screening programme or -ngoing checks (surveillance) after removal of adenomatous polyps. The NICE guideline on suspected cancer recommends that people should be referred for colorectal cancer investigations within 2 weeks if: they are aged 40 and over with unexplained weight loss and abdominal pain or they are aged 50 and over with unexplained rectal bleeding or they are aged 60 and over with iron-deficiency anaemia or changes in their bowel habit or tests show occult blood in their faeces. The guideline also recommends that people should be considered for referral for colorectal cancer investigations if: they have a rectal or abdominal mass they are aged under 50 with rectal bleeding and have any of the following unexplained symptoms or findings: abdominal pain changes in bowel habit weight loss or iron deficiency anaemia. The NHS bowel cancer screening programme offers screening every 2 years to men and women aged 60 to 74. The screening programme invites eligible adults to have a faecal occult blood test. This involves collecting 3 stool samples and posting them to the laboratory to be checked for the presence of blood, which could be an early sign of colorectal cancer. People with an abnormal faecal occult blood test result are offered a colonoscopy. The NICE guideline on colonoscopic surveillance recommends that colonoscopies are offered to people: with inflammatory bowel disease whose symptoms started 10 years ago or who have had adenomas removed and are at intermediate or high risk of developing colorectal cancer.It also recommends that colonoscopic surveillance is considered for people who have had adenomas removed and are at low risk of developing colorectal cancer. The frequency of surveillance may be every 1, 3 or 5 years, depending on the level of risk of developing colorectal cancer. For investigating possible colorectal cancer in secondary care, the NICE guideline on colorectal cancer recommends that: people without major comorbidity are offered colonoscopy people with major comorbidity are offered flexible sigmoidoscopy plus barium enema CT colonography is considered as an alternative to colonoscopy or flexible sigmoidoscopy plus barium enema, if the local radiology service can show competency in this technique people who have had an incomplete colonoscopy are offered repeat colonoscopy, CT colonography (if the local radiology service can show competency in this technique), or a barium enema. If colorectal polyps are found during a colonoscopy they can be removed using cauterisation or a snare (polypectomy). Polyps removed by polypectomy are sent for histopathology to determine whether they are hyperplastic or adenomatous. If colorectal cancer is suspected, biopsies are taken and sent to the laboratory to determine whether the sample contains benign or malignant cells. If colorectal cancer is confirmed, the NICE guideline on colorectal cancer recommends further imaging tests, such as CT or MRI, to stage the cancer and determine what treatment is needed. Colonoscopy is usually done as an outpatient procedure with the person having sedation or painkillers. People having colonoscopy may be concerned about the adverse effects of the colonoscopy, such as heavy bleeding or perforation of the bowel. Colonoscopy with polypectomy also has an increased risk of bleeding and perforation compared with colonoscopy without polypectomy. Some people may also have a reaction to the sedative which could result in temporary breathing or heart problems. ## Care If colorectal cancer is not diagnosed then surveillance colonoscopy is offered, and the length of time between assessments depends on the risk of cancer. The NICE guideline on colonoscopic surveillance recommends that people with: -r 2 small (less than 10 mm) adenomas are at low risk, and need either no, or 5‑yearly, colonoscopic surveillance until they have 1 negative examination, after which surveillance stops -r 4 small adenomas of less than 10 mm or at least 1 adenoma that is 10 mm or more are at intermediate risk and should be screened 3‑yearly until they have 2 consecutive negative examinations -r more adenomas smaller than 10 mm, or 3 or more adenomas at least one of which is 10 mm or more, are at high risk and should have an extra examination at 12 months before returning to 3‑yearly surveillance. If colorectal cancer is diagnosed, it may be treated with surgery, chemotherapy or radiotherapy, or sometimes with biological agents such as cetuximab. Treatment depends on the stage of the cancer and is described in more detail in the NICE guideline on colorectal cancer.# The diagnostic tests The assessment compared 3 intervention tests with 1 comparator. # The interventions A conventional endoscopy system includes an endoscope, a light source, a video processor and a monitor. The light source produces light which is sent to the end of the endoscope. The video processor converts electrical signals into video signals and shows them on the monitor. There are 2 types of virtual chromoendoscopy: optical chromoendoscopy and digital chromoendoscopy. Optical chromoendoscopy technologies have optical lenses, built into the endoscope's light source, which selectively filter white light to give narrow-band light. Digital chromoendoscopy technologies include digital processing of endoscopic images, which are produced in real-time by a video processor. Both methods can be switched on directly from an endoscope and are intended to allow high-contrast imaging of the mucosal surface without the need for dyes and additional equipment. ## Narrow Band Imaging Narrow Band Imaging (NBI; Olympus) is a feature of recent Olympus 200 series video endoscopy systems. The company states that NBI should only be used in models with high-definition or high-resolution imaging. NBI is produced by the light source and displayed through the video processor and monitor. Optical filters are used on white light, resulting in narrow-band light, which consists of 2 wavelengths: 415 nm blue light and 540 nm green light. Narrow-band light is absorbed by vessels but reflected by mucosa, which increases the contrast between the vessels and the surrounding mucosa compared with using standard white light. The endoscopist can turn the NBI filter on or off as needed, to switch between standard white light and narrow-band imaging. ## Flexible spectral imaging colour enhancement Flexible spectral imaging colour enhancement (FICE; manufactured by FujiFilm and distributed by Aquilant Endoscopy) is a software-based feature of Fuji endoscopy systems. Standard white light is directed at the tissue and the reflected light is captured and processed. Software turns conventional images into reconstructed spectral images by limiting the wavelengths of the light; the images are then shown in real-time. The image can be viewed in 10 different colour combinations. The pre-set wavelength patterns can also be changed manually. The endoscopist can move between the conventional image and the FICE image using a switch on the endoscope. ## i‑scan i‑scan (Pentax Medical) is a software-based image enhancement technology for use with Pentax endoscopy systems. Images from standard white light endoscopy can be processed using 3 algorithms: surface enhancement, which improves the contrast between light and dark regions contrast enhancement, which adds blue colour to relatively dark areas to show mucosal surface detail tone enhancement, which changes the colour contrast to improve visibility of mucosal structure and blood vessels. The 3 algorithms are used in different combinations to give 3 modes for detecting, characterising and demarcating lesions. The endoscopist can move between the conventional image and the different i‑scan image modes by pushing a button on the endoscope. # The comparator ## Histopathology The comparator for this assessment is histopathology. It is assumed that in current practice all detected polyps are removed and sent to the laboratory for histopathology assessment. Polyps are examined to determine whether they are adenomatous, and therefore at high risk of cancer, or hyperplastic, and so at low risk.# Evidence The diagnostics advisory committee considered evidence on virtual chromoendoscopy for real-time assessment of colorectal polyps during colonoscopy from several sources. Full details of all the evidence are in the committee papers. # Clinical effectiveness In total, 30 studies were included in the systematic review. There were 24 studies on Narrow Band Imaging (NBI), 3 studies on flexible spectral imaging colour enhancement (FICE) and 5 studies on i‑scan. Two studies included more than 1 technology (1 study on NBI and FICE; and 1 study on NBI and i‑scan). Fourteen studies were done in the US, 11 in Europe (of which, 4 were in the UK), 4 in Asia and 1 in Australia. Most of the studies were carried out in specialist centres. The QUADAS assessment found that all studies were at low risk of bias. None of the included studies reported on health-related quality of life, mortality, incidence of colorectal cancer, or number of outpatient appointments. ## Virtual chromoendoscopy using Narrow Band Imaging Twenty-four studies reported on the use of NBI. Most were done in a single centre and the results might not be generalisable to other centres. The endoscopists' levels of experience of using NBI varied: all endoscopists were experienced in 8 studies, some had experience in 4 studies, none had experience in 4 studies, and the experience levels were unclear for 8 studies. Seventeen studies reported on the sensitivity of NBI and 16 studies reported on the specificity of NBI for characterisations of polyps made with any level of confidence. The sensitivity ranged from 0.55 to 0.97 and the specificity ranged from 0.62 to 0.95. Bivariate meta-analysis of the 16 studies reporting on both sensitivity and specificity produced summary values of 0.88 (95% confidence interval 0.83 to 0.92) for sensitivity and 0.81 (95% CI 0.75 to 0.85) for specificity. The sensitivity and specificity of NBI was higher for polyps diagnosed with high confidence, compared with those diagnosed with any level of confidence (that is, those assessed with low and high confidence). Eleven studies reported on the sensitivity and specificity of NBI for assessing polyps that were characterised with high confidence. Bivariate meta-analysis produced summary values of 0.91 (95% CI 0.85 to 0.95) for sensitivity and 0.82 (95% CI 0.76 to 0.87) for specificity. A post-hoc bivariate meta-analysis was run for high-confidence characterisations, which only included studies with endoscopists who were experienced in using NBI (4 studies). The analysis produced summary values of 0.92 (95% CI 0.89 to 0.94) for sensitivity and 0.82 (95% CI 0.72 to 0.89) for specificity. Compared with the analysis for endoscopists with different levels of experience, the point estimate for sensitivity increased slightly from 0.91 to 0.92 and the specificity did not change. The confidence interval for sensitivity narrowed for experienced endoscopists compared with that for endoscopists with a variety of experience. The confidence interval for specificity for experienced endoscopists widened (0.72 to 0.89) compared with endoscopists with different levels of experience (0.76 to 0.87). Sixteen studies reported on the negative predictive value of NBI for characterising diminutive polyps in the whole colon, made with any level of confidence. The negative predictive value ranged from 43% to 96%. The lower bound of the 95% confidence interval fell below 90% in all studies, apart from Patel et al. (2016). Thirteen studies reported on the negative predictive value for high-confidence characterisations of polyps in the whole colon. The negative predictive value was higher for characterisations made with high confidence compared with those made with all levels of confidence. The range was 48% to 98%. When reported, the lower bound of the 95% confidence interval fell below 90% in all but 2 studies. One study looked at the difference between the negative predictive value of characterisations done by specialists in colonoscopy and general endoscopists. The study found that specialists achieved a higher negative predictive value (90.9%; CI 70.8 to 98.9) than generalists (71.4%; 95% CI 47.8 to 88.8). However, the difference was not statistically significant. Four studies reported on the sensitivity and specificity of NBI for assessing polyps in the rectosigmoid colon with high confidence and 3 studies reported data for assessing polyps in the rectosigmoid colon with any level of confidence. Bivariate meta-analysis for characterisations made with any level of confidence produced summary values of 0.85 (95% CI 0.75 to 0.91) for sensitivity and 0.87 (95% CI 0.74 to 0.94) for specificity. For characterisations made with high confidence, summary values were 0.87 (95% CI 0.80 to 0.92) for sensitivity and 0.95 (95% CI 0.87 to 0.98) for specificity. A post-hoc bivariate meta-analysis was run for the 2 studies that included endoscopists who were experienced in using NBI. For high-confidence characterisations, it produced summary values of 0.90 (95% CI 0.71 to 0.97) for sensitivity and 0.98 (95% CI 0.91 to 1.00) for specificity. When compared with the bivariate analysis for endoscopists with different levels of experience, the point estimate for sensitivity increased from 0.87 to 0.90 and the point estimate for specificity increased from 0.95 to 0.98. The confidence interval for sensitivity widened for experienced endoscopists (0.71 to 0.97) compared with that for endoscopists with different levels of experience (0.80 to 0.92). The confidence interval for specificity narrowed slightly for experienced endoscopists (0.91 to 1.00) compared with that for endoscopists with different levels of experience (0.87 to 0.98). Thirteen studies reported on the agreement between surveillance intervals set when using NBI compared with those set by histopathology; agreement ranged from 84% to 99%. ## Virtual chromoendoscopy using flexible spectral imaging colour enhancement Three studies reported on the use of FICE. All studies were carried out in single centres and none reported on high-confidence characterisations of diminutive polyps or on a specific part of the colon. One study reported that the endoscopists did not have any experience of using FICE. In the remaining 2 studies, it was unclear whether the endoscopists had any experience. All 3 studies reported the sensitivity and specificity of FICE for characterising polyps in any part of the colon. The sensitivity ranged from 0.74 to 0.88 and the specificity ranged from 0.82 to 0.88. Bivariate meta-analysis using all 3 studies produced summary values of 0.81 (95% CI 0.73 to 0.88) for sensitivity and 0.85 (95% CI 0.79 to 0.90) for specificity. The negative predictive values ranged from 70% to 84%. ## Virtual chromoendoscopy using i‑scan Five studies reported on the use of i‑scan. Most of the studies were done in a specialist endoscopy centre by 1 endoscopist. So, it is unclear how generalisable the results are to different settings. Three studies reported that the endoscopists had experience of using i‑scan. The remaining 2 studies did not report on level of experience. Two studies reported on high-confidence characterisations of polyps in the whole colon. Bivariate meta-analysis produced summary values of 0.96 (95% CI 0.92 to 0.98) for sensitivity and 0.91 (95% CI 0.84 to 0.95) for specificity. Two studies reported that the negative predictive value of i‑scan for detecting colorectal polyps in the whole colon was above 90%. But, the lower bound of the confidence interval for both studies was below 90%. Two studies reported that the negative predictive value of i‑scan for detecting colorectal polyps in the distal or rectosigmoid colon was above 90%. But, the lower bounds of the confidence interval were below 90%. # Cost effectiveness ## Review of economic evidence Two studies were found that reported full economic evaluations comparing virtual chromoendoscopy with histopathology. Hassan et al. (2010) found no difference in life expectancy between the 2 strategies and therefore could not calculate a cost per life year gained. Kessler et al. (2011) found that the cost per life year gained for sending all polyps detected during colonoscopy for histological analysis, compared with a resect and discard strategy using virtual chromoendoscopy, was US $377,460. It is unclear how generalisable the results are to the NHS, because non-UK resource costs were used and health outcomes were not valued in quality-adjusted life years (QALYs). ## Modelling approach The external assessment group (EAG) developed a de novo economic model to assess the cost effectiveness of virtual chromoendoscopy (NBI, FICE and i‑scan) compared with histopathology for assessing colorectal polyps. The model took the perspective of the NHS and personal social services and all costs and QALYs were discounted at a rate of 3.5% per year. The model consisted of 2 parts. The first part was a decision tree that estimated the short-term costs and outcomes of the first colonoscopy. In this model, polyps are assessed and a surveillance interval is assigned. The second part was an existing model used to estimate the long-term costs and QALYs for each surveillance classification, including incorrect surveillance classifications. The second model was a state transition model developed by the School of Health and Related Research (ScHARR), at the University of Sheffield, for the NHS bowel cancer screening programme. The model was chosen because it is a long-standing model that has been validated and was used to inform the introduction of the screening programme. The model was run independently and the cost and QALY estimates were entered as parameters at the end points of the decision tree model. The decision tree compared the virtual chromoendoscopy strategies with a histopathology strategy. It had 4 main arms, 1 for each test that was assessed: NBI, FICE, i‑scan and standard endoscopy with histopathology. The comparator arm of the decision tree assumed that all polyps are resected and sent to histopathology and everyone is given the correct surveillance interval. Firstly, the cohort was divided into 4 risk categories based on the number of adenomas that they have: no adenomas low risk (1 to 2 adenomas) intermediate risk (3 to 4 adenomas) high risk (5 or more adenomas). The model then calculated the proportion of patients in each category expected to have a correct surveillance interval assigned and the proportions expected to have an incorrect surveillance interval assigned. With a virtual chromoendoscopy strategy, the following errors could lead to an incorrect surveillance interval (too long or too short) being assigned in the model: -r more hyperplastic polyps might be misclassified as an adenoma and so be unnecessarily resected -r more adenomas might be misclassified as a hyperplastic polyp and left in place. The ScHARR bowel cancer screening (SBCS) model was designed to assess the cost effectiveness of different screening strategies for colorectal cancer for a lifetime time horizon. The model simulated the progression of colorectal cancer in people who are eligible for the bowel cancer screening programme in England. The population in the base-case analysis was people taking part in the bowel cancer screening programme who had been referred for colonoscopy. Patients were included if they had at least 1 diminutive polyp (5 mm or less), and were excluded if they had 1 or more non-diminutive polyps (more than 5 mm). In addition, scenario analyses looked at: people offered colonoscopy as surveillance because they previously had adenomas removed and people referred to colonoscopy by a GP because of symptoms of colorectal cancer. Two different diagnostic strategies were explored in the economic analyses, the virtual chromoendoscopy strategy (used in the base case) and the DISCARD strategy (Detect, InSpect, ChAracterise, Resect, and Discard; used in some scenario analyses). The criteria common to both strategies were that diminutive polyps: in the whole colon are optically characterised using virtual chromoendoscopy diagnosed with high confidence as adenomas are resected and discarded diagnosed with low confidence are resected and sent to histopathology. The characteristic unique to the virtual chromoendoscopy strategy was that diminutive polyps, in the whole of the colon, diagnosed with high confidence as hyperplastic are left in place. The characteristics unique to the DISCARD strategy were that diminutive polyps: in the proximal colon, characterised with high confidence as hyperplastic, are resected and discarded. in the rectosigmoid colon, diagnosed with high confidence as hyperplastic, are left in place. The model inputs were taken from various sources, including routine sources of cost data, published literature, and the clinical-effectiveness review and meta-analyses. The prevalence of adenomas was estimated for 3 populations: the screening population (base case), the surveillance population (scenario analysis) and the symptomatic population (scenario analysis). For the base-case analysis on the screening population, the prevalence of adenomas was taken from a published study by Raju et al. (2013) that retrospectively analysed data from a US colon cancer screening programme. The distributions of adenomas and the data sources for each population are reported in table 1. Risk category Screening population (Raju et al. 2013) Surveillance population (Martinez et al. 2009) Symptomatic population (McDonald et al. 2013) No adenoma Low risk Intermediate risk High risk Data on diagnostic accuracy were taken from the clinical-effectiveness review and meta-analysis for NBI, FICE and i‑scan, as shown in table 2. Data were used for polyps in the whole colon that were characterised with high confidence in the base-case analysis for NBI and i‑scan. Data were used for polyps in the whole colon that were characterised with any level of confidence in the base-case analysis for FICE. It was assumed that the proportion of low-confidence characterisations was the same for all 3 technologies, and was calculated using data from 12 NBI studies, because data were not available for FICE and i‑scan. The comparator, histopathology, was assumed to be 100% accurate. Parameter Value Lower 95% CI Upper 95% CI Source NBI sensitivity Meta-analysis NBI specificity Meta-analysis FICE sensitivity Meta-analysis FICE specificity Meta-analysis i‑scan sensitivity Meta-analysis i‑scan specificity Meta-analysis Proportion of polyp characterisations made with low confidence EAG literature review (the average value from 12 NBI studies that were included in the literature review; data were not available on the proportion of polyp characterisations made with low confidence for FICE and i scan) Abbreviations: CI, confidence interval; EAG, external assessment group; FICE, flexible spectral imaging colour enhancement; NBI, Narrow Band Imaging. The probabilities of adverse events occurring during colonoscopy were assumed to be 0.003 for hospitalisation for bleeding with polypectomy, 0.003 for perforation with polypectomy, and 0.052 for death of patients with perforation during polypectomy. These values were taken from published values used in the SBCS model. For the base-case analysis, the costs of colonoscopy, polypectomy, adverse events and histopathology were taken from the NHS reference costs for 2014/15 (see table 3). Training costs were assumed to be £14.72 per patient, based on the assumption that endoscopists complete 150 endoscopies per year and that training costs are equivalent to 2 days of pay (£1,104) per year. Parameter Value Lower 95% confidence interval Upper 95% confidence interval Cost of colonoscopy without polypectomy Cost of colonoscopy with polypectomy Cost of treating bowel perforation (major surgery) Cost of admission for bleeding (overnight stay on medical ward) Pathology cost per polyp examination The cost of upgrading equipment was not included in the model. It was assumed that most hospitals already had equipment with virtual-chromoendoscopy-enabled technology in place, and hospitals that do not have this equipment will get it in the future as part of standard procurement. Therefore, the base-case analysis assumes that the cost of maintaining and purchasing equipment is included in the Healthcare Resource Group (HRG) cost of colonoscopy. Health-related quality of life was calculated in the SBCS model. The base-case analysis used utility values taken from a study by Ara and Brazier (2011). The model assumes a utility of 0.697 for people with cancer and a utility of 0.798 for people without cancer. A scenario analysis was done using utility values from a study identified by the EAG through a targeted search (Farkkila et al. 2013). For the scenario analysis, it was assumed that the utility for people with cancer was 0.761 and for people without cancer was 0.798. No disutility values for adverse events during polypectomy, such as bowel perforation and bleeding, were found. Therefore, the values were taken from studies that reported on similar events. A QALY loss of 0.006 was taken from Dorian et al. (2014) for the disutility of a major gastrointestinal bleed and a QALY loss of 0.010 was taken from Ara and Brazier (2011) for the disutility of bowel perforation. The costs and QALYs for the end points of the decision tree were calculated by running the SBCS model with a cohort of patients aged 65. The following changes were made to the SBCS model for this assessment: Colonoscopy and adverse-event costs were updated to 2014/15 costs. The screening costs were updated. Adenoma recurrence rates were adjusted to model people with higher-disease risk and people with adenomas left in the body. ## Base-case results The following assumptions were applied in the base-case analysis: The long-term cost and QALY outcomes were estimated using the SBCS model, which assumed that standard colonoscopy with histopathology assessment of all polyps was used for follow‑up surveillance. Therefore, diagnostic accuracy data and training costs associated with virtual chromoendoscopy were not included in the long-term results. Studies did not report on the relationship between diagnostic accuracy and assigning people to the correct surveillance intervals, therefore the following was assumed: diagnostic accuracy data were applied to individual polyps the adenoma-to-hyperplastic-polyp ratio was assumed to be the same for each risk category. Only diminutive polyps were assessed, people with polyps larger than 5 mm were not included in the model. The proportion of polyps assessed with low confidence (21%) was assumed to be the same for NBI, FICE and i‑scan. The disutility for bleeding was assumed to be similar to a major gastrointestinal bleed. The disutility for perforation was assumed to be the same as for a stomach ulcer, abdominal hernia or rupture. The results of the base-case analysis can be seen in table 4a and table 4b. Pairwise analyses compared each of the 3 technologies in turn (NBI, FICE and i‑scan) with histopathology. Results showed that NBI and i‑scan dominated histopathology, that is, they were cheaper and more effective than histopathology. FICE was cost saving and less effective than histopathology, with an incremental cost-effectiveness ratio (ICER) of £671,383 saved per QALY lost. The differences in incremental QALYs ranged from −0.0001 when FICE was compared with histopathology to 0.0007 when i‑scan was compared with histopathology. The differences in costs ranged from −£87.70 when FICE was compared with histopathology to −£73.10 when NBI was compared with histopathology. The lifetime risk of colorectal cancer according to the method of assessing polyps, calculated from the model, was: % for histopathology % for NBI % for FICE % for i‑scan. The fully incremental analyses show that histopathology was dominated by NBI and i‑scan; and NBI was dominated by i‑scan. When i‑scan was compared with FICE it had an ICER of £10,466 per QALY gained. Assessment Costs Inc Costs QALYs Inc QALY ICER (£ per QALY) Histopathology Dominated FICE i‑scan NBI Dominated Assessment Costs Inc Costs QALYs Inc QALY ICER (£ per QALY) Histopathology NBI Dominates Histopathology FICE £671,383 (incremental cost saving per QALY lost) Histopathology i‑scan Dominates Abbreviations: FICE, flexible spectral imaging colour enhancement; ICER, incremental cost-effectiveness ratio; Inc, incremental; NBI, Narrow Band Imaging; QALY, quality-adjusted life year. The EAG did 12 scenario analyses, and a further 2 scenario analyses were done as an addendum to the assessment report. Fewer scenario analyses were done for FICE, because data were unavailable. Results of the scenario analyses show that NBI and i‑scan were dominant in all scenario analyses when compared with histopathology. When FICE was compared with histopathology, it was cost effective in all scenario analyses. FICE was cheaper and more effective than histopathology and therefore was dominant when: the risk-category distributions for the cohort were changed to reflect a population that was having surveillance colonoscopy the risk-category distributions for the cohort were changed to reflect a cohort with symptoms and the discard strategy was applied and diagnostic accuracy data were used for all levels of confidence for characterisations in the whole colon. When alternative utility values were used from Farkkila et al. (2013), FICE was cheaper and slightly less effective compared with histopathology and had an ICER of £1,273,941 saved per QALY lost. When diagnostic accuracy data were used from studies that reported data for endoscopists experienced in using NBI for the whole colon and the rectosigmoid colon, the results were similar to the base-case analyses for virtual chromoendoscopy and NBI dominated histopathology. The effect of using virtual chromoendoscopy (NBI) for surveillance was explored and found to be small; it was estimated to increase cost savings by £20 and increase QALYs gained by 0.0003. The EAG produced an addendum with 2 scenario analyses on adverse events. The first analysis varied the rate of perforation during colonoscopy using ratios from the data in Rutter et al. (2014), and found that cost savings for all 3 technologies decreased slightly in relative and absolute terms, and the QALYs decreased slightly in absolute terms, whereas the relative change was large (see table 5). NBI and i‑scan still dominated histopathology and the ICER for FICE increased to £126,229 saved per QALY lost. The second analysis included the risk of an adverse event happening during all colonoscopies, as well as for colonoscopies with polypectomy. This analysis also used data from Rutter et al. and found that cost savings for all 3 technologies decreased slightly in relative and absolute terms, and the QALYs decreased slightly in absolute terms, whereas the relative change was large (see table 6). NBI and i‑scan still dominated histopathology and the ICER for FICE increased to £342,438 saved per QALY lost. Assessment comparison Base‑case inc cost Revised inc cost Relative change in cost compared with base case Base-case inc QALYs Revised inc QALYs Relative change in QALYs compared with base case Histopathology versus NBI Histopathology versus FICE Histopathology versus i‑scan Abbreviations: FICE, flexible spectral imaging colour enhancement; Inc, incremental; NBI, Narrow Band Imaging; QALY, quality-adjusted life year. Assessment comparison Base‑case inc cost Revised inc cost Relative change in cost compared with base case Base-case inc QALYs Revised inc QALYs Relative change in QALYs compared with base case Histopathology versus NBI Histopathology versus FICE Histopathology versus i‑scan Abbreviations: FICE, flexible spectral imaging colour enhancement; inc, incremental; NBI, narrow band imaging; QALY, quality-adjusted life year. The one-way deterministic sensitivity analyses found that the parameters with the most influence on the cost effectiveness of the tests were pathology cost, the probability of perforation with polypectomy, and the proportion of patients who die from perforation. All one-way sensitivity analyses showed that NBI, FICE and i‑scan were cost effective compared with histopathology at a maximum acceptable ICER of £30,000 per QALY gained. The EAG did a probabilistic sensitivity analysis by varying the base-case inputs for the decision tree. The analysis was done by running the model 5,000 times. Each time it was run, the inputs were varied according to the distribution of the input. The probabilistic sensitivity analysis found that i‑scan was more likely to be cost effective than NBI and FICE. At a maximum acceptable ICER of £20,000 per QALY gained, i‑scan was cost effective in 85.2% of the analyses, and at a maximum acceptable ICER of £30,000 per QALY gained i‑scan was cost effective in 99.5% of the analyses.# Committee discussion The committee considered the potential benefits of using virtual chromoendoscopy technologies for real-time assessment of diminutive polyps during colonoscopy. The committee heard from a clinical expert that the purpose of colonoscopy with polypectomy is to protect against developing colorectal cancer. The committee also heard that if virtual chromoendoscopy was used to characterise diminutive polyps (5 mm or less), fewer hyperplastic polyps would be resected which may reduce adverse events and costs for histopathology. The committee noted that a large proportion of people assessed in the bowel cancer screening programme only have diminutive polyps, and that an analysis of the data from the bowel cancer screening programme has shown that only 0.19% of diminutive polyps were cancerous. The committee concluded that the risk of colorectal cancer in people who only have diminutive polyps is low. # Clinical effectiveness The committee considered the generalisability of the evidence base to clinical practice in the NHS. The committee noted that most of the endoscopies in the studies included in the assessment were done by experienced endoscopists in single academic centres, most of which were outside of the UK. The committee also noted that the UK‑based DISCARD 2 study was excluded from the assessment because only 22% of the participating centres had high-definition equipment. The committee heard from clinical experts that DISCARD 2 was a multicentre community-based study, with 28 endoscopists, which compared Narrow Band Imaging (NBI) with histopathology and was considered to reflect clinical practice in the NHS. The results of this study showed that the sensitivity of NBI for real-time assessment of diminutive polyps was lower than the accuracy estimated in this assessment (0.76 compared with 0.87 to 0.92). The committee concluded that the diagnostic accuracy of virtual chromoendoscopy technologies reported in this assessment reflect the accuracy that could be achieved by endoscopists with experience of using virtual chromoendoscopy and who work in specialist or academic settings. The committee concluded further that diagnostic accuracy results probably do not reflect the accuracy that would be achieved by endoscopists with limited experience of virtual chromoendoscopy and who work in community-based settings. The committee considered the differences between the 3 virtual chromoendoscopy technologies (NBI, flexible spectral imaging colour enhancement and i‑scan). The committee heard from clinical experts that FICE and i‑scan work differently to NBI; they are software-based image enhancement technologies, whereas NBI uses optical filters on white light, resulting in narrow-band light which enhances the contrast between the vessels and the surrounding mucosa. The committee also heard that the type of technology in place in centres is likely to vary, and equipment is replaced every 5 to 8 years. The committee then considered the different levels of evidence available for NBI, FICE and i‑scan. It noted that most studies were on NBI and very few studies were on FICE and i‑scan. It also noted that most of the studies on i‑scan were done in academic centres, by 1 endoscopist experienced in using virtual chromoendoscopy, and this resulted in higher accuracy results for i‑scan compared with NBI. It noted also that none of the studies on FICE limited the accuracy data to high-confidence characterisations of polyps, and this resulted in lower accuracy results for FICE compared with NBI. The committee concluded that, without direct comparative data, it is unclear whether one virtual chromoendoscopy technology is superior to others. It concluded further that NBI, FICE and i‑scan will probably perform similarly in clinical practice, because the diagnostic accuracy achieved is likely to depend on the experience level of the endoscopist and the level of confidence in the polyp characterisation more than on the virtual chromoendoscopy technology used. The committee considered the diagnostic accuracy of virtual chromoendoscopy technologies for real-time assessment of diminutive polyps. The committee noted that the American Society for Gastrointestinal Endoscopy has developed criteria on diagnostic accuracy that endoscopic technologies must meet before being considered appropriate for use in US clinical practice (the Preservation and incorporation of valuable endoscopic innovations criteria). The PIVI criteria on real-time assessment of diminutive colorectal polyps guides decisions on resecting and discarding polyps without histopathologic assessment. These criteria are: technologies should have an agreement of 90% or more with the surveillance intervals set by histopathology the negative predictive value of the technology for assessing adenomatous polyp histology should be 90% or more.The committee heard from clinical experts that the PIVI criteria, which are used in US clinical practice, were widely accepted in the UK gastrointestinal community. The committee concluded that the diagnostic accuracy of NBI, FICE and i‑scan were likely to meet the PIVI criteria if used by endoscopists with experience of virtual chromoendoscopy technologies. The committee discussed the accuracy of the comparator test, histopathology. The committee heard from clinical experts that histopathology is considered to be the gold standard in current practice, but it is actually an imperfect reference standard for diagnosing polyps. The committee also heard from clinical experts that currently about 8% to 10% of diminutive polyps do not have histopathology assessment because they are lost or destroyed before they reach the histopathologist and they are therefore assumed to be adenomatous. It heard further that polyp characterisation using histopathology assessment is 90% to 95% correct. The committee concluded that given the limitations of histopathological assessment of polyps, the diagnostic accuracy of the virtual chromoendoscopy technologies is likely to be more accurate than data from the studies suggests. The committee discussed the consequences of misdiagnosing diminutive polyps using virtual chromoendoscopy. The committee noted that if virtual chromoendoscopy is used for real-time assessment of polyps, 3% to 6% of the surveillance intervals are likely to be incorrectly assigned. The committee heard from clinical experts that if virtual chromoendoscopy is used, over-surveillance would be slightly more common than under-surveillance. The committee noted that the effect on clinical outcomes from incorrectly leaving diminutive adenomatous polyps in place and incorrectly assigning a surveillance interval that is too long is uncertain. The committee heard from the external assessment group (EAG), however, that the lifetime risk of colorectal cancer calculated from the model was similar for the 3 virtual chromoendoscopy technologies and histopathology (3.025% for histopathology, 3.020% for NBI, 3.045% for FICE and 3.021% for i‑scan; see section 4.44). It concluded that although there was some uncertainty over how the diagnostic accuracy data would translate into clinical outcomes, it was aware that an end-to-end study on clinical outcomes would need to be done on a large cohort over a long period of time and so may not be feasible. # Cost effectiveness The committee discussed the uncertainties around using the School of Health and Related Research's (ScHARR) bowel cancer screening (SBCS) model for the assessment. The committee was aware that ScHARR ran the SBCS model on behalf of the EAG, and therefore the EAG was unable to internally validate the model results. However, it noted that the model had previously been validated for use to inform the NHS bowel cancer screening programme strategy, and that the costs in the model had been updated to reflect current costs. The committee heard from the EAG that there were structural uncertainties in the model, for example, the accuracy of virtual chromoendoscopy was not used for ongoing surveillance. However, the committee noted that it would not have been possible for the EAG to build a de novo model because of the level of resource needed to develop such a complex model. The committee therefore concluded that although there was some uncertainty about the SBCS model's results, it was considered to be the most appropriate model for the assessment. The committee considered the cost of histopathology assessment of polyps used in the model. It heard from the EAG that in the base-case analysis, the cost of histopathology per polyp was based on the NHS reference cost for direct access pathology for 2014/15, which lists the cost of histopathology and histology as £28.82 (DAPS02). The committee noted that this reference cost is likely to include requests from community services, such as GPs, for histopathology and that there is no stratification by sample type (for example, type of specimen or tissue preparation), which may affect the cost. The committee noted further that the true cost of histopathology assessment of colorectal polyps was probably more than £50 per polyp. The committee concluded that the cost of histopathology was likely to be underestimated in the model, and so the cost savings for virtual chromoendoscopy technologies were likely to be greater than the model suggested. The committee discussed the proportion of hospitals that already have high-definition enabled virtual chromoendoscopy equipment in place. The committee heard from the EAG that the economic model assumed that the cost of upgrading colonoscopy equipment would be included in the NHS reference costs for colonoscopy (see table 3). The committee heard from clinical experts that most endoscopes were replaced every 5 to 8 years and the video system is likely to be replaced every 10 years because repairs after this period are often not supported. The committee heard further that most centres will have at least 1 virtual-chromoendoscopy-enabled machine. The committee concluded that the assumption made in the economic model was reasonable. The committee discussed the assumption used in the model that histopathology is 100% accurate when assigning surveillance intervals. It heard from clinical experts that although histopathology is considered to be the gold standard, the diagnostic accuracy is likely to be below 100% (see section 5.5). The committee concluded that the clinical effectiveness of histopathology was likely to have been overestimated in the model, and therefore the difference in clinical effectiveness between histopathology and the virtual chromoendoscopy technologies was likely to be smaller than the results suggested. The committee considered the implications for histopathology laboratories of adopting virtual chromoendoscopy for real-time assessment of colorectal polyps. The committee heard from clinical experts that histopathology laboratories are under considerable strain because of high workloads, and that diminutive colorectal polyp assessment is an important cause of this overload. The committee discussed whether using virtual chromoendoscopy for real-time assessment of diminutive polyps rather than sending all of these to histopathology could reduce this workload and result in cost savings or free histopathologists for other priorities. The committee noted that the endoscopist's level of experience would affect how many diminutive polyps are assessed with high confidence, and therefore how many polyps are sent to histopathology. For example, risk-averse practice (in which polyps that are likely to be hyperplastic are removed and sent to histopathology) is probably more common in endoscopists with less experience. Therefore, cost savings through avoiding histopathology assessment may not be as large in this group compared with experienced endoscopists, who are likely to assess more polyps with high confidence and send fewer to histopathology. The committee concluded that virtual chromoendoscopy used by experienced endoscopists could reduce the number of diminutive polyps sent to histopathology laboratories, therefore freeing histopathology resources. The committee discussed the results of the cost-effectiveness analysis and noted that in the base case, the NBI and i‑scan dominated histopathology, that is, they were cheaper and more clinically effective than histopathology. The committee also noted that in the base case, FICE could be considered cost effective with an incremental cost-effectiveness ratio (ICER) of £671,000 saved per quality-adjusted life year (QALY) lost (see section 4.42). However, the committee noted that the base-case analysis only included adverse events for colonoscopy with polypectomy. The committee heard from a clinical expert that there is also a risk of adverse events from a colonoscopy even without a polypectomy. It heard from the EAG that an analysis was done which included the risks of adverse events from all colonoscopies as well as for colonoscopy with polypectomy (see section 4.51). The committee noted that in this analysis, NBI and i‑scan still dominated histopathology and the ICER for FICE decreased to £342,000 saved per QALY lost. The committee concluded that the most plausible results came from the scenario analysis that included a risk for adverse events for colonoscopy without polypectomy. The committee further concluded that NBI, FICE and i‑scan could be cost-effective options for assessing diminutive polyps. The committee discussed the robustness of the results of the economic model. It noted that results of the sensitivity and scenario analyses showed that NBI and i‑scan were dominant compared with histopathology in all scenario analyses. It noted further that FICE dominated histopathology in some analyses and was considered cost effective in other analyses, with ICERs ranging from £126,000 to £1,270,000 saved per QALY lost. The committee considered that although there were limitations and uncertainties in the economic assessment (see section 5.7), the sensitivity analyses showed that the results were robust to changes. The committee concluded that the results of the economic model could be considered to be fairly robust. The committee considered all its discussions on virtual chromoendoscopy, and noted its conclusions that: -ptical diagnosis using virtual chromoendoscopy technologies was likely to meet the PIVI criteria if used by endoscopists with experience of virtual chromoendoscopy technologies (see section 5.4) the lifetime risk of colorectal cancer was estimated to be similar when diminutive polyps were assessed and surveillance intervals were set using virtual chromoendoscopy technologies or histopathology (see section 5.6) assessment of diminutive colorectal polyps with virtual chromoendoscopy technologies is cost effective compared with assessment of diminutive colorectal polyps using histopathology (see sections 5.12 and 5.13) the virtual chromoendoscopy technologies are cost saving when they are used to implement a management strategy which reduces the number of diminutive polyps sent for histopathological analysis (see section 5.11).The committee therefore concluded that virtual chromoendoscopy using NBI, FICE or i‑scan to assess diminutive polyps during colonoscopy, instead of sending polyps to histopathology, could be considered clinically effective and cost effective if done by a specialist group, that is, endoscopists with expertise in optical diagnosis using virtual chromoendoscopy technologies. # Other considerations The committee considered whether using virtual chromoendoscopy for real-time assessment of diminutive polyps and using a discard strategy was acceptable to people. The committee heard from a clinical expert that there were no UK‑based studies that looked at patient acceptability, but 2 studies from the US and 1 study from Australia with data on patient acceptability were available. In the US study, many patients stated that they would pay $150 from their own pocket to have polyps removed and assessed by histopathology, instead of using real-time assessment of polyps with a discard strategy (Vu et al. 2015). The committee concluded that further research on patient acceptability of virtual chromoendoscopy for real-time assessment of diminutive polyps and use of a discard strategy would be valuable. The committee considered the effect of training for endoscopists on the diagnostic accuracy of NBI, FICE and i‑scan. The committee heard from clinical experts that the DISCARD 2 study had implemented a programme consisting of a 1‑hour training session using PowerPoint images followed by a test. The committee noted that the results of the study suggested that training and monitoring for endoscopists needed to be more rigorous to maintain high levels of diagnostic accuracy for virtual chromoendoscopy technologies. The committee heard that the manufacturers of the technologies offer 2 forms of training for endoscopists, both developed with experts: peer-to-peer training at centres of excellence; and online training for self-study. The committee also heard that general experience in diagnosing polyps and familiarity with polyp classification systems, combined with acting on feedback from peers, were important factors in improving the skill levels of endoscopists. It concluded that the most effective forms of training should be determined, and that this could be done through collaboration between manufacturers of virtual chromoendoscopy technologies and professional organisations. The committee discussed the need for quality assurance measures to be in place before virtual chromoendoscopy for assessment of polyps during colonoscopy can be used in clinical practice. It heard from clinical experts that the skills of endoscopists who do colonoscopies are known to vary. The committee heard further that quality assurance measures, such as accreditation and monitoring of practice, were needed to ensure that virtual chromoendoscopy for making optical diagnoses is only used by endoscopists who can meet the PIVI criteria, and to maintain high levels of diagnostic accuracy over time. The committee also noted that there was currently no accreditation or monitoring system in place for virtual chromoendoscopy and heard that any accreditation and monitoring scheme would need to be rolled out to both clinicians and nurse-endoscopists. The committee concluded that a national accreditation scheme for using virtual chromoendoscopy to make optical diagnoses should be developed. It concluded further that when virtual chromoendoscopy technologies are used, intermediate measures should be monitored for quality assurance and to give endoscopists ongoing feedback.# Recommendations for further research Audit is recommended to monitor whether endoscopists using virtual chromoendoscopy (Narrow Band Imaging , flexible spectral imaging colour enhancement and i‑scan) are correctly assessing polyps as adenomatous and hyperplastic during colonoscopy. Measures may include: the diagnostic accuracy of polyp characterisation achieved and agreement with the surveillance interval for colonoscopy set by histopathology. Further research is recommended on patient acceptability of using virtual chromoendoscopy for real-time assessment of diminutive polyps compared with assessment using histopathology. Data collection and analysis are recommended to monitor the effect on endoscopy and histopathology services of using virtual chromoendoscopy instead of histopathology to assess diminutive polyps. Measures may include: the length of time to do colonoscopies the number of polyps sent for histopathology analysis cost savings or workload reductions associated with reductions in histopathology.	{'Recommendation': 'Virtual chromoendoscopy using NBI, FICE or i‑scan is recommended to assess polyps of 5\xa0mm or less during colonoscopy, instead of histopathology, to determine whether they are adenomatous or hyperplastic, only if:\n\nhigh-definition enabled virtual chromoendoscopy equipment is used\n\nthe endoscopist has been trained to use virtual chromoendoscopy, and accredited to use the technique under a national accreditation scheme\n\nthe endoscopy service includes systems to audit endoscopists and provide ongoing feedback on their performance (see section\xa06.1) and\n\nthe assessment is made with high confidence.', 'Clinical need and practice': '# The problem addressed\n\nColorectal polyps are small growths on the inner lining of the colon. Polyps are not usually cancerous; most are hyperplastic polyps with a low risk of cancer; but some (known as adenomatous polyps) will eventually turn into cancer if left untreated.\n\nDetecting and removing adenomas during colonoscopy has been shown to decrease the later development of colorectal cancers. However, removal of any polyps by polypectomy may have adverse effects such as bleeding and perforation of the bowel. Also, as imaging technologies improve, more polyps may be found, which may in turn increase the number of polyps removed from a person and affect the workload of gastroenterologists and histopathologists.\n\nIt can take 3\xa0weeks for a person to get the examination results for polyps that were removed during colonoscopy, and they may feel anxious during this waiting period.\n\nVirtual chromoendoscopy technologies (Narrow Band Imaging [NBI], flexible spectral imaging colour enhancement [FICE] and i‑scan), are intended to allow colour-enhanced visualisation of blood vessels and surface pattern compared with conventional colonoscopy, without using dyes.\n\nUsing virtual chromoendoscopy technologies may allow real-time differentiation of adenomas and hyperplastic colorectal polyps during colonoscopy, which could lead to: fewer resections of low‑risk hyperplastic polyps (resulting in a reduction in complications); quicker results and management decisions; and reduced resource use through fewer histopathology examinations.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of virtual chromoendoscopy (NBI, FICE and i‑scan) for assessing diminutive (5\xa0mm or less) colorectal polyps during colonoscopy to determine whether they are adenomatous or hyperplastic.\n\n# The condition\n\n## Colorectal polyps and colorectal cancer\n\nColorectal polyps are common, affecting 15% to 20% of the UK population. Most polyps produce no symptoms, but some larger polyps can cause a small amount of rectal bleeding, diarrhoea, constipation or abdominal pain.\n\nColorectal cancer is one of the most common cancers in the UK and is the second most common cause of cancer death. About 40,000\xa0new cases are registered each year. Colorectal cancer is strongly related to age, with almost three‑quarters of cases occurring in people aged\xa065 or over.\n\n# The diagnostic and care pathways\n\n## Diagnosis\n\nColonoscopy examinations may be done for several clinical reasons, including:\n\nfurther investigation of symptoms suggestive of colorectal cancer\n\nfurther investigation of a positive faecal occult blood test as part of the NHS bowel cancer screening programme or\n\nongoing checks (surveillance) after removal of adenomatous polyps.\n\nThe NICE guideline on suspected cancer recommends that people should be referred for colorectal cancer investigations within 2\xa0weeks if:\n\nthey are aged 40\xa0and over with unexplained weight loss and abdominal pain or\n\nthey are aged 50\xa0and over with unexplained rectal bleeding or\n\nthey are aged 60\xa0and over with iron-deficiency anaemia or changes in their bowel habit or\n\ntests show occult blood in their faeces.\n\nThe guideline also recommends that people should be considered for referral for colorectal cancer investigations if:\n\nthey have a rectal or abdominal mass\n\nthey are aged under\xa050 with rectal bleeding and have any of the following unexplained symptoms or findings:\n\n\n\nabdominal pain\n\nchanges in bowel habit\n\nweight loss or\n\niron deficiency anaemia.\n\n\n\nThe NHS bowel cancer screening programme offers screening every 2\xa0years to men and women aged 60\xa0to\xa074. The screening programme invites eligible adults to have a faecal occult blood test. This involves collecting 3\xa0stool samples and posting them to the laboratory to be checked for the presence of blood, which could be an early sign of colorectal cancer. People with an abnormal faecal occult blood test result are offered a colonoscopy.\n\nThe NICE guideline on colonoscopic surveillance recommends that colonoscopies are offered to people:\n\nwith inflammatory bowel disease whose symptoms started 10\xa0years ago or\n\nwho have had adenomas removed and are at intermediate or high risk of developing colorectal cancer.It also recommends that colonoscopic surveillance is considered for people who have had adenomas removed and are at low risk of developing colorectal cancer. The frequency of surveillance may be every\xa01, 3\xa0or 5\xa0years, depending on the level of risk of developing colorectal cancer.\n\nFor investigating possible colorectal cancer in secondary care, the NICE guideline on colorectal cancer recommends that:\n\npeople without major comorbidity are offered colonoscopy\n\npeople with major comorbidity are offered flexible sigmoidoscopy plus barium enema\n\nCT colonography is considered as an alternative to colonoscopy or flexible sigmoidoscopy plus barium enema, if the local radiology service can show competency in this technique\n\npeople who have had an incomplete colonoscopy are offered repeat colonoscopy, CT\xa0colonography (if the local radiology service can show competency in this technique), or a barium enema.\n\nIf colorectal polyps are found during a colonoscopy they can be removed using cauterisation or a snare (polypectomy). Polyps removed by polypectomy are sent for histopathology to determine whether they are hyperplastic or adenomatous.\n\nIf colorectal cancer is suspected, biopsies are taken and sent to the laboratory to determine whether the sample contains benign or malignant cells. If colorectal cancer is confirmed, the NICE guideline on colorectal cancer recommends further imaging tests, such as CT or MRI, to stage the cancer and determine what treatment is needed.\n\nColonoscopy is usually done as an outpatient procedure with the person having sedation or painkillers. People having colonoscopy may be concerned about the adverse effects of the colonoscopy, such as heavy bleeding or perforation of the bowel. Colonoscopy with polypectomy also has an increased risk of bleeding and perforation compared with colonoscopy without polypectomy. Some people may also have a reaction to the sedative which could result in temporary breathing or heart problems.\n\n## Care\n\nIf colorectal cancer is not diagnosed then surveillance colonoscopy is offered, and the length of time between assessments depends on the risk of cancer. The NICE guideline on colonoscopic surveillance recommends that people with:\n\nor 2\xa0small (less than 10\xa0mm) adenomas are at low risk, and need either no, or 5‑yearly, colonoscopic surveillance until they have 1\xa0negative examination, after which surveillance stops\n\nor 4\xa0small adenomas of less than 10\xa0mm or at least 1\xa0adenoma that is 10\xa0mm or more are at intermediate risk and should be screened 3‑yearly until they have 2\xa0consecutive negative examinations\n\nor more adenomas smaller than 10\xa0mm, or 3\xa0or more adenomas at least one of which is 10\xa0mm or more, are at high risk and should have an extra examination at 12\xa0months before returning to 3‑yearly surveillance.\n\nIf colorectal cancer is diagnosed, it may be treated with surgery, chemotherapy or radiotherapy, or sometimes with biological agents such as cetuximab. Treatment depends on the stage of the cancer and is described in more detail in the NICE guideline on colorectal cancer.', 'The diagnostic tests': "The assessment compared 3\xa0intervention tests with 1\xa0comparator.\n\n# The interventions\n\nA conventional endoscopy system includes an endoscope, a light source, a video processor and a monitor. The light source produces light which is sent to the end of the endoscope. The video processor converts electrical signals into video signals and shows them on the monitor.\n\nThere are 2\xa0types of virtual chromoendoscopy: optical chromoendoscopy and digital chromoendoscopy. Optical chromoendoscopy technologies have optical lenses, built into the endoscope's light source, which selectively filter white light to give narrow-band light. Digital chromoendoscopy technologies include digital processing of endoscopic images, which are produced in real-time by a video processor. Both methods can be switched on directly from an endoscope and are intended to allow high-contrast imaging of the mucosal surface without the need for dyes and additional equipment.\n\n## Narrow Band Imaging\n\nNarrow Band Imaging (NBI; Olympus) is a feature of recent Olympus 200\xa0series video endoscopy systems. The company states that NBI should only be used in models with high-definition or high-resolution imaging. NBI is produced by the light source and displayed through the video processor and monitor. Optical filters are used on white light, resulting in narrow-band light, which consists of 2\xa0wavelengths: 415\xa0nm blue light and 540\xa0nm green light. Narrow-band light is absorbed by vessels but reflected by mucosa, which increases the contrast between the vessels and the surrounding mucosa compared with using standard white light. The endoscopist can turn the NBI filter on or off as needed, to switch between standard white light and narrow-band imaging.\n\n## Flexible spectral imaging colour enhancement\n\nFlexible spectral imaging colour enhancement (FICE; manufactured by FujiFilm and distributed by Aquilant Endoscopy) is a software-based feature of Fuji endoscopy systems. Standard white light is directed at the tissue and the reflected light is captured and processed. Software turns conventional images into reconstructed spectral images by limiting the wavelengths of the light; the images are then shown in real-time. The image can be viewed in 10\xa0different colour combinations. The pre-set wavelength patterns can also be changed manually. The endoscopist can move between the conventional image and the FICE image using a switch on the endoscope.\n\n## i‑scan\n\ni‑scan (Pentax Medical) is a software-based image enhancement technology for use with Pentax endoscopy systems. Images from standard white light endoscopy can be processed using 3\xa0algorithms:\n\nsurface enhancement, which improves the contrast between light and dark regions\n\ncontrast enhancement, which adds blue colour to relatively dark areas to show mucosal surface detail\n\ntone enhancement, which changes the colour contrast to improve visibility of mucosal structure and blood vessels.\n\nThe 3\xa0algorithms are used in different combinations to give 3\xa0modes for detecting, characterising and demarcating lesions. The endoscopist can move between the conventional image and the different i‑scan image modes by pushing a button on the endoscope.\n\n# The comparator\n\n## Histopathology\n\nThe comparator for this assessment is histopathology. It is assumed that in current practice all detected polyps are removed and sent to the laboratory for histopathology assessment. Polyps are examined to determine whether they are adenomatous, and therefore at high risk of cancer, or hyperplastic, and so at low risk.", 'Evidence': "The diagnostics advisory committee considered evidence on virtual chromoendoscopy for real-time assessment of colorectal polyps during colonoscopy from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nIn total, 30\xa0studies were included in the systematic review. There were 24\xa0studies on Narrow Band Imaging (NBI), 3\xa0studies on flexible spectral imaging colour enhancement (FICE) and 5\xa0studies on i‑scan. Two studies included more than 1\xa0technology (1\xa0study on NBI and FICE; and 1\xa0study on NBI and i‑scan). Fourteen studies were done in the US, 11\xa0in Europe (of which, 4\xa0were in the UK), 4\xa0in Asia and 1\xa0in Australia. Most of the studies were carried out in specialist centres. The QUADAS assessment found that all studies were at low risk of bias.\n\nNone of the included studies reported on health-related quality of life, mortality, incidence of colorectal cancer, or number of outpatient appointments.\n\n## Virtual chromoendoscopy using Narrow Band Imaging\n\nTwenty-four studies reported on the use of NBI. Most were done in a single centre and the results might not be generalisable to other centres. The endoscopists' levels of experience of using NBI varied: all endoscopists were experienced in 8\xa0studies, some had experience in 4\xa0studies, none had experience in 4\xa0studies, and the experience levels were unclear for 8\xa0studies.\n\nSeventeen studies reported on the sensitivity of NBI and 16\xa0studies reported on the specificity of NBI for characterisations of polyps made with any level of confidence. The sensitivity ranged from 0.55 to 0.97 and the specificity ranged from 0.62 to 0.95. Bivariate meta-analysis of the 16\xa0studies reporting on both sensitivity and specificity produced summary values of 0.88 (95% confidence interval [CI] 0.83 to 0.92) for sensitivity and 0.81 (95% CI 0.75 to 0.85) for specificity.\n\nThe sensitivity and specificity of NBI was higher for polyps diagnosed with high confidence, compared with those diagnosed with any level of confidence (that is, those assessed with low and high confidence). Eleven studies reported on the sensitivity and specificity of NBI for assessing polyps that were characterised with high confidence. Bivariate meta-analysis produced summary values of 0.91 (95% CI 0.85 to 0.95) for sensitivity and 0.82 (95% CI 0.76 to 0.87) for specificity.\n\nA post-hoc bivariate meta-analysis was run for high-confidence characterisations, which only included studies with endoscopists who were experienced in using NBI (4\xa0studies). The analysis produced summary values of 0.92 (95% CI 0.89 to 0.94) for sensitivity and 0.82 (95% CI 0.72 to 0.89) for specificity. Compared with the analysis for endoscopists with different levels of experience, the point estimate for sensitivity increased slightly from 0.91 to 0.92 and the specificity did not change. The confidence interval for sensitivity narrowed for experienced endoscopists compared with that for endoscopists with a variety of experience. The confidence interval for specificity for experienced endoscopists widened (0.72 to 0.89) compared with endoscopists with different levels of experience (0.76\xa0to\xa00.87).\n\nSixteen studies reported on the negative predictive value of NBI for characterising diminutive polyps in the whole colon, made with any level of confidence. The negative predictive value ranged from 43% to 96%. The lower bound of the 95% confidence interval fell below 90% in all studies, apart from Patel et al.\xa0(2016).\n\nThirteen studies reported on the negative predictive value for high-confidence characterisations of polyps in the whole colon. The negative predictive value was higher for characterisations made with high confidence compared with those made with all levels of confidence. The range was 48% to 98%. When reported, the lower bound of the 95% confidence interval fell below 90% in all but 2\xa0studies.\n\nOne study looked at the difference between the negative predictive value of characterisations done by specialists in colonoscopy and general endoscopists. The study found that specialists achieved a higher negative predictive value (90.9%; CI 70.8 to 98.9) than generalists (71.4%; 95% CI 47.8 to 88.8). However, the difference was not statistically significant.\n\nFour studies reported on the sensitivity and specificity of NBI for assessing polyps in the rectosigmoid colon with high confidence and 3\xa0studies reported data for assessing polyps in the rectosigmoid colon with any level of confidence. Bivariate meta-analysis for characterisations made with any level of confidence produced summary values of 0.85 (95% CI 0.75 to 0.91) for sensitivity and 0.87 (95% CI 0.74 to 0.94) for specificity. For characterisations made with high confidence, summary values were 0.87 (95% CI 0.80 to 0.92) for sensitivity and 0.95 (95% CI 0.87 to 0.98) for specificity.\n\nA post-hoc bivariate meta-analysis was run for the 2\xa0studies that included endoscopists who were experienced in using NBI. For high-confidence characterisations, it produced summary values of 0.90 (95% CI 0.71 to 0.97) for sensitivity and 0.98 (95% CI 0.91 to 1.00) for specificity. When compared with the bivariate analysis for endoscopists with different levels of experience, the point estimate for sensitivity increased from 0.87 to 0.90 and the point estimate for specificity increased from 0.95 to 0.98. The confidence interval for sensitivity widened for experienced endoscopists (0.71 to 0.97) compared with that for endoscopists with different levels of experience (0.80 to 0.92). The confidence interval for specificity narrowed slightly for experienced endoscopists (0.91 to 1.00) compared with that for endoscopists with different levels of experience (0.87\xa0to\xa00.98).\n\nThirteen studies reported on the agreement between surveillance intervals set when using NBI compared with those set by histopathology; agreement ranged from 84%\xa0to\xa099%.\n\n## Virtual chromoendoscopy using flexible spectral imaging colour enhancement\n\nThree studies reported on the use of FICE. All studies were carried out in single centres and none reported on high-confidence characterisations of diminutive polyps or on a specific part of the colon. One study reported that the endoscopists did not have any experience of using FICE. In the remaining 2\xa0studies, it was unclear whether the endoscopists had any experience.\n\nAll 3\xa0studies reported the sensitivity and specificity of FICE for characterising polyps in any part of the colon. The sensitivity ranged from 0.74 to 0.88 and the specificity ranged from 0.82 to 0.88. Bivariate meta-analysis using all 3\xa0studies produced summary values of 0.81 (95% CI 0.73 to 0.88) for sensitivity and 0.85 (95% CI 0.79 to 0.90) for specificity. The negative predictive values ranged from 70%\xa0to\xa084%.\n\n## Virtual chromoendoscopy using i‑scan\n\nFive studies reported on the use of i‑scan. Most of the studies were done in a specialist endoscopy centre by 1\xa0endoscopist. So, it is unclear how generalisable the results are to different settings. Three studies reported that the endoscopists had experience of using i‑scan. The remaining 2\xa0studies did not report on level of experience.\n\nTwo studies reported on high-confidence characterisations of polyps in the whole colon. Bivariate meta-analysis produced summary values of 0.96 (95% CI 0.92 to 0.98) for sensitivity and 0.91 (95% CI 0.84 to 0.95) for specificity.\n\nTwo studies reported that the negative predictive value of i‑scan for detecting colorectal polyps in the whole colon was above 90%. But, the lower bound of the confidence interval for both studies was below\xa090%.\n\nTwo studies reported that the negative predictive value of i‑scan for detecting colorectal polyps in the distal or rectosigmoid colon was above 90%. But, the lower bounds of the confidence interval were below\xa090%.\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nTwo studies were found that reported full economic evaluations comparing virtual chromoendoscopy with histopathology. Hassan et al. (2010) found no difference in life expectancy between the 2\xa0strategies and therefore could not calculate a cost per life year gained. Kessler et al. (2011) found that the cost per life year gained for sending all polyps detected during colonoscopy for histological analysis, compared with a resect and discard strategy using virtual chromoendoscopy, was US\xa0$377,460. It is unclear how generalisable the results are to the NHS, because non-UK resource costs were used and health outcomes were not valued in quality-adjusted life years (QALYs).\n\n## Modelling approach\n\nThe external assessment group (EAG) developed a de novo economic model to assess the cost effectiveness of virtual chromoendoscopy (NBI, FICE and i‑scan) compared with histopathology for assessing colorectal polyps. The model took the perspective of the NHS and personal social services and all costs and QALYs were discounted at a rate of 3.5% per year. The model consisted of 2\xa0parts. The first part was a decision tree that estimated the short-term costs and outcomes of the first colonoscopy. In this model, polyps are assessed and a surveillance interval is assigned. The second part was an existing model used to estimate the long-term costs and QALYs for each surveillance classification, including incorrect surveillance classifications. The second model was a state transition model developed by the School of Health and Related Research (ScHARR), at the University of Sheffield, for the NHS bowel cancer screening programme. The model was chosen because it is a long-standing model that has been validated and was used to inform the introduction of the screening programme. The model was run independently and the cost and QALY estimates were entered as parameters at the end points of the decision tree model.\n\nThe decision tree compared the virtual chromoendoscopy strategies with a histopathology strategy. It had 4\xa0main arms, 1\xa0for each test that was assessed: NBI, FICE, i‑scan and standard endoscopy with histopathology. The comparator arm of the decision tree assumed that all polyps are resected and sent to histopathology and everyone is given the correct surveillance interval.\n\nFirstly, the cohort was divided into 4\xa0risk categories based on the number of adenomas that they have:\n\nno adenomas\n\nlow risk (1\xa0to 2\xa0adenomas)\n\nintermediate risk (3\xa0to 4\xa0adenomas)\n\nhigh risk (5\xa0or more adenomas).\n\nThe model then calculated the proportion of patients in each category expected to have a correct surveillance interval assigned and the proportions expected to have an incorrect surveillance interval assigned.\n\nWith a virtual chromoendoscopy strategy, the following errors could lead to an incorrect surveillance interval (too long or too short) being assigned in the model:\n\nor more hyperplastic polyps might be misclassified as an adenoma and so be unnecessarily resected\n\nor more adenomas might be misclassified as a hyperplastic polyp and left in place.\n\nThe ScHARR bowel cancer screening (SBCS) model was designed to assess the cost effectiveness of different screening strategies for colorectal cancer for a lifetime time horizon. The model simulated the progression of colorectal cancer in people who are eligible for the bowel cancer screening programme in England.\n\nThe population in the base-case analysis was people taking part in the bowel cancer screening programme who had been referred for colonoscopy. Patients were included if they had at least 1\xa0diminutive polyp (5\xa0mm or less), and were excluded if they had 1\xa0or more non-diminutive polyps (more than 5\xa0mm). In addition, scenario analyses looked at:\n\npeople offered colonoscopy as surveillance because they previously had adenomas removed and\n\npeople referred to colonoscopy by a GP because of symptoms of colorectal cancer.\n\nTwo different diagnostic strategies were explored in the economic analyses, the virtual chromoendoscopy strategy (used in the base case) and the DISCARD strategy (Detect, InSpect, ChAracterise, Resect, and Discard; used in some scenario analyses). The criteria common to both strategies were that diminutive polyps:\n\nin the whole colon are optically characterised using virtual chromoendoscopy\n\ndiagnosed with high confidence as adenomas are resected and discarded\n\ndiagnosed with low confidence are resected and sent to histopathology.\n\nThe characteristic unique to the virtual chromoendoscopy strategy was that diminutive polyps, in the whole of the colon, diagnosed with high confidence as hyperplastic are left in place.\n\nThe characteristics unique to the DISCARD strategy were that diminutive polyps:\n\nin the proximal colon, characterised with high confidence as hyperplastic, are resected and discarded.\n\nin the rectosigmoid colon, diagnosed with high confidence as hyperplastic, are left in place.\n\nThe model inputs were taken from various sources, including routine sources of cost data, published literature, and the clinical-effectiveness review and meta-analyses.\n\nThe prevalence of adenomas was estimated for 3\xa0populations: the screening population (base case), the surveillance population (scenario analysis) and the symptomatic population (scenario analysis). For the base-case analysis on the screening population, the prevalence of adenomas was taken from a published study by Raju et al. (2013) that retrospectively analysed data from a US colon cancer screening programme. The distributions of adenomas and the data sources for each population are reported in table\xa01.\n\nRisk category\n\nScreening population (Raju et al. 2013)\n\nSurveillance population (Martinez et al. 2009)\n\nSymptomatic population (McDonald et al. 2013)\n\nNo adenoma\n\n\n\n\n\n\n\nLow risk\n\n\n\n\n\n\n\nIntermediate risk\n\n\n\n\n\n\n\nHigh risk\n\n\n\n\n\n\n\nData on diagnostic accuracy were taken from the clinical-effectiveness review and meta-analysis for NBI, FICE and i‑scan, as shown in table\xa02. Data were used for polyps in the whole colon that were characterised with high confidence in the base-case analysis for NBI and i‑scan. Data were used for polyps in the whole colon that were characterised with any level of confidence in the base-case analysis for FICE. It was assumed that the proportion of low-confidence characterisations was the same for all 3\xa0technologies, and was calculated using data from 12\xa0NBI studies, because data were not available for FICE and i‑scan. The comparator, histopathology, was assumed to be 100% accurate.\n\nParameter\n\nValue\n\nLower 95% CI\n\nUpper 95% CI\n\nSource\n\nNBI sensitivity\n\n\n\n\n\n\n\nMeta-analysis\n\nNBI specificity\n\n\n\n\n\n\n\nMeta-analysis\n\nFICE sensitivity\n\n\n\n\n\n\n\nMeta-analysis\n\nFICE specificity\n\n\n\n\n\n\n\nMeta-analysis\n\ni‑scan sensitivity\n\n\n\n\n\n\n\nMeta-analysis\n\ni‑scan specificity\n\n\n\n\n\n\n\nMeta-analysis\n\nProportion of polyp characterisations made with low confidence\n\n\n\n\n\n\n\nEAG literature review (the average value from 12 NBI studies that were included in the literature review; data were not available on the proportion of polyp characterisations made with low confidence for FICE and i scan)\n\nAbbreviations: CI, confidence interval; EAG, external assessment group; FICE, flexible spectral imaging colour enhancement; NBI, Narrow Band Imaging.\n\nThe probabilities of adverse events occurring during colonoscopy were assumed to be 0.003 for hospitalisation for bleeding with polypectomy, 0.003 for perforation with polypectomy, and 0.052 for death of patients with perforation during polypectomy. These values were taken from published values used in the SBCS model.\n\nFor the base-case analysis, the costs of colonoscopy, polypectomy, adverse events and histopathology were taken from the NHS reference costs for 2014/15 (see table\xa03). Training costs were assumed to be £14.72 per patient, based on the assumption that endoscopists complete 150\xa0endoscopies per year and that training costs are equivalent to 2\xa0days of pay (£1,104) per year.\n\nParameter\n\nValue\n\nLower 95% confidence interval\n\nUpper 95% confidence interval\n\nCost of colonoscopy without polypectomy\n\n£518.36\n\n£340.89\n\n£695.83\n\nCost of colonoscopy with polypectomy\n\n£600.16\n\n£406.24\n\n£794.08\n\nCost of treating bowel perforation (major surgery)\n\n£2,152.77\n\n£902.21\n\n£3,403.33\n\nCost of admission for bleeding (overnight stay on medical ward)\n\n£475.54\n\n£327.69\n\n£623.39\n\nPathology cost per polyp examination\n\n£28.82\n\n£6.78\n\n£50.86\n\nThe cost of upgrading equipment was not included in the model. It was assumed that most hospitals already had equipment with virtual-chromoendoscopy-enabled technology in place, and hospitals that do not have this equipment will get it in the future as part of standard procurement. Therefore, the base-case analysis assumes that the cost of maintaining and purchasing equipment is included in the Healthcare Resource Group (HRG) cost of colonoscopy.\n\nHealth-related quality of life was calculated in the SBCS model. The base-case analysis used utility values taken from a study by Ara and Brazier (2011). The model assumes a utility of 0.697 for people with cancer and a utility of 0.798 for people without cancer.\n\nA scenario analysis was done using utility values from a study identified by the EAG through a targeted search (Farkkila et al. 2013). For the scenario analysis, it was assumed that the utility for people with cancer was 0.761 and for people without cancer was 0.798.\n\nNo disutility values for adverse events during polypectomy, such as bowel perforation and bleeding, were found. Therefore, the values were taken from studies that reported on similar events. A QALY loss of 0.006 was taken from Dorian et al. (2014) for the disutility of a major gastrointestinal bleed and a QALY loss of 0.010 was taken from Ara and Brazier (2011) for the disutility of bowel perforation.\n\nThe costs and QALYs for the end points of the decision tree were calculated by running the SBCS model with a cohort of patients aged\xa065.\n\nThe following changes were made to the SBCS model for this assessment:\n\nColonoscopy and adverse-event costs were updated to 2014/15 costs.\n\nThe screening costs were updated.\n\nAdenoma recurrence rates were adjusted to model people with higher-disease risk and people with adenomas left in the body.\n\n## Base-case results\n\nThe following assumptions were applied in the base-case analysis:\n\nThe long-term cost and QALY outcomes were estimated using the SBCS model, which assumed that standard colonoscopy with histopathology assessment of all polyps was used for follow‑up surveillance. Therefore, diagnostic accuracy data and training costs associated with virtual chromoendoscopy were not included in the long-term results.\n\nStudies did not report on the relationship between diagnostic accuracy and assigning people to the correct surveillance intervals, therefore the following was assumed:\n\n\n\ndiagnostic accuracy data were applied to individual polyps\n\nthe adenoma-to-hyperplastic-polyp ratio was assumed to be the same for each risk category.\n\n\n\nOnly diminutive polyps were assessed, people with polyps larger than 5\xa0mm were not included in the model.\n\nThe proportion of polyps assessed with low confidence (21%) was assumed to be the same for NBI, FICE and i‑scan.\n\nThe disutility for bleeding was assumed to be similar to a major gastrointestinal bleed.\n\nThe disutility for perforation was assumed to be the same as for a stomach ulcer, abdominal hernia or rupture.\n\nThe results of the base-case analysis can be seen in table\xa04a and table 4b. Pairwise analyses compared each of the 3\xa0technologies in turn (NBI, FICE and i‑scan) with histopathology. Results showed that NBI and i‑scan dominated histopathology, that is, they were cheaper and more effective than histopathology. FICE was cost saving and less effective than histopathology, with an incremental cost-effectiveness ratio (ICER) of £671,383 saved per QALY lost.\n\nThe differences in incremental QALYs ranged from −0.0001 when FICE was compared with histopathology to 0.0007 when i‑scan was compared with histopathology. The differences in costs ranged from −£87.70 when FICE was compared with histopathology to −£73.10 when NBI was compared with histopathology.\n\nThe lifetime risk of colorectal cancer according to the method of assessing polyps, calculated from the model, was:\n\n% for histopathology\n\n% for NBI\n\n% for FICE\n\n% for i‑scan.\n\nThe fully incremental analyses show that histopathology was dominated by NBI and i‑scan; and NBI was dominated by i‑scan. When i‑scan was compared with FICE it had an ICER of £10,466 per QALY gained.\n\nAssessment\n\nCosts\n\nInc\n\nCosts\n\nQALYs\n\nInc\n\nQALY\n\nICER (£ per QALY)\n\nHistopathology\n\n£988.95\n\n–\n\n\n\n–\n\nDominated\n\nFICE\n\n£901.25\n\n−£87.70\n\n\n\n−0.0001\n\n–\n\ni‑scan\n\n£909.74\n\n£8.49\n\n\n\n\n\n£10,465.74\n\nNBI\n\n£915.85\n\n£6.11\n\n\n\n−0.0001\n\nDominated\n\nAssessment\n\nCosts\n\nInc\n\nCosts\n\nQALYs\n\nInc\n\nQALY\n\nICER (£ per QALY)\n\nHistopathology\n\n£988.95\n\n–\n\n\n\n–\n\n–\n\nNBI\n\n£915.85\n\n−£73.10\n\n\n\n\n\nDominates\n\nHistopathology\n\n£988.95\n\n–\n\n\n\n–\n\n–\n\nFICE\n\n£901.25\n\n−£87.70\n\n\n\n−0.0001\n\n£671,383 (incremental cost saving per QALY lost)\n\nHistopathology\n\n£988.95\n\n–\n\n\n\n–\n\n–\n\ni‑scan\n\n£909.74\n\n−£79.21\n\n\n\n\n\nDominates\n\nAbbreviations: FICE, flexible spectral imaging colour enhancement; ICER, incremental cost-effectiveness ratio; Inc, incremental; NBI, Narrow Band Imaging; QALY, quality-adjusted life year.\n\nThe EAG did 12\xa0scenario analyses, and a further 2\xa0scenario analyses were done as an addendum to the assessment report. Fewer scenario analyses were done for FICE, because data were unavailable. Results of the scenario analyses show that NBI and i‑scan were dominant in all scenario analyses when compared with histopathology.\n\nWhen FICE was compared with histopathology, it was cost effective in all scenario analyses. FICE was cheaper and more effective than histopathology and therefore was dominant when:\n\nthe risk-category distributions for the cohort were changed to reflect a population that was having surveillance colonoscopy\n\nthe risk-category distributions for the cohort were changed to reflect a cohort with symptoms and\n\nthe discard strategy was applied and diagnostic accuracy data were used for all levels of confidence for characterisations in the whole colon.\n\nWhen alternative utility values were used from Farkkila et al. (2013), FICE was cheaper and slightly less effective compared with histopathology and had an ICER of £1,273,941 saved per QALY lost.\n\nWhen diagnostic accuracy data were used from studies that reported data for endoscopists experienced in using NBI for the whole colon and the rectosigmoid colon, the results were similar to the base-case analyses for virtual chromoendoscopy and NBI dominated histopathology.\n\nThe effect of using virtual chromoendoscopy (NBI) for surveillance was explored and found to be small; it was estimated to increase cost savings by £20 and increase QALYs gained by 0.0003.\n\nThe EAG produced an addendum with 2\xa0scenario analyses on adverse events. The first analysis varied the rate of perforation during colonoscopy using ratios from the data in Rutter et al. (2014), and found that cost savings for all 3\xa0technologies decreased slightly in relative and absolute terms, and the QALYs decreased slightly in absolute terms, whereas the relative change was large (see table\xa05). NBI and i‑scan still dominated histopathology and the ICER for FICE increased to £126,229 saved per QALY lost. The second analysis included the risk of an adverse event happening during all colonoscopies, as well as for colonoscopies with polypectomy. This analysis also used data from Rutter et al. and found that cost savings for all 3\xa0technologies decreased slightly in relative and absolute terms, and the QALYs decreased slightly in absolute terms, whereas the relative change was large (see table\xa06). NBI and i‑scan still dominated histopathology and the ICER for FICE increased to £342,438 saved per QALY lost.\n\nAssessment comparison\n\nBase‑case inc\xa0cost\n\nRevised\xa0inc cost\n\nRelative change\xa0in cost compared with base case\n\nBase-case inc QALYs\n\nRevised inc QALYs\n\nRelative change in QALYs compared with base case\n\nHistopathology versus NBI\n\n−£73.10\n\n−£72.47\n\n−0.9%\n\n\n\n\n\n−80%\n\nHistopathology versus FICE\n\n−£87.70\n\n−£86.92\n\n−0.9%\n\n−0.0001\n\n−0.0007\n\n−600%\n\nHistopathology versus i‑scan\n\n−£79.21\n\n−£78.60\n\n−0.8%\n\n\n\n\n\n−71%\n\nAbbreviations: FICE, flexible spectral imaging colour enhancement; Inc, incremental; NBI, Narrow Band Imaging; QALY, quality-adjusted life year.\n\nAssessment comparison\n\nBase‑case inc\xa0cost\n\nRevised\xa0inc cost\n\nRelative change\xa0in cost compared with base case\n\nBase-case\xa0inc QALYs\n\nRevised inc QALYs\n\nRelative change in QALYs compared with base case\n\nHistopathology versus NBI\n\n−£73.10\n\n−£73.06\n\n−0.05%\n\n\n\n\n\n−20%\n\nHistopathology versus FICE\n\n−£87.70\n\n−£87.65\n\n−0.06%\n\n−0.0001\n\n−0.0003\n\n−200%\n\nHistopathology versus i‑scan\n\n−£79.21\n\n−£79.16\n\n−0.06%\n\n\n\n\n\n−15%\n\nAbbreviations: FICE, flexible spectral imaging colour enhancement; inc, incremental; NBI, narrow band imaging; QALY, quality-adjusted life year.\n\nThe one-way deterministic sensitivity analyses found that the parameters with the most influence on the cost effectiveness of the tests were pathology cost, the probability of perforation with polypectomy, and the proportion of patients who die from perforation. All one-way sensitivity analyses showed that NBI, FICE and i‑scan were cost effective compared with histopathology at a maximum acceptable ICER of £30,000 per QALY gained.\n\nThe EAG did a probabilistic sensitivity analysis by varying the base-case inputs for the decision tree. The analysis was done by running the model 5,000\xa0times. Each time it was run, the inputs were varied according to the distribution of the input.\n\nThe probabilistic sensitivity analysis found that i‑scan was more likely to be cost effective than NBI and FICE. At a maximum acceptable ICER of £20,000 per QALY gained, i‑scan was cost effective in 85.2% of the analyses, and at a maximum acceptable ICER of £30,000 per QALY gained i‑scan was cost effective in 99.5% of the analyses.", 'Committee discussion': "The committee considered the potential benefits of using virtual chromoendoscopy technologies for real-time assessment of diminutive polyps during colonoscopy. The committee heard from a clinical expert that the purpose of colonoscopy with polypectomy is to protect against developing colorectal cancer. The committee also heard that if virtual chromoendoscopy was used to characterise diminutive polyps (5\xa0mm or less), fewer hyperplastic polyps would be resected which may reduce adverse events and costs for histopathology. The committee noted that a large proportion of people assessed in the bowel cancer screening programme only have diminutive polyps, and that an analysis of the data from the bowel cancer screening programme has shown that only 0.19% of diminutive polyps were cancerous. The committee concluded that the risk of colorectal cancer in people who only have diminutive polyps is low.\n\n# Clinical effectiveness\n\nThe committee considered the generalisability of the evidence base to clinical practice in the NHS. The committee noted that most of the endoscopies in the studies included in the assessment were done by experienced endoscopists in single academic centres, most of which were outside of the UK. The committee also noted that the UK‑based DISCARD\xa02 study was excluded from the assessment because only 22% of the participating centres had high-definition equipment. The committee heard from clinical experts that DISCARD\xa02 was a multicentre community-based study, with 28\xa0endoscopists, which compared Narrow Band Imaging (NBI) with histopathology and was considered to reflect clinical practice in the NHS. The results of this study showed that the sensitivity of NBI for real-time assessment of diminutive polyps was lower than the accuracy estimated in this assessment (0.76 compared with 0.87 to 0.92). The committee concluded that the diagnostic accuracy of virtual chromoendoscopy technologies reported in this assessment reflect the accuracy that could be achieved by endoscopists with experience of using virtual chromoendoscopy and who work in specialist or academic settings. The committee concluded further that diagnostic accuracy results probably do not reflect the accuracy that would be achieved by endoscopists with limited experience of virtual chromoendoscopy and who work in community-based settings.\n\nThe committee considered the differences between the 3\xa0virtual chromoendoscopy technologies (NBI, flexible spectral imaging colour enhancement [FICE] and i‑scan). The committee heard from clinical experts that FICE and i‑scan work differently to NBI; they are software-based image enhancement technologies, whereas NBI uses optical filters on white light, resulting in narrow-band light which enhances the contrast between the vessels and the surrounding mucosa. The committee also heard that the type of technology in place in centres is likely to vary, and equipment is replaced every 5\xa0to 8\xa0years. The committee then considered the different levels of evidence available for NBI, FICE and i‑scan. It noted that most studies were on NBI and very few studies were on FICE and i‑scan. It also noted that most of the studies on i‑scan were done in academic centres, by 1\xa0endoscopist experienced in using virtual chromoendoscopy, and this resulted in higher accuracy results for i‑scan compared with NBI. It noted also that none of the studies on FICE limited the accuracy data to high-confidence characterisations of polyps, and this resulted in lower accuracy results for FICE compared with NBI. The committee concluded that, without direct comparative data, it is unclear whether one virtual chromoendoscopy technology is superior to others. It concluded further that NBI, FICE and i‑scan will probably perform similarly in clinical practice, because the diagnostic accuracy achieved is likely to depend on the experience level of the endoscopist and the level of confidence in the polyp characterisation more than on the virtual chromoendoscopy technology used.\n\nThe committee considered the diagnostic accuracy of virtual chromoendoscopy technologies for real-time assessment of diminutive polyps. The committee noted that the American Society for Gastrointestinal Endoscopy has developed criteria on diagnostic accuracy that endoscopic technologies must meet before being considered appropriate for use in US clinical practice (the Preservation and incorporation of valuable endoscopic innovations [PIVI] criteria). The PIVI criteria on real-time assessment of diminutive colorectal polyps guides decisions on resecting and discarding polyps without histopathologic assessment. These criteria are:\n\ntechnologies should have an agreement of 90% or more with the surveillance intervals set by histopathology\n\nthe negative predictive value of the technology for assessing adenomatous polyp histology should be 90% or more.The committee heard from clinical experts that the PIVI criteria, which are used in US clinical practice, were widely accepted in the UK gastrointestinal community. The committee concluded that the diagnostic accuracy of NBI, FICE and i‑scan were likely to meet the PIVI criteria if used by endoscopists with experience of virtual chromoendoscopy technologies.\n\nThe committee discussed the accuracy of the comparator test, histopathology. The committee heard from clinical experts that histopathology is considered to be the gold standard in current practice, but it is actually an imperfect reference standard for diagnosing polyps. The committee also heard from clinical experts that currently about 8% to 10% of diminutive polyps do not have histopathology assessment because they are lost or destroyed before they reach the histopathologist and they are therefore assumed to be adenomatous. It heard further that polyp characterisation using histopathology assessment is 90% to 95% correct. The committee concluded that given the limitations of histopathological assessment of polyps, the diagnostic accuracy of the virtual chromoendoscopy technologies is likely to be more accurate than data from the studies suggests.\n\nThe committee discussed the consequences of misdiagnosing diminutive polyps using virtual chromoendoscopy. The committee noted that if virtual chromoendoscopy is used for real-time assessment of polyps, 3% to 6% of the surveillance intervals are likely to be incorrectly assigned. The committee heard from clinical experts that if virtual chromoendoscopy is used, over-surveillance would be slightly more common than under-surveillance. The committee noted that the effect on clinical outcomes from incorrectly leaving diminutive adenomatous polyps in place and incorrectly assigning a surveillance interval that is too long is uncertain. The committee heard from the external assessment group (EAG), however, that the lifetime risk of colorectal cancer calculated from the model was similar for the 3\xa0virtual chromoendoscopy technologies and histopathology (3.025% for histopathology, 3.020% for NBI, 3.045% for FICE and 3.021% for i‑scan; see section 4.44). It concluded that although there was some uncertainty over how the diagnostic accuracy data would translate into clinical outcomes, it was aware that an end-to-end study on clinical outcomes would need to be done on a large cohort over a long period of time and so may not be feasible.\n\n# Cost effectiveness\n\nThe committee discussed the uncertainties around using the School of Health and Related Research's (ScHARR) bowel cancer screening (SBCS) model for the assessment. The committee was aware that ScHARR ran the SBCS model on behalf of the EAG, and therefore the EAG was unable to internally validate the model results. However, it noted that the model had previously been validated for use to inform the NHS bowel cancer screening programme strategy, and that the costs in the model had been updated to reflect current costs. The committee heard from the EAG that there were structural uncertainties in the model, for example, the accuracy of virtual chromoendoscopy was not used for ongoing surveillance. However, the committee noted that it would not have been possible for the EAG to build a de novo model because of the level of resource needed to develop such a complex model. The committee therefore concluded that although there was some uncertainty about the SBCS model's results, it was considered to be the most appropriate model for the assessment.\n\nThe committee considered the cost of histopathology assessment of polyps used in the model. It heard from the EAG that in the base-case analysis, the cost of histopathology per polyp was based on the NHS reference cost for direct access pathology for 2014/15, which lists the cost of histopathology and histology as £28.82 (DAPS02). The committee noted that this reference cost is likely to include requests from community services, such as GPs, for histopathology and that there is no stratification by sample type (for example, type of specimen or tissue preparation), which may affect the cost. The committee noted further that the true cost of histopathology assessment of colorectal polyps was probably more than £50 per polyp. The committee concluded that the cost of histopathology was likely to be underestimated in the model, and so the cost savings for virtual chromoendoscopy technologies were likely to be greater than the model suggested.\n\nThe committee discussed the proportion of hospitals that already have high-definition enabled virtual chromoendoscopy equipment in place. The committee heard from the EAG that the economic model assumed that the cost of upgrading colonoscopy equipment would be included in the NHS reference costs for colonoscopy (see table 3). The committee heard from clinical experts that most endoscopes were replaced every 5\xa0to 8\xa0years and the video system is likely to be replaced every 10\xa0years because repairs after this period are often not supported. The committee heard further that most centres will have at least 1\xa0virtual-chromoendoscopy-enabled machine. The committee concluded that the assumption made in the economic model was reasonable.\n\nThe committee discussed the assumption used in the model that histopathology is 100% accurate when assigning surveillance intervals. It heard from clinical experts that although histopathology is considered to be the gold standard, the diagnostic accuracy is likely to be below 100% (see section 5.5). The committee concluded that the clinical effectiveness of histopathology was likely to have been overestimated in the model, and therefore the difference in clinical effectiveness between histopathology and the virtual chromoendoscopy technologies was likely to be smaller than the results suggested.\n\nThe committee considered the implications for histopathology laboratories of adopting virtual chromoendoscopy for real-time assessment of colorectal polyps. The committee heard from clinical experts that histopathology laboratories are under considerable strain because of high workloads, and that diminutive colorectal polyp assessment is an important cause of this overload. The committee discussed whether using virtual chromoendoscopy for real-time assessment of diminutive polyps rather than sending all of these to histopathology could reduce this workload and result in cost savings or free histopathologists for other priorities. The committee noted that the endoscopist's level of experience would affect how many diminutive polyps are assessed with high confidence, and therefore how many polyps are sent to histopathology. For example, risk-averse practice (in which polyps that are likely to be hyperplastic are removed and sent to histopathology) is probably more common in endoscopists with less experience. Therefore, cost savings through avoiding histopathology assessment may not be as large in this group compared with experienced endoscopists, who are likely to assess more polyps with high confidence and send fewer to histopathology. The committee concluded that virtual chromoendoscopy used by experienced endoscopists could reduce the number of diminutive polyps sent to histopathology laboratories, therefore freeing histopathology resources.\n\nThe committee discussed the results of the cost-effectiveness analysis and noted that in the base case, the NBI and i‑scan dominated histopathology, that is, they were cheaper and more clinically effective than histopathology. The committee also noted that in the base case, FICE could be considered cost effective with an incremental cost-effectiveness ratio (ICER) of £671,000 saved per quality-adjusted life year (QALY) lost (see section\xa04.42). However, the committee noted that the base-case analysis only included adverse events for colonoscopy with polypectomy. The committee heard from a clinical expert that there is also a risk of adverse events from a colonoscopy even without a polypectomy. It heard from the EAG that an analysis was done which included the risks of adverse events from all colonoscopies as well as for colonoscopy with polypectomy (see section\xa04.51). The committee noted that in this analysis, NBI and i‑scan still dominated histopathology and the ICER for FICE decreased to £342,000 saved per QALY lost. The committee concluded that the most plausible results came from the scenario analysis that included a risk for adverse events for colonoscopy without polypectomy. The committee further concluded that NBI, FICE and i‑scan could be cost-effective options for assessing diminutive polyps.\n\nThe committee discussed the robustness of the results of the economic model. It noted that results of the sensitivity and scenario analyses showed that NBI and i‑scan were dominant compared with histopathology in all scenario analyses. It noted further that FICE dominated histopathology in some analyses and was considered cost effective in other analyses, with ICERs ranging from £126,000 to £1,270,000 saved per QALY lost. The committee considered that although there were limitations and uncertainties in the economic assessment (see section\xa05.7), the sensitivity analyses showed that the results were robust to changes. The committee concluded that the results of the economic model could be considered to be fairly robust.\n\nThe committee considered all its discussions on virtual chromoendoscopy, and noted its conclusions that:\n\noptical diagnosis using virtual chromoendoscopy technologies was likely to meet the PIVI criteria if used by endoscopists with experience of virtual chromoendoscopy technologies (see section\xa05.4)\n\nthe lifetime risk of colorectal cancer was estimated to be similar when diminutive polyps were assessed and surveillance intervals were set using virtual chromoendoscopy technologies or histopathology (see section\xa05.6)\n\nassessment of diminutive colorectal polyps with virtual chromoendoscopy technologies is cost effective compared with assessment of diminutive colorectal polyps using histopathology (see sections\xa05.12 and\xa05.13)\n\nthe virtual chromoendoscopy technologies are cost saving when they are used to implement a management strategy which reduces the number of diminutive polyps sent for histopathological analysis (see section 5.11).The committee therefore concluded that virtual chromoendoscopy using NBI, FICE or i‑scan to assess diminutive polyps during colonoscopy, instead of sending polyps to histopathology, could be considered clinically effective and cost effective if done by a specialist group, that is, endoscopists with expertise in optical diagnosis using virtual chromoendoscopy technologies.\n\n# Other considerations\n\nThe committee considered whether using virtual chromoendoscopy for real-time assessment of diminutive polyps and using a discard strategy was acceptable to people. The committee heard from a clinical expert that there were no UK‑based studies that looked at patient acceptability, but 2\xa0studies from the US and 1\xa0study from Australia with data on patient acceptability were available. In the US study, many patients stated that they would pay $150 from their own pocket to have polyps removed and assessed by histopathology, instead of using real-time assessment of polyps with a discard strategy (Vu et al. 2015). The committee concluded that further research on patient acceptability of virtual chromoendoscopy for real-time assessment of diminutive polyps and use of a discard strategy would be valuable.\n\nThe committee considered the effect of training for endoscopists on the diagnostic accuracy of NBI, FICE and i‑scan. The committee heard from clinical experts that the DISCARD\xa02 study had implemented a programme consisting of a 1‑hour training session using PowerPoint images followed by a test. The committee noted that the results of the study suggested that training and monitoring for endoscopists needed to be more rigorous to maintain high levels of diagnostic accuracy for virtual chromoendoscopy technologies. The committee heard that the manufacturers of the technologies offer 2\xa0forms of training for endoscopists, both developed with experts: peer-to-peer training at centres of excellence; and online training for self-study. The committee also heard that general experience in diagnosing polyps and familiarity with polyp classification systems, combined with acting on feedback from peers, were important factors in improving the skill levels of endoscopists. It concluded that the most effective forms of training should be determined, and that this could be done through collaboration between manufacturers of virtual chromoendoscopy technologies and professional organisations.\n\nThe committee discussed the need for quality assurance measures to be in place before virtual chromoendoscopy for assessment of polyps during colonoscopy can be used in clinical practice. It heard from clinical experts that the skills of endoscopists who do colonoscopies are known to vary. The committee heard further that quality assurance measures, such as accreditation and monitoring of practice, were needed to ensure that virtual chromoendoscopy for making optical diagnoses is only used by endoscopists who can meet the PIVI criteria, and to maintain high levels of diagnostic accuracy over time. The committee also noted that there was currently no accreditation or monitoring system in place for virtual chromoendoscopy and heard that any accreditation and monitoring scheme would need to be rolled out to both clinicians and nurse-endoscopists. The committee concluded that a national accreditation scheme for using virtual chromoendoscopy to make optical diagnoses should be developed. It concluded further that when virtual chromoendoscopy technologies are used, intermediate measures should be monitored for quality assurance and to give endoscopists ongoing feedback.", 'Recommendations for further research': 'Audit is recommended to monitor whether endoscopists using virtual chromoendoscopy (Narrow Band Imaging [NBI], flexible spectral imaging colour enhancement [FICE] and i‑scan) are correctly assessing polyps as adenomatous and hyperplastic during colonoscopy. Measures may include:\n\nthe diagnostic accuracy of polyp characterisation achieved and\n\nagreement with the surveillance interval for colonoscopy set by histopathology.\n\nFurther research is recommended on patient acceptability of using virtual chromoendoscopy for real-time assessment of diminutive polyps compared with assessment using histopathology.\n\nData collection and analysis are recommended to monitor the effect on endoscopy and histopathology services of using virtual chromoendoscopy instead of histopathology to assess diminutive polyps. Measures may include:\n\nthe length of time to do colonoscopies\n\nthe number of polyps sent for histopathology analysis\n\ncost savings or workload reductions associated with reductions in histopathology.'}	https://www.nice.org.uk/guidance/dg28	Evidence-based recommendations on virtual chromoendoscopy (VCE) using NBI, FICE or i-scan to assess colorectal polyps of 5 mm or less during colonoscopy.
3ef13cc48b8080a3916292dcbda4d50ec02cd3d5	nice	Intravenous fluid therapy in adults in hospital	Intravenous fluid therapy in adults in hospital This guideline covers the general principles for managing intravenous (IV) fluid therapy in hospital inpatients aged 16 and over with a range of conditions. It aims to help prescribers understand the optimal amount and composition of IV fluids to be administered and the best rate at which to give them, to improve fluid prescribing and outcomes among people in hospital. It does not cover pregnant women, and those with severe liver or renal disease, diabetes or burns. # Introduction This guideline contains recommendations about general principles for managing intravenous (IV) fluids, and applies to a range of conditions and different settings. It does not include recommendations relating to specific conditions. Many adult hospital inpatients need intravenous (IV) fluid therapy to prevent or correct problems with their fluid and/or electrolyte status. Deciding on the optimal amount and composition of IV fluids to be administered and the best rate at which to give them can be a difficult and complex task, and decisions must be based on careful assessment of the patient's individual needs. Errors in prescribing IV fluids and electrolytes are particularly likely in emergency departments, acute admission units, and general medical and surgical wards rather than in operating theatres and critical care units. Surveys have shown that many staff who prescribe IV fluids know neither the likely fluid and electrolyte needs of individual patients, nor the specific composition of the many choices of IV fluids available to them. Standards of recording and monitoring IV fluid and electrolyte therapy may also be poor in these settings. IV fluid management in hospital is often delegated to the most junior medical staff who frequently lack the relevant experience and may have received little or no specific training on the subject. The National Confidential Enquiry into Perioperative Deaths report in 1999 highlighted that a significant number of hospitalised patients were dying as a result of infusion of too much or too little fluid. The report recommended that fluid prescribing should be given the same status as drug prescribing. Although mismanagement of fluid therapy is rarely reported as being responsible for patient harm, it is likely that as many as 1 in 5 patients on IV fluids and electrolytes suffer complications or morbidity due to their inappropriate administration. There is also considerable debate about the best IV fluids to use (particularly for more seriously ill or injured patients), resulting in wide variation in clinical practice. Many reasons underlie the ongoing debate, but most revolve around difficulties in interpretation of both trial evidence and clinical experience, including the following factors: Many accepted practices of IV fluid prescribing were developed for historical reasons rather than through clinical trials. Trials cannot easily be included in meta-analyses because they examine varied outcome measures in heterogeneous groups, comparing not only different types of fluid with different electrolyte content, but also different volumes and rates of administration and, in some cases, the additional use of inotropes or vasopressors. Most trials have been undertaken in operating theatres and critical care units rather than admission units or general and elderly care settings. Trials claiming to examine best early therapy for fluid resuscitation have actually evaluated therapy choices made after initial fluid resuscitation, with patients already in critical care or operating theatres. Many trials inferring best therapy for fluid resuscitation after acute fluid loss have actually examined situations of hypovolaemia induced by anaesthesia. There is a clear need for guidance on IV fluid therapy for general areas of hospital practice, covering both the prescription and monitoring of IV fluid and electrolyte therapy, and the training and educational needs of all hospital staff involved in IV fluid management. The aim of this NICE guideline is to help prescribers understand the: physiological principles that underpin fluid prescribing pathophysiological changes that affect fluid balance in disease states indications for IV fluid therapy reasons for the choice of the various fluids available and principles of assessing fluid balance. In developing the guideline, it was necessary to limit the scope by excluding patient groups with more specialised fluid prescribing needs. It is important to emphasise that the recommendations do not apply to patients under 16 years, pregnant women, and those with severe liver or renal disease, diabetes or burns. They also do not apply to patients needing inotropes and those on intensive monitoring, and so they have less relevance to intensive care settings and patients during surgical anaesthesia. Patients with traumatic brain injury (including patients needing neurosurgery) are also excluded. The scope of the guideline does not cover the practical aspects of administration (as opposed to the prescription) of IV fluids. It is hoped that this guideline will lead to better fluid prescribing in hospitalised patients, reduce morbidity and mortality, and lead to better patient outcomes. Strategies for further research into the subject have also been proposed. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.# Patient-centred care This guideline offers best practice advice on the care of people over 16 years who are in hospital receiving intravenous fluid therapy. Patients and healthcare professionals have rights and responsibilities as set out in the NHS Constitution for England – all NICE guidance is written to reflect these. Treatment and care should take into account individual needs and preferences. Patients should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. Healthcare professionals should follow the Department of Health's advice on consent. If someone does not have capacity to make decisions, healthcare professionals should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards. In Wales, healthcare professionals should follow advice on consent from the Welsh Government. NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in patient experience in adult NHS services.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # Terms used in this guideline In this guideline, the term 'expert' refers to a healthcare professional who has core competencies to diagnose and manage acute illness. These competencies can be delivered by a variety of models at a local level, such as a critical care outreach team, a hospital-at-night team or a specialist trainee in an acute medical or surgical specialty. For more information, see Acutely ill patients in hospital (NICE clinical guideline 50). # Principles and protocols for intravenous fluid therapy The assessment and management of patients' fluid and electrolyte needs is fundamental to good patient care. Assess and manage patients' fluid and electrolyte needs as part of every ward review. Provide intravenous (IV) fluid therapy only for patients whose needs cannot be met by oral or enteral routes, and stop as soon as possible. Skilled and competent healthcare professionals should prescribe and administer IV fluids, and assess and monitor patients receiving IV fluids (see recommendations 1.6.1–1.6.3). When prescribing IV fluids, remember the 5 Rs: Resuscitation, Routine maintenance, Replacement, Redistribution and Reassessment. Offer IV fluid therapy as part of a protocol (see Algorithms for IV fluid therapy): Assess patients' fluid and electrolyte needs following Algorithm 1: Assessment. If patients need IV fluids for fluid resuscitation, follow Algorithm 2: Fluid resuscitation. If patients need IV fluids for routine maintenance, follow Algorithm 3: Routine maintenance. If patients need IV fluids to address existing deficits or excesses, ongoing abnormal losses or abnormal fluid distribution, follow Algorithm 4: Replacement and redistribution. ## Algorithms for IV fluid therapy Download the PDF here. Include the following information in IV fluid prescriptions: The type of fluid to be administered. The rate and volume of fluid to be administered. Patients should have an IV fluid management plan, which should include details of: the fluid and electrolyte prescription over the next 24 hours the assessment and monitoring plan.Initially, the IV fluid management plan should be reviewed by an expert daily. IV fluid management plans for patients on longer-term IV fluid therapy whose condition is stable may be reviewed less frequently. When prescribing IV fluids and electrolytes, take into account all other sources of fluid and electrolyte intake, including any oral or enteral intake, and intake from drugs, IV nutrition, blood and blood products. Patients have a valuable contribution to make to their fluid balance. If a patient needs IV fluids, explain the decision, and discuss the signs and symptoms they need to look out for if their fluid balance needs adjusting. If possible or when asked, provide written information (for example, NICE's Information for the public), and involve the patient's family members or carers (as appropriate). # Assessment and monitoring ## Initial assessment Assess whether the patient is hypovolaemic. Indicators that a patient may need urgent fluid resuscitation include: systolic blood pressure is less than 100 mmHg heart rate is more than 90 beats per minute capillary refill time is more than 2 seconds or peripheries are cold to touch respiratory rate is more than 20 breaths per minute National Early Warning Score (NEWS) is 5 or more passive leg raising suggests fluid responsiveness. Assess the patient's likely fluid and electrolyte needs from their history, clinical examination, current medications, clinical monitoring and laboratory investigations: History should include any previous limited intake, thirst, the quantity and composition of abnormal losses (see Diagram of ongoing losses), and any comorbidities, including patients who are malnourished and at risk of refeeding syndrome (see Nutrition support in adults ). Clinical examination should include an assessment of the patient's fluid status, including: pulse, blood pressure, capillary refill and jugular venous pressure presence of pulmonary or peripheral oedema presence of postural hypotension. Clinical monitoring should include current status and trends in: NEWS fluid balance charts weight. Laboratory investigations should include current status and trends in: full blood count urea, creatinine and electrolytes. ## Reassessment If patients are receiving IV fluids for resuscitation, reassess the patient using the ABCDE approach (Airway, Breathing, Circulation, Disability, Exposure), monitor their respiratory rate, pulse, blood pressure and perfusion continuously, and measure their venous lactate levels and/or arterial pH and base excess according to guidance on advanced life support (Resuscitation Council , 2011). All patients continuing to receive IV fluids need regular monitoring. This should initially include at least daily reassessments of clinical fluid status, laboratory values (urea, creatinine and electrolytes) and fluid balance charts, along with weight measurement twice weekly. Be aware that: Patients receiving IV fluid therapy to address replacement or redistribution problems may need more frequent monitoring. Additional monitoring of urinary sodium may be helpful in patients with high-volume gastrointestinal losses. (Reduced urinary sodium excretion may indicate total body sodium depletion even if plasma sodium levels are normal. Urinary sodium may also indicate the cause of hyponatraemia, and guide the achievement of a negative sodium balance in patients with oedema. However, urinary sodium values may be misleading in the presence of renal impairment or diuretic therapy.) Patients on longer-term IV fluid therapy whose condition is stable may be monitored less frequently, although decisions to reduce monitoring frequency should be detailed in their IV fluid management plan. If patients have received IV fluids containing chloride concentrations greater than 120 mmol/l (for example, sodium chloride 0.9%), monitor their serum chloride concentration daily. If patients develop hyperchloraemia or acidaemia, reassess their IV fluid prescription and assess their acid–base status. Consider less frequent monitoring for patients who are stable. Clear incidents of fluid mismanagement (for example, unnecessarily prolonged dehydration or inadvertent fluid overload due to IV fluid therapy) should be reported through standard critical incident reporting to encourage improved training and practice (see Consequences of fluid mismanagement to be reported as critical incidents). If patients are transferred to a different location, reassess their fluid status and IV fluid management plan on arrival in the new setting. # Resuscitation If patients need IV fluid resuscitation, use crystalloids that contain sodium in the range 130–154 mmol/l, with a bolus of 500 ml over less than 15 minutes. (For more information, see the Composition of commonly used crystalloids table.) Do not use tetrastarch for fluid resuscitation. Consider human albumin solution 4–5% for fluid resuscitation only in patients with severe sepsis. # Routine maintenance If patients need IV fluids for routine maintenance alone, restrict the initial prescription to: –30 ml/kg/day of water and approximately 1 mmol/kg/day of potassium, sodium and chloride and approximately 50–100 g/day of glucose to limit starvation ketosis. (This quantity will not address patients' nutritional needs; see Nutrition support in adults .) For more information see IV fluid prescription for routine maintenance over a 24-hour period. For patients who are obese, adjust the IV fluid prescription to their ideal body weight. Use lower range volumes per kg (patients rarely need more than a total of 3 litres of fluid per day) and seek expert help if their BMI is more than 40 kg/m2. Consider prescribing less fluid (for example, 20–25 ml/kg/day fluid) for patients who: are older or frail have renal impairment or cardiac failure are malnourished and at risk of refeeding syndrome (see Nutrition support in adults ). When prescribing for routine maintenance alone, consider using 25–30 ml/kg/day sodium chloride 0.18% in 4% glucose with 27 mmol/l potassium on day 1 (there are other regimens to achieve this). Prescribing more than 2.5 litres per day increases the risk of hyponatraemia. These are initial prescriptions and further prescriptions should be guided by monitoring. Consider delivering IV fluids for routine maintenance during daytime hours to promote sleep and wellbeing. # Replacement and redistribution Adjust the IV prescription (add to or subtract from maintenance needs) to account for existing fluid and/or electrolyte deficits or excesses, ongoing losses (see Diagram of ongoing losses) or abnormal distribution. Seek expert help if patients have a complex fluid and/or electrolyte redistribution issue or imbalance, or significant comorbidity, for example: gross oedema severe sepsis hyponatraemia or hypernatraemia renal, liver and/or cardiac impairment post-operative fluid retention and redistribution malnourished and refeeding issues (see Nutrition support in adults ). # Training and education Hospitals should establish systems to ensure that all healthcare professionals involved in prescribing and delivering IV fluid therapy are trained on the principles covered in this guideline, and are then formally assessed and reassessed at regular intervals to demonstrate competence in: understanding the physiology of fluid and electrolyte balance in patients with normal physiology and during illness assessing patients' fluid and electrolyte needs (the 5 Rs: Resuscitation, Routine maintenance, Replacement, Redistribution and Reassessment) assessing the risks, benefits and harms of IV fluids prescribing and administering IV fluids monitoring the patient response evaluating and documenting changes and taking appropriate action as required. Healthcare professionals should receive training and education about, and be competent in, recognising, assessing and preventing consequences of mismanaged IV fluid therapy, including: pulmonary oedema peripheral oedema volume depletion and shock. Hospitals should have an IV fluids lead, responsible for training, clinical governance, audit and review of IV fluid prescribing and patient outcomes. ## Diagram of ongoing losses Download the PDF here. Source: Copyright – National Clinical Guideline Centre ## Consequences of fluid mismanagement to be reported as critical incidents Consequence of fluid mismanagement Identifying features Time frame of identification Hypovolaemia Patient's fluid needs not met by oral, enteral or IV intake and Features of dehydration on clinical examination Low urine output or concentrated urine Biochemical indicators, such as more than 50% increase in urea or creatinine with no other identifiable cause Before and during IV fluid therapy Pulmonary oedema (breathlessness during infusion) No other obvious cause identified (for example, pneumonia, pulmonary embolus or asthma) Features of pulmonary oedema on clinical examination Features of pulmonary oedema on X‑ray During IV fluid therapy or within 6 hours of stopping IV fluids Hyponatraemia Serum sodium less than 130 mmol/l No other likely cause of hyponatraemia identified During IV fluid therapy or within 24 hours of stopping IV fluids Hypernatraemia Serum sodium 155 mmol/l or more Baseline sodium normal or low IV fluid regimen included 0.9% sodium chloride No other likely cause of hypernatraemia identified During IV fluid therapy or within 24 hours of stopping IV fluids Peripheral oedema Pitting oedema in extremities and/or lumbar sacral area No other obvious cause identified (for example, nephrotic syndrome or known cardiac failure) During IV fluid therapy or within 24 hours of stopping IV fluids Hyperkalaemia Serum potassium more than 5.5 mmol/l No other obvious cause identified During IV fluid therapy or within 24 hours of stopping IV fluids Hypokalaemia Serum potassium less than 3.0 mmol/l likely to be due to infusion of fluids without adequate potassium provision No other obvious cause (for example, potassium-wasting diuretics, refeeding syndrome) During IV fluid therapy or within 24 hours of stopping IV fluids Source: This table was drafted based on the consensus decision of the members of the Guideline Development Group. Weight-based potassium prescriptions should be rounded to the nearest common fluids available (for example, a 67 kg person should have fluids containing 20 mmol and 40 mmol of potassium in a 24-hour period). Potassium should not be added to intravenous fluid bags as this is dangerous. ## IV fluid prescription (by body weight) for routine maintenance over a 24‑hour period Body weight Water Sodium, chloride, potassium Body weight Water Sodium, chloride, potassium kg –30 ml/kg/day approx. 1 mmol/kg/day of each kg –30ml/kg/day approx. 1 mmol/kg/day of each Add 50–100 grams/day glucose (e.g. glucose 5% contains 5g/100ml). For special considerations refer to the recommendations for routine maintenance. Weight-based potassium prescriptions should be rounded to the nearest common fluids available (for example, a 67 kg person should have fluids containing 20 mmol and 40 mmol of potassium in a 24-hour period). Potassium should not be added to intravenous fluid bags as this is dangerous. Source: This table was drafted based on the consensus decision of the members of the Guideline Development Group. # More information You can also see this guideline in the NICE pathways on intravenous fluid therapy in hospital and sepsis. To find out what NICE has said on topics related to this guideline, see our web page on hospitals. See also the guideline committee's discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee. Passive leg raising is a bedside method to assess fluid responsiveness in a patient. It is best undertaken with the patient initially semi-recumbent and then tilting the entire bed through 45°. Alternatively it can be done by lying the patient flat and passively raising their legs to greater than 45°. If, at 30–90 seconds, the patient shows signs of haemodynamic improvement, it indicates that volume replacement may be required. If the condition of the patient deteriorates, in particular breathlessness, it indicates that the patient may be fluid overloaded. Weight-based potassium prescriptions should be rounded to the nearest common fluids available (for example, a 67 kg person should have fluids containing 20 mmol and 40 mmol of potassium in a 24-hour period). Potassium should not be added to intravenous fluid bags as this is dangerous.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline. # Assessment and monitoring What is the incidence of complications during, and as a consequence of, IV fluid therapy? ## Why this is important This is almost certainly under-reported in the ward setting with significant implications for patients, predominantly morbidity through to mortality. It is probable that complications of fluid therapy are frequent and may be associated with increased clinical needs, such as critical care and, on occasion, may necessitate fluid resuscitation. Lack of a set of clearly defined features of the complications of fluid mismanagement compounds the problem. It is important to define these features and then undertake an observational study in a hospital setting to determine the epidemiology of these complications. Such a study would highlight the prevalence of fluid related complications and inform the development of preventive measures.	{'Introduction ': "This guideline contains recommendations about general principles for managing intravenous (IV) fluids, and applies to a range of conditions and different settings. It does not include recommendations relating to specific conditions.\n\nMany adult hospital inpatients need intravenous (IV) fluid therapy to prevent or correct problems with their fluid and/or electrolyte status. Deciding on the optimal amount and composition of IV fluids to be administered and the best rate at which to give them can be a difficult and complex task, and decisions must be based on careful assessment of the patient's individual needs.\n\nErrors in prescribing IV fluids and electrolytes are particularly likely in emergency departments, acute admission units, and general medical and surgical wards rather than in operating theatres and critical care units. Surveys have shown that many staff who prescribe IV fluids know neither the likely fluid and electrolyte needs of individual patients, nor the specific composition of the many choices of IV fluids available to them. Standards of recording and monitoring IV fluid and electrolyte therapy may also be poor in these settings. IV fluid management in hospital is often delegated to the most junior medical staff who frequently lack the relevant experience and may have received little or no specific training on the subject.\n\nThe National Confidential Enquiry into Perioperative Deaths report in 1999 highlighted that a significant number of hospitalised patients were dying as a result of infusion of too much or too little fluid. The report recommended that fluid prescribing should be given the same status as drug prescribing. Although mismanagement of fluid therapy is rarely reported as being responsible for patient harm, it is likely that as many as 1 in 5\xa0patients on IV\xa0fluids and electrolytes suffer complications or morbidity due to their inappropriate administration.\n\nThere is also considerable debate about the best IV fluids to use (particularly for more seriously ill or injured patients), resulting in wide variation in clinical practice. Many reasons underlie the ongoing debate, but most revolve around difficulties in interpretation of both trial evidence and clinical experience, including the following factors:\n\nMany accepted practices of IV fluid prescribing were developed for historical reasons rather than through clinical trials.\n\nTrials cannot easily be included in meta-analyses because they examine varied outcome measures in heterogeneous groups, comparing not only different types of fluid with different electrolyte content, but also different volumes and rates of administration and, in some cases, the additional use of inotropes or vasopressors.\n\nMost trials have been undertaken in operating theatres and critical care units rather than admission units or general and elderly care settings.\n\nTrials claiming to examine best early therapy for fluid resuscitation have actually evaluated therapy choices made after initial fluid resuscitation, with patients already in critical care or operating theatres.\n\nMany trials inferring best therapy for fluid resuscitation after acute fluid loss have actually examined situations of hypovolaemia induced by anaesthesia.\n\nThere is a clear need for guidance on IV fluid therapy for general areas of hospital practice, covering both the prescription and monitoring of IV fluid and electrolyte therapy, and the training and educational needs of all hospital staff involved in IV fluid management.\n\nThe aim of this NICE guideline is to help prescribers understand the:\n\nphysiological principles that underpin fluid prescribing\n\npathophysiological changes that affect fluid balance in disease states\n\nindications for IV fluid therapy\n\nreasons for the choice of the various fluids available and\n\nprinciples of assessing fluid balance.\n\nIn developing the guideline, it was necessary to limit the scope by excluding patient groups with more specialised fluid prescribing needs. It is important to emphasise that the recommendations do not apply to patients under 16\xa0years, pregnant women, and those with severe liver or renal disease, diabetes or burns. They also do not apply to patients needing inotropes and those on intensive monitoring, and so they have less relevance to intensive care settings and patients during surgical anaesthesia. Patients with traumatic brain injury (including patients needing neurosurgery) are also excluded. The scope of the guideline does not cover the practical aspects of administration (as opposed to the prescription) of IV fluids.\n\nIt is hoped that this guideline will lead to better fluid prescribing in hospitalised patients, reduce morbidity and mortality, and lead to better patient outcomes.\n\nStrategies for further research into the subject have also been proposed.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.", 'Patient-centred care': "This guideline offers best practice advice on the care of people over 16\xa0years who are in hospital receiving intravenous fluid therapy.\n\nPatients and healthcare professionals have rights and responsibilities as set out in the NHS Constitution for England – all NICE guidance is written to reflect these. Treatment and care should take into account individual needs and preferences. Patients should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. Healthcare professionals should follow the Department of Health's advice on consent. If someone does not have capacity to make decisions, healthcare professionals should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards. In Wales, healthcare professionals should follow advice on consent from the Welsh Government.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in patient experience in adult NHS services.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Terms used in this guideline\n\nIn this guideline, the term 'expert' refers to a healthcare professional who has core competencies to diagnose and manage acute illness. These competencies can be delivered by a variety of models at a local level, such as a critical care outreach team, a hospital-at-night team or a specialist trainee in an acute medical or surgical specialty. For more information, see Acutely ill patients in hospital (NICE clinical guideline 50).\n\n# Principles and protocols for intravenous fluid therapy\n\nThe assessment and management of patients' fluid and electrolyte needs is fundamental to good patient care.\n\nAssess and manage patients' fluid and electrolyte needs as part of every ward review. Provide intravenous (IV) fluid therapy only for patients whose needs cannot be met by oral or enteral routes, and stop as soon as possible.\n\nSkilled and competent healthcare professionals should prescribe and administer IV fluids, and assess and monitor patients receiving IV fluids (see recommendations 1.6.1–1.6.3).\n\nWhen prescribing IV fluids, remember the 5\xa0Rs: Resuscitation, Routine maintenance, Replacement, Redistribution and Reassessment.\n\nOffer IV fluid therapy as part of a protocol (see Algorithms for IV fluid therapy):\n\nAssess patients' fluid and electrolyte needs following Algorithm\xa01: Assessment.\n\nIf patients need IV fluids for fluid resuscitation, follow Algorithm\xa02: Fluid resuscitation.\n\nIf patients need IV fluids for routine maintenance, follow Algorithm\xa03: Routine maintenance.\n\nIf patients need IV fluids to address existing deficits or excesses, ongoing abnormal losses or abnormal fluid distribution, follow Algorithm\xa04: Replacement and redistribution.\n\n## Algorithms for IV fluid therapy\n\nDownload the PDF here.\n\nInclude the following information in IV fluid prescriptions:\n\nThe type of fluid to be administered.\n\nThe rate and volume of fluid to be administered.\n\nPatients should have an IV fluid management plan, which should include details of:\n\nthe fluid and electrolyte prescription over the next 24\xa0hours\n\nthe assessment and monitoring plan.Initially, the IV fluid management plan should be reviewed by an expert daily. IV fluid management plans for patients on longer-term IV fluid therapy whose condition is stable may be reviewed less frequently.\n\nWhen prescribing IV fluids and electrolytes, take into account all other sources of fluid and electrolyte intake, including any oral or enteral intake, and intake from drugs, IV nutrition, blood and blood products.\n\nPatients have a valuable contribution to make to their fluid balance. If a patient needs IV fluids, explain the decision, and discuss the signs and symptoms they need to look out for if their fluid balance needs adjusting. If possible or when asked, provide written information (for example, NICE's Information for the public), and involve the patient's family members or carers (as appropriate).\n\n# Assessment and monitoring\n\n## Initial assessment\n\nAssess whether the patient is hypovolaemic. Indicators that a patient may need urgent fluid resuscitation include:\n\nsystolic blood pressure is less than 100\xa0mmHg\n\nheart rate is more than 90\xa0beats per minute\n\ncapillary refill time is more than 2\xa0seconds or peripheries are cold to touch\n\nrespiratory rate is more than 20\xa0breaths per minute\n\nNational Early Warning Score (NEWS) is 5\xa0or more\n\npassive leg raising suggests fluid responsiveness.\n\nAssess the patient's likely fluid and electrolyte needs from their history, clinical examination, current medications, clinical monitoring and laboratory investigations:\n\nHistory should include any previous limited intake, thirst, the quantity and composition of abnormal losses (see Diagram of ongoing losses), and any comorbidities, including patients who are malnourished and at risk of refeeding syndrome (see Nutrition support in adults [NICE clinical guideline\xa032]).\n\nClinical examination should include an assessment of the patient's fluid status, including:\n\n\n\npulse, blood pressure, capillary refill and jugular venous pressure\n\npresence of pulmonary or peripheral oedema\n\npresence of postural hypotension.\n\n\n\nClinical monitoring should include current status and trends in:\n\n\n\nNEWS\n\nfluid balance charts\n\nweight.\n\n\n\nLaboratory investigations should include current status and trends in:\n\n\n\nfull blood count\n\nurea, creatinine and electrolytes.\n\n\n\n## Reassessment\n\nIf patients are receiving IV fluids for resuscitation, reassess the patient using the ABCDE approach (Airway, Breathing, Circulation, Disability, Exposure), monitor their respiratory rate, pulse, blood pressure and perfusion continuously, and measure their venous lactate levels and/or arterial pH and base excess according to guidance on advanced life support (Resuscitation Council [UK], 2011).\n\nAll patients continuing to receive IV fluids need regular monitoring. This should initially include at least daily reassessments of clinical fluid status, laboratory values (urea, creatinine and electrolytes) and fluid balance charts, along with weight measurement twice weekly. Be aware that:\n\nPatients receiving IV fluid therapy to address replacement or redistribution problems may need more frequent monitoring.\n\nAdditional monitoring of urinary sodium may be helpful in patients with high-volume gastrointestinal losses. (Reduced urinary sodium excretion [less than 30\xa0mmol/l] may indicate total body sodium depletion even if plasma sodium levels are normal. Urinary sodium may also indicate the cause of hyponatraemia, and guide the achievement of a negative sodium balance in patients with oedema. However, urinary sodium values may be misleading in the presence of renal impairment or diuretic therapy.)\n\nPatients on longer-term IV fluid therapy whose condition is stable may be monitored less frequently, although decisions to reduce monitoring frequency should be detailed in their IV fluid management plan.\n\nIf patients have received IV fluids containing chloride concentrations greater than 120\xa0mmol/l (for example, sodium chloride\xa00.9%), monitor their serum chloride concentration daily. If patients develop hyperchloraemia or acidaemia, reassess their IV fluid prescription and assess their acid–base status. Consider less frequent monitoring for patients who are stable.\n\nClear incidents of fluid mismanagement (for example, unnecessarily prolonged dehydration or inadvertent fluid overload due to IV fluid therapy) should be reported through standard critical incident reporting to encourage improved training and practice (see Consequences of fluid mismanagement to be reported as critical incidents).\n\nIf patients are transferred to a different location, reassess their fluid status and IV fluid management plan on arrival in the new setting.\n\n# Resuscitation\n\nIf patients need IV fluid resuscitation, use crystalloids that contain sodium in the range 130–154\xa0mmol/l, with a bolus of 500\xa0ml over less than 15\xa0minutes. (For more information, see the Composition of commonly used crystalloids table.)\n\nDo not use tetrastarch for fluid resuscitation.\n\nConsider human albumin solution 4–5% for fluid resuscitation only in patients with severe sepsis.\n\n# Routine maintenance\n\nIf patients need IV fluids for routine maintenance alone, restrict the initial prescription to:\n\n–30\xa0ml/kg/day of water and\n\napproximately 1\xa0mmol/kg/day of potassium, sodium and chloride and\n\napproximately 50–100\xa0g/day of glucose to limit starvation ketosis. (This quantity will not address patients' nutritional needs; see Nutrition support in adults [NICE clinical guideline\xa032].) For more information see IV fluid prescription for routine maintenance over a 24-hour period.\n\nFor patients who are obese, adjust the IV fluid prescription to their ideal body weight. Use lower range volumes per kg (patients rarely need more than a total of 3\xa0litres of fluid per day) and seek expert help if their BMI is more than 40\xa0kg/m2.\n\nConsider prescribing less fluid (for example, 20–25\xa0ml/kg/day fluid) for patients who:\n\nare older or frail\n\nhave renal impairment or cardiac failure\n\nare malnourished and at risk of refeeding syndrome (see Nutrition support in adults [NICE clinical guideline 32]).\n\nWhen prescribing for routine maintenance alone, consider using 25–30\xa0ml/kg/day sodium chloride 0.18% in 4% glucose with 27\xa0mmol/l potassium on day\xa01 (there are other regimens to achieve this). Prescribing more than 2.5\xa0litres per day increases the risk of hyponatraemia. These are initial prescriptions and further prescriptions should be guided by monitoring.\n\nConsider delivering IV fluids for routine maintenance during daytime hours to promote sleep and wellbeing.\n\n# Replacement and redistribution\n\nAdjust the IV prescription (add to or subtract from maintenance needs) to account for existing fluid and/or electrolyte deficits or excesses, ongoing losses (see Diagram of ongoing losses) or abnormal distribution.\n\nSeek expert help if patients have a complex fluid and/or electrolyte redistribution issue or imbalance, or significant comorbidity, for example:\n\ngross oedema\n\nsevere sepsis\n\nhyponatraemia or hypernatraemia\n\nrenal, liver and/or cardiac impairment\n\npost-operative fluid retention and redistribution\n\nmalnourished and refeeding issues (see Nutrition support in adults [NICE clinical guideline 32]).\n\n# Training and education\n\nHospitals should establish systems to ensure that all healthcare professionals involved in prescribing and delivering IV fluid therapy are trained on the principles covered in this guideline, and are then formally assessed and reassessed at regular intervals to demonstrate competence in:\n\nunderstanding the physiology of fluid and electrolyte balance in patients with normal physiology and during illness\n\nassessing patients' fluid and electrolyte needs (the 5\xa0Rs: Resuscitation, Routine maintenance, Replacement, Redistribution and Reassessment)\n\nassessing the risks, benefits and harms of IV fluids\n\nprescribing and administering IV fluids\n\nmonitoring the patient response\n\nevaluating and documenting changes and\n\ntaking appropriate action as required.\n\nHealthcare professionals should receive training and education about, and be competent in, recognising, assessing and preventing consequences of mismanaged IV fluid therapy, including:\n\npulmonary oedema\n\nperipheral oedema\n\nvolume depletion and shock.\n\nHospitals should have an IV fluids lead, responsible for training, clinical governance, audit and review of IV fluid prescribing and patient outcomes.\n\n## Diagram of ongoing losses\n\nDownload the PDF here.\n\nSource: Copyright – National Clinical Guideline Centre\n\n## Consequences of fluid mismanagement to be reported as critical incidents\n\nConsequence of fluid mismanagement\n\nIdentifying features\n\nTime frame of identification\n\nHypovolaemia\n\nPatient's fluid needs not met by oral, enteral or IV intake and\n\nFeatures of dehydration on clinical examination\n\nLow urine output or concentrated urine\n\nBiochemical indicators, such as more than 50% increase in urea or creatinine with no other identifiable cause\n\nBefore and during IV fluid therapy\n\nPulmonary oedema\n\n(breathlessness during infusion)\n\nNo other obvious cause identified (for example, pneumonia, pulmonary embolus or asthma)\n\nFeatures of pulmonary oedema on clinical examination\n\nFeatures of pulmonary oedema on X‑ray\n\nDuring IV fluid therapy or within 6\xa0hours of stopping IV fluids\n\nHyponatraemia\n\nSerum sodium less than 130\xa0mmol/l\n\nNo other likely cause of hyponatraemia identified\n\nDuring IV fluid therapy or within 24\xa0hours of stopping IV fluids\n\nHypernatraemia\n\nSerum sodium 155\xa0mmol/l or more\n\nBaseline sodium normal or low\n\nIV fluid regimen included 0.9% sodium chloride\n\nNo other likely cause of hypernatraemia identified\n\nDuring IV fluid therapy or within 24\xa0hours of stopping IV fluids\n\nPeripheral oedema\n\nPitting oedema in extremities and/or lumbar sacral area\n\nNo other obvious cause identified (for example, nephrotic syndrome or known cardiac failure)\n\nDuring IV fluid therapy or within 24\xa0hours of stopping IV fluids\n\nHyperkalaemia\n\nSerum potassium more than 5.5\xa0mmol/l\n\nNo other obvious cause identified\n\nDuring IV fluid therapy or within 24\xa0hours of stopping IV fluids\n\nHypokalaemia\n\nSerum potassium less than 3.0\xa0mmol/l likely to be due to infusion of fluids without adequate potassium provision\n\nNo other obvious cause (for example, potassium-wasting diuretics, refeeding syndrome)\n\nDuring IV fluid therapy or within 24\xa0hours of stopping IV fluids\n\nSource: This table was drafted based on the consensus decision of the members of the Guideline Development Group. Weight-based potassium prescriptions should be rounded to the nearest common fluids available (for example, a 67\xa0kg person should have fluids containing 20\xa0mmol and 40\xa0mmol of potassium in a 24-hour period). Potassium should not be added to intravenous fluid bags as this is dangerous.\n\n## IV fluid prescription (by body weight) for routine maintenance over a 24‑hour period\n\nBody weight\n\nWater\n\nSodium, chloride, potassium\n\n\n\nBody weight\n\nWater\n\nSodium, chloride, potassium\n\nkg\n\n–30 ml/kg/day\n\napprox. 1\xa0mmol/kg/day of each\n\nkg\n\n–30ml/kg/day\n\napprox. 1\xa0mmol/kg/day of each\n\n\n\n–1200\n\n\n\n\n\n–2130\n\n\n\n\n\n–1230\n\n\n\n\n\n–2160\n\n\n\n\n\n–1260\n\n\n\n\n\n–2190\n\n\n\n\n\n–1290\n\n\n\n\n\n–2220\n\n\n\n\n\n–1320\n\n\n\n\n\n–2250\n\n\n\n\n\n–1350\n\n\n\n\n\n–2280\n\n\n\n\n\n–1380\n\n\n\n\n\n–2310\n\n\n\n\n\n–1410\n\n\n\n\n\n–2340\n\n\n\n\n\n–1440\n\n\n\n\n\n–2370\n\n\n\n\n\n–1470\n\n\n\n\n\n–2400\n\n\n\n\n\n–1500\n\n\n\n\n\n–2430\n\n\n\n\n\n–1530\n\n\n\n\n\n–2460\n\n\n\n\n\n–1560\n\n\n\n\n\n–2490\n\n\n\n\n\n–1590\n\n\n\n\n\n–2520\n\n\n\n\n\n–1620\n\n\n\n\n\n–2550\n\n\n\n\n\n–1650\n\n\n\n\n\n–2580\n\n\n\n\n\n–1680\n\n\n\n\n\n–2610\n\n\n\n\n\n–1710\n\n\n\n\n\n–2640\n\n\n\n\n\n–1740\n\n\n\n\n\n–2670\n\n\n\n\n\n–1770\n\n\n\n\n\n–2700\n\n\n\n\n\n–1800\n\n\n\n\n\n–2730\n\n\n\n\n\n–1830\n\n\n\n\n\n–2760\n\n\n\n\n\n–1860\n\n\n\n\n\n–2790\n\n\n\n\n\n–1890\n\n\n\n\n\n–2820\n\n\n\n\n\n–1920\n\n\n\n\n\n–2850\n\n\n\n\n\n–1950\n\n\n\n\n\n–2880\n\n\n\n\n\n–1980\n\n\n\n\n\n–2910\n\n\n\n\n\n–2010\n\n\n\n\n\n–2940\n\n\n\n\n\n–2040\n\n\n\n\n\n–2970\n\n\n\n\n\n–2070\n\n\n\n\n\n–3000\n\n\n\n\n\n–2100\n\n\n\n>100\n\n–3000\n\n\n\nAdd 50–100 grams/day glucose (e.g. glucose 5% contains 5g/100ml).\n\nFor special considerations refer to the recommendations for routine maintenance.\n\nWeight-based potassium prescriptions should be rounded to the nearest common fluids available (for example, a 67 kg person should have fluids containing 20 mmol and 40 mmol of potassium in a 24-hour period). Potassium should not be added to intravenous fluid bags as this is dangerous.\n\nSource: This table was drafted based on the consensus decision of the members of the Guideline Development Group.\n\n# More information\n\nYou can also see this guideline in the NICE pathways on intravenous fluid therapy in hospital and sepsis.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on hospitals.\n\nSee also the guideline committee's discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee.\n\n Passive leg raising is a bedside method to assess fluid responsiveness in a patient. It is best undertaken with the patient initially semi-recumbent and then tilting the entire bed through 45°. Alternatively it can be done by lying the patient flat and passively raising their legs to greater than 45°. If, at 30–90\xa0seconds, the patient shows signs of haemodynamic improvement, it indicates that volume replacement may be required. If the condition of the patient deteriorates, in particular breathlessness, it indicates that the patient may be fluid overloaded.\n\n Weight-based potassium prescriptions should be rounded to the nearest common fluids available (for example, a 67\xa0kg person should have fluids containing 20\xa0mmol and 40\xa0mmol of potassium in a 24-hour period). Potassium should not be added to intravenous fluid bags as this is dangerous.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# Assessment and monitoring\n\nWhat is the incidence of complications during, and as a consequence of, IV fluid therapy?\n\n## Why this is important\n\nThis is almost certainly under-reported in the ward setting with significant implications for patients, predominantly morbidity through to mortality. It is probable that complications of fluid therapy are frequent and may be associated with increased clinical needs, such as critical care and, on occasion, may necessitate fluid resuscitation. Lack of a set of clearly defined features of the complications of fluid mismanagement compounds the problem. It is important to define these features and then undertake an observational study in a hospital setting to determine the epidemiology of these complications. Such a study would highlight the prevalence of fluid related complications and inform the development of preventive measures."}	https://www.nice.org.uk/guidance/cg174	This guideline covers the general principles for managing intravenous (IV) fluid therapy in hospital inpatients aged 16 and over with a range of conditions. It aims to help prescribers understand the optimal amount and composition of IV fluids to be administered and the best rate at which to give them, to improve fluid prescribing and outcomes among people in hospital. It does not cover pregnant women, and those with severe liver or renal disease, diabetes or burns.
349c5d4259482fc27f67d51456cb06af71f06842	nice	Irreversible electroporation for treating pancreatic cancer	Irreversible electroporation for treating pancreatic cancer Evidence-based recommendations on irreversible electroporation for treating pancreatic cancer. This involves inserting special needles into the tumour in the pancreas. Short electrical pulses of a high voltage current are then passed through the needles. The aim is to destroy the cancer cells. # Recommendations Current evidence on the safety and efficacy of irreversible electroporation for treating pancreatic cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Further research, preferably in the form of randomised controlled trials, should assess the effect of the procedure on local tumour control, patient survival, pain control and quality of life.# Indications and current treatments Pancreatic cancer usually causes few symptoms until the disease has reached an advanced stage, so most cases are diagnosed when curative treatment is not possible. Because potentially curative surgery is rarely an option, most patients can only be offered palliative treatment to relieve their symptoms. Stenting of the bile duct and duodenum can be used to relieve obstruction caused by pancreatic cancer, and sometimes surgical bypass is needed. Other treatment options include palliative chemotherapy and radiotherapy.# The procedure The aim of irreversible electroporation (IRE) is to destroy cancerous cells using a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cells' homeostatic mechanisms and leading to cell death. In pancreatic cancer, IRE is usually done to increase survival in people with locally advanced disease, or to treat resection margins to increase the success of curative surgical resection. The procedure is done with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Several electrode needles (typically 3 to 5) are introduced percutaneously (or by open surgical or laparoscopic approaches), and inserted in and adjacent to the tumour using image guidance. A series of very short electrical pulses is delivered over several minutes to destroy the tumour. The electrodes may be repositioned under imaging guidance to extend the zone of electroporation until the entire tumour and an appropriate margin have been destroyed. To minimise the risk of arrhythmia, cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a registry of 200 patients with locally advanced (stage III) pancreatic adenocarcinoma (LAPC) treated by irreversible electroporation (IRE; n=50 for IRE plus resection for margin enhancement and n=150 for IRE alone), the median overall survival from the date of diagnosis was 28.3 months (range 9.2 to 85.0 months) for the resection plus IRE group (n=50) and 23.2 months (range 4.9 to 76.1 months) for the IRE alone group (n=150). The median overall survival from the day of IRE treatment for the resection plus IRE group was 23.0 months (range 8.3 to 36.3 months) and for the IRE alone group was 18.0 months (range 4.9 to 55.4 months). The median overall progression-free survival for all patients was 12.4. In a case series of 50 patients with LAPC (T4 lesions) treated by IRE for primary treatment (n=29) or margin extension (n=24), the median overall survival for all patients was 12.03 months (95% confidence interval 7.71 to 23.12). For the primary treatment group it was 7.71 months (95% CI 6.03 to 12.0 months) and overall survival was not reached in the margin-extension group (p=0.01, log rank). In a case series of 21 patients with unresectable pancreatic carcinoma without metastatic disease (TNM stage III) treated by IRE, the median survival after treatment was 10.2 months compared with 9.3 months in a matched cohort (hazard ratio=0.54, p=0.053). A propensity matched case control study compared IRE plus chemotherapy or radiotherapy (n=54) with chemotherapy or radiotherapy alone (n=85). Some patients in the IRE group also had resection at the same time as the IRE procedure (19/54 patients). There are some inconsistencies between the data in the main text, the figure, and the abstract in this paper. In the text, the authors reported that local progression-free survival in the IRE group was 14.0 months compared with 6.0 months in the comparison group, p=0.01; distant progression-free survival was 15.0 months compared with 9.0 months, p=0.02; and median overall survival was 20 months compared with 11 months, p=0.03. The figure in this paper suggests median OS in the IRE group was 17 months. The survival curves for the 2 groups overlap at 20 months. The patients who had resection with simultaneous IRE (19/54) did not have statistically significantly improved survival compared with IRE alone (35/54; 23.1 months compared with 17.2 months, p=0.1). In the registry of 200 patients with LAPC (TNM stage III) treated by IRE plus resection for margin enhancement (n=50) or IRE alone (n=150), recurrence (defined as persistent viable tumour assessed using dynamic imaging and compared with pre-IRE scanning or tissue diagnosis) was reported in 29% (58/200) of patients. The most common site of disease recurrence was the liver (n=34), followed by lymph nodes (n=11) and the peritoneum (n=7). Local recurrence after IRE success (defined as new low density lesions of 1 cm in the IRE region even without symptoms) was reported in 6 patients. In a case series of 50 patients with LAPC (T4 lesions) treated by IRE for primary treatment (n=29) or margin extension (n=24), overall recurrence was 58% after a median follow-up of 8.69 months (range 0.26 to 16.26 months). Distant recurrence was 47% at a median of 9.20 months (95% CI 6.66 to 16.98) and local recurrence was 11% at a median of 8.60 months (95% CI 5.51 to not reached). Neither local nor distant recurrence differed statistically significantly between the primary treatment group (p=0.500, log rank) and the margin-extension group (p=0.361, log rank).In the case series of 25 patients with LAPC treated by percutaneous computed tomographic-guided IRE, after a median follow-up of 12 months, median event-free survival after IRE was 8 months (95% CI 4 months to 12 months). In a case series of 21 patients with unresectable LAPC (TNM stage III) treated by IRE, quality of life was measured at each follow-up using the Karnofsky performance scale (range 0% to 100%, with 100 representing 'completely normal' life). Quality of life declined slowly until about 8 weeks before death, when there was a sharp decline. The specialist advisers listed key efficacy outcomes as overall and relapse-free patient survival, local tumour control, and tumour response (complete or partial).# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of innovative ablative therapies for locally advanced pancreatic cancer (LAPC) including 141 patients (from 4 studies) treated by irreversible electroporation (IRE), overall mortality rate was 3% (3/92) in 3 studies using IRE. Two of these deaths were in patients treated by an open approach and 1 was in a patient treated by a percutaneous approach. The IRE-related mortality rate was 2% (2/87) in patients treated by an open approach. Death within 90 days (median 26 days, range 8 to 42 days) after an IRE procedure was reported in 11% (6/50) of patients in a case series of 50 patients with LAPC (T4 lesions) treated by IRE for primary treatment (n=29) or margin extension (n=24). Five of these deaths were in the primary treatment group (n=29) and 1 was in the margin-extension group (n=24). In the systematic review of 141 patients, 48% (44/92) of patients reported complications. Of these, 51% (41/81) were in patients treated by an open approach and 27% (3/11) were in patients treated by a percutaneous approach. Overall, 13% (5/38) of complications were related to an IRE procedure (open 15% ; percutaneous 9% ). Morbidity related to IRE mainly consisted of duodenal leakage (in patients with transduodenal needle placement or stent removal), pancreatic leakage, bile leakage and progression of portal vein thrombosis. Pancreatic complications (including pancreatic leakage, pancreatitis and pancreatic failure) were reported in 4% (2/50) of patients in the IRE plus resection group (n=50) and none in the IRE alone group (n=150) at 90-day follow-up in a registry of 200 patients with stage 3 LAPC treated by IRE. Pancreatic fistula (treated with a stoma bag and antibiotics) in 1 patient and peripancreatic abscess (treated with percutaneous drainage and antibiotics) in 1 patient were reported in a case series of 21 patients with unresectable pancreatic cancer treated by IRE. Liver complications (including ascites, biliary stricture, liver dysfunction and failure) were reported in 14% (7/50) of patients in the IRE plus resection group (n=50) and 9% (13/150) of patients in the IRE alone group (n=150) at 90-day follow-up in the registry of 200 patients. Biliary peritonitis, cholangitis and liver abscess (needing revision surgery and antibiotics) were reported in 1 patient in the case series of 21 patients. Duodenal and bile duct necrosis (needing trans-hepatic drain insertion) and haemorrhage (needing transfusion) were reported in 1 patient in the case series of 50 patients. Bile duct obstruction and biliary stent obstruction after IRE treatment were reported as the most common reasons for readmission in another case series (conference abstract) of 50 patients with LAPC treated by IRE. Bile leakage was reported in 3 patients in a case series of 48 patients with borderline resectable pancreatic cancer or LAPC treated by IRE. Liver insufficiency was reported in 4 patients in a case series of 65 patients with LAPC treated by IRE. Severe complications including bowel perforation (abscess formation and perforation of the duodenum and transverse colon close to the stent) and bleeding from a pancreatic branch of the superior mesenteric artery (due to pseudo-aneurysm) leading to death were reported after IRE treatment in a case report of 1 patient with pancreatic cancer who had a metallic stent in the common bile duct. Duodenal leakage (from transduodenal IRE needle placement) was reported in 1 patient in 1 study included in a systematic review of 74 patients with LAPC treated by IRE. Fistula and abscess in the abdominal wall (treated with drainage and antibiotics) was reported in 1 patient in the case series of 21 patients. Delayed gastric emptying (needing total parenteral nutrition and percutaneous endoscopic gastrostomy tube insertion) in 4 patients, upper gastrointestinal bleeding (needing transfusion and medical management) in 3 patients, duodenal cutaneous fistula in 1 patient and perforated gastric ulcer (needing drain placement) in 1 patient were reported in the case series of 50 patients. Ileus was reported in 5 patients in the case series of 65 patients treated with IRE. Small bowel leakage (grade 2) was reported in 1 patient in the case series of 48 patients. Other gastrointestinal complications (including anorexia, dehydration, gastritis, heartburn, nausea, vomiting) were reported in 16% (8/50) of patients in the IRE plus resection group (n=50) and 25% (38/150) of patients in the IRE alone group (n=150) at 90‑day follow-up in the registry of 200 patients. Vascular complications (including deep vein thrombosis, pseudo-aneurysm, hepatic arterial thrombosis, non-occlusive superior mesenteric vein/portal vein thrombosis) were reported in 8% (4/50) of patients in the IRE plus resection group (n=50) and 5% (7/150) of patients in the IRE alone group (n=150) at 90‑day follow-up in the registry of 200 patients. Intraoperative haemorrhage (needing transfusion) and angiogram embolisation of the gastroduodenal artery leading to multi-organ failure was reported in 1 patient in the case series of 50 patients. Disseminated intravascular coagulopathy (leading to death 7 days after IRE because of intracranial haemorrhage) was reported in 1 patient in a case series of 8 patients with borderline resectable PC or LAPC treated by IRE. Hepatic artery graft failure was reported in 1 patient in the case series of 48 patients. Partial splenic infarction (needing no treatment) in 1 patient was reported during percutaneous IRE ablation in a case series of 15 patients with LAPC or metastatic disease treated by IRE. Cardiovascular complications (including atrial fibrillation) were reported in 4% (2/50) of patients in the IRE plus resection group (n=50) at 90–day follow-up in the registry of 200 patients. Arrhythmia developed in 2 patients during IRE procedures in the case series of 8 patients. Pneumothorax (n=1) and pulmonary problems (n=3) were reported in the studies included in the systematic review of 74 patients. Sepsis needing reoperation was reported in 1 patient in the case series (conference abstract) of 50 patients treated by IRE. The patient died postoperatively. Infection was reported in 6% (3/50) of patients in the IRE plus resection group (n=50) and 9% (13/150) of patients in the IRE alone group (n=150) at 90‑day follow-up in the registry of 200 patients. Deep surgical site infection (needing drain placement) was reported in 3 patients in the case series of 50 patients treated by IRE. In the registry of 200 patients other complications included urinary tract problems (in 7 patients), renal failure (in 1 patient), wound problems (in 6 patients), neurological changes (in 4 patients), haematological events (in 2 patients) and other adverse events (in 23 patients). The case series of 48 patients also reported complications such as hepatojejunostomy stricture (in 1 patient), pain (in 1 patient) and postoperative bleeding (in 2 patients). In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: vessel occlusion (permanent or transient and due to oedema post-IRE causing compression of an involved superior mesenteric vein). They considered that the following were theoretical adverse events: damage to major arteries or veins, gastrointestinal tract injury (for example, stomach, duodenum, small or large bowel).# Further information For related NICE guidance, see the NICE website. Patient commentary was sought but none was received. However, the committee noted the views and experiences of patients (submitted during consultation) in their discussions. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2453-0	{'Recommendations': 'Current evidence on the safety and efficacy of irreversible electroporation for treating pancreatic cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research.\n\nFurther research, preferably in the form of randomised controlled trials, should assess the effect of the procedure on local tumour control, patient survival, pain control and quality of life.', 'Indications and current treatments': 'Pancreatic cancer usually causes few symptoms until the disease has reached an advanced stage, so most cases are diagnosed when curative treatment is not possible.\n\nBecause potentially curative surgery is rarely an option, most patients can only be offered palliative treatment to relieve their symptoms. Stenting of the bile duct and duodenum can be used to relieve obstruction caused by pancreatic cancer, and sometimes surgical bypass is needed. Other treatment options include palliative chemotherapy and radiotherapy.', 'The procedure': "The aim of irreversible electroporation (IRE) is to destroy cancerous cells using a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cells' homeostatic mechanisms and leading to cell death.\n\nIn pancreatic cancer, IRE is usually done to increase survival in people with locally advanced disease, or to treat resection margins to increase the success of curative surgical resection.\n\nThe procedure is done with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Several electrode needles (typically 3 to 5) are introduced percutaneously (or by open surgical or laparoscopic approaches), and inserted in and adjacent to the tumour using image guidance. A series of very short electrical pulses is delivered over several minutes to destroy the tumour. The electrodes may be repositioned under imaging guidance to extend the zone of electroporation until the entire tumour and an appropriate margin have been destroyed.\n\nTo minimise the risk of arrhythmia, cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle.", 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a registry of 200\xa0patients with locally advanced (stage\xa0III) pancreatic adenocarcinoma (LAPC) treated by irreversible electroporation (IRE; n=50 for IRE plus resection for margin enhancement and n=150 for IRE alone), the median overall survival from the date of diagnosis was 28.3\xa0months (range 9.2 to 85.0\xa0months) for the resection plus IRE group (n=50) and 23.2\xa0months (range 4.9 to 76.1\xa0months) for the IRE alone group (n=150). The median overall survival from the day of IRE treatment for the resection plus IRE group was 23.0\xa0months (range 8.3 to 36.3\xa0months) and for the IRE alone group was 18.0\xa0months (range 4.9 to 55.4\xa0months). The median overall progression-free survival for all patients was 12.4. In a case series of 50\xa0patients with LAPC (T4 lesions) treated by IRE for primary treatment (n=29) or margin extension (n=24), the median overall survival for all patients was 12.03\xa0months (95% confidence interval [CI] 7.71 to 23.12). For the primary treatment group it was 7.71\xa0months (95% CI 6.03 to 12.0\xa0months) and overall survival was not reached in the margin-extension group (p=0.01, log rank). In a case series of 21\xa0patients with unresectable pancreatic carcinoma without metastatic disease (TNM stage III) treated by IRE, the median survival after treatment was 10.2\xa0months compared with 9.3\xa0months in a matched cohort (hazard ratio=0.54, p=0.053). A propensity matched case control study compared IRE plus chemotherapy or radiotherapy (n=54) with chemotherapy or radiotherapy alone (n=85). Some patients in the IRE group also had resection at the same time as the IRE procedure (19/54\xa0patients). There are some inconsistencies between the data in the main text, the figure, and the abstract in this paper. In the text, the authors reported that local progression-free survival in the IRE group was 14.0\xa0months compared with 6.0\xa0months in the comparison group, p=0.01; distant progression-free survival was 15.0\xa0months compared with 9.0\xa0months, p=0.02; and median overall survival was 20\xa0months compared with 11\xa0months, p=0.03. The figure in this paper suggests median OS in the IRE group was 17\xa0months. The survival curves for the 2 groups overlap at 20\xa0months. The patients who had resection with simultaneous IRE (19/54) did not have statistically significantly improved survival compared with IRE alone (35/54; 23.1\xa0months compared with 17.2\xa0months, p=0.1).\n\nIn the registry of 200\xa0patients with LAPC (TNM stage\xa0III) treated by IRE plus resection for margin enhancement (n=50) or IRE alone (n=150), recurrence (defined as persistent viable tumour assessed using dynamic imaging and compared with pre-IRE scanning or tissue diagnosis) was reported in 29% (58/200) of patients. The most common site of disease recurrence was the liver (n=34), followed by lymph nodes (n=11) and the peritoneum (n=7). Local recurrence after IRE success (defined as new low density lesions of 1\xa0cm in the IRE region even without symptoms) was reported in 6\xa0patients. In a case series of 50\xa0patients with LAPC (T4\xa0lesions) treated by IRE for primary treatment (n=29) or margin extension (n=24), overall recurrence was 58% after a median follow-up of 8.69\xa0months (range 0.26 to 16.26\xa0months). Distant recurrence was 47% at a median of 9.20\xa0months (95% CI 6.66 to 16.98) and local recurrence was 11% at a median of 8.60\xa0months (95%\xa0CI 5.51 to not reached). Neither local nor distant recurrence differed statistically significantly between the primary treatment group (p=0.500, log rank) and the margin-extension group (p=0.361, log rank).In the case series of 25\xa0patients with LAPC treated by percutaneous computed tomographic-guided IRE, after a median follow-up of 12\xa0months, median event-free survival after IRE was 8\xa0months (95% CI 4\xa0months to 12\xa0months).\n\nIn a case series of 21\xa0patients with unresectable LAPC (TNM stage\xa0III) treated by IRE, quality of life was measured at each follow-up using the Karnofsky performance scale (range 0% to 100%, with 100 representing 'completely normal' life). Quality of life declined slowly until about 8\xa0weeks before death, when there was a sharp decline.\n\nThe specialist advisers listed key efficacy outcomes as overall and relapse-free patient survival, local tumour control, and tumour response (complete or partial).", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of innovative ablative therapies for locally advanced pancreatic cancer (LAPC) including 141\xa0patients (from 4\xa0studies) treated by irreversible electroporation (IRE), overall mortality rate was 3% (3/92) in 3\xa0studies using IRE. Two of these deaths were in patients treated by an open approach and 1\xa0was in a patient treated by a percutaneous approach. The IRE-related mortality rate was 2% (2/87) in patients treated by an open approach. Death within 90\xa0days (median 26\xa0days, range 8 to 42\xa0days) after an IRE procedure was reported in 11% (6/50) of patients in a case series of 50\xa0patients with LAPC (T4\xa0lesions) treated by IRE for primary treatment (n=29) or margin extension (n=24). Five of these deaths were in the primary treatment group (n=29) and 1\xa0was in the margin-extension group (n=24).\n\nIn the systematic review of 141\xa0patients, 48% (44/92) of patients reported complications. Of these, 51% (41/81) were in patients treated by an open approach and 27% (3/11) were in patients treated by a percutaneous approach. Overall, 13% (5/38) of complications were related to an IRE procedure (open 15% [4/27]; percutaneous 9% [1/11]). Morbidity related to IRE mainly consisted of duodenal leakage (in patients with transduodenal needle placement or stent removal), pancreatic leakage, bile leakage and progression of portal vein thrombosis.\n\nPancreatic complications (including pancreatic leakage, pancreatitis and pancreatic failure) were reported in 4% (2/50) of patients in the IRE plus resection group (n=50) and none in the IRE alone group (n=150) at 90-day follow-up in a registry of 200\xa0patients with stage\xa03 LAPC treated by IRE. Pancreatic fistula (treated with a stoma bag and antibiotics) in 1\xa0patient and peripancreatic abscess (treated with percutaneous drainage and antibiotics) in 1\xa0patient were reported in a case series of 21\xa0patients with unresectable pancreatic cancer treated by IRE.\n\nLiver complications (including ascites, biliary stricture, liver dysfunction and failure) were reported in 14% (7/50) of patients in the IRE plus resection group (n=50) and 9% (13/150) of patients in the IRE alone group (n=150) at 90-day follow-up in the registry of 200\xa0patients. Biliary peritonitis, cholangitis and liver abscess (needing revision surgery and antibiotics) were reported in 1\xa0patient in the case series of 21\xa0patients. Duodenal and bile duct necrosis (needing trans-hepatic drain insertion) and haemorrhage (needing transfusion) were reported in 1\xa0patient in the case series of 50\xa0patients. Bile duct obstruction and biliary stent obstruction after IRE treatment were reported as the most common reasons for readmission in another case series (conference abstract) of 50\xa0patients with LAPC treated by IRE. Bile leakage was reported in 3\xa0patients in a case series of 48\xa0patients with borderline resectable pancreatic cancer or LAPC treated by IRE. Liver insufficiency was reported in 4\xa0patients in a case series of 65\xa0patients with LAPC treated by IRE.\n\nSevere complications including bowel perforation (abscess formation and perforation of the duodenum and transverse colon close to the stent) and bleeding from a pancreatic branch of the superior mesenteric artery (due to pseudo-aneurysm) leading to death were reported after IRE treatment in a case report of 1\xa0patient with pancreatic cancer who had a metallic stent in the common bile duct. Duodenal leakage (from transduodenal IRE needle placement) was reported in 1\xa0patient in 1\xa0study included in a systematic review of 74\xa0patients with LAPC treated by IRE. Fistula and abscess in the abdominal wall (treated with drainage and antibiotics) was reported in 1\xa0patient in the case series of 21\xa0patients. Delayed gastric emptying (needing total parenteral nutrition and percutaneous endoscopic gastrostomy tube insertion) in 4\xa0patients, upper gastrointestinal bleeding (needing transfusion and medical management) in 3\xa0patients, duodenal cutaneous fistula in 1\xa0patient and perforated gastric ulcer (needing drain placement) in 1\xa0patient were reported in the case series of 50\xa0patients. Ileus was reported in 5\xa0patients in the case series of 65\xa0patients treated with IRE. Small bowel leakage (grade\xa02) was reported in 1\xa0patient in the case series of 48\xa0patients. Other gastrointestinal complications (including anorexia, dehydration, gastritis, heartburn, nausea, vomiting) were reported in 16% (8/50) of patients in the IRE plus resection group (n=50) and 25% (38/150) of patients in the IRE alone group (n=150) at 90‑day follow-up in the registry of 200\xa0patients.\n\nVascular complications (including deep vein thrombosis, pseudo-aneurysm, hepatic arterial thrombosis, non-occlusive superior mesenteric vein/portal vein thrombosis) were reported in 8% (4/50) of patients in the IRE plus resection group (n=50) and 5% (7/150) of patients in the IRE alone group (n=150) at 90‑day follow-up in the registry of 200\xa0patients. Intraoperative haemorrhage (needing transfusion) and angiogram embolisation of the gastroduodenal artery leading to multi-organ failure was reported in 1\xa0patient in the case series of 50\xa0patients. Disseminated intravascular coagulopathy (leading to death 7\xa0days after IRE because of intracranial haemorrhage) was reported in 1\xa0patient in a case series of 8\xa0patients with borderline resectable PC or LAPC treated by IRE. Hepatic artery graft failure was reported in 1\xa0patient in the case series of 48\xa0patients. Partial splenic infarction (needing no treatment) in 1\xa0patient was reported during percutaneous IRE ablation in a case series of 15\xa0patients with LAPC or metastatic disease treated by IRE.\n\nCardiovascular complications (including atrial fibrillation) were reported in 4% (2/50) of patients in the IRE plus resection group (n=50) at 90–day follow-up in the registry of 200\xa0patients. Arrhythmia developed in 2\xa0patients during IRE procedures in the case series of 8\xa0patients.\n\nPneumothorax (n=1) and pulmonary problems (n=3) were reported in the studies included in the systematic review of 74\xa0patients.\n\nSepsis needing reoperation was reported in 1\xa0patient in the case series (conference abstract) of 50\xa0patients treated by IRE. The patient died postoperatively. Infection was reported in 6% (3/50) of patients in the IRE plus resection group (n=50) and 9% (13/150) of patients in the IRE alone group (n=150) at 90‑day follow-up in the registry of 200\xa0patients. Deep surgical site infection (needing drain placement) was reported in 3\xa0patients in the case series of 50 patients treated by IRE.\n\nIn the registry of 200\xa0patients other complications included urinary tract problems (in 7\xa0patients), renal failure (in 1\xa0patient), wound problems (in 6\xa0patients), neurological changes (in 4\xa0patients), haematological events (in 2\xa0patients) and other adverse events (in 23\xa0patients). The case series of 48\xa0patients also reported complications such as hepatojejunostomy stricture (in\xa01 patient), pain (in 1\xa0patient) and postoperative bleeding (in 2\xa0patients).\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: vessel occlusion (permanent or transient and due to oedema post-IRE causing compression of an involved superior mesenteric vein). They considered that the following were theoretical adverse events: damage to major arteries or veins, gastrointestinal tract injury (for example, stomach, duodenum, small or large bowel).', 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received. However, the committee noted the views and experiences of patients (submitted during consultation) in their discussions.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2453-0'}	https://www.nice.org.uk/guidance/ipg579	Evidence-based recommendations on irreversible electroporation for treating pancreatic cancer. This involves inserting special needles into the tumour in the pancreas. Short electrical pulses of a high voltage current are then passed through the needles. The aim is to destroy the cancer cells.
addd24f7ab89320d2a72ec34299f17ecca1bfb75	nice	Pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine	Pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine Evidence-based recommendations on pegylated liposomal irinotecan (Onivyde) for treating pancreatic cancer in adults. # Recommendations Pegylated liposomal irinotecan, in combination with 5‑fluorouracil and leucovorin, is not recommended, within its marketing authorisation, for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy. This guidance is not intended to affect the position of patients whose treatment with pegylated liposomal irinotecan was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Pegylated liposomal irinotecan (Onivyde, Shire) consists of the anticancer drug irinotecan contained within tiny fat particles called nanoliposomes. The nanoliposomes accumulate in the tumour and release irinotecan slowly. Irinotecan blocks an enzyme called topoisomerase I, which causes DNA strands to break. This stops the cancer cells dividing and they eventually die. Marketing authorisation Pegylated liposomal irinotecan, in combination with 5‑fluorouracil (5‑FU) and leucovorin (LV), has a marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy. Adverse reactions The company submission includes the following as common adverse events for pegylated liposomal irinotecan plus 5‑FU and LV: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis and pyrexia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Intravenous infusion of 80 mg/m2 pegylated liposomal irinotecan, 400 mg/m2 LV, followed by 2,400 mg/m2 5‑FU over 46 hours given every 2 weeks. Price £615.35 per 50 mg vial (company submission). Cost per 2‑week treatment cycle for pegylated liposomal irinotecan is £1,846.05 based on 3 vials per dose. The company has agreed a patient access scheme with the Department of Health. If pegylated liposomal irinotecan plus 5‑FU and LV had been recommended, this scheme would provide a simple discount to the list price of pegylated liposomal irinotecan plus 5‑FU and LV with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 5) considered evidence submitted by Shire and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of pegylated liposomal irinotecan plus 5-fluorouracil (5‑FU) and leucovorin (LV), having considered evidence on the nature of pancreatic cancer and the value placed on the benefits of pegylated liposomal irinotecan plus 5‑FU and LV by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical need and practice ## Unmet need The committee heard from the clinical and patient experts that metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine is associated with a poor prognosis because there are few treatments available. Survival may be less than 6 months. It heard from the patient experts that diagnosis is devastating and that symptoms, which include weight loss, pain, depression and anxiety, can be debilitating and difficult to manage. The committee recognised that extension to life and also quality of life were therefore very important to people with this condition. It understood that there have been few new treatments in this area. The committee concluded that the prognosis for people with metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine is poor and that current treatments are limited in efficacy. It therefore recognised the value of additional treatment options. ## Treatment pathway The committee noted that the treatment options for untreated metastatic pancreatic cancer include curative surgery (only suitable for 10 to 20% of the population), gemcitabine as recommended in NICE's technology appraisal guidance on gemcitabine for treating pancreatic cancer or FOLFIRINOX (folinic acid, 5‑FU, irinotecan, oxaliplatin). Treatment received at this stage would affect treatment later. The committee understood from the clinical expert that oxaliplatin plus 5‑FU and LV or capecitabine monotherapy are used in clinical practice in England after gemcitabine treatment, and that 5‑FU plus LV alone is rarely used. The committee also heard from the clinical expert that treatment decisions take into account the balance between the risk and severity of adverse events and the effectiveness of treatment. Double and triple therapies are preferred to monotherapies if the adverse events are tolerable. The clinical and patient experts emphasised the importance of patient choice in treatment decisions. The committee agreed with the company, the evidence review group (ERG) and advice from the clinical expert that the most appropriate comparator for pegylated liposomal irinotecan plus 5‑FU and LV in NHS practice would be oxaliplatin plus 5‑FU and LV. The committee concluded that an alternative treatment to oxaliplatin plus 5‑FU and LV would be of value. # Clinical effectiveness The committee considered the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV, although it acknowledged that 5‑FU plus LV is rarely used in clinical practice, and is therefore not established practice. It noted that in the NAPOLI‑1 trial, overall survival on pegylated liposomal irinotecan plus 5‑FU and LV was statistically significantly longer than on 5‑FU plus LV (6.2 months; 95% confidence interval 4.8 to 8.4 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 4.2 months; 95% CI 3.3 to 5.3 for 5‑FU plus LV ). Progression-free survival was also statistically significantly longer than on 5‑FU plus LV (3.1 months; 95% CI 2.7 to 4.2, compared with 1.5 months; 95% CI 1.4 to 1.8, p=0.0001). The committee heard from the clinical expert that for ovarian cancer the nanoliposomal particle delivery system has been shown to have better effectiveness than equivalent treatments without the delivery system and the same could apply to pegylated liposomal irinotecan compared with irinotecan. The committee also understood that combining therapies increased the effectiveness of the treatment but may also increase the adverse events. In NAPOLI‑1, treatment-emergent serious adverse events (that is, events that first appear during treatment, or worsen during treatment) were more common in the pegylated liposomal irinotecan plus 5‑FU and LV group than in the 5‑FU plus LV group (47.9% compared with 44.8%). The committee noted that the health-related quality-of-life data collected in NAPOLI‑1 showed no real differences between the groups at 6 weeks and 12 weeks, suggesting that there was no negative effect of pegylated liposomal irinotecan on health-related quality of life. The committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV was more clinically effective than 5‑FU plus LV but was associated with more treatment-emergent serious adverse events. ## Company's indirect treatment comparison with oxaliplatin plus 5‑FU and LV The company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous. Issues included different trial populations, incomplete data on patient baseline characteristics and different oxaliplatin plus 5‑FU and LV regimens in the oxaliplatin trials. But, to compare the cost effectiveness of the treatments, the company did an indirect comparison which generated hazard ratios to plot the oxaliplatin plus 5‑FU and LV Kaplan–Meier curve, using the 5‑FU plus LV curve from NAPOLI‑1. The committee acknowledged that the validity of the results relied on an assumption of proportional hazards (that is, the relative risk of an event is fixed irrespective of time) between treatments for overall survival and progression-free survival for all the trials included in the mixed treatment comparison, and that the company and ERG stated this was not true for NAPOLI‑1. The committee considered that for both overall survival and progression-free survival there was a violation of the proportional hazards assumption. The committee also noted that the ERG had reviewed the literature given the uncertainties in the indirect treatment comparison. The ERG concluded that, in general, the progression-free survival and overall survival estimates appeared very similar for oxaliplatin plus 5‑FU and LV and for pegylated liposomal irinotecan plus 5‑FU and LV. The clinical expert commented that oxaliplatin plus 5‑FU and LV would be more effective than 5‑FU plus LV, but its relative effectiveness compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate. Recognising the uncertainty in the indirect comparison, the committee concluded that the company's approach could not be considered reliable for comparing the relative treatment effect of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV. However the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV could be considered broadly similar to oxaliplatin plus 5‑FU and LV. # Cost effectiveness The committee considered the company's de novo model, the associated assumptions and the ERG's critique. It considered that the structure of the company's model captured the main aspects of metastatic adenocarcinoma of the pancreas after gemcitabine treatment and concluded that it was appropriate to use for decision-making. ## Use of parametric modelling The committee considered how the company had modelled overall survival, progression-free survival and time to treatment failure data using parametric modelling (a log-normal model for the company's base case). The company assumed that proportional hazards applied, but had fitted a log-normal curve to the results from both the pegylated liposomal irinotecan plus 5‑FU and LV and the 5‑FU plus LV groups. The committee heard that the ERG considered curve fitting to be inappropriate because most of the trial data were complete. It agreed with the ERG that of the 3 approaches explored, the preferred method used the Kaplan–Meier data directly from the trial with extrapolation for the 1 remaining patient in the 5‑FU plus LV group. The committee noted that the company did not provide a biological rationale for using the log-normal model, which estimated a 4.8% greater progression-free survival gain than the trial data when comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV. Modelling time to treatment failure also underestimated the overall time on treatment and the company's modelling showed that benefit continued even after the patient had stopped treatment. The committee concluded that because the data for progression-free survival and time on treatment are complete and virtually complete for overall survival, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling. When comparing survival on pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the committee heard from the ERG that using the company's indirect treatment comparison hazard ratios (assuming proportional hazards) to adjust the parametric curves was unreliable because of the issues with the indirect treatment comparison (see section 4.4). The committee also noted that the total quality-adjusted life years (QALYs) for oxaliplatin plus 5‑FU and LV were significantly lower than for 5‑FU plus LV in the company's analysis. It acknowledged that this result was not in agreement with comments from the clinical expert, who stated that oxaliplatin plus 5‑FU and LV is the preferred option; it is more clinically effective than 5‑FU plus LV and is standard clinical practice in the NHS. The committee concluded that the company's approach for modelling survival to compare pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV gave clinically implausible results and lacked robustness for decision-making. ## Cost-related model assumptions The committee considered the costs of pegylated liposomal irinotecan plus 5‑FU and LV and of the comparators (5‑FU plus LV and oxaliplatin plus 5‑FU and LV) included in the company's model. It noted that the company's model assumed that a reduced or missed dose because of adverse events in NAPOLI‑1 would reduce drug acquisition costs. The committee heard from the clinical expert that in clinical practice, parenteral treatments are often prepared by the pharmacy department when the patient is seen at the outpatient clinic and not when the patient is treated. Therefore planned treatment variations can be accounted for when treatment is given but are difficult to predict in advance. The committee concluded that it was not appropriate to assume that cost savings from dose reductions would always be accounted for in clinical practice and that full costing should be assumed in the base case. The committee considered the costs of the generic comparators used in the company's model. It noted that the company used the list prices from the British national formulary, rather than taking costs from the Electronic Market Information Tool (eMit), which provides details of average prices paid by NHS hospitals in England for generic drugs. The committee also heard from the ERG that the company had assumed that only 1 vial size is available for each generic drug; 500 mg for 5‑FU, 50 mg for oxaliplatin and 50 mg for LV. However, the eMit database shows that there are multiple vial sizes for each of these generic drugs and that generally the larger the vial, the lower the cost per mg of the drug. The committee noted that the ERG had recalculated the average cost per dose of the intervention and the comparators using eMit prices, taking into account the range of vial sizes available for the generic drugs and the best combination of vial sizes for the dose needed. The committee concluded that it was not appropriate to assume use of the smallest sized vials in the company's model and that the ERG's method of calculating costs was more appropriate. ## Utility values used in the company's model The committee noted that health-related quality-of-life data were collected in NAPOLI‑1 but these were incomplete and not used in the company's economic modelling. The company's health state utility values for all treatments were 0.742 for the pre-progression health state and 0.671 for the post-progression health state, taken from NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles for untreated pancreatic cancer. The committee was aware that the EQ‑5D values were weighted using the general US population tariff but adjusted for the UK population, and incorporated disutility values to account for adverse events of treatment. It also noted that the company used the same utility values regardless of the treatment the patient had (pegylated liposomal irinotecan plus 5‑FU and LV, oxaliplatin plus 5‑FU and LV, or 5‑FU plus LV). The committee heard that the ERG considered these values to overestimate patient health-related quality of life because they were taken from a population who had not had treatment and who were likely to be in better health. The committee heard from the company that it considered the performance status of patients in NAPOLI‑1 to be similar to that of the population in CA046 (the trial considered in NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles for untreated pancreatic cancer), because the patients in NAPOLI‑1 were fitter than those generally seen in clinical practice. Also, the distribution of the performance status scores was similar between the studies. The committee noted that the ERG had explored using utility values from people with gastric cancer, but it heard from the clinical expert that these utility values may not be comparable to people with pancreatic cancer. The committee concluded that although there was uncertainty about the most appropriate utility values to use for a second-line treatment population with pancreatic cancer, the values used by the company were acceptable for decision-making. ## Most plausible ICERs The committee considered the most plausible incremental cost-effectiveness ratio (ICER) for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV, including the patient access scheme. The committee noted that the company's base-case ICER including the patient access scheme was £96,591 per QALY gained. However, the committee considered that all the ERG's amendments, except the ERG's preferred health state utility values, should be included in the base case. The committee noted it did not have an ICER that reflected all of its preferred assumptions. The ERG's exploratory ICER, combining all ERG amendments, was £162,887 per QALY gained. When only amending the committee's preferred extrapolation of survival, with the remaining assumptions taken from the company's analyses, the ICER was £137,354 per QALY gained. It therefore concluded that taking into account all of the ICERs presented, the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over £100,000 per QALY gained. The committee considered that the ICER was much higher than would normally be considered a cost-effective use of NHS resources. Acknowledging that the analysis in section 4.12 compared pegylated liposomal irinotecan with a treatment (5‑FU plus LV) not considered to be established practice in the NHS, the committee considered the most plausible ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV (the appropriate comparator), including the patient access scheme for pegylated liposomal irinotecan. The committee noted that the company's base-case ICER including the patient access scheme was £54,412 per QALY gained. It also noted that the ERG's exploratory ICER, combining all the ERG's scenarios including the committee's preferred extrapolation of survival, was £106,898 per QALY gained. The committee also noted that because of the uncertain clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV, particularly with the total QALYs for oxaliplatin plus 5‑FU and LV being implausibly lower than 5‑FU plus LV in the company's submission (see section 4.8), the ERG did further exploratory analyses altering the QALY difference between the 2 treatments. When taking into account these scenarios, the ICER ranged from £201,019 per QALY gained (when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% less than for pegylated liposomal irinotecan plus 5‑FU and LV) to pegylated liposomal irinotecan plus 5‑FU and LV being dominated (that is, less effective and more expensive than oxaliplatin plus 5‑FU and LV ). The committee concluded that although the analyses comparing pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV were subject to considerable uncertainty, it was confident that pegylated liposomal irinotecan plus 5‑FU and LV would not be considered a cost-effective use of NHS resources. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee heard from the clinical and patient experts that the life expectancy of patients with metastatic adenocarcinoma of the pancreas after gemcitabine treatment was considerably less than 2 years. It also heard from the company that people with metastatic pancreatic cancer have a median survival of 2.8 to 5.7 months. The committee concluded that the criterion for short life expectancy was met. The committee considered the criterion for extension to life. It noted that the median extension in overall survival in NAPOLI‑1 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was 1.9 months. The committee noted that its preferred estimate of overall survival (using the Kaplan–Meier data and extrapolation for 1 patient in the 5‑FU plus LV comparator group who had yet to have an event) was 1.8 months. The committee also noted that when the company fitted log-logistic models to the NAPOLI‑1 data but did not extrapolate for the 1 remaining patient in the 5‑FU plus LV group, the overall survival gain was 2.2 months. The committee considered that the overall survival gain would be less than 2.2 months given that the surviving patient was in the 5‑FU plus LV group. The committee acknowledged that 5‑FU plus LV was not established practice in the NHS, and therefore not the appropriate comparator to assess the end-of-life criteria. Even if it were, the committee did not accept that the extension to life criterion had been met for this comparison, even taking into consideration the very short life expectancy for this population. It also noted that both the company and the ERG were unable to produce a reliable estimate of the difference in overall survival between pegylated liposomal irinotecan plus 5‑FU and LV and oxaliplatin plus 5‑FU and LV, the most appropriate comparator. But when comparing 3 trials of oxaliplatin plus 5‑FU and LV, the median overall survival was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1. The committee did not accept that the extension to life criterion was met for pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV. The committee concluded that pegylated liposomal irinotecan did not fulfil the criteria for a life-extending treatment at the end of life. The committee discussed the new arrangements for the Cancer Drugs Fund recently agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee understood that the company was not making a case for pegylated liposomal irinotecan plus 5‑FU and LV to be considered for funding through the Cancer Drugs Fund. The committee considered that the most plausible ICERs for pegylated liposomal irinotecan plus 5‑FU and LV (see sections 4.12 and 4.13) for both comparisons were substantially higher than the range normally considered a cost-effective use of NHS resources. Therefore pegylated liposomal irinotecan plus 5‑FU and LV did not have plausible potential to satisfy the criteria for routine use. The committee also considered that although there were uncertainties in the evidence for this appraisal, the clinical-effectiveness evidence from NAPOLI‑1 was complete (see section 4.7). It heard from the company that there were no ongoing trials that could be used to inform the clinical uncertainty around the comparison with oxaliplatin plus 5‑FU and LV and therefore a subsequent update of the guidance. The committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV did not meet the criteria to be considered for funding through the Cancer Drugs Fund. # Innovation The committee discussed whether pegylated liposomal irinotecan plus 5‑FU and LV was innovative in its potential to make a significant and substantial impact on health-related benefits. It heard from the clinical and patient experts that there were few options for treating metastatic adenocarcinoma of the pancreas and that pegylated liposomal irinotecan plus 5‑FU and LV would provide another option. However, the committee concluded that having an extra treatment option for metastatic adenocarcinoma of the pancreas did not mean that pegylated liposomal irinotecan plus 5‑FU and LV was innovative. It also concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations. # Summary of appraisal committee's key conclusions TA440 Appraisal title: Pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine Section Key conclusion Pegylated liposomal irinotecan, in combination with 5‑fluorouracil (5‑FU) and leucovorin (LV), is not recommended, within its marketing authorisation, for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy. The committee considered that the NAPOLI‑1 trial showed that overall survival was statistically significantly longer on pegylated liposomal irinotecan plus 5‑FU and LV than on 5‑FU plus LV. The company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous. But the company did an indirect comparison to generate hazard ratios, so it could then compare the cost effectiveness of the treatments. Taking into account all of the incremental cost-effectiveness ratio (ICERs) presented, the committee concluded that the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over £100,000 per quality-adjusted life year (QALY) gained. The committee concluded that although the analyses comparing pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV were subject to considerable uncertainty, it was confident that pegylated liposomal irinotecan plus 5‑FU and LV would not be considered a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments Metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine treatment is associated with a poor prognosis because there are few treatments available, and survival may be less than 6 months. Current treatments are limited in efficacy so there is value in more treatment options in this area. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee heard from the clinical and patient experts that there were few options for treating metastatic adenocarcinoma of the pancreas and that pegylated liposomal irinotecan plus 5‑FU and LV would provide another option. However, the committee concluded that having an extra treatment option did not mean that pegylated liposomal irinotecan plus 5‑FU and LV was innovative. It also concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations. What is the position of the treatment in the pathway of care for the condition? The committee understood from the clinical expert that oxaliplatin plus 5‑FU and LV or capecitabine monotherapy are used in clinical practice in England after gemcitabine treatment. The committee agreed with the company, ERG and advice from the clinical expert that the most appropriate comparator for pegylated liposomal irinotecan plus 5‑FU and LV in NHS practice would be oxaliplatin plus 5‑FU and LV. Adverse reactions In NAPOLI‑1, treatment-emergent serious adverse events (that is, events that first appear during treatment, or worsen during treatment) were more common in the pegylated liposomal irinotecan plus 5‑FU and LV group than in the 5‑FU plus LV group (47.9% compared with 44.8%). The committee noted that health-related quality-of-life data were collected in NAPOLI‑1 and that the results at 6 weeks and 12 weeks showed no real differences between the groups, suggesting no negative effect of pegylated liposomal irinotecan on health-related quality of life. Evidence for clinical effectiveness Availability, nature and quality of evidence The company's submission presented clinical-effectiveness evidence from NAPOLI-1, comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV. The company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous. Relevance to general clinical practice in the NHS The patients in NAPOLI‑1 were fitter than those generally seen in clinical practice. Uncertainties generated by the evidence The committee noted that given the uncertainties inherent in the indirect treatment comparison, the ERG reviewed the literature and concluded that, in general, the progression-free survival and overall survival estimates appeared very similar for oxaliplatin plus 5‑FU and LV and pegylated liposomal irinotecan plus 5‑FU and LV. The committee also noted that the relative effectiveness of oxaliplatin plus 5‑FU and LV compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable. Estimate of the size of the clinical effectiveness including strength of supporting evidence The median extension in overall survival in NAPOLI‑1 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was 1.9 months. Both the company and the ERG were unable to produce a reliable estimate of the difference in overall survival between pegylated liposomal irinotecan plus 5‑FU and LV and oxaliplatin plus 5‑FU and LV, but when comparing 3 trials of oxaliplatin plus 5‑FU and LV the median overall survival was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1. Evidence for cost effectiveness Availability and nature of evidence The company submitted a de novo economic model to estimate the cost effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV and with oxaliplatin plus 5‑FU and LV, in people with metastatic adenocarcinoma of the pancreas after gemcitabine treatment. The company used an indirect treatment comparison to estimate overall survival, progression-free survival and time-on-treatment curves for the comparison with oxaliplatin plus 5‑FU and LV. Uncertainties around and plausibility of assumptions and inputs in the economic model The company made assumptions about the costs and survival estimates. The committee noted that the total QALYs for oxaliplatin plus 5‑FU and LV were significantly lower than for 5‑FU plus LV in the company's analysis. It acknowledged that this result was not in agreement with comments from the clinical expert, who stated that oxaliplatin plus 5‑FU and LV is the preferred option; it is more clinically effective than 5‑FU and LV and is standard clinical practice in the NHS. The committee concluded that because the data were complete for progression-free survival and time on treatment, and virtually complete for overall survival, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling. The committee concluded that it was not appropriate to assume dose reductions would always apply in the company's model and that full costing should be assumed in the base case. It also concluded that it was not appropriate to assume use of the smallest sized vials in the company's model and that the ERG's method of calculating costs was more appropriate. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee concluded that although there was uncertainty about the most appropriate utility values to use for a second-line treatment population with pancreatic cancer, the values used by the company were acceptable for decision-making. The committee concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? For the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV the committee considered that all the changes, except the ERG's preferred health state utility values, should be included in the base case. The committee therefore concluded that the ICER for pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV, was over £100,000 per QALY gained. For the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the ERG carried out scenarios altering the QALY difference between the 2 treatments. When taking into account these scenarios, the ICER ranged from £201,019 per QALY gained (when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% less than for pegylated liposomal irinotecan plus 5‑FU and LV) to pegylated liposomal irinotecan plus 5‑FU and LV being dominated (that is, less effective and more expensive than oxaliplatin plus 5‑FU and LV) when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% more. Most likely cost-effectiveness estimate (given as an ICER) The committee concluded that taking into account all of the ICERs presented, the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over £100,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) The committee considered analyses incorporating the confidential patient access scheme for pegylated liposomal irinotecan plus 5‑FU and LV. End-of-life considerations The committee concluded that the criterion for short life expectancy was met. However, pegylated liposomal irinotecan plus 5‑FU and LV survival estimates from the trial and model showed that the criterion for extension to life was not met for the comparison with 5‑FU plus LV or with oxaliplatin plus 5‑FU and LV. The committee noted that when comparing 3 trials of oxaliplatin plus 5‑FU and LV, the median overall survival was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1. Therefore, the committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV did not meet the NICE supplementary advice criteria to be considered as a life-extending, end-of-life treatment. Equalities considerations and social value judgements No equalities issues were raised during this appraisal.	{'Recommendations': 'Pegylated liposomal irinotecan, in combination with 5‑fluorouracil and leucovorin, is not recommended, within its marketing authorisation, for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.\n\nThis guidance is not intended to affect the position of patients whose treatment with pegylated liposomal irinotecan was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': 'Description of the technology\n\nPegylated liposomal irinotecan (Onivyde, Shire) consists of the anticancer drug irinotecan contained within tiny fat particles called nanoliposomes. The nanoliposomes accumulate in the tumour and release irinotecan slowly. Irinotecan blocks an enzyme called topoisomerase\xa0I, which causes DNA strands to break. This stops the cancer cells dividing and they eventually die.\n\nMarketing authorisation\n\nPegylated liposomal irinotecan, in combination with 5‑fluorouracil (5‑FU) and leucovorin (LV), has a marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.\n\nAdverse reactions\n\nThe company submission includes the following as common adverse events for pegylated liposomal irinotecan plus 5‑FU and LV: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis and pyrexia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nIntravenous infusion of 80\xa0mg/m2 pegylated liposomal irinotecan, 400\xa0mg/m2 LV, followed by 2,400\xa0mg/m2 5‑FU over 46\xa0hours given every 2\xa0weeks.\n\nPrice\n\n£615.35 per 50\xa0mg vial (company submission).\n\nCost per 2‑week treatment cycle for pegylated liposomal irinotecan is £1,846.05 based on 3\xa0vials per dose.\n\nThe company has agreed a patient access scheme with the Department of Health. If pegylated liposomal irinotecan plus 5‑FU and LV had been recommended, this scheme would provide a simple discount to the list price of pegylated liposomal irinotecan plus 5‑FU and LV with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.', 'Evidence': 'The appraisal committee (section\xa05) considered evidence submitted by Shire and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of pegylated liposomal irinotecan plus 5-fluorouracil (5‑FU) and leucovorin (LV), having considered evidence on the nature of pancreatic cancer and the value placed on the benefits of pegylated liposomal irinotecan plus 5‑FU and LV by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and practice\n\n## Unmet need\n\nThe committee heard from the clinical and patient experts that metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine is associated with a poor prognosis because there are few treatments available. Survival may be less than 6\xa0months. It heard from the patient experts that diagnosis is devastating and that symptoms, which include weight loss, pain, depression and anxiety, can be debilitating and difficult to manage. The committee recognised that extension to life and also quality of life were therefore very important to people with this condition. It understood that there have been few new treatments in this area. The committee concluded that the prognosis for people with metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine is poor and that current treatments are limited in efficacy. It therefore recognised the value of additional treatment options.\n\n## Treatment pathway\n\nThe committee noted that the treatment options for untreated metastatic pancreatic cancer include curative surgery (only suitable for 10\xa0to\xa020% of the population), gemcitabine as recommended in NICE's technology appraisal guidance on gemcitabine for treating pancreatic cancer or FOLFIRINOX (folinic acid, 5‑FU, irinotecan, oxaliplatin). Treatment received at this stage would affect treatment later. The committee understood from the clinical expert that oxaliplatin plus 5‑FU and LV or capecitabine monotherapy are used in clinical practice in England after gemcitabine treatment, and that 5‑FU plus LV alone is rarely used. The committee also heard from the clinical expert that treatment decisions take into account the balance between the risk and severity of adverse events and the effectiveness of treatment. Double and triple therapies are preferred to monotherapies if the adverse events are tolerable. The clinical and patient experts emphasised the importance of patient choice in treatment decisions. The committee agreed with the company, the evidence review group (ERG) and advice from the clinical expert that the most appropriate comparator for pegylated liposomal irinotecan plus 5‑FU and LV in NHS practice would be oxaliplatin plus 5‑FU and LV. The committee concluded that an alternative treatment to oxaliplatin plus 5‑FU and LV would be of value.\n\n# Clinical effectiveness\n\nThe committee considered the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV, although it acknowledged that 5‑FU plus LV is rarely used in clinical practice, and is therefore not established practice. It noted that in the NAPOLI‑1 trial, overall survival on pegylated liposomal irinotecan plus 5‑FU and LV was statistically significantly longer than on 5‑FU plus LV (6.2\xa0months; 95% confidence interval [CI] 4.8 to 8.4 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 4.2\xa0months; 95%\xa0CI 3.3 to 5.3 for 5‑FU plus LV [May 2015 cut‑off; final cut‑off data were also presented but are academic in confidence so cannot be reported here]). Progression-free survival was also statistically significantly longer than on 5‑FU plus LV (3.1\xa0months; 95%\xa0CI 2.7 to 4.2, compared with 1.5\xa0months; 95%\xa0CI 1.4 to 1.8, p=0.0001). The committee heard from the clinical expert that for ovarian cancer the nanoliposomal particle delivery system has been shown to have better effectiveness than equivalent treatments without the delivery system and the same could apply to pegylated liposomal irinotecan compared with irinotecan. The committee also understood that combining therapies increased the effectiveness of the treatment but may also increase the adverse events. In NAPOLI‑1, treatment-emergent serious adverse events (that is, events that first appear during treatment, or worsen during treatment) were more common in the pegylated liposomal irinotecan plus 5‑FU and LV group than in the 5‑FU plus LV group (47.9% compared with 44.8%). The committee noted that the health-related quality-of-life data collected in NAPOLI‑1 showed no real differences between the groups at 6\xa0weeks and 12\xa0weeks, suggesting that there was no negative effect of pegylated liposomal irinotecan on health-related quality of life. The committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV was more clinically effective than 5‑FU plus LV but was associated with more treatment-emergent serious adverse events.\n\n## Company's indirect treatment comparison with oxaliplatin plus 5‑FU and LV\n\nThe company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous. Issues included different trial populations, incomplete data on patient baseline characteristics and different oxaliplatin plus 5‑FU and LV regimens in the oxaliplatin trials. But, to compare the cost effectiveness of the treatments, the company did an indirect comparison which generated hazard ratios to plot the oxaliplatin plus 5‑FU and LV Kaplan–Meier curve, using the 5‑FU plus LV curve from NAPOLI‑1. The committee acknowledged that the validity of the results relied on an assumption of proportional hazards (that is, the relative risk of an event is fixed irrespective of time) between treatments for overall survival and progression-free survival for all the trials included in the mixed treatment comparison, and that the company and ERG stated this was not true for NAPOLI‑1. The committee considered that for both overall survival and progression-free survival there was a violation of the proportional hazards assumption.\n\nThe committee also noted that the ERG had reviewed the literature given the uncertainties in the indirect treatment comparison. The ERG concluded that, in general, the progression-free survival and overall survival estimates appeared very similar for oxaliplatin plus 5‑FU and LV and for pegylated liposomal irinotecan plus 5‑FU and LV. The clinical expert commented that oxaliplatin plus 5‑FU and LV would be more effective than 5‑FU plus LV, but its relative effectiveness compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate. Recognising the uncertainty in the indirect comparison, the committee concluded that the company's approach could not be considered reliable for comparing the relative treatment effect of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV. However the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV could be considered broadly similar to oxaliplatin plus 5‑FU and LV.\n\n# Cost effectiveness\n\nThe committee considered the company's de novo model, the associated assumptions and the ERG's critique. It considered that the structure of the company's model captured the main aspects of metastatic adenocarcinoma of the pancreas after gemcitabine treatment and concluded that it was appropriate to use for decision-making.\n\n## Use of parametric modelling\n\nThe committee considered how the company had modelled overall survival, progression-free survival and time to treatment failure data using parametric modelling (a log-normal model for the company's base case). The company assumed that proportional hazards applied, but had fitted a log-normal curve to the results from both the pegylated liposomal irinotecan plus 5‑FU and LV and the 5‑FU plus LV groups. The committee heard that the ERG considered curve fitting to be inappropriate because most of the trial data were complete. It agreed with the ERG that of the 3\xa0approaches explored, the preferred method used the Kaplan–Meier data directly from the trial with extrapolation for the 1\xa0remaining patient in the 5‑FU plus LV group. The committee noted that the company did not provide a biological rationale for using the log-normal model, which estimated a 4.8% greater progression-free survival gain than the trial data when comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV. Modelling time to treatment failure also underestimated the overall time on treatment and the company's modelling showed that benefit continued even after the patient had stopped treatment. The committee concluded that because the data for progression-free survival and time on treatment are complete and virtually complete for overall survival, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling.\n\nWhen comparing survival on pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the committee heard from the ERG that using the company's indirect treatment comparison hazard ratios (assuming proportional hazards) to adjust the parametric curves was unreliable because of the issues with the indirect treatment comparison (see section\xa04.4). The committee also noted that the total quality-adjusted life years (QALYs) for oxaliplatin plus 5‑FU and LV were significantly lower than for 5‑FU plus LV in the company's analysis. It acknowledged that this result was not in agreement with comments from the clinical expert, who stated that oxaliplatin plus 5‑FU and LV is the preferred option; it is more clinically effective than 5‑FU plus LV and is standard clinical practice in the NHS. The committee concluded that the company's approach for modelling survival to compare pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV gave clinically implausible results and lacked robustness for decision-making.\n\n## Cost-related model assumptions\n\nThe committee considered the costs of pegylated liposomal irinotecan plus 5‑FU and LV and of the comparators (5‑FU plus LV and oxaliplatin plus 5‑FU and LV) included in the company's model. It noted that the company's model assumed that a reduced or missed dose because of adverse events in NAPOLI‑1 would reduce drug acquisition costs. The committee heard from the clinical expert that in clinical practice, parenteral treatments are often prepared by the pharmacy department when the patient is seen at the outpatient clinic and not when the patient is treated. Therefore planned treatment variations can be accounted for when treatment is given but are difficult to predict in advance. The committee concluded that it was not appropriate to assume that cost savings from dose reductions would always be accounted for in clinical practice and that full costing should be assumed in the base case.\n\nThe committee considered the costs of the generic comparators used in the company's model. It noted that the company used the list prices from the British national formulary, rather than taking costs from the Electronic Market Information Tool (eMit), which provides details of average prices paid by NHS hospitals in England for generic drugs. The committee also heard from the ERG that the company had assumed that only 1\xa0vial size is available for each generic drug; 500\xa0mg for 5‑FU, 50\xa0mg for oxaliplatin and 50\xa0mg for LV. However, the eMit database shows that there are multiple vial sizes for each of these generic drugs and that generally the larger the vial, the lower the cost per mg of the drug. The committee noted that the ERG had recalculated the average cost per dose of the intervention and the comparators using eMit prices, taking into account the range of vial sizes available for the generic drugs and the best combination of vial sizes for the dose needed. The committee concluded that it was not appropriate to assume use of the smallest sized vials in the company's model and that the ERG's method of calculating costs was more appropriate.\n\n## Utility values used in the company's model\n\nThe committee noted that health-related quality-of-life data were collected in NAPOLI‑1 but these were incomplete and not used in the company's economic modelling. The company's health state utility values for all treatments were 0.742 for the pre-progression health state and 0.671 for the post-progression health state, taken from NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles for untreated pancreatic cancer. The committee was aware that the EQ‑5D values were weighted using the general US population tariff but adjusted for the UK population, and incorporated disutility values to account for adverse events of treatment. It also noted that the company used the same utility values regardless of the treatment the patient had (pegylated liposomal irinotecan plus 5‑FU and LV, oxaliplatin plus 5‑FU and LV, or 5‑FU plus LV). The committee heard that the ERG considered these values to overestimate patient health-related quality of life because they were taken from a population who had not had treatment and who were likely to be in better health. The committee heard from the company that it considered the performance status of patients in NAPOLI‑1 to be similar to that of the population in CA046 (the trial considered in NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles for untreated pancreatic cancer), because the patients in NAPOLI‑1 were fitter than those generally seen in clinical practice. Also, the distribution of the performance status scores was similar between the studies. The committee noted that the ERG had explored using utility values from people with gastric cancer, but it heard from the clinical expert that these utility values may not be comparable to people with pancreatic cancer. The committee concluded that although there was uncertainty about the most appropriate utility values to use for a second-line treatment population with pancreatic cancer, the values used by the company were acceptable for decision-making.\n\n## Most plausible ICERs\n\nThe committee considered the most plausible incremental cost-effectiveness ratio (ICER) for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV, including the patient access scheme. The committee noted that the company's base-case ICER including the patient access scheme was £96,591 per QALY gained. However, the committee considered that all the ERG's amendments, except the ERG's preferred health state utility values, should be included in the base case. The committee noted it did not have an ICER that reflected all of its preferred assumptions. The ERG's exploratory ICER, combining all ERG amendments, was £162,887 per QALY gained. When only amending the committee's preferred extrapolation of survival, with the remaining assumptions taken from the company's analyses, the ICER was £137,354 per QALY gained. It therefore concluded that taking into account all of the ICERs presented, the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over £100,000 per QALY gained. The committee considered that the ICER was much higher than would normally be considered a cost-effective use of NHS resources.\n\nAcknowledging that the analysis in section\xa04.12 compared pegylated liposomal irinotecan with a treatment (5‑FU plus LV) not considered to be established practice in the NHS, the committee considered the most plausible ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV (the appropriate comparator), including the patient access scheme for pegylated liposomal irinotecan. The committee noted that the company's base-case ICER including the patient access scheme was £54,412 per QALY gained. It also noted that the ERG's exploratory ICER, combining all the ERG's scenarios including the committee's preferred extrapolation of survival, was £106,898 per QALY gained. The committee also noted that because of the uncertain clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV, particularly with the total QALYs for oxaliplatin plus 5‑FU and LV being implausibly lower than 5‑FU plus LV in the company's submission (see section\xa04.8), the ERG did further exploratory analyses altering the QALY difference between the 2\xa0treatments. When taking into account these scenarios, the ICER ranged from £201,019 per QALY gained (when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% less than for pegylated liposomal irinotecan plus 5‑FU and LV) to pegylated liposomal irinotecan plus 5‑FU and LV being dominated (that is, less effective and more expensive than oxaliplatin plus 5‑FU and LV [when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% more]). The committee concluded that although the analyses comparing pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV were subject to considerable uncertainty, it was confident that pegylated liposomal irinotecan plus 5‑FU and LV would not be considered a cost-effective use of NHS resources.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee heard from the clinical and patient experts that the life expectancy of patients with metastatic adenocarcinoma of the pancreas after gemcitabine treatment was considerably less than 2\xa0years. It also heard from the company that people with metastatic pancreatic cancer have a median survival of 2.8\xa0to 5.7\xa0months. The committee concluded that the criterion for short life expectancy was met.\n\nThe committee considered the criterion for extension to life. It noted that the median extension in overall survival in NAPOLI‑1 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was 1.9\xa0months. The committee noted that its preferred estimate of overall survival (using the Kaplan–Meier data and extrapolation for 1\xa0patient in the 5‑FU plus LV comparator group who had yet to have an event) was 1.8\xa0months. The committee also noted that when the company fitted log-logistic models to the NAPOLI‑1 data but did not extrapolate for the 1\xa0remaining patient in the 5‑FU plus LV group, the overall survival gain was 2.2\xa0months. The committee considered that the overall survival gain would be less than 2.2\xa0months given that the surviving patient was in the 5‑FU plus LV group. The committee acknowledged that 5‑FU plus LV was not established practice in the NHS, and therefore not the appropriate comparator to assess the end-of-life criteria. Even if it were, the committee did not accept that the extension to life criterion had been met for this comparison, even taking into consideration the very short life expectancy for this population. It also noted that both the company and the ERG were unable to produce a reliable estimate of the difference in overall survival between pegylated liposomal irinotecan plus 5‑FU and LV and oxaliplatin plus 5‑FU and LV, the most appropriate comparator. But when comparing 3\xa0trials of oxaliplatin plus 5‑FU and LV, the median overall survival was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1. The committee did not accept that the extension to life criterion was met for pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV. The committee concluded that pegylated liposomal irinotecan did not fulfil the criteria for a life-extending treatment at the end of life.\n\nThe committee discussed the new arrangements for the Cancer Drugs Fund recently agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee understood that the company was not making a case for pegylated liposomal irinotecan plus 5‑FU and LV to be considered for funding through the Cancer Drugs Fund. The committee considered that the most plausible ICERs for pegylated liposomal irinotecan plus 5‑FU and LV (see sections\xa04.12 and\xa04.13) for both comparisons were substantially higher than the range normally considered a cost-effective use of NHS resources. Therefore pegylated liposomal irinotecan plus 5‑FU and LV did not have plausible potential to satisfy the criteria for routine use. The committee also considered that although there were uncertainties in the evidence for this appraisal, the clinical-effectiveness evidence from NAPOLI‑1 was complete (see section\xa04.7). It heard from the company that there were no ongoing trials that could be used to inform the clinical uncertainty around the comparison with oxaliplatin plus 5‑FU and LV and therefore a subsequent update of the guidance. The committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV did not meet the criteria to be considered for funding through the Cancer Drugs Fund.\n\n# Innovation\n\nThe committee discussed whether pegylated liposomal irinotecan plus 5‑FU and LV was innovative in its potential to make a significant and substantial impact on health-related benefits. It heard from the clinical and patient experts that there were few options for treating metastatic adenocarcinoma of the pancreas and that pegylated liposomal irinotecan plus 5‑FU and LV would provide another option. However, the committee concluded that having an extra treatment option for metastatic adenocarcinoma of the pancreas did not mean that pegylated liposomal irinotecan plus 5‑FU and LV was innovative. It also concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n# Summary of appraisal committee's key conclusions\n\nTA440\n\nAppraisal title: Pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine\n\nSection\n\nKey conclusion\n\nPegylated liposomal irinotecan, in combination with 5‑fluorouracil (5‑FU) and leucovorin (LV), is not recommended, within its marketing authorisation, for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.\n\nThe committee considered that the NAPOLI‑1 trial showed that overall survival was statistically significantly longer on pegylated liposomal irinotecan plus 5‑FU and LV than on 5‑FU plus LV.\n\nThe company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous. But the company did an indirect comparison to generate hazard ratios, so it could then compare the cost effectiveness of the treatments.\n\nTaking into account all of the incremental cost-effectiveness ratio (ICERs) presented, the committee concluded that the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over £100,000 per quality-adjusted life year (QALY) gained.\n\nThe committee concluded that although the analyses comparing pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV were subject to considerable uncertainty, it was confident that pegylated liposomal irinotecan plus 5‑FU and LV would not be considered a cost-effective use of NHS resources.\n\n, 4.3, 4.4, 4.12, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nMetastatic adenocarcinoma of the pancreas that has progressed after gemcitabine treatment is associated with a poor prognosis because there are few treatments available, and survival may be less than 6\xa0months. Current treatments are limited in efficacy so there is value in more treatment options in this area.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard from the clinical and patient experts that there were few options for treating metastatic adenocarcinoma of the pancreas and that pegylated liposomal irinotecan plus 5‑FU and LV would provide another option. However, the committee concluded that having an extra treatment option did not mean that pegylated liposomal irinotecan plus 5‑FU and LV was innovative. It also concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee understood from the clinical expert that oxaliplatin plus 5‑FU and LV or capecitabine monotherapy are used in clinical practice in England after gemcitabine treatment. The committee agreed with the company, ERG and advice from the clinical expert that the most appropriate comparator for pegylated liposomal irinotecan plus 5‑FU and LV in NHS practice would be oxaliplatin plus 5‑FU and LV.\n\n\n\nAdverse reactions\n\nIn NAPOLI‑1, treatment-emergent serious adverse events (that is, events that first appear during treatment, or worsen during treatment) were more common in the pegylated liposomal irinotecan plus 5‑FU and LV group than in the 5‑FU plus LV group (47.9% compared with 44.8%). The committee noted that health-related quality-of-life data were collected in NAPOLI‑1 and that the results at 6\xa0weeks and 12\xa0weeks showed no real differences between the groups, suggesting no negative effect of pegylated liposomal irinotecan on health-related quality of life.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe company's submission presented clinical-effectiveness evidence from NAPOLI-1, comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV.\n\nThe company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous.\n\n, 4.4\n\nRelevance to general clinical practice in the NHS\n\nThe patients in NAPOLI‑1 were fitter than those generally seen in clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that given the uncertainties inherent in the indirect treatment comparison, the ERG reviewed the literature and concluded that, in general, the progression-free survival and overall survival estimates appeared very similar for oxaliplatin plus 5‑FU and LV and pegylated liposomal irinotecan plus 5‑FU and LV. The committee also noted that the relative effectiveness of oxaliplatin plus 5‑FU and LV compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe median extension in overall survival in NAPOLI‑1 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was 1.9\xa0months.\n\nBoth the company and the ERG were unable to produce a reliable estimate of the difference in overall survival between pegylated liposomal irinotecan plus 5‑FU and LV and oxaliplatin plus 5‑FU and LV, but when comparing 3\xa0trials of oxaliplatin plus 5‑FU and LV the median overall survival was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company submitted a de novo economic model to estimate the cost effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV and with oxaliplatin plus 5‑FU and LV, in people with metastatic adenocarcinoma of the pancreas after gemcitabine treatment.\n\nThe company used an indirect treatment comparison to estimate overall survival, progression-free survival and time-on-treatment curves for the comparison with oxaliplatin plus 5‑FU and LV.\n\n, 4.7\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe company made assumptions about the costs and survival estimates.\n\nThe committee noted that the total QALYs for oxaliplatin plus 5‑FU and LV were significantly lower than for 5‑FU plus LV in the company's analysis. It acknowledged that this result was not in agreement with comments from the clinical expert, who stated that oxaliplatin plus 5‑FU and LV is the preferred option; it is more clinically effective than 5‑FU and LV and is standard clinical practice in the NHS.\n\nThe committee concluded that because the data were complete for progression-free survival and time on treatment, and virtually complete for overall survival, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling.\n\nThe committee concluded that it was not appropriate to assume dose reductions would always apply in the company's model and that full costing should be assumed in the base case. It also concluded that it was not appropriate to assume use of the smallest sized vials in the company's model and that the ERG's method of calculating costs was more appropriate.\n\n–4.10\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee concluded that although there was uncertainty about the most appropriate utility values to use for a second-line treatment population with pancreatic cancer, the values used by the company were acceptable for decision-making.\n\nThe committee concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n, 4.17\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nFor the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV the committee considered that all the changes, except the ERG's preferred health state utility values, should be included in the base case. The committee therefore concluded that the ICER for pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV, was over £100,000 per QALY gained.\n\nFor the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the ERG carried out scenarios altering the QALY difference between the 2\xa0treatments. When taking into account these scenarios, the ICER ranged from £201,019 per QALY gained (when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% less than for pegylated liposomal irinotecan plus 5‑FU and LV) to pegylated liposomal irinotecan plus 5‑FU and LV being dominated (that is, less effective and more expensive than oxaliplatin plus 5‑FU and LV) when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% more.\n\n, 4.13\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that taking into account all of the ICERs presented, the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over £100,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee considered analyses incorporating the confidential patient access scheme for pegylated liposomal irinotecan plus 5‑FU and LV.\n\n, 4.13\n\nEnd-of-life considerations\n\nThe committee concluded that the criterion for short life expectancy was met.\n\nHowever, pegylated liposomal irinotecan plus 5‑FU and LV survival estimates from the trial and model showed that the criterion for extension to life was not met for the comparison with 5‑FU plus LV or with oxaliplatin plus 5‑FU and LV. The committee noted that when comparing 3\xa0trials of oxaliplatin plus 5‑FU and LV, the median overall survival was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1.\n\nTherefore, the committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV did not meet the NICE supplementary advice criteria to be considered as a life-extending, end-of-life treatment.\n\n, 4.15\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised during this appraisal.\n\n–"}	https://www.nice.org.uk/guidance/ta440	Evidence-based recommendations on pegylated liposomal irinotecan (Onivyde) for treating pancreatic cancer in adults.
f5f1cb297251c9784c5c3db92d81247fd34dcf5d	nice	Ixekizumab for treating moderate to severe plaque psoriasis	Ixekizumab for treating moderate to severe plaque psoriasis Evidence-based recommendations on ixekizumab (Taltz) for moderate to severe plaque psoriasis in adults. # Recommendations Ixekizumab is recommended as an option for treating plaque psoriasis in adults, only if: the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 the disease has not responded to standard systemic therapies, for example, ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or these treatments are contraindicated or the person cannot tolerate them, and the company provides the drug with the discount agreed in the patient access scheme. Stop ixekizumab treatment at 12 weeks if the psoriasis has not responded adequately. An adequate response is defined as: a 75% reduction in the PASI score (PASI 75) from when treatment started or a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started. When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate. These recommendations are not intended to affect treatment with ixekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Ixekizumab (Taltz, Eli Lilly) is an antibody that inhibits IL‑17A (interleukin-17A, a pro-inflammatory cytokine). Marketing authorisation Ixekizumab is 'indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'. Adverse reactions The most common adverse reactions with ixekizumab in clinical trials were upper respiratory tract infection and injection-site reactions (occurring in at least 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule By subcutaneous injection; 160 mg at week 0, followed by 80 mg every 2 weeks until week 12. After week 12, 80 mg every 4 weeks. Price The list price is £1,125 for 80 mg, and £2,250 for 2×80 mg. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ixekizumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of ixekizumab, having considered evidence on the nature of moderate to severe psoriasis and the value placed on the benefits of ixekizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee heard about the experience of people with psoriasis. It acknowledged that psoriasis can be a debilitating disease that affects all aspects of a person's life: physically, psychologically and socially. It noted that clearing symptoms with treatments associated with few or manageable side effects is important to people with psoriasis, as is having a choice of treatments. # Treatment pathway The committee heard from the clinical experts that biological treatment is offered to patients whose disease has not responded to standard systemic therapies (such as ciclosporin and methotrexate) or when these treatments are contraindicated or not tolerated. It heard from the clinical experts that, because there are long-term data available for other biologicals and clinicians are familiar with using them, ixekizumab was likely to be offered to 2 groups: patients who had already had a biological treatment to which their disease had not responded patients for whom other biological agents were contraindicated.The committee heard that clinicians might offer ixekizumab as a first biological treatment when doctors become more familiar with the treatment and there are more long-term data. The committee accepted that ixekizumab was likely to be used as a second biological treatment in a sequence of biological agents, but could be used as a first biological treatment for people for whom other biological agents are not appropriate. The committee also accepted that over time as more data become available, ixekizumab could replace older, less effective biologicals as a first biological treatment. # Comparators The committee was aware that the company's clinical evidence and economic model compared ixekizumab with biological treatments (etanercept, adalimumab, ustekinumab, secukinumab and infliximab), and only included comparisons with standard systemic therapies in scenario analyses. The committee considered that this was appropriate because it agreed with the company that in clinical practice, ixekizumab would be offered at the same place in the treatment pathway as the existing biological treatments (see section 4.2). The committee therefore concluded that the most appropriate comparators for ixekizumab were other biological treatments. # Clinical effectiveness ## Generalisability of the trial populations The committee noted that the evidence for ixekizumab mostly came from 3 trials: UNCOVER‑1, -2 and -3, which were double-blinded, randomised controlled trials that included 3,866 patients. UNCOVER‑1 compared ixekizumab with placebo, and UNCOVER‑2 and ‑3 compared ixekizumab with placebo and with etanercept. The primary outcome was Psoriasis Area and Severity Index (PASI) 75, which is a 75% reduction in the PASI score from when treatment started, measured at 12 weeks (the end of the induction period). The committee was aware that the trials included patients with a PASI score of 12 or more and that in previous appraisals of technologies for treating psoriasis, a PASI score of 10 or more had been defined as severe disease. The committee heard from the clinical experts that the PASI is a composite measure of disease severity that combines the extent of the body surface area involved and the severity of the redness, thickness and scaling in each area. It understood that higher values represent increased severity. The committee also understood that the trials included patients with Dermatology Life Quality Index (DLQI) scores ranging from 0 to 30, and that in previous NICE appraisals of technologies for treating psoriasis, a DLQI score of more than 10 had been defined as severe disease. It was aware that the DLQI is a questionnaire that aims to measure how much psoriasis affects the life of people who have it. It heard from the company that the trial eligibility criteria had also included a static Physician Global Assessment score of 3 or more, where scores of 3, 4 and 5 are defined as moderate, severe and very severe disease, respectively. The committee heard from the clinical experts that in clinical practice disease severity is rarely defined in this way. The committee heard from the clinical experts that patients being considered for biological treatment would tend to have a PASI score of 10 or 12 or above, and that the patients in the UNCOVER trials were representative of patients seen in the NHS who would be considered for biological treatment. The committee noted that the population in the trials and the marketing authorisation for ixekizumab included people who are candidates for systemic therapy, which includes both non-biological and biological treatments. It noted that the UNCOVER trials included patients who had never had systemic treatment, had had systemic treatment, or had already had biological treatment. Overall, the committee concluded that although previous treatment for trial participants varied, the populations of the UNCOVER trials were likely to be generalisable to patients in the NHS who would be considered for biological treatment, and were appropriate for decision-making on the clinical effectiveness of ixekizumab. ## Ixekizumab compared with placebo and etanercept The committee noted that patients randomised to ixekizumab had clinically and statistically significantly higher PASI 75 response rates at week 12 than placebo and etanercept. The odds ratios for ixekizumab producing a higher PASI 75 response rate at week 12 are detailed in table 1. ## Table 1 Odds ratios for ixekizumab producing higher PASI 75 response rate at week 12 UNCOVER-1 UNCOVER-2 UNCOVER-3 Compared with placebo % CI 125.05 to 401.03 % CI 173.11 to 5,745.5 % CI 36.11 to 144.73 Compared with etanercept N/A % CI 8.66 to 20.34 % CI 4.42 to 9.45 Abbreviations: CI, confidence interval; N/A, not applicable. The committee noted that the dose of etanercept given in the trials was double that which is recommended in NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis, and was considered by the clinicians to be more effective than lower doses of etanercept. Therefore the committee considered that the odds ratios could underestimate the treatment effect of ixekizumab compared with etanercept. The committee concluded that ixekizumab was more clinically effective than placebo and etanercept. ## Ixekizumab in patients who have already had biological treatment The committee noted that the benefit of treatment with ixekizumab compared with placebo and etanercept could be seen in the subgroup of patients who had already had biological treatment, as well as those who had not previously had biological treatment. It heard that the company did a test for interaction that showed little difference between the results of the trials across subgroups defined by baseline disease severity and previous biological treatment. The committee noted that the trials were not powered to detect statistically significant differences between subgroups, and so it could not be certain that the treatment effect did not differ across subgroups, however it agreed there was no evidence of a subgroup effect. The committee heard from the clinical experts that biological treatments generally work less well in patients who have already had a biological treatment, but that it depends on the particular biological treatment, and factors such as disease severity. The committee therefore concluded that, based on the data available, ixekizumab was more effective than etanercept or placebo both for patients who had previously had biological treatment and for those who had not. ## Network meta-analysis results The committee discussed the company's network meta-analysis that compared ixekizumab with adalimumab, ustekinumab, secukinumab and infliximab indirectly. The results showed that the relative risk of ixekizumab achieving a PASI 75 response at 12 weeks was significantly higher than that of all the biological treatment comparators except infliximab. The committee noted that the relative risk of secukinumab achieving a PASI 75 response compared with placebo and other biological treatments was lower than that seen in NICE's technology appraisal guidance on secukinumab for treating moderate to severe plaque psoriasis. It heard from the company that it had included trials of secukinumab in its analysis that had not been included in the secukinumab appraisal. The committee understood from the clinical experts that some of the biological treatments are known to work less well if they are used after another biological treatment. It heard from the company that it was not feasible to analyse the data separately for patients who had previously had biological treatment and those who had not because some of the trials included in the network meta-analysis did not report information for these groups separately. The committee concluded that, because the network meta-analysis reflected a mixture of people who had and had not already had biological treatments, it was uncertain how generalisable the results were to ixekizumab being given as a first or second biological treatment in a sequence of biological treatments (see section 4.2). The committee considered the comment received during consultation noting that data from the British Association of Dermatologists' Biologic Intervention Register showed higher PASI scores for adalimumab than those presented to the committee. The committee recognised that network meta-analyses use trial-based estimates of relative treatment effects rather than registry data. Furthermore, the patients in the registry may differ from those included in the trials. The committee noted the evidence review group's (ERG's) comment that the results of the network meta-analysis were similar to those presented in previous technology appraisals for psoriasis. Because of this, the committee agreed that the network meta-analysis remained the more reliable estimate for decision-making.Acknowledging these uncertainties, the committee concluded that the network meta-analysis showed that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab. ## Adverse events The committee was aware that the rates of serious adverse events including non-melanoma skin cancer, malignancies other than non-melanoma skin cancer, and severe infection, were very low, and that most of the adverse events related to treatment were mild to moderately severe and did not lead to stopping treatment. It heard from the clinical experts that serious infection was the main concern with biologicals, but that treatment was generally well tolerated. The committee concluded that the tolerability of ixekizumab was similar to that for other biological treatments approved for treating psoriasis. # Cost effectiveness ## Model structure The committee considered the Markov state transition model the company used to model the cost effectiveness of ixekizumab. It modelled 7 biological treatment sequences and contained 4 health states: Induction period: All patients start in this health state and have treatment in the induction period. Moving from induction to maintenance occurs when a patient's disease has achieved a 75% reduction in PASI score at the end of the induction period. If their disease responds inadequately, patients move on to the next treatment in the sequence. Maintenance: Patients stay on treatment until it is stopped for any reason. After treatment stops, patients move to the induction phase of the next treatment in the sequence. Best supportive care: Patients enter this health state after having up to 3 biological treatments. Patients can have non-biological therapies and maintain a level of response until death. Death: Moving to this state is possible from any of the above states. The general population mortality rate is applied. The committee noted that the ERG considered the treatment sequencing approach to be better than comparing individual treatments because it more closely reflected clinical practice. It noted that the model represented both patients who had never had systemic treatments, and those who had already had biological treatment. The committee concluded that the company's model structure reflected clinical practice. The committee understood that the company had used market share information to determine the most commonly used treatment sequences in the NHS. Each of the 7 biological treatments was modelled first in a sequence of 3 biologicals, as follows: ixekizumab, ustekinumab (90 mg), infliximab adalimumab, ustekinumab (90 mg), infliximab etanercept, ustekinumab (90 mg), infliximab infliximab, ustekinumab (90 mg), adalimumab secukinumab, ustekinumab (90 mg), infliximab ustekinumab (45 mg), adalimumab, infliximab ustekinumab (90 mg), adalimumab, infliximab. It heard from the clinical experts that the sequences of treatment included in the company's economic model mostly reflected current practice in the NHS, except that etanercept and infliximab were not used as a first biological treatment. Also, depending on the weight of the patient, ustekinumab 90 mg may be used as a second biological treatment if there is an inadequate response to ustekinumab 45 mg. This sequence was not included in the company's economic model. The committee also considered whether ixekizumab would replace an existing biological treatment, or extend a sequence of biological treatments. It heard from clinical experts that although ixekizumab could initially extend an existing biological treatment sequence, over time as more data become available it may replace an older, less efficient biological treatment. The committee recognised that the treatment sequences presented did not cover all possible sequences but concluded that the sequences included by the company in its economic model reasonably represented current NHS practice. ## Modelling utility benefit The committee understood that the company had used the subgroup of patients with a DLQI of more than 10 from the UNCOVER trials to estimate utility benefit. It noted that this differed from the intention-to-treat populations (that is, those with a DLQI ranging from 0 to 30) from the UNCOVER trials and from other trials included in the company's network meta-analysis, that were used to model treatment effectiveness. The committee acknowledged that this subgroup could not be used to model treatment effectiveness because not all the trials included in the network meta-analysis reported subgroup data. It accepted that because the subgroup population with a DLQI of more than 10 represented the patients seen in clinical practice, it was appropriate to analyse this subgroup where possible. It concluded that it was therefore appropriate to use this subgroup of patients to estimate utility benefit. The committee considered when patients would get the benefit of treatment, and when to apply the utility gains from treatment in the model. It was aware that the company had applied utility gains in the maintenance period of treatment, but not the induction period. It heard from both the ERG and the company that ixekizumab is associated with a rapid response and therefore utility gains during the induction period were likely. The committee concluded that it would be appropriate to include utility gains for ixekizumab in the induction period, and that excluding this underestimates the quality-adjusted life year (QALY) gain associated with ixekizumab. The committee noted that the company did not include the disutility of adverse events in its model. It considered that this did not reflect the importance of manageable side effects (see section 4.1). It heard from the company that there were little data available on severe adverse events that led to stopping treatment. The committee heard from the clinical experts that biological treatments were generally well tolerated (see section 4.10) and that their side effects profiles were similar, and concluded that it was therefore acceptable to exclude the adverse events in the model. ## Costs of adverse events The committee acknowledged that serious adverse events including non-melanoma skin cancer, malignancies other than non-melanoma skin cancer and severe infection did not occur very often (see section 4.10). However, the committee considered that it was appropriate to capture all the benefits and costs, including the costs of adverse events over the time horizon of the model. The committee concluded that the company should have included the costs of adverse events in its economic model, particularly given that the quality-of-life data were likely to already include any disutility from adverse events. ## Costs of best supportive care The committee noted that the costs of best supportive care had been estimated used the Fonia et al. (2010) study. It was aware from previous appraisals for psoriasis that when this study had been used, the conclusion was that it was likely to overestimate the costs of best supportive care. The committee understood from the ERG's analysis that if the costs of best supportive care were lower, the incremental cost-effectiveness ratios (ICERs) for ixekizumab compared with other biological treatments would increase. It considered that the estimates from Fonia et al. do not represent best supportive care after many biological treatments have not worked because they include costs of systemic treatments that are unlikely to be given after 3 biological treatments. The committee concluded that the costs of best supportive care remained uncertain, but given that data are lacking in this area, considered that the Fonia et al. estimates were appropriate for the company to use in the economic model. ## Results of cost-effectiveness analysis The committee noted that the company had given deterministic results in its base case. The committee preferred to use a probabilistic base-case analysis for decision-making. It agreed that the cost of adverse events should be included and that utility gains should be applied in the induction period of treatment, which the ERG had done in its base-case analysis. The committee noted that the ERG had also fixed errors in the company's model for adverse event rates and costs, calculating the standard error for NHS reference costs, and calculating the number of doses of secukinumab in the maintenance period. The committee therefore preferred to consider the results of the ERG's base-case analysis in its decision-making. The committee noted that when validating the company's model, the ERG's ICERs for each comparator alone (that is, not in a sequence with other treatments) compared with best supportive care were more than £30,000 per QALY gained. The committee considered that including potentially non-cost-effective comparators, especially within sequences of treatments could result in misleading ICERs. The committee therefore also took into account comparisons against best supportive care in its decision-making. It noted that the ERG had presented analyses with ixekizumab at different positions within the treatment pathway (as the first biological treatment or as the second), and considered each in turn. The committee considered the cost-effectiveness analyses for ixekizumab as the first biological treatment in a treatment sequence, taking into account the patient access schemes associated with ixekizumab and secukinumab. It noted: The incremental analysis included sequences with etanercept and infliximab as the first biological treatments in a sequence, which the committee heard does not represent current clinical practice (see section 4.14). The analysis also included a sequence which included ixekizumab as the second biological treatment in a sequence, which also does not represent current clinical practice. The committee therefore concluded that it would not use this analysis for decision-making. Pairwise comparisons of the relevant sequences showed that ixekizumab as the first biological treatment in the treatment pathway either dominated other biological sequences (was more effective and cost less), or the ICERs for that sequence were less than £30,000 per QALY gained. The committee considered the cost-effectiveness analyses for ixekizumab as the second biological treatment in a treatment sequence, taking into account the patient access schemes associated with ixekizumab and secukinumab. It noted: The incremental analysis included sequences that do not represent current clinical practice (see section 4.22), so the committee concluded that it would not use this analysis for decision-making. Pairwise comparisons of the relevant sequences showed that the sequence including ixekizumab dominated all other treatment sequences. The exception was the comparison with the sequence of secukinumab followed by ustekinumab and infliximab because the sequence of adalimumab followed by ixekizumab and infliximab had fewer total costs and QALYs than the sequence including secukinumab. The committee was aware that, in a sequencing model, the costs and benefits are driven by all the treatments in the sequence. It noted that the ICER for the sequence including ixekizumab compared with the sequence including secukinumab was more than £50,000 saved per QALY lost. The committee considered the cost-effectiveness analyses for ixekizumab (not in a sequence) compared with best supportive care, and the ICERs for each comparator (not in a sequence) compared with best supportive care, which were used by the ERG to validate the model (see section 4.21). The committee recognised these analyses used the company's assumptions. It noted: Pairwise comparisons of the other biological treatments compared with best supportive care gave ICERs in the range of £46,000 to £74,000 per QALY gained. Pairwise comparison of ixekizumab compared with best supportive care gave an ICER of £41,000 per QALY gained. The committee therefore concluded that the cost effectiveness of ixekizumab was similar to that of other biological treatments when compared with best supportive care. The committee was aware that the company had not explored the full range of treatment sequences that might be offered in current NHS practice (see section 4.14). The committee recognised that best supportive care was not a relevant comparator given the position of ixekizumab in the treatment pathway, but it considered the comparison in its decision-making to account for potential bias from including non-cost-effective comparators within all other analyses. The committee considered the cost effectiveness of ixekizumab in the light of previous appraisals in this disease area and concluded that the most plausible ICER was likely to be in line with the other biological treatments already recommended in previous NICE guidance. The committee concluded that the ICER was within the range that could be considered a cost-effective use of NHS resources. ## Stopping rule The committee was aware that previous appraisals for treating psoriasis recommended stopping treatment if there was an inadequate response; an adequate response was defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The latter stopping rule was originally included based on clinical advice, rather than specific evidence on the clinical- and cost effectiveness of this treatment strategy. The committee agreed that if there was no response to ixekizumab, the patient should not continue treatment. The committee noted that PASI 75 was the primary outcome in the trial data used to model the cost effectiveness of ixekizumab. It also considered the cost-effectiveness evidence for a PASI 50 stopping rule submitted by the company as a scenario analysis during consultation. It noted that the cost effectiveness of ixekizumab improved when a PASI 50 stopping rule was applied. The committee thought this may be counter-intuitive because there would be a smaller benefit for those with a PASI 50 response for the same cost. It heard from the company that, when the PASI 50 stopping rule is applied, patients remain on ixekizumab for longer, which increases the benefit accrued from having active treatment. The committee acknowledged that the sequencing model made it difficult to ascertain what was driving the results. The committee appreciated that, in patients with psoriasis affecting their hands and feet, a PASI 75 may be difficult to achieve because gains in quality of life from having treatment could represent clinical improvement but not be accounted for in the PASI score. The committee therefore concluded that, for consistency with previous appraisals for biological treatments in psoriasis, ixekizumab should be stopped if there is an inadequate response at 12 weeks, with an adequate response defined as a 75% reduction in the PASI score from when treatment started or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. # Innovation The committee considered whether ixekizumab was an innovative treatment. It heard from the clinical experts that ixekizumab did not differ substantially in its mechanism of action from secukinumab. The committee concluded that the company had not given the committee any additional evidence of benefits that were not captured in estimating the QALYs. # Equality issues The committee noted the potential equality issues raised in the consultee submissions, that the PASI can underestimate disease severity in those with darker skin, and that the DLQI has limited validity in older people and those not working, and may also miss anxiety and depression. The committee concluded that when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA442 Appraisal title: ixekizumab for treating moderate to severe plaque psoriasis Section Key conclusion Ixekizumab is recommended as an option for treating plaque psoriasis in adults, only if: the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 the disease has not responded to standard systemic therapies, for example, ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or these treatments are contraindicated or the person cannot tolerate them, and the company provides the drug with the discount agreed in the patient access scheme. The committee concluded that ixekizumab was more clinically effective than placebo and etanercept. The evidence review group's (ERG's) pairwise comparison of ixekizumab as the first biological treatment in the treatment pathway compared with other relevant sequences showed that ixekizumab either: dominated other biological sequences (was more effective and cost less) or the incremental cost-effectiveness ratios (ICERs) for that sequence were less than £30,000 per quality-adjusted life year (QALY) gained. Pairwise comparisons of the relevant sequences showed that the sequence including ixekizumab as the second biological treatment dominated all other treatment sequences. The exception was the comparison with the sequence of secukinumab followed by ustekinumab and infliximab because the sequence of adalimumab followed by ixekizumab and infliximab had fewer total costs and QALYs than the sequence including secukinumab. However, the committee noted that the ICER for the sequence including ixekizumab compared with the sequence including secukinumab was more than £50,000 saved per QALY lost. The committee concluded that the ICER was within the range that could be considered a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments Clearing symptoms with treatments associated with few or manageable side effects is important to people with psoriasis, as is having a choice of treatments. Biological treatment is offered to patients whose disease has not responded to standard systemic therapies (such as ciclosporin, methotrexate and PUVA) or when these treatments are contraindicated or not tolerated. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The results of the 3 UNCOVER trials showed that ixekizumab is more clinically effective than placebo and etanercept. Treatment with biologicals is generally well tolerated and the tolerability of ixekizumab was considered to be similar to that for other biological treatments. What is the position of the treatment in the pathway of care for the condition? Ixekizumab is likely to be primarily offered to patients whose disease has not responded to a previous biological treatment and to patients who cannot have other biological treatments. Adverse reactions The most common adverse reactions with ixekizumab in clinical trials were upper respiratory tract infection and injection site reactions. Evidence for clinical effectiveness Availability, nature and quality of evidence The evidence mostly came from 3 trials: UNCOVER‑1, -2 and -3, which were double-blinded, randomised controlled trials that included a total of 3,866 patients. UNCOVER‑1 compared ixekizumab with placebo, and UNCOVER‑2 and ‑3 compared ixekizumab with placebo and with etanercept. Relevance to general clinical practice in the NHS The committee concluded that the patients in the UNCOVER trials were representative of patients seen in the NHS who would be considered for biological treatment, and so the results were generalisable to patients in the NHS. Uncertainties generated by the evidence The dose of etanercept given in the trials was double that which is recommended NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis, and was considered by the clinicians to be more effective than lower doses of etanercept. Therefore the committee considered that the treatment effect of ixekizumab compared with etanercept could be underestimated. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The benefit of treatment with ixekizumab compared with placebo and etanercept could be seen in the subgroup of patients who had already had biological treatment, as well as those who had not previously had biological treatment. The committee noted that the trials were not powered to detect statistically significant differences between subgroups, and so could not be certain that the treatment effect of ixekizumab did not differ across these subgroups, but agreed there was no evidence of a subgroup effect. Estimate of the size of the clinical effectiveness including strength of supporting evidence Patients randomised to ixekizumab had clinically and statistically significantly higher PASI 75 response rates (that is, a 75% reduction in PASI score from when treatment started) at week 12 than placebo and etanercept. Evidence for cost effectiveness Availability and nature of evidence The company presented a Markov state transition model comparing a treatment sequence with ixekizumab given as the first in a sequence of 3 biological treatments, with 6 other biological treatment sequences. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee concluded that the treatment sequences included by the company in its economic model reasonably represented current NHS practice, although it heard that 2 of the treatment sequences are not used in current practice. The committee concluded that the company should have included the costs of adverse events in its economic model. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee concluded that it would be appropriate to include utility gains associated with treatment benefit in the induction period, and not just in the maintenance period. The company had not given the committee any additional evidence of benefits that were not captured in estimating the QALYs. What are the key drivers of cost effectiveness? Treatment sequences included. Utility benefit and when it is applied. Costs of adverse events. Costs of best supportive care. Most likely cost-effectiveness estimate (given as an ICER) The ERG's pairwise comparison of ixekizumab as the first biological treatment in the treatment pathway compared with other relevant sequences, showed that ixekizumab either dominated other biological sequences), or the ICERs for that sequence were less than £30,000 per QALY gained. Pairwise comparisons of the relevant sequences showed that the sequence including ixekizumab as the second biological treatment dominated all other treatment sequences. The exception was the comparison with the sequence of secukinumab followed by ustekinumab and infliximab because the sequence of adalimumab followed by ixekizumab and infliximab had fewer total costs and QALYs than the sequence including secukinumab. However, the committee noted that the ICER for the sequence including ixekizumab compared with the sequence including secukinumab was more than £50,000 saved per QALY lost. The committee concluded that the ICER was within the range that could be considered a cost-effective use of NHS resources. Additional factors taken into account Patient access schemes (PPRS) The company presented analysis that included the confidential patient access scheme for ixekizumab. The ERG presented analysis that included the confidential discounts for both ixekizumab and secukinumab. End-of-life considerations Not applicable. Equalities considerations and social value judgements When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.	{'Recommendations': 'Ixekizumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10\xa0or more and a Dermatology Life Quality Index (DLQI) of more than\xa010\n\nthe disease has not responded to standard systemic therapies, for example, ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or these treatments are contraindicated or the person cannot tolerate them, and\n\nthe company provides the drug with the discount agreed in the patient access scheme.\n\nStop ixekizumab treatment at 12\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with ixekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nIxekizumab (Taltz, Eli Lilly) is an antibody that inhibits IL‑17A (interleukin-17A, a pro-inflammatory cytokine).\n\nMarketing authorisation\n\nIxekizumab is 'indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.\n\nAdverse reactions\n\nThe most common adverse reactions with ixekizumab in clinical trials were upper respiratory tract infection and injection-site reactions (occurring in at least 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nBy subcutaneous injection; 160\xa0mg at week\xa00, followed by 80\xa0mg every 2\xa0weeks until week\xa012. After week\xa012, 80\xa0mg every 4\xa0weeks.\n\nPrice\n\nThe list price is £1,125 for 80\xa0mg, and £2,250 for 2×80\xa0mg.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ixekizumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of ixekizumab, having considered evidence on the nature of moderate to severe psoriasis and the value placed on the benefits of ixekizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee heard about the experience of people with psoriasis. It acknowledged that psoriasis can be a debilitating disease that affects all aspects of a person's life: physically, psychologically and socially. It noted that clearing symptoms with treatments associated with few or manageable side effects is important to people with psoriasis, as is having a choice of treatments.\n\n# Treatment pathway\n\nThe committee heard from the clinical experts that biological treatment is offered to patients whose disease has not responded to standard systemic therapies (such as ciclosporin and methotrexate) or when these treatments are contraindicated or not tolerated. It heard from the clinical experts that, because there are long-term data available for other biologicals and clinicians are familiar with using them, ixekizumab was likely to be offered to 2\xa0groups:\n\npatients who had already had a biological treatment to which their disease had not responded\n\npatients for whom other biological agents were contraindicated.The committee heard that clinicians might offer ixekizumab as a first biological treatment when doctors become more familiar with the treatment and there are more long-term data. The committee accepted that ixekizumab was likely to be used as a second biological treatment in a sequence of biological agents, but could be used as a first biological treatment for people for whom other biological agents are not appropriate. The committee also accepted that over time as more data become available, ixekizumab could replace older, less effective biologicals as a first biological treatment.\n\n# Comparators\n\nThe committee was aware that the company's clinical evidence and economic model compared ixekizumab with biological treatments (etanercept, adalimumab, ustekinumab, secukinumab and infliximab), and only included comparisons with standard systemic therapies in scenario analyses. The committee considered that this was appropriate because it agreed with the company that in clinical practice, ixekizumab would be offered at the same place in the treatment pathway as the existing biological treatments (see section\xa04.2). The committee therefore concluded that the most appropriate comparators for ixekizumab were other biological treatments.\n\n# Clinical effectiveness\n\n## Generalisability of the trial populations\n\nThe committee noted that the evidence for ixekizumab mostly came from 3\xa0trials: UNCOVER‑1, -2 and -3, which were double-blinded, randomised controlled trials that included 3,866\xa0patients. UNCOVER‑1 compared ixekizumab with placebo, and UNCOVER‑2 and ‑3 compared ixekizumab with placebo and with etanercept. The primary outcome was Psoriasis Area and Severity Index (PASI) 75, which is a 75% reduction in the PASI score from when treatment started, measured at 12\xa0weeks (the end of the induction period).\n\nThe committee was aware that the trials included patients with a PASI score of 12\xa0or more and that in previous appraisals of technologies for treating psoriasis, a PASI score of 10\xa0or more had been defined as severe disease. The committee heard from the clinical experts that the PASI is a composite measure of disease severity that combines the extent of the body surface area involved and the severity of the redness, thickness and scaling in each area. It understood that higher values represent increased severity. The committee also understood that the trials included patients with Dermatology Life Quality Index (DLQI) scores ranging from 0\xa0to\xa030, and that in previous NICE appraisals of technologies for treating psoriasis, a DLQI score of more than\xa010 had been defined as severe disease. It was aware that the DLQI is a questionnaire that aims to measure how much psoriasis affects the life of people who have it. It heard from the company that the trial eligibility criteria had also included a static Physician Global Assessment score of 3\xa0or more, where scores of\xa03,\xa04 and\xa05 are defined as moderate, severe and very severe disease, respectively. The committee heard from the clinical experts that in clinical practice disease severity is rarely defined in this way. The committee heard from the clinical experts that patients being considered for biological treatment would tend to have a PASI score of 10\xa0or\xa012 or above, and that the patients in the UNCOVER trials were representative of patients seen in the NHS who would be considered for biological treatment.\n\nThe committee noted that the population in the trials and the marketing authorisation for ixekizumab included people who are candidates for systemic therapy, which includes both non-biological and biological treatments. It noted that the UNCOVER trials included patients who had never had systemic treatment, had had systemic treatment, or had already had biological treatment. Overall, the committee concluded that although previous treatment for trial participants varied, the populations of the UNCOVER trials were likely to be generalisable to patients in the NHS who would be considered for biological treatment, and were appropriate for decision-making on the clinical effectiveness of ixekizumab.\n\n## Ixekizumab compared with placebo and etanercept\n\nThe committee noted that patients randomised to ixekizumab had clinically and statistically significantly higher PASI\xa075 response rates at week\xa012 than placebo and etanercept. The odds ratios for ixekizumab producing a higher PASI\xa075 response rate at week\xa012 are detailed in table\xa01.\n\n## Table 1 Odds ratios for ixekizumab producing higher PASI\xa075 response rate at week\xa012\n\nUNCOVER-1\n\nUNCOVER-2\n\nUNCOVER-3\n\nCompared with placebo\n\n\n\n% CI 125.05 to 401.03\n\n\n\n% CI 173.11 to 5,745.5\n\n\n\n% CI 36.11 to 144.73\n\nCompared with etanercept\n\nN/A\n\n\n\n% CI 8.66 to 20.34\n\n\n\n% CI 4.42 to 9.45\n\nAbbreviations: CI, confidence interval; N/A, not applicable.\n\nThe committee noted that the dose of etanercept given in the trials was double that which is recommended in NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis, and was considered by the clinicians to be more effective than lower doses of etanercept. Therefore the committee considered that the odds ratios could underestimate the treatment effect of ixekizumab compared with etanercept. The committee concluded that ixekizumab was more clinically effective than placebo and etanercept.\n\n## Ixekizumab in patients who have already had biological treatment\n\nThe committee noted that the benefit of treatment with ixekizumab compared with placebo and etanercept could be seen in the subgroup of patients who had already had biological treatment, as well as those who had not previously had biological treatment. It heard that the company did a test for interaction that showed little difference between the results of the trials across subgroups defined by baseline disease severity and previous biological treatment. The committee noted that the trials were not powered to detect statistically significant differences between subgroups, and so it could not be certain that the treatment effect did not differ across subgroups, however it agreed there was no evidence of a subgroup effect. The committee heard from the clinical experts that biological treatments generally work less well in patients who have already had a biological treatment, but that it depends on the particular biological treatment, and factors such as disease severity. The committee therefore concluded that, based on the data available, ixekizumab was more effective than etanercept or placebo both for patients who had previously had biological treatment and for those who had not.\n\n## Network meta-analysis results\n\nThe committee discussed the company's network meta-analysis that compared ixekizumab with adalimumab, ustekinumab, secukinumab and infliximab indirectly. The results showed that the relative risk of ixekizumab achieving a PASI\xa075 response at 12\xa0weeks was significantly higher than that of all the biological treatment comparators except infliximab.\n\nThe committee noted that the relative risk of secukinumab achieving a PASI\xa075 response compared with placebo and other biological treatments was lower than that seen in NICE's technology appraisal guidance on secukinumab for treating moderate to severe plaque psoriasis. It heard from the company that it had included trials of secukinumab in its analysis that had not been included in the secukinumab appraisal.\n\nThe committee understood from the clinical experts that some of the biological treatments are known to work less well if they are used after another biological treatment. It heard from the company that it was not feasible to analyse the data separately for patients who had previously had biological treatment and those who had not because some of the trials included in the network meta-analysis did not report information for these groups separately. The committee concluded that, because the network meta-analysis reflected a mixture of people who had and had not already had biological treatments, it was uncertain how generalisable the results were to ixekizumab being given as a first or second biological treatment in a sequence of biological treatments (see section\xa04.2).\n\nThe committee considered the comment received during consultation noting that data from the British Association of Dermatologists' Biologic Intervention Register showed higher PASI scores for adalimumab than those presented to the committee. The committee recognised that network meta-analyses use trial-based estimates of relative treatment effects rather than registry data. Furthermore, the patients in the registry may differ from those included in the trials. The committee noted the evidence review group's (ERG's) comment that the results of the network meta-analysis were similar to those presented in previous technology appraisals for psoriasis. Because of this, the committee agreed that the network meta-analysis remained the more reliable estimate for decision-making.Acknowledging these uncertainties, the committee concluded that the network meta-analysis showed that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab.\n\n## Adverse events\n\nThe committee was aware that the rates of serious adverse events including non-melanoma skin cancer, malignancies other than non-melanoma skin cancer, and severe infection, were very low, and that most of the adverse events related to treatment were mild to moderately severe and did not lead to stopping treatment. It heard from the clinical experts that serious infection was the main concern with biologicals, but that treatment was generally well tolerated. The committee concluded that the tolerability of ixekizumab was similar to that for other biological treatments approved for treating psoriasis.\n\n# Cost effectiveness\n\n## Model structure\n\nThe committee considered the Markov state transition model the company used to model the cost effectiveness of ixekizumab. It modelled 7\xa0biological treatment sequences and contained 4\xa0health states:\n\nInduction period: All patients start in this health state and have treatment in the induction period. Moving from induction to maintenance occurs when a patient's disease has achieved a 75% reduction in PASI score at the end of the induction period. If their disease responds inadequately, patients move on to the next treatment in the sequence.\n\nMaintenance: Patients stay on treatment until it is stopped for any reason. After treatment stops, patients move to the induction phase of the next treatment in the sequence.\n\nBest supportive care: Patients enter this health state after having up to 3\xa0biological treatments. Patients can have non-biological therapies and maintain a level of response until death.\n\nDeath: Moving to this state is possible from any of the above states. The general population mortality rate is applied.\n\nThe committee noted that the ERG considered the treatment sequencing approach to be better than comparing individual treatments because it more closely reflected clinical practice. It noted that the model represented both patients who had never had systemic treatments, and those who had already had biological treatment. The committee concluded that the company's model structure reflected clinical practice.\n\nThe committee understood that the company had used market share information to determine the most commonly used treatment sequences in the NHS. Each of the 7\xa0biological treatments was modelled first in a sequence of 3\xa0biologicals, as follows:\n\nixekizumab, ustekinumab (90\xa0mg), infliximab\n\nadalimumab, ustekinumab (90\xa0mg), infliximab\n\netanercept, ustekinumab (90\xa0mg), infliximab\n\ninfliximab, ustekinumab (90\xa0mg), adalimumab\n\nsecukinumab, ustekinumab (90\xa0mg), infliximab\n\nustekinumab (45\xa0mg), adalimumab, infliximab\n\nustekinumab (90\xa0mg), adalimumab, infliximab.\n\nIt heard from the clinical experts that the sequences of treatment included in the company's economic model mostly reflected current practice in the NHS, except that etanercept and infliximab were not used as a first biological treatment. Also, depending on the weight of the patient, ustekinumab 90\xa0mg may be used as a second biological treatment if there is an inadequate response to ustekinumab 45\xa0mg. This sequence was not included in the company's economic model. The committee also considered whether ixekizumab would replace an existing biological treatment, or extend a sequence of biological treatments. It heard from clinical experts that although ixekizumab could initially extend an existing biological treatment sequence, over time as more data become available it may replace an older, less efficient biological treatment. The committee recognised that the treatment sequences presented did not cover all possible sequences but concluded that the sequences included by the company in its economic model reasonably represented current NHS practice.\n\n## Modelling utility benefit\n\nThe committee understood that the company had used the subgroup of patients with a DLQI of more than 10 from the UNCOVER trials to estimate utility benefit. It noted that this differed from the intention-to-treat populations (that is, those with a DLQI ranging from 0\xa0to\xa030) from the UNCOVER trials and from other trials included in the company's network meta-analysis, that were used to model treatment effectiveness. The committee acknowledged that this subgroup could not be used to model treatment effectiveness because not all the trials included in the network meta-analysis reported subgroup data. It accepted that because the subgroup population with a DLQI of more than\xa010 represented the patients seen in clinical practice, it was appropriate to analyse this subgroup where possible. It concluded that it was therefore appropriate to use this subgroup of patients to estimate utility benefit.\n\nThe committee considered when patients would get the benefit of treatment, and when to apply the utility gains from treatment in the model. It was aware that the company had applied utility gains in the maintenance period of treatment, but not the induction period. It heard from both the ERG and the company that ixekizumab is associated with a rapid response and therefore utility gains during the induction period were likely. The committee concluded that it would be appropriate to include utility gains for ixekizumab in the induction period, and that excluding this underestimates the quality-adjusted life year (QALY) gain associated with ixekizumab.\n\nThe committee noted that the company did not include the disutility of adverse events in its model. It considered that this did not reflect the importance of manageable side effects (see section\xa04.1). It heard from the company that there were little data available on severe adverse events that led to stopping treatment. The committee heard from the clinical experts that biological treatments were generally well tolerated (see section\xa04.10) and that their side effects profiles were similar, and concluded that it was therefore acceptable to exclude the adverse events in the model.\n\n## Costs of adverse events\n\nThe committee acknowledged that serious adverse events including non-melanoma skin cancer, malignancies other than non-melanoma skin cancer and severe infection did not occur very often (see section\xa04.10). However, the committee considered that it was appropriate to capture all the benefits and costs, including the costs of adverse events over the time horizon of the model. The committee concluded that the company should have included the costs of adverse events in its economic model, particularly given that the quality-of-life data were likely to already include any disutility from adverse events.\n\n## Costs of best supportive care\n\nThe committee noted that the costs of best supportive care had been estimated used the Fonia et al. (2010) study. It was aware from previous appraisals for psoriasis that when this study had been used, the conclusion was that it was likely to overestimate the costs of best supportive care. The committee understood from the ERG's analysis that if the costs of best supportive care were lower, the incremental cost-effectiveness ratios (ICERs) for ixekizumab compared with other biological treatments would increase. It considered that the estimates from Fonia et al. do not represent best supportive care after many biological treatments have not worked because they include costs of systemic treatments that are unlikely to be given after 3\xa0biological treatments. The committee concluded that the costs of best supportive care remained uncertain, but given that data are lacking in this area, considered that the Fonia et al. estimates were appropriate for the company to use in the economic model.\n\n## Results of cost-effectiveness analysis\n\nThe committee noted that the company had given deterministic results in its base case. The committee preferred to use a probabilistic base-case analysis for decision-making. It agreed that the cost of adverse events should be included and that utility gains should be applied in the induction period of treatment, which the ERG had done in its base-case analysis. The committee noted that the ERG had also fixed errors in the company's model for adverse event rates and costs, calculating the standard error for NHS reference costs, and calculating the number of doses of secukinumab in the maintenance period. The committee therefore preferred to consider the results of the ERG's base-case analysis in its decision-making.\n\nThe committee noted that when validating the company's model, the ERG's ICERs for each comparator alone (that is, not in a sequence with other treatments) compared with best supportive care were more than £30,000 per QALY gained. The committee considered that including potentially non-cost-effective comparators, especially within sequences of treatments could result in misleading ICERs. The committee therefore also took into account comparisons against best supportive care in its decision-making. It noted that the ERG had presented analyses with ixekizumab at different positions within the treatment pathway (as the first biological treatment or as the second), and considered each in turn.\n\nThe committee considered the cost-effectiveness analyses for ixekizumab as the first biological treatment in a treatment sequence, taking into account the patient access schemes associated with ixekizumab and secukinumab. It noted:\n\nThe incremental analysis included sequences with etanercept and infliximab as the first biological treatments in a sequence, which the committee heard does not represent current clinical practice (see section\xa04.14). The analysis also included a sequence which included ixekizumab as the second biological treatment in a sequence, which also does not represent current clinical practice. The committee therefore concluded that it would not use this analysis for decision-making.\n\nPairwise comparisons of the relevant sequences showed that ixekizumab as the first biological treatment in the treatment pathway either dominated other biological sequences (was more effective and cost less), or the ICERs for that sequence were less than £30,000 per QALY gained.\n\nThe committee considered the cost-effectiveness analyses for ixekizumab as the second biological treatment in a treatment sequence, taking into account the patient access schemes associated with ixekizumab and secukinumab. It noted:\n\nThe incremental analysis included sequences that do not represent current clinical practice (see section\xa04.22), so the committee concluded that it would not use this analysis for decision-making.\n\nPairwise comparisons of the relevant sequences showed that the sequence including ixekizumab dominated all other treatment sequences. The exception was the comparison with the sequence of secukinumab followed by ustekinumab and infliximab because the sequence of adalimumab followed by ixekizumab and infliximab had fewer total costs and QALYs than the sequence including secukinumab. The committee was aware that, in a sequencing model, the costs and benefits are driven by all the treatments in the sequence. It noted that the ICER for the sequence including ixekizumab compared with the sequence including secukinumab was more than £50,000 saved per QALY lost.\n\nThe committee considered the cost-effectiveness analyses for ixekizumab (not in a sequence) compared with best supportive care, and the ICERs for each comparator (not in a sequence) compared with best supportive care, which were used by the ERG to validate the model (see section\xa04.21). The committee recognised these analyses used the company's assumptions. It noted:\n\nPairwise comparisons of the other biological treatments compared with best supportive care gave ICERs in the range of £46,000 to £74,000 per QALY gained.\n\nPairwise comparison of ixekizumab compared with best supportive care gave an ICER of £41,000 per QALY gained. The committee therefore concluded that the cost effectiveness of ixekizumab was similar to that of other biological treatments when compared with best supportive care.\n\nThe committee was aware that the company had not explored the full range of treatment sequences that might be offered in current NHS practice (see section\xa04.14). The committee recognised that best supportive care was not a relevant comparator given the position of ixekizumab in the treatment pathway, but it considered the comparison in its decision-making to account for potential bias from including non-cost-effective comparators within all other analyses. The committee considered the cost effectiveness of ixekizumab in the light of previous appraisals in this disease area and concluded that the most plausible ICER was likely to be in line with the other biological treatments already recommended in previous NICE guidance. The committee concluded that the ICER was within the range that could be considered a cost-effective use of NHS resources.\n\n## Stopping rule\n\nThe committee was aware that previous appraisals for treating psoriasis recommended stopping treatment if there was an inadequate response; an adequate response was defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The latter stopping rule was originally included based on clinical advice, rather than specific evidence on the clinical- and cost effectiveness of this treatment strategy. The committee agreed that if there was no response to ixekizumab, the patient should not continue treatment. The committee noted that PASI\xa075 was the primary outcome in the trial data used to model the cost effectiveness of ixekizumab. It also considered the cost-effectiveness evidence for a PASI\xa050 stopping rule submitted by the company as a scenario analysis during consultation. It noted that the cost effectiveness of ixekizumab improved when a PASI\xa050 stopping rule was applied. The committee thought this may be counter-intuitive because there would be a smaller benefit for those with a PASI\xa050 response for the same cost. It heard from the company that, when the PASI\xa050 stopping rule is applied, patients remain on ixekizumab for longer, which increases the benefit accrued from having active treatment. The committee acknowledged that the sequencing model made it difficult to ascertain what was driving the results. The committee appreciated that, in patients with psoriasis affecting their hands and feet, a PASI\xa075 may be difficult to achieve because gains in quality of life from having treatment could represent clinical improvement but not be accounted for in the PASI score. The committee therefore concluded that, for consistency with previous appraisals for biological treatments in psoriasis, ixekizumab should be stopped if there is an inadequate response at 12\xa0weeks, with an adequate response defined as a 75% reduction in the PASI score from when treatment started or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started.\n\n# Innovation\n\nThe committee considered whether ixekizumab was an innovative treatment. It heard from the clinical experts that ixekizumab did not differ substantially in its mechanism of action from secukinumab. The committee concluded that the company had not given the committee any additional evidence of benefits that were not captured in estimating the QALYs.\n\n# Equality issues\n\nThe committee noted the potential equality issues raised in the consultee submissions, that the PASI can underestimate disease severity in those with darker skin, and that the DLQI has limited validity in older people and those not working, and may also miss anxiety and depression. The committee concluded that when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA442\n\nAppraisal title: ixekizumab for treating moderate to severe plaque psoriasis\n\nSection\n\nKey conclusion\n\nIxekizumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10\n\nthe disease has not responded to standard systemic therapies, for example, ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or these treatments are contraindicated or the person cannot tolerate them, and\n\nthe company provides the drug with the discount agreed in the patient access scheme.\n\n\n\nThe committee concluded that ixekizumab was more clinically effective than placebo and etanercept.\n\n\n\nThe evidence review group's (ERG's) pairwise comparison of ixekizumab as the first biological treatment in the treatment pathway compared with other relevant sequences showed that ixekizumab either:\n\ndominated other biological sequences (was more effective and cost less) or\n\nthe incremental cost-effectiveness ratios (ICERs) for that sequence were less than £30,000 per quality-adjusted life year (QALY) gained.\n\n\n\nPairwise comparisons of the relevant sequences showed that the sequence including ixekizumab as the second biological treatment dominated all other treatment sequences. The exception was the comparison with the sequence of secukinumab followed by ustekinumab and infliximab because the sequence of adalimumab followed by ixekizumab and infliximab had fewer total costs and QALYs than the sequence including secukinumab. However, the committee noted that the ICER for the sequence including ixekizumab compared with the sequence including secukinumab was more than £50,000 saved per QALY lost.\n\n\n\nThe committee concluded that the ICER was within the range that could be considered a cost-effective use of NHS resources.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nClearing symptoms with treatments associated with few or manageable side effects is important to people with psoriasis, as is having a choice of treatments.\n\n\n\nBiological treatment is offered to patients whose disease has not responded to standard systemic therapies (such as ciclosporin, methotrexate and PUVA) or when these treatments are contraindicated or not tolerated.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe results of the 3\xa0UNCOVER trials showed that ixekizumab is more clinically effective than placebo and etanercept.\n\n\n\nTreatment with biologicals is generally well tolerated and the tolerability of ixekizumab was considered to be similar to that for other biological treatments.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nIxekizumab is likely to be primarily offered to patients whose disease has not responded to a previous biological treatment and to patients who cannot have other biological treatments.\n\n\n\nAdverse reactions\n\nThe most common adverse reactions with ixekizumab in clinical trials were upper respiratory tract infection and injection site reactions.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence mostly came from 3 trials: UNCOVER‑1, -2 and -3, which were double-blinded, randomised controlled trials that included a total of 3,866\xa0patients. UNCOVER‑1 compared ixekizumab with placebo, and UNCOVER‑2 and ‑3 compared ixekizumab with placebo and with etanercept.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that the patients in the UNCOVER trials were representative of patients seen in the NHS who would be considered for biological treatment, and so the results were generalisable to patients in the NHS.\n\n, 4.6\n\nUncertainties generated by the evidence\n\nThe dose of etanercept given in the trials was double that which is recommended NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis, and was considered by the clinicians to be more effective than lower doses of etanercept. Therefore the committee considered that the treatment effect of ixekizumab compared with etanercept could be underestimated.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe benefit of treatment with ixekizumab compared with placebo and etanercept could be seen in the subgroup of patients who had already had biological treatment, as well as those who had not previously had biological treatment. The committee noted that the trials were not powered to detect statistically significant differences between subgroups, and so could not be certain that the treatment effect of ixekizumab did not differ across these subgroups, but agreed there was no evidence of a subgroup effect.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nPatients randomised to ixekizumab had clinically and statistically significantly higher PASI\xa075 response rates (that is, a 75% reduction in PASI score from when treatment started) at week\xa012 than placebo and etanercept.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented a Markov state transition model comparing a treatment sequence with ixekizumab given as the first in a sequence of 3\xa0biological treatments, with 6\xa0other biological treatment sequences.\n\n, 4.13\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee concluded that the treatment sequences included by the company in its economic model reasonably represented current NHS practice, although it heard that 2\xa0of the treatment sequences are not used in current practice.\n\n\n\nThe committee concluded that the company should have included the costs of adverse events in its economic model.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee concluded that it would be appropriate to include utility gains associated with treatment benefit in the induction period, and not just in the maintenance period.\n\n\n\nThe company had not given the committee any additional evidence of benefits that were not captured in estimating the QALYs.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nTreatment sequences included.\n\nUtility benefit and when it is applied.\n\nCosts of adverse events.\n\nCosts of best supportive care.\n\n, 4.16, 4.18, 4.19\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe ERG's pairwise comparison of ixekizumab as the first biological treatment in the treatment pathway compared with other relevant sequences, showed that ixekizumab either dominated other biological sequences), or the ICERs for that sequence were less than £30,000 per QALY gained. Pairwise comparisons of the relevant sequences showed that the sequence including ixekizumab as the second biological treatment dominated all other treatment sequences. The exception was the comparison with the sequence of secukinumab followed by ustekinumab and infliximab because the sequence of adalimumab followed by ixekizumab and infliximab had fewer total costs and QALYs than the sequence including secukinumab. However, the committee noted that the ICER for the sequence including ixekizumab compared with the sequence including secukinumab was more than £50,000 saved per QALY lost.\n\n, 4.23\n\nThe committee concluded that the ICER was within the range that could be considered a cost-effective use of NHS resources.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company presented analysis that included the confidential patient access scheme for ixekizumab. The ERG presented analysis that included the confidential discounts for both ixekizumab and secukinumab.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\n\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\n"}	https://www.nice.org.uk/guidance/ta442	Evidence-based recommendations on ixekizumab (Taltz) for moderate to severe plaque psoriasis in adults.
e2fa5b14c14c33510399129850c955e165bd92ec	nice	Obeticholic acid for treating primary biliary cholangitis	Obeticholic acid for treating primary biliary cholangitis Evidence-based recommendations on obeticholic acid (Ocaliva) for treating primary biliary cholangitis in adults. # Recommendations Obeticholic acid is recommended, within its marketing authorisation, as an option for treating primary biliary cholangitis in combination with ursodeoxycholic acid for people whose disease has responded inadequately to ursodeoxycholic acid or as monotherapy for people who cannot tolerate ursodeoxycholic acid. Obeticholic acid is recommended only if the company provides it with the discount agreed in the patient access scheme. Assess the response to obeticholic acid after 12 months. Only continue if there is evidence of clinical benefit.# The technology Description of the technology Ocaliva, Intercept Pharma. Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR is thought to be an important regulator of bile acid, inflammatory, fibrotic and metabolic pathways. FXR activation lowers intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, and by increasing transport of bile acids out of the hepatocytes. These mechanisms limit the overall amount of bile acid circulating in the body while promoting secretion of bile by the liver and reducing hepatic exposure to bile acids. Marketing authorisation A conditional marketing authorisation was received for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid in people whose disease responded inadequately to ursodeoxycholic acid or as monotherapy in people who cannot tolerate ursodeoxycholic acid. Adverse reactions For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The starting dose is 5 mg once daily. Based on an assessment of tolerability after 6 months, the dose should be increased to 10 mg once daily to have optimal response. Price Obeticholic acid 5 mg or 10 mg costs £2,384.04 per 30‑tablet pack. Costs may vary in different settings because of negotiated procurement discounts. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of obeticholic acid, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Intercept Pharma and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of obeticholic acid, having considered evidence on the nature of primary biliary cholangitis (PBC, previously known as primary biliary cirrhosis) and the value placed on the benefits of obeticholic acid by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical management of primary biliary cholangitis The committee heard from patient experts that PBC has an asymptomatic phase, and may be diagnosed incidentally when blood tests are done for other reasons. Most patients are women, and when symptoms develop they can be non-specific and may be thought to be because of other causes, such as the menopause. But they can become debilitating, and include chronic fatigue, pruritus and joint pain. The committee was aware that if untreated, PBC shows an unpredictable rate of progression through various phases: preclinical, asymptomatic, symptomatic, and liver insufficiency. This can lead to premature death unless the patient has a successful liver transplant. Unfortunately, PBC can recur even after a successful transplant. The only disease-modifying treatment currently available is ursodeoxycholic acid and this is recommended for all patients diagnosed with PBC, to restore their liver function to as close to normal as possible. If PBC is successfully treated with ursodeoxycholic acid, the risk of progression is kept low and patients have a normal life expectancy. The patient experts explained that adjusting to a diagnosis of a progressive incurable disease was very difficult and to then find that the only available treatment was not working is a devastating blow. The committee heard that patients whose disease has responded inadequately to ursodeoxycholic acid are likely to progress rapidly and die from the disease within 5 to 7 years. The committee concluded that there is a high unmet need for patients who cannot tolerate ursodeoxycholic acid, or whose disease does not respond to it, and recognised that the availability of additional treatment options would be highly valued by patients and families. The clinical experts advised that because the disease is asymptomatic in its early stages and diagnosis is difficult, patients may not be diagnosed until significant liver damage has occurred. The first biochemical sign of PBC is an elevated alkaline phosphatase level (ALP). As liver disease progresses, the total bilirubin level will also rise, which is an indicator of significant liver damage. Cirrhosis is probably already present at this stage. When managing PBC, it is important to define the person's risk of progression to severe liver complications and death from the disease. This mainly includes the biomarkers ALP and total bilirubin, but there are other factors such as early age of onset, which may be associated with more aggressive disease. The clinical experts explained that biochemical markers such as ALP and total bilirubin levels are appropriate to decide whether patients are at low or high risk of disease progression. The committee was aware that ALP and total bilirubin levels have been shown to correlate with transplant-free survival up to 15 years. The clinical experts confirmed that these biochemical markers are appropriate and validated surrogate outcomes for PBC. The committee concluded that it was appropriate to use ALP and total bilirubin levels as surrogate outcomes to assess the clinical effectiveness of obeticholic acid. The clinical experts advised that guidelines from the British Society of Gastroenterology and UK-PBC and European Association for the Study of the Liver recommend ursodeoxycholic acid for all patients with PBC. Response to treatment is assessed at 1 year based on ALP levels. The committee heard that threshold ALP levels of at least 1.67 times the upper limit of normal (or elevated total bilirubin levels consistent with later stage disease ) are widely used to identify patients whose condition has responded inadequately to treatment with ursodeoxycholic acid. The experts noted that about 20 to 30% of patients have disease which does not respond to treatment with ursodeoxycholic acid, and a further 5 to 10% cannot tolerate it because of adverse effects. The clinical experts stated that although fibrates were included in the final scope, they are not used very often in clinical practice. Also, they are not disease-modifying drugs and so for these reasons fibrates are not an appropriate comparator. Therefore, for patients who cannot tolerate ursodeoxycholic acid, or whose disease does not respond to it, liver transplant is the only available effective treatment. The committee heard from the patient expert that there is a high level of fear associated with liver transplant because it involves major surgery with potential complications, and uncertain outcomes. Patients feel helpless while waiting for a liver transplant because their condition is rapidly progressing and there is limited availability of donated livers; many patients die while on the waiting list. Also, patients are concerned that a liver transplant does not always cure the disease and there is a risk of transplant failure or recurrence of PBC. The committee concluded that ursodeoxycholic acid monotherapy is the most appropriate comparator for obeticholic acid plus ursodeoxycholic acid in people with PBC that does not adequately respond to ursodeoxycholic acid. No treatment is the most relevant comparator for people who cannot tolerate ursodeoxycholic acid. # Clinical effectiveness of obeticholic acid The committee considered the clinical evidence for obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid plus placebo from the POISE trial, and obeticholic acid monotherapy compared with placebo for adults who cannot tolerate ursodeoxycholic acid. The committee heard that people who took part in POISE were mainly women (91%) and younger than 65 years (81%). The mean age of patients entering the trial was 55.8 years, with a mean age at diagnosis of 47. Inclusion criteria included a serum ALP level of at least 1.67 times the upper limit of normal, and/or elevated total bilirubin level of at least 1.0 times the upper limit of normal. The clinical experts confirmed that these patient characteristics reflect those of people who would be considered for treatment with obeticholic acid in clinical practice. The committee heard that a small number of patients (n=11) in the trial could not tolerate ursodeoxycholic acid. It heard from the clinical experts that this reflects the relatively small number of patients in clinical practice who cannot take ursodeoxycholic acid. These patients were randomised to placebo or obeticholic acid monotherapy. The clinical expert stated that a phase II trial of obeticholic acid monotherapy in 50 patients had a similar response rate to that in POISE. The committee heard from clinical experts that the primary outcome (ALP level lower than 1.67 times the upper limit of normal, total bilirubin within the below or equal to upper limit normal and ALP decrease of at least 15% from baseline) used in POISE was quite challenging because of the need to fulfil all 3 criteria. They considered that ALP decrease of less than 15% was clinically meaningful. The committee also noted that not all patients in the titration arm of POISE had their dose of obeticholic acid adjusted up from 5 mg to the higher dose of 10 mg as recommended in the summary of product characteristics. Therefore they might not have had as great a benefit in the trial as would be seen in clinical practice. The committee concluded that the results of POISE are generalisable to the intended use of obeticholic acid in clinical practice in England, but noted the lack of evidence for the clinical effectiveness of obeticholic acid monotherapy in those who cannot tolerate ursodeoxycholic acid. The committee noted the higher number of people who were classed as responders according to the primary outcome in POISE for obeticholic acid plus ursodeoxycholic acid compared with placebo plus ursodeoxycholic acid (47% in the obeticholic acid 10 mg group and 46% in the obeticholic acid titration group compared with 10% in the placebo group, p<0.0001 for both comparisons). Obeticholic acid plus ursodeoxycholic acid was also more effective at lowering ALP levels by at least 40% from the baseline (34% in the obeticholic acid 10 mg group and 30% in the obeticholic acid titration group, compared with 1% in the placebo group). Obeticholic acid plus ursodeoxycholic acid was more effective at lowering the total bilirubin level, which at 12 months was 9.7 for the obeticholic acid 10 mg group, 9.9 for the obeticholic acid titration group, and 13.2 for the placebo group. The committee concluded that obeticholic acid plus ursodeoxycholic acid is clinically effective in improving the surrogate outcomes associated with the progression of PBC. # Adverse events The committee noted that in POISE the overall frequency of adverse events was similar in the 3 treatment groups. The committee heard that pruritus was the most common adverse event with obeticholic acid, occurring in 66% of patients taking 10 mg, and 50% of patients taking 5 mg, compared with 37% in the placebo arm. The clinical experts explained that pruritus is also a common symptom of PBC and they are experienced in managing it effectively. The patient expert told the committee that there is anecdotal evidence from the US that the pruritus may be temporary and may resolve after 3 months. The committee concluded that obeticholic acid is generally well tolerated and the adverse events can be managed satisfactorily. # Cost effectiveness ## The model The committee considered the company's cost-effectiveness evidence and the evidence review group (ERG) review. The company's de novo economic model assessed the cost effectiveness of obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone based on the POISE population. The model comprised 2 parts: biomarker and liver disease. The biomarker part of the model had 3 health states: low, moderate and severe, which reflect the risk of disease progression. The liver disease part included significant liver disease, including decompensated cirrhosis, hepatocellular carcinoma, pre-transplant state, transplantation, re-emergence of PBC and death. Patients entered the biomarker part of the model in the moderate or severe risk state but could move between the 3 health states. They could only move to the liver disease part of the model from the severe risk state of the biomarker component. The committee noted that the model was similar to those used in previous appraisals, with the addition of a pre-liver transplant health state. It heard from the company that this health state was added to capture the deterioration in quality of life and the costs associated with rapidly progressing disease, and the significant and documented risk of PBC patients dying while awaiting transplant. The committee concluded that the structure of the model was suitable for decision-making and further considered some of the key assumptions within the model where it agreed that the ERG had raised valid issues for further consideration. ## Transition probabilities The transition probabilities governing the movement of patients in the biomarker part of the company's model in the first 12 months were based on several sources. Transition probabilities for the obeticholic acid plus ursodeoxycholic acid and obeticholic acid monotherapy arm were based on individual patient data from POISE. Transition probabilities for people whose disease has responded inadequately to ursodeoxycholic acid were calibrated based on PBC-specific data from the literature. These used 10 year liver transplant-free survival estimated from GLOBE (an international collaboration between medical centres doing PBC research) and UK risk scores. This was because POISE data for this arm were not available for all health states in the model or beyond the 12 months of the trial. For patients who cannot tolerate ursodeoxycholic acid, transition probabilities were estimated from a study of ursodeoxycholic acid compared with no treatment in PBC (Corpechot et al. 2000). Transition probabilities in the liver disease component were mostly derived from those used in NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis C. The ERG noted that the way transition probabilities were calibrated in the ursodeoxycholic acid arm was not transparent, and for consistency it would be better to derive them from trial data. Also, the committee considered whether the assumption of no progression from the low or moderate risk state to the severe risk state after 12 months was plausible. The committee noted that clinical advice to the ERG was that this assumption was reasonable, based on the fact that existing data on ursodeoxycholic acid showed that an ALP level of normal or less than 1.67 times the upper limit of normal (which corresponds to the low-risk health state in the biomarker model) was associated with an excellent long-term prognosis with no overall effect on life expectancy. The committee heard from the company that this assumption was supported not only by data for ursodeoxycholic acid, but also by 5-year data from the extension of POISE, which showed a lasting response with obeticholic acid. The clinical experts also stated that a phase II trial of obeticholic acid as monotherapy reported only 5% progression over a 15‑year time horizon, indicating lasting benefit. The committee concluded that the transition probabilities used in the obeticholic acid arm of the model are plausible but there is uncertainty about whether the transition probabilities used in the ursodeoxycholic acid arm are the most appropriate. Given the 12‑month duration of the trial, there is some uncertainty about the long-term modelling in both treatment arms. ## Utility values Health-related quality-of-life data were not collected in POISE so the company used utility values from published literature (Younossi et al. 2001 and Wright et al. 2006, used in NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis C). Utility values were assumed to be constant over time in each of the health states of the biomarker part of the model but decreased as patients moved to the liver disease part. The committee considered whether the confidential decrement applied to the decompensated cirrhosis, pre-transplant and liver transplant states based on clinical advice to the company was appropriate. The committee heard from the clinical experts that they considered it reasonable to consider a lower utility for some of the advanced liver disease states in PBC compared with hepatitis because of the additional morbidity related to having cholestasis as well as fibrosis. Also, the committee noted that the company used a utility value of 0.84 for the low and moderate risk states in the biomarker part of the model. The ERG noted that this is higher than the UK age-adjusted utility, and also that utility was not age adjusted over time. The committee noted that the utility values were derived from published sources and that patients with PBC may be asymptomatic. It was aware of a study of utility in people with hepatitis C (Vera-Llonch et al. 2013, considered in NICE's guidance on sofosbuvir for treating chronic hepatitis C). This reported a utility of 0.91 pre-treatment, which was also noted by the authors to be higher than the corresponding published US population norm for people aged 45 to 54. The committee acknowledged the uncertainty associated with the utility values but accepted that they had been derived from published sources. ## Cost-effectiveness results The committee noted that the company's model predicted that obeticholic acid plus ursodeoxycholic acid increased both length of life and quality of life compared with ursodeoxycholic acid alone. The company's deterministic base-case incremental cost-effectiveness ratio (ICER, using the patient access scheme) for obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone was £28,281 per quality-adjusted life year (QALY) gained (incremental costs £164,814; incremental QALYs 5.83). The committee also noted that the ICER for obeticholic acid compared with placebo in the population who cannot tolerate ursodeoxycholic acid was lower, at £21,351 per QALY gained. It considered that it would not be able to make separate recommendations for one or other group, particularly given the very limited clinical data for the population who cannot tolerate ursodeoxycholic acid. Therefore it gave further detailed consideration to the company's higher ICER for obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone. It also examined the impact of uncertainty around the use of POISE data and the utilities in the model. The committee considered the effect of the ERG's amendments to the company's model. It considered the transition probabilities in the ursodeoxycholic acid arm and the utilities used in the model (see the committee papers) to be the key areas of uncertainty in modelling the cost effectiveness of obeticholic acid in PBC. The committee noted that in clinical practice, obeticholic acid would be recommended for a mixed group of patients: some who cannot tolerate ursodeoxycholic acid (5% to 10% of people) and a larger number (20% to 30%) whose disease had not responded adequately to ursodeoxycholic acid. Although the number of people in the trial who could not tolerate ursodeoxycholic acid was small, the cost-effectiveness estimates were consistently lower than for those whose disease did not respond to ursodeoxycholic acid. Therefore the ICER for the whole population of patients considered for treatment with obeticholic acid would be somewhere between the ICERs for the population who cannot tolerate ursodeoxycholic acid and the population whose disease has not responded to ursodeoxycholic acid. The committee noted the ERG's concern related to the derivation of the transition probabilities used in the ursodeoxycholic acid arm for both the first 12 months and the longer term. This was an attempt to achieve consistency between progression of PBC in the model and that in the published literature. The committee noted that the ERG considered replacing existing trial data with the short-term transition probabilities obtained from the literature to be inappropriate. Although it considered calibrating the trial data to published evidence to obtain long-term data was justified by the lack of long-term data to inform patients' prognosis, the ERG noted that the calibration approach employed by the company was not transparent and that the resulting model predictions did not match the published evidence. The ERG considered unadjusted POISE data more appropriate in the ursodeoxycholic acid arm for the first 12 months, which increased the company base case from £28,425 per QALY gained to £32,897 per QALY gained (incremental costs £171,036; incremental QALYs 5.20). The ERG also considered that extrapolating the POISE 12‑month data over the long term (beyond 12 months) in the biomarker component of the model was more appropriate than the company's approach of using published data on long-term outcomes in PBC. This would result in a further rise in the ERG's base case. The committee appreciated that long-term modelling presented significant challenges. It accepted that without effective treatment people whose disease had not responded to ursodeoxycholic acid may progress at slightly different rates, but have a very poor prognosis. Liver disease may progress faster once it becomes established. This may not be captured in the first 12 months of treatment. The committee concluded that it was not unreasonable to use other published data to try to replicate the expected course of disease in those whose disease had not responded to ursodeoxycholic acid and considered the company's approach for decision making acceptable, although there remained uncertainty in the trajectory of disease progression in the ursodeoxycholic acid arm. The committee further considered the utility values used. It noted that the ERG's suggested adjustment of utilities, to take account of lower utility in the UK population, and an age-related decrement, increased the ICER for obeticholic acid plus ursodeoxycholic acid to £33,458 per QALY gained compared with ursodeoxycholic acid alone (incremental cost £164,808; incremental QALYs 4.93). The committee concluded that there were many uncertainties around the utility values used in the model but considered that a utility value of 0.84 in the low and moderate risk group was not implausible and was in line with published evidence, and it agreed that an age-related decrement over time should have been incorporated into the model. The committee concluded that the most plausible ICER for people whose disease had not responded to ursodeoxycholic acid would be around the upper limit of what could be considered cost effective. It therefore considered what other factors might justify accepting it as a cost-effective use of NHS resources. # Innovation The committee heard from the company that obeticholic acid is innovative because of its mechanism of action as a farnesoid X receptor agonist. Obeticholic acid also has an anti-inflammatory action, which may provide additional efficacy in this disease. The committee accepted the innovative nature of the treatment, and considered that this was a major change in the management of PBC. The committee noted in particular that the results in 47% of people in the obeticholic acid arm of POISE met the strict criteria for response, despite the current standard of care, ursodeoxycholic acid, not having been effective. This response would be associated with a very favourable prognosis. # Other considerations The committee was aware that if PBC was controlled, people could have an excellent outcome and normal life expectancy. However, people whose disease had not responded to, or had been unable to tolerate the only available preventative treatment, were likely to decline rapidly. The committee considered that the potential restoration of normal life expectancy was a huge benefit, and this was not often possible in such serious conditions. The committee was aware that because people whose disease responds to obeticholic acid are at a much lower risk of disease progression, the drug may delay or prevent the need for liver transplant. The committee considered that avoiding liver transplant was of great importance to PBC patients. The committee heard that PBC is the most common indication for liver transplant in women over 50. It was also aware of the scarcity of donor organs and that other patients on the transplant waiting list for other reasons might benefit if obeticholic acid were available. The committee noted that this opportunity cost of liver transplant on other people on the waiting list had not been captured in the cost-effectiveness estimates of obeticholic acid for people with PBC. The committee was aware that the clinical benefit of obeticholic acid may be underestimated in the trial because of the lack of adjustment up to the recommended dose in some patients. Taking all factors into consideration, the committee concluded that obeticholic acid could be considered a cost-effective use of NHS resources. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA443 Appraisal title: Obeticholic acid for treating primary biliary cholangitis Section Key conclusion Obeticholic acid is clinically effective in people with primary biliary cholangitis (PBC) who cannot tolerate or whose disease does not respond to ursodeoxycholic acid. A higher number of people on obeticholic acid plus ursodeoxycholic acid met the primary outcome based on alkaline phosphatase and total bilirubin levels than people treated with ursodeoxycholic acid alone. The committee has taken into consideration the innovative nature of obeticholic acid and the unmet need of patients for whom there was no effective treatment. The committee noted that the benefits of not needing a liver transplant for people whose disease is treated with obeticholic acid have not been included in the model. Obeticholic acid could be considered a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments Patients with PBC are currently treated with ursodeoxycholic acid, but patients who cannot tolerate it or whose disease does not respond to ursodeoxycholic acid have no other treatment option. The committee heard that there is a high unmet need for patients whose disease does not respond to, or who cannot tolerate ursodeoxycholic acid, and recognised that the availability of additional treatment options would be highly valued by patients and families. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Obeticholic acid in combination with ursodeoxycholic acid or alone helps to normalise alkaline phosphatase (ALP) and total bilirubin levels and reduces the risk of PBC progression. People with normal liver biochemistry are expected to have an excellent prognosis with a normal life expectancy. Obeticholic acid is innovative because of its mechanism of action as a farnesoid X receptor agonist. It is a novel, innovative therapy for patients with PBC. It also has an anti-inflammatory action, which may provide additional efficacy in this disease. What is the position of the treatment in the pathway of care for the condition? Obeticholic acid is recommended in combination with ursodeoxycholic acid or as monotherapy in patients whose disease has responded inadequately to, or who cannot tolerate ursodeoxycholic acid. Adverse reactions Obeticholic acid is generally well tolerated and the adverse events can be managed satisfactorily. The main adverse effect of the treatment is pruritus. Evidence for clinical effectiveness Availability, nature and quality of evidence Evidence for clinical effectiveness of obeticholic acid plus ursodeoxycholic acid and obeticholic acid monotherapy was based on a randomised controlled double blinded trial (POISE) which was assessed as good quality. Relevance to general clinical practice in the NHS The committee considered the people enrolled in the POISE to be generalisable to people with PBC in the NHS in England. Uncertainties generated by the evidence The committee considered there to be uncertainty in the clinical effectiveness of obeticholic acid monotherapy in those who cannot tolerate ursodeoxycholic acid because of the small number of patients in the pivotal trial. Clinical experts noted that the small patient number in the trial reflect the minority of patients who are unable to take ursodeoxycholic acid in clinical practice. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No. Estimate of the size of the clinical effectiveness including strength of supporting evidence The higher number of people whose results met the primary outcome in POISE for obeticholic acid plus ursodeoxycholic acid compared with placebo plus ursodeoxycholic acid (47% in the obeticholic acid 10 mg group and 46% in the obeticholic acid titration group compared with 10% in the placebo group, p<0.0001 for both comparisons). Obeticholic acid plus ursodeoxycholic acid was also more effective at lowering ALP levels by at least 40% from the baseline (34% in the obeticholic acid 10 mg group and 30% in the obeticholic acid titration group compared with 1% in the placebo group). Obeticholic acid plus ursodeoxycholic acid was more effective at lowering the total bilirubin level, which at 12 months was 9.7 for the obeticholic acid 10 mg group, 9.9 for the obeticholic acid titration group, and 13.2 for the placebo group. Evidence for cost effectiveness Availability and nature of evidence The company's de novo economic model assessed the cost effectiveness of obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone based on the POISE population. Also obeticholic acid monotherapy compared with placebo was assessed based on small patient numbers (n=11). Uncertainties around and plausibility of assumptions and inputs in the economic model The uncalibrated transition probabilities in the ursodeoxycholic acid arm and the age adjustment of utilities in health states of the model were considered to be the key areas of uncertainty in modelling the cost effectiveness of obeticholic acid in PBC. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The utility values were derived from published sources of people with hepatitis C which were adjusted because people with PBC and substantial liver disease have a worse quality of life than people with hepatitis. There was uncertainty in the utility values because the utility for low and moderate risk of progression of PBC was higher than the UK age adjusted utility. However, the committee was aware that a study of utility in people with hepatitis C, a pre-treatment of 0.91 was also higher than the corresponding published US population norm for people aged 45 to 54. The committee acknowledged the uncertainty associated with the utility values. The committee agreed that an age-related decrement over time should have been incorporated into the model. Are there specific groups of people for whom the technology is particularly cost effective? No. What are the key drivers of cost effectiveness? Using unadjusted POISE data in the ursodeoxycholic acid arm for the first 12 months increased the company base case from £28,425 per quality-adjusted life year (QALY) gained to £32,897 per QALY gained. Using lower utility in the UK population and an age-related decrement, increased the incremental cost-effectiveness ratio to £33,458 per QALY gained. Most likely cost-effectiveness estimate (given as an ICER) The committee was not able to define a most plausible ICER but concluded for people whose disease had not responded to ursodeoxycholic acid that it would be around the upper limit of what could be considered cost effective. Additional factors taken into account Patient access schemes (PPRS) Yes. End-of-life considerations None. Equalities considerations and social value judgements None.	{'Recommendations': 'Obeticholic acid is recommended, within its marketing authorisation, as an option for treating primary biliary cholangitis in combination with ursodeoxycholic acid for people whose disease has responded inadequately to ursodeoxycholic acid or as monotherapy for people who cannot tolerate ursodeoxycholic acid. Obeticholic acid is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\nAssess the response to obeticholic acid after 12\xa0months. Only continue if there is evidence of clinical benefit.', 'The technology': 'Description of the technology\n\nOcaliva, Intercept Pharma. Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR is thought to be an important regulator of bile acid, inflammatory, fibrotic and metabolic pathways. FXR activation lowers intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, and by increasing transport of bile acids out of the hepatocytes. These mechanisms limit the overall amount of bile acid circulating in the body while promoting secretion of bile by the liver and reducing hepatic exposure to bile acids.\n\nMarketing authorisation\n\nA conditional marketing authorisation was received for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid in people whose disease responded inadequately to ursodeoxycholic acid or as monotherapy in people who cannot tolerate ursodeoxycholic acid.\n\nAdverse reactions\n\nFor full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe starting dose is 5\xa0mg once daily. Based on an assessment of tolerability after 6\xa0months, the dose should be increased to 10\xa0mg once daily to have optimal response.\n\nPrice\n\nObeticholic acid 5\xa0mg or 10\xa0mg costs £2,384.04 per 30‑tablet pack. Costs may vary in different settings because of negotiated procurement discounts.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of obeticholic acid, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Intercept Pharma and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of obeticholic acid, having considered evidence on the nature of primary biliary cholangitis (PBC, previously known as primary biliary cirrhosis) and the value placed on the benefits of obeticholic acid by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management of primary biliary cholangitis\n\nThe committee heard from patient experts that PBC has an asymptomatic phase, and may be diagnosed incidentally when blood tests are done for other reasons. Most patients are women, and when symptoms develop they can be non-specific and may be thought to be because of other causes, such as the menopause. But they can become debilitating, and include chronic fatigue, pruritus and joint pain. The committee was aware that if untreated, PBC shows an unpredictable rate of progression through various phases: preclinical, asymptomatic, symptomatic, and liver insufficiency. This can lead to premature death unless the patient has a successful liver transplant. Unfortunately, PBC can recur even after a successful transplant. The only disease-modifying treatment currently available is ursodeoxycholic acid and this is recommended for all patients diagnosed with PBC, to restore their liver function to as close to normal as possible. If PBC is successfully treated with ursodeoxycholic acid, the risk of progression is kept low and patients have a normal life expectancy. The patient experts explained that adjusting to a diagnosis of a progressive incurable disease was very difficult and to then find that the only available treatment was not working is a devastating blow. The committee heard that patients whose disease has responded inadequately to ursodeoxycholic acid are likely to progress rapidly and die from the disease within 5\xa0to 7\xa0years. The committee concluded that there is a high unmet need for patients who cannot tolerate ursodeoxycholic acid, or whose disease does not respond to it, and recognised that the availability of additional treatment options would be highly valued by patients and families.\n\nThe clinical experts advised that because the disease is asymptomatic in its early stages and diagnosis is difficult, patients may not be diagnosed until significant liver damage has occurred. The first biochemical sign of PBC is an elevated alkaline phosphatase level (ALP). As liver disease progresses, the total bilirubin level will also rise, which is an indicator of significant liver damage. Cirrhosis is probably already present at this stage. When managing PBC, it is important to define the person's risk of progression to severe liver complications and death from the disease. This mainly includes the biomarkers ALP and total bilirubin, but there are other factors such as early age of onset, which may be associated with more aggressive disease. The clinical experts explained that biochemical markers such as ALP and total bilirubin levels are appropriate to decide whether patients are at low or high risk of disease progression. The committee was aware that ALP and total bilirubin levels have been shown to correlate with transplant-free survival up to 15\xa0years. The clinical experts confirmed that these biochemical markers are appropriate and validated surrogate outcomes for PBC. The committee concluded that it was appropriate to use ALP and total bilirubin levels as surrogate outcomes to assess the clinical effectiveness of obeticholic acid.\n\nThe clinical experts advised that guidelines from the British Society of Gastroenterology and UK-PBC and European Association for the Study of the Liver recommend ursodeoxycholic acid for all patients with PBC. Response to treatment is assessed at 1\xa0year based on ALP levels. The committee heard that threshold ALP levels of at least 1.67\xa0times the upper limit of normal (or elevated total bilirubin levels consistent with later stage disease [greater than the upper limit of normal]) are widely used to identify patients whose condition has responded inadequately to treatment with ursodeoxycholic acid. The experts noted that about 20 to 30% of patients have disease which does not respond to treatment with ursodeoxycholic acid, and a further 5 to 10% cannot tolerate it because of adverse effects. The clinical experts stated that although fibrates were included in the final scope, they are not used very often in clinical practice. Also, they are not disease-modifying drugs and so for these reasons fibrates are not an appropriate comparator. Therefore, for patients who cannot tolerate ursodeoxycholic acid, or whose disease does not respond to it, liver transplant is the only available effective treatment. The committee heard from the patient expert that there is a high level of fear associated with liver transplant because it involves major surgery with potential complications, and uncertain outcomes. Patients feel helpless while waiting for a liver transplant because their condition is rapidly progressing and there is limited availability of donated livers; many patients die while on the waiting list. Also, patients are concerned that a liver transplant does not always cure the disease and there is a risk of transplant failure or recurrence of PBC. The committee concluded that ursodeoxycholic acid monotherapy is the most appropriate comparator for obeticholic acid plus ursodeoxycholic acid in people with PBC that does not adequately respond to ursodeoxycholic acid. No treatment is the most relevant comparator for people who cannot tolerate ursodeoxycholic acid.\n\n# Clinical effectiveness of obeticholic acid\n\nThe committee considered the clinical evidence for obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid plus placebo from the POISE trial, and obeticholic acid monotherapy compared with placebo for adults who cannot tolerate ursodeoxycholic acid. The committee heard that people who took part in POISE were mainly women (91%) and younger than 65\xa0years (81%). The mean age of patients entering the trial was 55.8\xa0years, with a mean age at diagnosis of 47. Inclusion criteria included a serum ALP level of at least 1.67\xa0times the upper limit of normal, and/or elevated total bilirubin level of at least 1.0\xa0times the upper limit of normal. The clinical experts confirmed that these patient characteristics reflect those of people who would be considered for treatment with obeticholic acid in clinical practice. The committee heard that a small number of patients (n=11) in the trial could not tolerate ursodeoxycholic acid. It heard from the clinical experts that this reflects the relatively small number of patients in clinical practice who cannot take ursodeoxycholic acid. These patients were randomised to placebo or obeticholic acid monotherapy. The clinical expert stated that a phase\xa0II trial of obeticholic acid monotherapy in 50\xa0patients had a similar response rate to that in POISE. The committee heard from clinical experts that the primary outcome (ALP level lower than 1.67\xa0times the upper limit of normal, total bilirubin within the below or equal to upper limit normal and ALP decrease of at least 15% from baseline) used in POISE was quite challenging because of the need to fulfil all 3\xa0criteria. They considered that ALP decrease of less than 15% was clinically meaningful. The committee also noted that not all patients in the titration arm of POISE had their dose of obeticholic acid adjusted up from 5\xa0mg to the higher dose of 10\xa0mg as recommended in the summary of product characteristics. Therefore they might not have had as great a benefit in the trial as would be seen in clinical practice. The committee concluded that the results of POISE are generalisable to the intended use of obeticholic acid in clinical practice in England, but noted the lack of evidence for the clinical effectiveness of obeticholic acid monotherapy in those who cannot tolerate ursodeoxycholic acid.\n\nThe committee noted the higher number of people who were classed as responders according to the primary outcome in POISE for obeticholic acid plus ursodeoxycholic acid compared with placebo plus ursodeoxycholic acid (47% in the obeticholic acid 10\xa0mg group and 46% in the obeticholic acid titration group compared with 10% in the placebo group, p<0.0001 for both comparisons). Obeticholic acid plus ursodeoxycholic acid was also more effective at lowering ALP levels by at least 40% from the baseline (34% in the obeticholic acid 10\xa0mg group and 30% in the obeticholic acid titration group, compared with 1% in the placebo group). Obeticholic acid plus ursodeoxycholic acid was more effective at lowering the total bilirubin level, which at 12\xa0months was 9.7 for the obeticholic acid 10\xa0mg group, 9.9 for the obeticholic acid titration group, and 13.2 for the placebo group. The committee concluded that obeticholic acid plus ursodeoxycholic acid is clinically effective in improving the surrogate outcomes associated with the progression of PBC.\n\n# Adverse events\n\nThe committee noted that in POISE the overall frequency of adverse events was similar in the 3\xa0treatment groups. The committee heard that pruritus was the most common adverse event with obeticholic acid, occurring in 66% of patients taking 10\xa0mg, and 50% of patients taking 5\xa0mg, compared with 37% in the placebo arm. The clinical experts explained that pruritus is also a common symptom of PBC and they are experienced in managing it effectively. The patient expert told the committee that there is anecdotal evidence from the US that the pruritus may be temporary and may resolve after 3\xa0months. The committee concluded that obeticholic acid is generally well tolerated and the adverse events can be managed satisfactorily.\n\n# Cost effectiveness\n\n## The model\n\nThe committee considered the company's cost-effectiveness evidence and the evidence review group (ERG) review. The company's de novo economic model assessed the cost effectiveness of obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone based on the POISE population. The model comprised 2\xa0parts: biomarker and liver disease. The biomarker part of the model had 3\xa0health states: low, moderate and severe, which reflect the risk of disease progression. The liver disease part included significant liver disease, including decompensated cirrhosis, hepatocellular carcinoma, pre-transplant state, transplantation, re-emergence of PBC and death. Patients entered the biomarker part of the model in the moderate or severe risk state but could move between the 3\xa0health states. They could only move to the liver disease part of the model from the severe risk state of the biomarker component. The committee noted that the model was similar to those used in previous appraisals, with the addition of a pre-liver transplant health state. It heard from the company that this health state was added to capture the deterioration in quality of life and the costs associated with rapidly progressing disease, and the significant and documented risk of PBC patients dying while awaiting transplant. The committee concluded that the structure of the model was suitable for decision-making and further considered some of the key assumptions within the model where it agreed that the ERG had raised valid issues for further consideration.\n\n## Transition probabilities\n\nThe transition probabilities governing the movement of patients in the biomarker part of the company's model in the first 12\xa0months were based on several sources. Transition probabilities for the obeticholic acid plus ursodeoxycholic acid and obeticholic acid monotherapy arm were based on individual patient data from POISE. Transition probabilities for people whose disease has responded inadequately to ursodeoxycholic acid were calibrated based on PBC-specific data from the literature. These used 10\xa0year liver transplant-free survival estimated from GLOBE (an international collaboration between medical centres doing PBC research) and UK risk scores. This was because POISE data for this arm were not available for all health states in the model or beyond the 12\xa0months of the trial. For patients who cannot tolerate ursodeoxycholic acid, transition probabilities were estimated from a study of ursodeoxycholic acid compared with no treatment in PBC (Corpechot et al. 2000). Transition probabilities in the liver disease component were mostly derived from those used in NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis\xa0C. The ERG noted that the way transition probabilities were calibrated in the ursodeoxycholic acid arm was not transparent, and for consistency it would be better to derive them from trial data. Also, the committee considered whether the assumption of no progression from the low or moderate risk state to the severe risk state after 12\xa0months was plausible. The committee noted that clinical advice to the ERG was that this assumption was reasonable, based on the fact that existing data on ursodeoxycholic acid showed that an ALP level of normal or less than 1.67\xa0times the upper limit of normal (which corresponds to the low-risk health state in the biomarker model) was associated with an excellent long-term prognosis with no overall effect on life expectancy. The committee heard from the company that this assumption was supported not only by data for ursodeoxycholic acid, but also by 5-year data from the extension of POISE, which showed a lasting response with obeticholic acid. The clinical experts also stated that a phase\xa0II trial of obeticholic acid as monotherapy reported only 5% progression over a 15‑year time horizon, indicating lasting benefit. The committee concluded that the transition probabilities used in the obeticholic acid arm of the model are plausible but there is uncertainty about whether the transition probabilities used in the ursodeoxycholic acid arm are the most appropriate. Given the 12‑month duration of the trial, there is some uncertainty about the long-term modelling in both treatment arms.\n\n## Utility values\n\nHealth-related quality-of-life data were not collected in POISE so the company used utility values from published literature (Younossi et al. 2001 and Wright et al. 2006, used in NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis\xa0C). Utility values were assumed to be constant over time in each of the health states of the biomarker part of the model but decreased as patients moved to the liver disease part. The committee considered whether the confidential decrement applied to the decompensated cirrhosis, pre-transplant and liver transplant states based on clinical advice to the company was appropriate. The committee heard from the clinical experts that they considered it reasonable to consider a lower utility for some of the advanced liver disease states in PBC compared with hepatitis because of the additional morbidity related to having cholestasis as well as fibrosis. Also, the committee noted that the company used a utility value of 0.84 for the low and moderate risk states in the biomarker part of the model. The ERG noted that this is higher than the UK age-adjusted utility, and also that utility was not age adjusted over time. The committee noted that the utility values were derived from published sources and that patients with PBC may be asymptomatic. It was aware of a study of utility in people with hepatitis\xa0C (Vera-Llonch et al. 2013, considered in NICE's guidance on sofosbuvir for treating chronic hepatitis\xa0C). This reported a utility of 0.91 pre-treatment, which was also noted by the authors to be higher than the corresponding published US population norm [mean (standard error) index 0.87 (0.01)] for people aged 45 to 54. The committee acknowledged the uncertainty associated with the utility values but accepted that they had been derived from published sources.\n\n## Cost-effectiveness results\n\nThe committee noted that the company's model predicted that obeticholic acid plus ursodeoxycholic acid increased both length of life and quality of life compared with ursodeoxycholic acid alone. The company's deterministic base-case incremental cost-effectiveness ratio (ICER, using the patient access scheme) for obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone was £28,281 per quality-adjusted life year (QALY) gained (incremental costs £164,814; incremental QALYs 5.83). The committee also noted that the ICER for obeticholic acid compared with placebo in the population who cannot tolerate ursodeoxycholic acid was lower, at £21,351 per QALY gained. It considered that it would not be able to make separate recommendations for one or other group, particularly given the very limited clinical data for the population who cannot tolerate ursodeoxycholic acid. Therefore it gave further detailed consideration to the company's higher ICER for obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone. It also examined the impact of uncertainty around the use of POISE data and the utilities in the model. The committee considered the effect of the ERG's amendments to the company's model. It considered the transition probabilities in the ursodeoxycholic acid arm and the utilities used in the model (see the committee papers) to be the key areas of uncertainty in modelling the cost effectiveness of obeticholic acid in PBC.\n\nThe committee noted that in clinical practice, obeticholic acid would be recommended for a mixed group of patients: some who cannot tolerate ursodeoxycholic acid (5% to 10% of people) and a larger number (20% to 30%) whose disease had not responded adequately to ursodeoxycholic acid. Although the number of people in the trial who could not tolerate ursodeoxycholic acid was small, the cost-effectiveness estimates were consistently lower than for those whose disease did not respond to ursodeoxycholic acid. Therefore the ICER for the whole population of patients considered for treatment with obeticholic acid would be somewhere between the ICERs for the population who cannot tolerate ursodeoxycholic acid and the population whose disease has not responded to ursodeoxycholic acid.\n\nThe committee noted the ERG's concern related to the derivation of the transition probabilities used in the ursodeoxycholic acid arm for both the first 12\xa0months and the longer term. This was an attempt to achieve consistency between progression of PBC in the model and that in the published literature. The committee noted that the ERG considered replacing existing trial data with the short-term transition probabilities obtained from the literature to be inappropriate. Although it considered calibrating the trial data to published evidence to obtain long-term data was justified by the lack of long-term data to inform patients' prognosis, the ERG noted that the calibration approach employed by the company was not transparent and that the resulting model predictions did not match the published evidence. The ERG considered unadjusted POISE data more appropriate in the ursodeoxycholic acid arm for the first 12\xa0months, which increased the company base case from £28,425 per QALY gained to £32,897 per QALY gained (incremental costs £171,036; incremental QALYs 5.20). The ERG also considered that extrapolating the POISE 12‑month data over the long term (beyond 12\xa0months) in the biomarker component of the model was more appropriate than the company's approach of using published data on long-term outcomes in PBC. This would result in a further rise in the ERG's base case. The committee appreciated that long-term modelling presented significant challenges. It accepted that without effective treatment people whose disease had not responded to ursodeoxycholic acid may progress at slightly different rates, but have a very poor prognosis. Liver disease may progress faster once it becomes established. This may not be captured in the first 12\xa0months of treatment. The committee concluded that it was not unreasonable to use other published data to try to replicate the expected course of disease in those whose disease had not responded to ursodeoxycholic acid and considered the company's approach for decision making acceptable, although there remained uncertainty in the trajectory of disease progression in the ursodeoxycholic acid arm.\n\nThe committee further considered the utility values used. It noted that the ERG's suggested adjustment of utilities, to take account of lower utility in the UK population, and an age-related decrement, increased the ICER for obeticholic acid plus ursodeoxycholic acid to £33,458 per QALY gained compared with ursodeoxycholic acid alone (incremental cost £164,808; incremental QALYs 4.93). The committee concluded that there were many uncertainties around the utility values used in the model but considered that a utility value of 0.84 in the low and moderate risk group was not implausible and was in line with published evidence, and it agreed that an age-related decrement over time should have been incorporated into the model. The committee concluded that the most plausible ICER for people whose disease had not responded to ursodeoxycholic acid would be around the upper limit of what could be considered cost effective. It therefore considered what other factors might justify accepting it as a cost-effective use of NHS resources.\n\n# Innovation\n\nThe committee heard from the company that obeticholic acid is innovative because of its mechanism of action as a farnesoid X receptor agonist. Obeticholic acid also has an anti-inflammatory action, which may provide additional efficacy in this disease. The committee accepted the innovative nature of the treatment, and considered that this was a major change in the management of PBC. The committee noted in particular that the results in 47% of people in the obeticholic acid arm of POISE met the strict criteria for response, despite the current standard of care, ursodeoxycholic acid, not having been effective. This response would be associated with a very favourable prognosis.\n\n# Other considerations\n\nThe committee was aware that if PBC was controlled, people could have an excellent outcome and normal life expectancy. However, people whose disease had not responded to, or had been unable to tolerate the only available preventative treatment, were likely to decline rapidly. The committee considered that the potential restoration of normal life expectancy was a huge benefit, and this was not often possible in such serious conditions.\n\nThe committee was aware that because people whose disease responds to obeticholic acid are at a much lower risk of disease progression, the drug may delay or prevent the need for liver transplant. The committee considered that avoiding liver transplant was of great importance to PBC patients. The committee heard that PBC is the most common indication for liver transplant in women over 50. It was also aware of the scarcity of donor organs and that other patients on the transplant waiting list for other reasons might benefit if obeticholic acid were available. The committee noted that this opportunity cost of liver transplant on other people on the waiting list had not been captured in the cost-effectiveness estimates of obeticholic acid for people with PBC.\n\nThe committee was aware that the clinical benefit of obeticholic acid may be underestimated in the trial because of the lack of adjustment up to the recommended dose in some patients. Taking all factors into consideration, the committee concluded that obeticholic acid could be considered a cost-effective use of NHS resources.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA443\n\nAppraisal title: Obeticholic acid for treating primary biliary cholangitis\n\nSection\n\nKey conclusion\n\nObeticholic acid is clinically effective in people with primary biliary cholangitis (PBC) who cannot tolerate or whose disease does not respond to ursodeoxycholic acid. A higher number of people on obeticholic acid plus ursodeoxycholic acid met the primary outcome based on alkaline phosphatase and total bilirubin levels than people treated with ursodeoxycholic acid alone. The committee has taken into consideration the innovative nature of obeticholic acid and the unmet need of patients for whom there was no effective treatment. The committee noted that the benefits of not needing a liver transplant for people whose disease is treated with obeticholic acid have not been included in the model. Obeticholic acid could be considered a cost-effective use of NHS resources.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nPatients with PBC are currently treated with ursodeoxycholic acid, but patients who cannot tolerate it or whose disease does not respond to ursodeoxycholic acid have no other treatment option. The committee heard that there is a high unmet need for patients whose disease does not respond to, or who cannot tolerate ursodeoxycholic acid, and recognised that the availability of additional treatment options would be highly valued by patients and families.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nObeticholic acid in combination with ursodeoxycholic acid or alone helps to normalise alkaline phosphatase (ALP) and total bilirubin levels and reduces the risk of PBC progression. People with normal liver biochemistry are expected to have an excellent prognosis with a normal life expectancy.\n\nObeticholic acid is innovative because of its mechanism of action as a farnesoid X receptor agonist. It is a novel, innovative therapy for patients with PBC. It also has an anti-inflammatory action, which may provide additional efficacy in this disease.\n\n, 4.14\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nObeticholic acid is recommended in combination with ursodeoxycholic acid or as monotherapy in patients whose disease has responded inadequately to, or who cannot tolerate ursodeoxycholic acid.\n\n\n\nAdverse reactions\n\nObeticholic acid is generally well tolerated and the adverse events can be managed satisfactorily. The main adverse effect of the treatment is pruritus.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nEvidence for clinical effectiveness of obeticholic acid plus ursodeoxycholic acid and obeticholic acid monotherapy was based on a randomised controlled double blinded trial (POISE) which was assessed as good quality.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee considered the people enrolled in the POISE to be generalisable to people with PBC in the NHS in England.\n\n\n\nUncertainties generated by the evidence\n\nThe committee considered there to be uncertainty in the clinical effectiveness of obeticholic acid monotherapy in those who cannot tolerate ursodeoxycholic acid because of the small number of patients in the pivotal trial. Clinical experts noted that the small patient number in the trial reflect the minority of patients who are unable to take ursodeoxycholic acid in clinical practice.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe higher number of people whose results met the primary outcome in POISE for obeticholic acid plus ursodeoxycholic acid compared with placebo plus ursodeoxycholic acid (47% in the obeticholic acid 10 mg group and 46% in the obeticholic acid titration group compared with 10% in the placebo group, p<0.0001 for both comparisons). Obeticholic acid plus ursodeoxycholic acid was also more effective at lowering ALP levels by at least 40% from the baseline (34% in the obeticholic acid 10\xa0mg group and 30% in the obeticholic acid titration group compared with 1% in the placebo group). Obeticholic acid plus ursodeoxycholic acid was more effective at lowering the total bilirubin level, which at 12 months was 9.7 for the obeticholic acid 10\xa0mg group, 9.9 for the obeticholic acid titration group, and 13.2 for the placebo group.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company's de novo economic model assessed the cost effectiveness of obeticholic acid plus ursodeoxycholic acid compared with ursodeoxycholic acid alone based on the POISE population. Also obeticholic acid monotherapy compared with placebo was assessed based on small patient numbers (n=11).\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe uncalibrated transition probabilities in the ursodeoxycholic acid arm and the age adjustment of utilities in health states of the model were considered to be the key areas of uncertainty in modelling the cost effectiveness of obeticholic acid in PBC.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe utility values were derived from published sources of people with hepatitis\xa0C which were adjusted because people with PBC and substantial liver disease have a worse quality of life than people with hepatitis. There was uncertainty in the utility values because the utility for low and moderate risk of progression of PBC was higher than the UK age adjusted utility. However, the committee was aware that a study of utility in people with hepatitis\xa0C, a pre-treatment of 0.91 was also higher than the corresponding published US population norm for people aged 45 to 54. The committee acknowledged the uncertainty associated with the utility values. The committee agreed that an age-related decrement over time should have been incorporated into the model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nUsing unadjusted POISE data in the ursodeoxycholic acid arm for the first 12\xa0months increased the company base case from £28,425 per quality-adjusted life year (QALY) gained to £32,897 per QALY gained. Using lower utility in the UK population and an age-related decrement, increased the incremental cost-effectiveness ratio to £33,458 per QALY gained.\n\n; 4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee was not able to define a most plausible ICER but concluded for people whose disease had not responded to ursodeoxycholic acid that it would be around the upper limit of what could be considered cost effective.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nYes.\n\n\n\nEnd-of-life considerations\n\nNone.\n\n–\n\nEqualities considerations and social value judgements\n\nNone.\n\n–"}	https://www.nice.org.uk/guidance/ta443	Evidence-based recommendations on obeticholic acid (Ocaliva) for treating primary biliary cholangitis in adults.
fea1c3a09795b49912c7bc72220222fcbe8d0bf9	nice	Antisocial behaviour and conduct disorders in children and young people: recognition and management	Antisocial behaviour and conduct disorders in children and young people: recognition and management This guideline covers recognising and managing antisocial behaviour and conduct disorders in children and young people aged under 19. It aims to improve care by identifying children and young people who are at risk and when interventions can prevent conduct disorders from developing. The guideline also makes recommendations on communication, to help professionals build relationships with children and young people and involve them in their own care. # Introduction This guidance updates and replaces NICE technology appraisal guidance 102 (published July 2006). This guidance has been developed jointly by the National Institute for Health and Clinical Excellence (NICE) and the Social Care Institute for Excellence (SCIE). Conduct disorders, and associated antisocial behaviour, are the most common mental and behavioural problems in children and young people. The Office of National Statistics (ONS) surveys of 1999 and 2004 reported that their prevalence was 5% among children and young people aged between 5 and 16 years. Conduct disorders nearly always have a significant impact on functioning and quality of life. The 1999 ONS survey demonstrated that conduct disorders have a steep social class gradient, with a three- to fourfold increase in prevalence in social classes D and E compared with social class A. The 2004 survey found that almost 40% of looked-after children, those who had been abused and those on child protection or safeguarding registers had a conduct disorder. Conduct disorders are characterised by repetitive and persistent patterns of antisocial, aggressive or defiant behaviour that amounts to significant and persistent violations of age-appropriate social expectations. The World Health Organization's ICD-10 classification of mental and behavioural disorders divides conduct disorders into socialised conduct disorder, unsocialised conduct disorder, conduct disorders confined to the family context and oppositional defiant disorder. The major distinction between oppositional defiant disorder and the other subtypes of conduct disorder is the extent and severity of the antisocial behaviour. Isolated antisocial or criminal acts are not sufficient to support a diagnosis of conduct disorder or oppositional defiant disorder. Oppositional defiant disorder is more common in children aged 10 years or younger; the other subtypes of conduct disorder are more common in those aged over 11 years or older. The prevalence of conduct disorders increases throughout childhood and they are more common in boys than girls. For example, 7% of boys and 3% of girls aged 5 to 10 years have conduct disorders; in children aged 11 to 16 years the proportion rises to 8% of boys and 5% of girls. Conduct disorders commonly coexist with other mental health problems: 46% of boys and 36% of girls have at least 1 coexisting mental health problem. The coexistence of conduct disorders with attention deficit hyperactivity disorder (ADHD) is particularly prevalent and in some groups more than 40% of children and young people with a diagnosis of conduct disorder also have a diagnosis of ADHD. Conduct disorders in childhood are also associated with a significantly increased rate of mental health problems in adult life, including antisocial personality disorder – up to 50% of children and young people with a conduct disorder go on to develop antisocial personality disorder. The prevalence of conduct disorders in the UK varies across ethnic groups; for example, their prevalence is lower than average in children and young people of south Asian family origin and higher than average in children and young people of African-Caribbean family origin. A diagnosis of a conduct disorder is strongly associated with poor educational performance, social isolation and, in adolescence, substance misuse and increased contact with the criminal justice system. This association continues into adult life with poorer educational and occupational outcomes, involvement with the criminal justice system (as high as 50% in some groups) and a high level of mental health problems (at some point in their lives 90% of people with antisocial personality disorder will have another mental health problem). Conduct disorders are the most common reason for referral of young children to child and adolescent mental health services (CAMHS). Children with conduct disorders also comprise a considerable proportion of the work of the health and social care system. For example, 30% of a typical GP's child consultations are for behavioural problems, 45% of community child health referrals are for behaviour disturbances and psychiatric disorders are a factor in 28% of all paediatric outpatient referrals. In addition, social care services have significant involvement with children and young people with conduct disorders, with more vulnerable or disturbed children often being placed with a foster family or, less commonly, in residential care. The demands on the educational system are also considerable and include the provision of special-needs education. The criminal justice system also has significant involvement with older children with conduct disorders. Multiple agencies may be involved in the care and treatment of children with conduct disorders, which presents a major challenge for services in the effective coordination of care across agencies. Several interventions have been developed for children with conduct disorder and related problems, such as parenting programmes typically focused on younger children and multisystemic approaches usually focused on older children. Other interventions focused on prevention, such as the Nurse Family Partnership (known as the Family Nurse Partnership in the UK), have recently been implemented in the UK and are currently being evaluated. Three themes are common to these interventions: a strong focus on working with parents and families, recognition of the importance of the wider social system in enabling effective interventions and a focus on preventing or reducing the escalation of existing problems. Uptake of these interventions and the outcomes achieved vary across England and Wales. Parenting programmes are the best established; implementation of multisystemic approaches and early intervention programmes is more variable. In addition to the programmes developed specifically for children with a conduct disorder, a number of children (and their parents or carers) are treated by both specialist CAMHS teams and general community-based services such as Sure Start. Identifying which interventions and agencies are the most appropriate is challenging, especially for non-specialist health, social care and educational services. Further challenges arise when considering the use of preventive and early intervention programmes and identifying which vulnerable groups stand to gain from such interventions. Factors that may be associated with a higher risk of developing conduct disorders include parental factors such as harsh and inconsistent parenting style and parental mental health problems (for example depression, antisocial personality disorder and substance misuse), environmental factors such as poverty and being looked after, and individual factors such as low educational attainment and the presence of other mental health problems. The guideline covers a range of interventions including treatment, indicated prevention and selective prevention (but not universal prevention), adapting definitions developed by the Institute of Medicine. For a description of the criteria used to determine whether an intervention was judged to be selective or indicated prevention see chapter 5 of the full guideline. (In this guideline selective prevention refers to interventions targeted to individuals or to a subgroup of the population whose risk of developing a conduct disorder is significantly higher than average, as evidenced by individual, family and social risk factors. Individual risk factors include low school achievement and impulsiveness; family risk factors include parental contact with the criminal justice system and child abuse; social risk factors include low family income and little education.) Some recommendations in this guideline have been adapted from recommendations in other NICE clinical guidance. In these cases the Guideline Development Group was careful to preserve the meaning and intent of the original recommendations. Changes to wording or structure were made to fit the recommendations into this guideline. The original sources of the adapted recommendations are shown in footnotes.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. All recommendations relate to children and young people aged under 18 years unless otherwise specified. # General principles of care See also NICE's guideline on babies, children and young people's experience of healthcare. ## Working safely and effectively with children and young people Health and social care professionals working with children and young people who present with behaviour suggestive of a conduct disorder, or who have a conduct disorder, should be trained and competent to work with children and young people of all levels of learning ability, cognitive capacity, emotional maturity and development. Health and social care professionals should ensure that they: can assess capacity and competence, including 'Gillick competence', in children and young people of all ages and understand how to apply legislation, including the Children Act (1989), the Mental Health Act (1983; amended 1995 and 2007) and the Mental Capacity Act (2005), in the care and treatment of children and young people. Health and social care providers should ensure that children and young people: can routinely receive care and treatment from a single team or professional are not passed from one team to another unnecessarily do not undergo multiple assessments unnecessarily. When providing assessment or treatment interventions for children and young people, ensure that the nature and content of the intervention is suitable for the child or young person's developmental level. Consider children and young people for assessment according to local safeguarding procedures if there are concerns regarding exploitation or self-care, or if they have been in contact with the criminal justice system. ## Establishing relationships with children and young people and their parents or carers Be aware that many children and young people with a conduct disorder may have had poor or punitive experiences of care and be mistrustful or dismissive of offers of help as a result. Develop a positive, caring and trusting relationship with the child or young person and their parents or carers to encourage their engagement with services. Health and social care professionals working with children and young people should be trained and skilled in: negotiating and working with parents and carers and managing issues relating to information sharing and confidentiality as these apply to children and young people. If a young person is 'Gillick competent' ask them what information can be shared before discussing their condition with their parents or carers. When working with children and young people with a conduct disorder and their parents or carers: make sure that discussions take place in settings in which confidentiality, privacy and dignity are respected be clear with the child or young person and their parents or carers about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others). When coordinating care and discussing treatment decisions with children and young people and their parents or carers, ensure that: everyone involved understands the purpose of any meetings and why information might need to be shared between services and the right to confidentiality is respected throughout the process. ## Working with parents and carers If parents or carers are involved in the treatment of young people with a conduct disorder, discuss with young people of an appropriate developmental level, emotional maturity and cognitive capacity how they want them to be involved. Such discussions should take place at intervals to take account of any changes in circumstances, including developmental level, and should not happen only once. Be aware that parents and carers of children and young people with a conduct disorder might feel blamed for their child's problems or stigmatised by their contact with services. When offering or providing interventions such as parent training programmes, directly address any concerns they have and set out the reasons for and purpose of the intervention. Offer parents and carers an assessment of their own needs including: personal, social and emotional support and support in their caring role, including emergency plans and advice on practical matters such as childcare, housing and finances, and help to obtain support. ## Communication and information When communicating with children and young people with a conduct disorder and their parents or carers: take into account the child or young person's developmental level, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems, or delays in language development or social communication difficulties use plain language if possible and clearly explain any clinical language; adjust strategies to the person's language ability, for example, breaking up information, checking back, summarising and recapping check that the child or young person and their parents or carers understand what is being said use communication aids (such as pictures, symbols, large print, braille, different languages or sign language) if needed. When giving information to children and young people with a conduct disorder and their parents or carers, ensure you are: familiar with local and national sources (organisations and websites) of information and/or support for children and young people with a conduct disorder and their parents or carers able to discuss and advise how to access these resources able to discuss and actively support children and young people and their parents or carers to engage with these resources. When communicating with a child or young person use diverse media, including letters, phone calls, emails or text messages, according to their preference. ## Culture, ethnicity and social inclusion When working with children and young people with a conduct disorder and their parents or carers: take into account that stigma and discrimination are often associated with using mental health services be respectful of and sensitive to children and young people's gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability be aware of possible variations in the presentation of mental health problems in children and young people of different genders, ages, cultural, ethnic, religious or other diverse backgrounds. When working with children and young people and their parents or carers who have difficulties speaking or reading English: provide and work proficiently with interpreters if needed -ffer a list of local education providers who can provide English language teaching. Health and social care professionals working with children and young people with a conduct disorder and their parents or carers should have competence in: assessment skills and using explanatory models of conduct disorder for people from different cultural, ethnic, religious or other diverse backgrounds explaining the possible causes of different mental health problems, and care, treatment and support options addressing cultural, ethnic, religious or other differences in treatment expectations and adherence addressing cultural, ethnic, religious or other beliefs about biological, social and familial influences on the possible causes of mental health problems conflict management and conflict resolution. ## Staff supervision Health and social care services should ensure that staff supervision is built into the routine working of the service, is properly resourced within local systems and is monitored. Supervision should: make use of direct observation (for example, recordings of sessions) and routine outcome measures support adherence to the specific intervention focus on outcomes be regular and apply to the whole caseload. ## Transfer and discharge Anticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in children and young people with a conduct disorder and their parents or carers. Ensure that: such changes, especially discharge and transfer from CAMHS to adult services, are discussed and planned carefully beforehand with the child or young person and their parents or carers, and are structured and phased children and young people and their parents or carers are given comprehensive information about the way adult services work and the nature of any potential interventions provided any care plan supports effective collaboration with social care and other care providers during endings and transitions, and includes details of how to access services in times of crisis when referring a child or young person for an assessment in other services (including for psychological interventions), they are supported during the referral period and arrangements for support are agreed beforehand with them. For young people who continue to exhibit antisocial behaviour or meet criteria for a conduct disorder while in transition to adult services (in particular those who are still vulnerable, such as those who have been looked after or who have limited access to care) refer to NICE's guideline on antisocial personality disorder. For those who have other mental health problems refer to other NICE guidance for the specific mental health problem. # Selective prevention In this guideline selective prevention refers to interventions targeted to individuals or to a subgroup of the population whose risk of developing a conduct disorder is significantly higher than average, as evidenced by individual, family and social risk factors. Individual risk factors include low school achievement and impulsiveness; family risk factors include parental contact with the criminal justice system and child abuse; social risk factors include low family income and little education. Offer classroom-based emotional learning and problem-solving programmes for children aged typically between 3 and 7 years in schools where classroom populations have a high proportion of children identified to be at risk of developing oppositional defiant disorder or conduct disorder as a result of any of the following factors: low socioeconomic status low school achievement child abuse or parental conflict separated or divorced parents parental mental health or substance misuse problems parental contact with the criminal justice system. Classroom-based emotional learning and problem-solving programmes should be provided in a positive atmosphere and consist of interventions intended to: increase children's awareness of their own and others' emotions teach self-control of arousal and behaviour promote a positive self-concept and good peer relations develop children's problem-solving skills. Typically the programmes should consist of up to 30 classroom-based sessions over the course of 1 school year. # Identification and assessment ## Initial assessment of children and young people with a possible conduct disorder Adjust delivery of initial assessment methods to: the needs of children and young people with a suspected conduct disorder and the setting in which they are delivered (for example, health and social care, educational settings or the criminal justice system). Undertake an initial assessment for a suspected conduct disorder if a child or young person's parents or carers, health or social care professionals, school or college, or peer group raise concerns about persistent antisocial behaviour. Do not regard a history of a neurodevelopmental condition (for example, attention deficit hyperactivity disorder ) as a barrier to assessment. For the initial assessment of a child or young person with a suspected conduct disorder, consider using the Strengths and Difficulties Questionnaire (completed by a parent, carer or teacher). Assess for the presence of the following significant complicating factors: a coexisting mental health problem (for example, depression, post-traumatic stress disorder) a neurodevelopmental condition (in particular ADHD and autism) a learning disability or difficulty substance misuse in young people. If any significant complicating factors are present refer the child or young person to a specialist CAMHS for a comprehensive assessment. If no significant complicating factors are present consider direct referral for an intervention. ## Comprehensive assessment A comprehensive assessment of a child or young person with a suspected conduct disorder should be undertaken by a health or social care professional who is competent to undertake the assessment and should: -ffer the child or young person the opportunity to meet the professional on their own involve a parent, carer or other third party known to the child or young person who can provide information about current and past behaviour if necessary involve more than 1 health or social care professional to ensure a comprehensive assessment is undertaken. Before starting a comprehensive assessment, explain to the child or young person how the outcome of the assessment will be communicated to them. Involve a parent, carer or advocate to help explain the outcome. The standard components of a comprehensive assessment of conduct disorders should include asking about and assessing the following: core conduct disorders symptoms including: patterns of negativistic, hostile, or defiant behaviour in children aged under 11 years aggression to people and animals, destruction of property, deceitfulness or theft and serious violations of rules in children aged over 11 years current functioning at home, at school or college and with peers parenting quality history of any past or current mental or physical health problems. Take into account and address possible coexisting conditions such as: learning difficulties or disabilities neurodevelopmental conditions such as ADHD and autism neurological disorders including epilepsy and motor impairments -ther mental health problems (for example, depression, post-traumatic stress disorder and bipolar disorder) substance misuse communication disorders (for example, speech and language problems). Consider using formal assessment instruments to aid the diagnosis of coexisting conditions, such as: the Child Behavior Checklist for all children and young people the Strengths and Difficulties Questionnaire for all children or young people the Connors Rating Scales – Revised for a child or young person with suspected ADHD a validated measure of autistic behaviour for a child or young person with a suspected autism spectrum disorder (see NICE's guideline on autism diagnosis in children and young people) a validated measure of cognitive ability for a child or young person with a suspected learning disability a validated reading test for a child or young person with a suspected reading difficulty. Assess the risks faced by the child or young person and if needed develop a risk management plan for self-neglect, exploitation by others, self-harm or harm to others. Assess for the presence or risk of physical, sexual and emotional abuse in line with local protocols for the assessment and management of these problems. Conduct a comprehensive assessment of the child or young person's parents or carers, which should cover: positive and negative aspects of parenting, in particular any use of coercive discipline the parent–child relationship positive and negative adult relationships within the child or young person's family, including domestic violence parental wellbeing, encompassing mental health, substance misuse (including whether alcohol or drugs were used during pregnancy) and criminal behaviour. Develop a care plan with the child or young person and their parents or carers that includes a profile of their needs, risks to self or others, and any further assessments that may be needed. This should encompass the development and maintenance of the conduct disorder and any associated behavioural problems, any coexisting mental or physical health problems and speech, language and communication difficulties, in the context of: any personal, social, occupational, housing or educational needs the needs of parents or carers the strengths of the child or young person and their parents or carers. # Identifying effective treatment and care options When discussing treatment or care interventions with a child or young person with a conduct disorder and, if appropriate, their parents or carers, take account of: their past and current experience of the disorder their experience of, and response to, previous interventions and services the nature, severity and duration of the problems the impact of the disorder on educational performance any chronic physical health problem any social or family factors that may have a role in the development or maintenance of the identified problems any coexisting conditions. When discussing treatment or care interventions with a child or young person and, if appropriate, their parents or carers, provide information about: the nature, content and duration of any proposed intervention the acceptability and tolerability of any proposed intervention the possible impact on interventions for any other behavioural or mental health problem the implications for the continuing provision of any current interventions. When making a referral for treatment or care interventions for a conduct disorder, take account of the preferences of the child or young person and, if appropriate, their parents or carers when choosing from a range of evidence-based interventions. # Psychosocial interventions – treatment and indicated prevention In this guideline indicated prevention refers to interventions targeted to high-risk individuals who are identified as having detectable signs or symptoms that may lead to the development of conduct disorders but who do not meet diagnostic criteria for conduct disorders when offered an intervention. The interventions in recommendations 1.5.1 to 1.5.12 are suitable for children and young people who have a diagnosis of oppositional defiant disorder or conduct disorder, are in contact with the criminal justice system for antisocial behaviour, or have been identified as being at high risk of a conduct disorder using established rating scales of antisocial behaviour (for example, the Child Behavior Checklist and the Eyberg Child Behavior Inventory). ## Parent training programmes Offer a group parent training programme to the parents of children and young people aged between 3 and 11 years who: have been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or have oppositional defiant disorder or conduct disorder or are in contact with the criminal justice system because of antisocial behaviour. Group parent training programmes should involve both parents if this is possible and in the best interests of the child or young person, and should: typically have between 10 and 12 parents in a group be based on a social learning model, using modelling, rehearsal and feedback to improve parenting skills typically consist of 10 to 16 meetings of 90 to 120 minutes' duration adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). Offer an individual parent training programme to the parents of children and young people aged between 3 and 11 years who are not able to participate in a group parent training programme and whose child: has been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or has oppositional defiant disorder or conduct disorder or is in contact with the criminal justice system because of antisocial behaviour. Individual parent training programmes should involve both parents if this is possible and in the best interests of the child or young person, and should: be based on a social learning model using modelling, rehearsal and feedback to improve parenting skills typically consist of 8 to 10 meetings of 60 to 90 minutes' duration adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). ## Parent and child training programmes for children with complex needs Offer individual parent and child training programmes to children and young people aged between 3 and 11 years if their problems are severe and complex and they: have been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or have oppositional defiant disorder or conduct disorder or are in contact with the criminal justice system because of antisocial behaviour. Individual parent and child training programmes should involve both parents, foster carers or guardians if this is possible and in the best interests of the child or young person, and should: be based on a social learning model using modelling, rehearsal and feedback to improve parenting skills consist of up to 10 meetings of 60 minutes' duration adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). ## Foster carer/guardian training programmes Offer a group foster carer/guardian training programme to foster carers and guardians of children and young people aged between 3 and 11 years who: have been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or have oppositional defiant disorder or conduct disorder or are in contact with the criminal justice system because of antisocial behaviour. Group foster carer or guardian training programmes should involve both of the foster carers or guardians if this is possible and in the best interests of the child or young person, and should: modify the intervention to take account of the care setting in which the child is living typically have between 8 and 12 foster carers or guardians in a group be based on a social learning model using modelling, rehearsal and feedback to improve parenting skills typically consist of between 12 and 16 meetings of 90 to 120 minutes' duration adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). Offer an individual foster carer/guardian training programme to the foster carers or guardians of children and young people aged between 3 and 11 years who are not able to participate in a group programme and whose child: has been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or has oppositional defiant disorder or conduct disorder or is in contact with the criminal justice system because of antisocial behaviour. Individual foster carer/guardian training programmes should involve both of the foster carers if this is possible and in the best interests of the child or young person, and should: modify the intervention to take account of the care setting in which the child is living be based on a social learning model using modelling, rehearsal and feedback to improve parenting skills consist of up to 10 meetings of 60 minutes' duration adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). ## Child-focused programmes Offer group social and cognitive problem-solving programmes to children and young people aged between 9 and 14 years who: have been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or have oppositional defiant disorder or conduct disorder or are in contact with the criminal justice system because of antisocial behaviour. Group social and cognitive problem-solving programmes should be adapted to the children's or young people's developmental level and should: be based on a cognitive–behavioural problem-solving model use modelling, rehearsal and feedback to improve skills typically consist of 10 to 18 weekly meetings of 2 hours' duration adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). ## Multimodal interventions Offer multimodal interventions, for example, multisystemic therapy, to children and young people aged between 11 and 17 years for the treatment of conduct disorder. Multimodal interventions should involve the child or young person and their parents and carers and should: have an explicit and supportive family focus be based on a social learning model with interventions provided at individual, family, school, criminal justice and community levels be provided by specially trained case managers typically consist of 3 to 4 meetings per week over a 3- to 5‑month period adhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial). # Pharmacological interventions Do not offer pharmacological interventions for the routine management of behavioural problems in children and young people with oppositional defiant disorder or conduct disorder. Offer methylphenidate or atomoxetine, within their licensed indications, for the management of ADHD in children and young people with oppositional defiant disorder or conduct disorder, in line with NICE's guideline on attention deficit hyperactivity disorder. Consider risperidone for the short-term management of severely aggressive behaviour in young people with a conduct disorder who have problems with explosive anger and severe emotional dysregulation and who have not responded to psychosocial interventions.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines. Provide young people and their parents or carers with age-appropriate information and discuss the likely benefits and possible side effects of risperidone including: metabolic (including weight gain and diabetes) extrapyramidal (including akathisia, dyskinesia and dystonia) cardiovascular (including prolonging the QT interval) hormonal (including increasing plasma prolactin) -ther (including unpleasant subjective experiences).In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines. Risperidone should be started by an appropriately qualified healthcare professional with expertise in conduct disorders and should be based on a comprehensive assessment and diagnosis. The healthcare professional should undertake and record the following baseline investigations: weight and height (both plotted on a growth chart) waist and hip measurements pulse and blood pressure fasting blood glucose or glycosylated haemoglobin (HbA1c) blood lipid and prolactin levels assessment of any movement disorders assessment of nutritional status, diet and level of physical activity.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines. Treatment with risperidone should be carefully evaluated, and include the following: Record the indications and expected benefits and risks, and the expected time for a change in symptoms and appearance of side effects. At the start of treatment give a dose at the lower end of the licensed range and slowly titrate upwards within the dose range given in the British national formulary for children (BNFC) or the summary of product characteristics (SPC). Justify and record reasons for dosages above the range given in the BNFC or SPC. Monitor and record systematically throughout treatment, but especially during titration: efficacy, including changes in symptoms and behaviour the emergence of movement disorders weight and height (weekly) fasting blood glucose or HbA1c blood lipid and prolactin levels adherence to medication physical health, including warning parents or carers and the young person about symptoms and signs of neuroleptic malignant syndrome. Record the rationale for continuing or stopping treatment and the effects of these decisions.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines. Review the effects of risperidone after 3 to 4 weeks and discontinue it if there is no indication of a clinically important response at 6 weeks.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines. # Organisation and delivery of care ## Improving access to services Health and social care professionals, managers and commissioners should collaborate with colleagues in educational settings to develop local care pathways that promote access to services for children and young people with a conduct disorder and their parents and carers by: supporting the integrated delivery of services across all care settings having clear and explicit criteria for entry to the service focusing on entry and not exclusion criteria having multiple means (including self-referral) of access to the service providing multiple points of access that facilitate links with the wider care system, including educational and social care services and the community in which the service is located. Provide information about the services and interventions that constitute the local care pathway, including the: range and nature of the interventions provided settings in which services are delivered processes by which a child or young person moves through the pathway means by which progress and outcomes are assessed delivery of care in related health and social care services. When providing information about local care pathways for children and young people with a conduct disorder and their parents and carers: take into account the person's knowledge and understanding of conduct disorders and their care and treatment ensure that such information is appropriate to the communities using the pathway. Provide all information about services in a range of languages and formats (visual, verbal and aural) and ensure that it is available in a range of settings throughout the whole community to which the service is responsible. Health and social care professionals, managers and commissioners should collaborate with colleagues in educational settings to develop local care pathways that promote access for a range of groups at risk of under-utilising services, including: girls and young women black and minority ethnic groups people with a coexisting condition (such as ADHD or autism). Support access to services and increase the uptake of interventions by: ensuring systems are in place to provide for the overall coordination and continuity of care designating a professional to oversee the whole period of care (for example, a staff member in a CAMHS or social care setting). Support access to services and increase the uptake of interventions by providing services for children and young people with a conduct disorder and their parents and carers, in a variety of settings. Use an assessment of local needs as a basis for the structure and distribution of services, which should typically include delivery of: assessment and interventions outside normal working hours assessment and interventions in the person's home or other residential settings specialist assessment and interventions in accessible community-based settings (for example, community centres, schools and colleges and social centres) and if appropriate, in conjunction with staff from those settings both generalist and specialist assessment and intervention services in primary care settings. Health and social care professionals, managers and commissioners should collaborate with colleagues in educational settings to look at a range of services to support access to and uptake of services. These could include: crèche facilities assistance with travel advocacy services. ## Developing local care pathways Local care pathways should be developed to promote implementation of key principles of good care. Pathways should be: negotiable, workable and understandable for children and young people with a conduct disorder and their parents and carers as well as professionals accessible and acceptable to all people in need of the services served by the pathway responsive to the needs of children and young people with a conduct disorder and their parents and carers integrated so that there are no barriers to movement between different levels of the pathway focused on outcomes (including measures of quality, service user experience and harm). Responsibility for the development, management and evaluation of local care pathways should lie with a designated leadership team, which should include health and social care professionals, managers and commissioners. The leadership team should work in collaboration with colleagues in educational settings and take particular responsibility for: developing clear policy and protocols for the operation of the pathway providing training and support on the operation of the pathway auditing and reviewing the performance of the pathway. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that promote a model of service delivery that: has clear and explicit criteria for the thresholds determining access to and movement between the different levels of the pathway does not use single criteria such as symptom severity or functional impairment to determine movement within the pathway monitors progress and outcomes to ensure the most effective interventions are delivered. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that promote a range of evidence-based interventions in the pathway and support children and young people with a conduct disorder and their parents and carers in their choice of interventions. All staff should ensure effective engagement with parents and carers, if appropriate, to: inform and improve the care of the child or young person with a conduct disorder meet the needs of parents and carers. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that promote the active engagement of all populations served by the pathway. Pathways should: -ffer prompt assessments and interventions that are appropriately adapted to the cultural, gender, age and communication needs of children and young people with a conduct disorder and their parents and carers keep to a minimum the number of assessments needed to access interventions. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that respond promptly and effectively to the changing needs of all populations served by the pathways. Pathways should have in place: clear and agreed goals for the services offered to children and young people with a conduct disorder and their parents and carers robust and effective means for measuring and evaluating the outcomes associated with the agreed goals clear and agreed mechanisms for responding promptly to changes in individual needs. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that provide an integrated programme of care across all care settings. Pathways should: minimise the need for transition between different services or providers allow services to be built around the pathway and not the pathway around the services establish clear links (including access and entry points) to other care pathways (including those for physical healthcare needs) have designated staff who are responsible for the coordination of people's engagement with the pathway. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to ensure effective communication about the functioning of the local care pathway. There should be protocols for: sharing information with children and young people with a conduct disorder, and their parents and carers, about their care sharing and communicating information about the care of children and young people with other professionals (including GPs) communicating information between the services provided within the pathway communicating information to services outside the pathway. Health and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that have robust systems for outcome measurement in place, which should be used to inform all involved in a pathway about its effectiveness. This should include providing: individual routine outcome measurement systems effective electronic systems for the routine reporting and aggregation of outcome measures effective systems for the audit and review of the overall clinical and cost effectiveness of the pathway.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline. # Parent training programmes for children aged 12 years and over with a conduct disorder What is the effectiveness of parent training programmes for conduct disorders in children and young people aged 12 years and over? ## Why this is important The evidence for parent training programmes is well established for children with conduct disorders aged 11 years and younger, with well-developed models for the delivery of care. In contrast there is little evidence for these programmes in older children despite the recognition that parenting problems continue to play a part in the development and maintenance of conduct disorders. This question should be answered using a randomised controlled trial (RCT) design reporting short- and medium-term outcomes, including cost effectiveness, over at least 18 months. Attention should be paid to the adaptation of parent training programmes to older children, and to training and supervision of staff delivering the programmes to ensure robust and generalisable results. The outcomes and acceptability of the intervention should be rated by parents, teachers and independent observers. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators of response should also be investigated.	{'Introduction': "This guidance updates and replaces NICE technology appraisal guidance\xa0102 (published July 2006).\n\nThis guidance has been developed jointly by the National Institute for Health and Clinical Excellence (NICE) and the Social Care Institute for Excellence (SCIE).\n\nConduct disorders, and associated antisocial behaviour, are the most common mental and behavioural problems in children and young people. The Office of National Statistics (ONS) surveys of 1999 and 2004 reported that their prevalence was 5% among children and young people aged between 5 and 16\xa0years. Conduct disorders nearly always have a significant impact on functioning and quality of life. The 1999 ONS survey demonstrated that conduct disorders have a steep social class gradient, with a three- to fourfold increase in prevalence in social classes D and E compared with social class A. The 2004 survey found that almost 40% of looked-after children, those who had been abused and those on child protection or safeguarding registers had a conduct disorder.\n\nConduct disorders are characterised by repetitive and persistent patterns of antisocial, aggressive or defiant behaviour that amounts to significant and persistent violations of age-appropriate social expectations. The World Health Organization's ICD-10 classification of mental and behavioural disorders divides conduct disorders into socialised conduct disorder, unsocialised conduct disorder, conduct disorders confined to the family context and oppositional defiant disorder. The major distinction between oppositional defiant disorder and the other subtypes of conduct disorder is the extent and severity of the antisocial behaviour. Isolated antisocial or criminal acts are not sufficient to support a diagnosis of conduct disorder or oppositional defiant disorder. Oppositional defiant disorder is more common in children aged 10\xa0years or younger; the other subtypes of conduct disorder are more common in those aged over 11\xa0years or older.\n\nThe prevalence of conduct disorders increases throughout childhood and they are more common in boys than girls. For example, 7% of boys and 3% of girls aged 5 to 10\xa0years have conduct disorders; in children aged 11 to 16\xa0years the proportion rises to 8% of boys and 5% of girls.\n\nConduct disorders commonly coexist with other mental health problems: 46% of boys and 36% of girls have at least 1 coexisting mental health problem. The coexistence of conduct disorders with attention deficit hyperactivity disorder (ADHD) is particularly prevalent and in some groups more than 40% of children and young people with a diagnosis of conduct disorder also have a diagnosis of ADHD. Conduct disorders in childhood are also associated with a significantly increased rate of mental health problems in adult life, including antisocial personality disorder – up to 50% of children and young people with a conduct disorder go on to develop antisocial personality disorder. The prevalence of conduct disorders in the UK varies across ethnic groups; for example, their prevalence is lower than average in children and young people of south Asian family origin and higher than average in children and young people of African-Caribbean family origin.\n\nA diagnosis of a conduct disorder is strongly associated with poor educational performance, social isolation and, in adolescence, substance misuse and increased contact with the criminal justice system. This association continues into adult life with poorer educational and occupational outcomes, involvement with the criminal justice system (as high as 50% in some groups) and a high level of mental health problems (at some point in their lives 90% of people with antisocial personality disorder will have another mental health problem).\n\nConduct disorders are the most common reason for referral of young children to child and adolescent mental health services (CAMHS). Children with conduct disorders also comprise a considerable proportion of the work of the health and social care system. For example, 30% of a typical GP's child consultations are for behavioural problems, 45% of community child health referrals are for behaviour disturbances and psychiatric disorders are a factor in 28% of all paediatric outpatient referrals. In addition, social care services have significant involvement with children and young people with conduct disorders, with more vulnerable or disturbed children often being placed with a foster family or, less commonly, in residential care. The demands on the educational system are also considerable and include the provision of special-needs education. The criminal justice system also has significant involvement with older children with conduct disorders.\n\nMultiple agencies may be involved in the care and treatment of children with conduct disorders, which presents a major challenge for services in the effective coordination of care across agencies.\n\nSeveral interventions have been developed for children with conduct disorder and related problems, such as parenting programmes typically focused on younger children and multisystemic approaches usually focused on older children. Other interventions focused on prevention, such as the Nurse Family Partnership (known as the Family Nurse Partnership in the UK), have recently been implemented in the UK and are currently being evaluated. Three themes are common to these interventions: a strong focus on working with parents and families, recognition of the importance of the wider social system in enabling effective interventions and a focus on preventing or reducing the escalation of existing problems.\n\nUptake of these interventions and the outcomes achieved vary across England and Wales. Parenting programmes are the best established; implementation of multisystemic approaches and early intervention programmes is more variable. In addition to the programmes developed specifically for children with a conduct disorder, a number of children (and their parents or carers) are treated by both specialist CAMHS teams and general community-based services such as Sure Start.\n\nIdentifying which interventions and agencies are the most appropriate is challenging, especially for non-specialist health, social care and educational services. Further challenges arise when considering the use of preventive and early intervention programmes and identifying which vulnerable groups stand to gain from such interventions. Factors that may be associated with a higher risk of developing conduct disorders include parental factors such as harsh and inconsistent parenting style and parental mental health problems (for example depression, antisocial personality disorder and substance misuse), environmental factors such as poverty and being looked after, and individual factors such as low educational attainment and the presence of other mental health problems.\n\nThe guideline covers a range of interventions including treatment, indicated prevention and selective prevention (but not universal prevention), adapting definitions developed by the Institute of Medicine. For a description of the criteria used to determine whether an intervention was judged to be selective or indicated prevention see chapter 5 of the full guideline. (In this guideline selective prevention refers to interventions targeted to individuals or to a subgroup of the population whose risk of developing a conduct disorder is significantly higher than average, as evidenced by individual, family and social risk factors. Individual risk factors include low school achievement and impulsiveness; family risk factors include parental contact with the criminal justice system and child abuse; social risk factors include low family income and little education.)\n\nSome recommendations in this guideline have been adapted from recommendations in other NICE clinical guidance. In these cases the Guideline Development Group was careful to preserve the meaning and intent of the original recommendations. Changes to wording or structure were made to fit the recommendations into this guideline. The original sources of the adapted recommendations are shown in footnotes.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nAll recommendations relate to children and young people aged under 18\xa0years unless otherwise specified.\n\n# General principles of care\n\nSee also NICE's guideline on babies, children and young people's experience of healthcare.\n\n## Working safely and effectively with children and young people\n\nHealth and social care professionals working with children and young people who present with behaviour suggestive of a conduct disorder, or who have a conduct disorder, should be trained and competent to work with children and young people of all levels of learning ability, cognitive capacity, emotional maturity and development.\n\nHealth and social care professionals should ensure that they:\n\ncan assess capacity and competence, including 'Gillick competence', in children and young people of all ages and\n\nunderstand how to apply legislation, including the Children Act (1989), the Mental Health Act (1983; amended 1995 and 2007) and the Mental Capacity Act (2005), in the care and treatment of children and young people.\n\nHealth and social care providers should ensure that children and young people:\n\ncan routinely receive care and treatment from a single team or professional\n\nare not passed from one team to another unnecessarily\n\ndo not undergo multiple assessments unnecessarily.\n\nWhen providing assessment or treatment interventions for children and young people, ensure that the nature and content of the intervention is suitable for the child or young person's developmental level.\n\nConsider children and young people for assessment according to local safeguarding procedures if there are concerns regarding exploitation or self-care, or if they have been in contact with the criminal justice system.\n\n## Establishing relationships with children and young people and their parents or carers\n\nBe aware that many children and young people with a conduct disorder may have had poor or punitive experiences of care and be mistrustful or dismissive of offers of help as a result.\n\nDevelop a positive, caring and trusting relationship with the child or young person and their parents or carers to encourage their engagement with services.\n\nHealth and social care professionals working with children and young people should be trained and skilled in:\n\nnegotiating and working with parents and carers and\n\nmanaging issues relating to information sharing and confidentiality as these apply to children and young people.\n\nIf a young person is 'Gillick competent' ask them what information can be shared before discussing their condition with their parents or carers.\n\nWhen working with children and young people with a conduct disorder and their parents or carers:\n\nmake sure that discussions take place in settings in which confidentiality, privacy and dignity are respected\n\nbe clear with the child or young person and their parents or carers about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others).\n\nWhen coordinating care and discussing treatment decisions with children and young people and their parents or carers, ensure that:\n\neveryone involved understands the purpose of any meetings and why information might need to be shared between services and\n\nthe right to confidentiality is respected throughout the process.\n\n## Working with parents and carers\n\nIf parents or carers are involved in the treatment of young people with a conduct disorder, discuss with young people of an appropriate developmental level, emotional maturity and cognitive capacity how they want them to be involved. Such discussions should take place at intervals to take account of any changes in circumstances, including developmental level, and should not happen only once.\n\nBe aware that parents and carers of children and young people with a conduct disorder might feel blamed for their child's problems or stigmatised by their contact with services. When offering or providing interventions such as parent training programmes, directly address any concerns they have and set out the reasons for and purpose of the intervention.\n\nOffer parents and carers an assessment of their own needs including:\n\npersonal, social and emotional support and\n\nsupport in their caring role, including emergency plans and\n\nadvice on practical matters such as childcare, housing and finances, and help to obtain support.\n\n## Communication and information\n\nWhen communicating with children and young people with a conduct disorder and their parents or carers:\n\ntake into account the child or young person's developmental level, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems, or delays in language development or social communication difficulties\n\nuse plain language if possible and clearly explain any clinical language; adjust strategies to the person's language ability, for example, breaking up information, checking back, summarising and recapping\n\ncheck that the child or young person and their parents or carers understand what is being said\n\nuse communication aids (such as pictures, symbols, large print, braille, different languages or sign language) if needed.\n\nWhen giving information to children and young people with a conduct disorder and their parents or carers, ensure you are:\n\nfamiliar with local and national sources (organisations and websites) of information and/or support for children and young people with a conduct disorder and their parents or carers\n\nable to discuss and advise how to access these resources\n\nable to discuss and actively support children and young people and their parents or carers to engage with these resources.\n\nWhen communicating with a child or young person use diverse media, including letters, phone calls, emails or text messages, according to their preference.\n\n## Culture, ethnicity and social inclusion\n\nWhen working with children and young people with a conduct disorder and their parents or carers:\n\ntake into account that stigma and discrimination are often associated with using mental health services\n\nbe respectful of and sensitive to children and young people's gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability\n\nbe aware of possible variations in the presentation of mental health problems in children and young people of different genders, ages, cultural, ethnic, religious or other diverse backgrounds.\n\nWhen working with children and young people and their parents or carers who have difficulties speaking or reading English:\n\nprovide and work proficiently with interpreters if needed\n\noffer a list of local education providers who can provide English language teaching.\n\nHealth and social care professionals working with children and young people with a conduct disorder and their parents or carers should have competence in:\n\nassessment skills and using explanatory models of conduct disorder for people from different cultural, ethnic, religious or other diverse backgrounds\n\nexplaining the possible causes of different mental health problems, and care, treatment and support options\n\naddressing cultural, ethnic, religious or other differences in treatment expectations and adherence\n\naddressing cultural, ethnic, religious or other beliefs about biological, social and familial influences on the possible causes of mental health problems\n\nconflict management and conflict resolution.\n\n## Staff supervision\n\nHealth and social care services should ensure that staff supervision is built into the routine working of the service, is properly resourced within local systems and is monitored. Supervision should:\n\nmake use of direct observation (for example, recordings of sessions) and routine outcome measures\n\nsupport adherence to the specific intervention\n\nfocus on outcomes\n\nbe regular and apply to the whole caseload.\n\n## Transfer and discharge\n\nAnticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in children and young people with a conduct disorder and their parents or carers. Ensure that:\n\nsuch changes, especially discharge and transfer from CAMHS to adult services, are discussed and planned carefully beforehand with the child or young person and their parents or carers, and are structured and phased\n\nchildren and young people and their parents or carers are given comprehensive information about the way adult services work and the nature of any potential interventions provided\n\nany care plan supports effective collaboration with social care and other care providers during endings and transitions, and includes details of how to access services in times of crisis\n\nwhen referring a child or young person for an assessment in other services (including for psychological interventions), they are supported during the referral period and arrangements for support are agreed beforehand with them.\n\nFor young people who continue to exhibit antisocial behaviour or meet criteria for a conduct disorder while in transition to adult services (in particular those who are still vulnerable, such as those who have been looked after or who have limited access to care) refer to NICE's guideline on antisocial personality disorder. For those who have other mental health problems refer to other NICE guidance for the specific mental health problem.\n\n# Selective prevention\n\nIn this guideline selective prevention refers to interventions targeted to individuals or to a subgroup of the population whose risk of developing a conduct disorder is significantly higher than average, as evidenced by individual, family and social risk factors. Individual risk factors include low school achievement and impulsiveness; family risk factors include parental contact with the criminal justice system and child abuse; social risk factors include low family income and little education.\n\nOffer classroom-based emotional learning and problem-solving programmes for children aged typically between 3 and 7\xa0years in schools where classroom populations have a high proportion of children identified to be at risk of developing oppositional defiant disorder or conduct disorder as a result of any of the following factors:\n\nlow socioeconomic status\n\nlow school achievement\n\nchild abuse or parental conflict\n\nseparated or divorced parents\n\nparental mental health or substance misuse problems\n\nparental contact with the criminal justice system.\n\nClassroom-based emotional learning and problem-solving programmes should be provided in a positive atmosphere and consist of interventions intended to:\n\nincrease children's awareness of their own and others' emotions\n\nteach self-control of arousal and behaviour\n\npromote a positive self-concept and good peer relations\n\ndevelop children's problem-solving skills. Typically the programmes should consist of up to 30\xa0classroom-based sessions over the course of 1\xa0school year.\n\n# Identification and assessment\n\n## Initial assessment of children and young people with a possible conduct disorder\n\nAdjust delivery of initial assessment methods to:\n\nthe needs of children and young people with a suspected conduct disorder and\n\nthe setting in which they are delivered (for example, health and social care, educational settings or the criminal justice system).\n\nUndertake an initial assessment for a suspected conduct disorder if a child or young person's parents or carers, health or social care professionals, school or college, or peer group raise concerns about persistent antisocial behaviour.\n\nDo not regard a history of a neurodevelopmental condition (for example, attention deficit hyperactivity disorder [ADHD]) as a barrier to assessment.\n\nFor the initial assessment of a child or young person with a suspected conduct disorder, consider using the Strengths and Difficulties Questionnaire (completed by a parent, carer or teacher).\n\nAssess for the presence of the following significant complicating factors:\n\na coexisting mental health problem (for example, depression, post-traumatic stress disorder)\n\na neurodevelopmental condition (in particular ADHD and autism)\n\na learning disability or difficulty\n\nsubstance misuse in young people.\n\nIf any significant complicating factors are present refer the child or young person to a specialist CAMHS for a comprehensive assessment.\n\nIf no significant complicating factors are present consider direct referral for an intervention.\n\n## Comprehensive assessment\n\nA comprehensive assessment of a child or young person with a suspected conduct disorder should be undertaken by a health or social care professional who is competent to undertake the assessment and should:\n\noffer the child or young person the opportunity to meet the professional on their own\n\ninvolve a parent, carer or other third party known to the child or young person who can provide information about current and past behaviour\n\nif necessary involve more than 1\xa0health or social care professional to ensure a comprehensive assessment is undertaken.\n\nBefore starting a comprehensive assessment, explain to the child or young person how the outcome of the assessment will be communicated to them. Involve a parent, carer or advocate to help explain the outcome.\n\nThe standard components of a comprehensive assessment of conduct disorders should include asking about and assessing the following:\n\ncore conduct disorders symptoms including:\n\n\n\npatterns of negativistic, hostile, or defiant behaviour in children aged under 11\xa0years\n\naggression to people and animals, destruction of property, deceitfulness or theft and serious violations of rules in children aged over 11\xa0years\n\n\n\ncurrent functioning at home, at school or college and with peers\n\nparenting quality\n\nhistory of any past or current mental or physical health problems.\n\nTake into account and address possible coexisting conditions such as:\n\nlearning difficulties or disabilities\n\nneurodevelopmental conditions such as ADHD and autism\n\nneurological disorders including epilepsy and motor impairments\n\nother mental health problems (for example, depression, post-traumatic stress disorder and bipolar disorder)\n\nsubstance misuse\n\ncommunication disorders (for example, speech and language problems).\n\nConsider using formal assessment instruments to aid the diagnosis of coexisting conditions, such as:\n\nthe Child Behavior Checklist for all children and young people\n\nthe Strengths and Difficulties Questionnaire for all children or young people\n\nthe Connors Rating Scales – Revised for a child or young person with suspected ADHD\n\na validated measure of autistic behaviour for a child or young person with a suspected autism spectrum disorder (see NICE's guideline on autism diagnosis in children and young people)\n\na validated measure of cognitive ability for a child or young person with a suspected learning disability\n\na validated reading test for a child or young person with a suspected reading difficulty.\n\nAssess the risks faced by the child or young person and if needed develop a risk management plan for self-neglect, exploitation by others, self-harm or harm to others.\n\nAssess for the presence or risk of physical, sexual and emotional abuse in line with local protocols for the assessment and management of these problems.\n\nConduct a comprehensive assessment of the child or young person's parents or carers, which should cover:\n\npositive and negative aspects of parenting, in particular any use of coercive discipline\n\nthe parent–child relationship\n\npositive and negative adult relationships within the child or young person's family, including domestic violence\n\nparental wellbeing, encompassing mental health, substance misuse (including whether alcohol or drugs were used during pregnancy) and criminal behaviour.\n\nDevelop a care plan with the child or young person and their parents or carers that includes a profile of their needs, risks to self or others, and any further assessments that may be needed. This should encompass the development and maintenance of the conduct disorder and any associated behavioural problems, any coexisting mental or physical health problems and speech, language and communication difficulties, in the context of:\n\nany personal, social, occupational, housing or educational needs\n\nthe needs of parents or carers\n\nthe strengths of the child or young person and their parents or carers.\n\n# Identifying effective treatment and care options\n\nWhen discussing treatment or care interventions with a child or young person with a conduct disorder and, if appropriate, their parents or carers, take account of:\n\ntheir past and current experience of the disorder\n\ntheir experience of, and response to, previous interventions and services\n\nthe nature, severity and duration of the problems\n\nthe impact of the disorder on educational performance\n\nany chronic physical health problem\n\nany social or family factors that may have a role in the development or maintenance of the identified problems\n\nany coexisting conditions.\n\nWhen discussing treatment or care interventions with a child or young person and, if appropriate, their parents or carers, provide information about:\n\nthe nature, content and duration of any proposed intervention\n\nthe acceptability and tolerability of any proposed intervention\n\nthe possible impact on interventions for any other behavioural or mental health problem\n\nthe implications for the continuing provision of any current interventions.\n\nWhen making a referral for treatment or care interventions for a conduct disorder, take account of the preferences of the child or young person and, if appropriate, their parents or carers when choosing from a range of evidence-based interventions.\n\n# Psychosocial interventions – treatment and indicated prevention\n\nIn this guideline indicated prevention refers to interventions targeted to high-risk individuals who are identified as having detectable signs or symptoms that may lead to the development of conduct disorders but who do not meet diagnostic criteria for conduct disorders when offered an intervention.\n\nThe interventions in recommendations 1.5.1 to 1.5.12 are suitable for children and young people who have a diagnosis of oppositional defiant disorder or conduct disorder, are in contact with the criminal justice system for antisocial behaviour, or have been identified as being at high risk of a conduct disorder using established rating scales of antisocial behaviour (for example, the Child Behavior Checklist and the Eyberg Child Behavior Inventory).\n\n## Parent training programmes\n\nOffer a group parent training programme to the parents of children and young people aged between 3 and 11\xa0years who:\n\nhave been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or\n\nhave oppositional defiant disorder or conduct disorder or\n\nare in contact with the criminal justice system because of antisocial behaviour.\n\nGroup parent training programmes should involve both parents if this is possible and in the best interests of the child or young person, and should:\n\ntypically have between 10 and 12\xa0parents in a group\n\nbe based on a social learning model, using modelling, rehearsal and feedback to improve parenting skills\n\ntypically consist of 10 to 16\xa0meetings of 90 to 120\xa0minutes' duration\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\nOffer an individual parent training programme to the parents of children and young people aged between 3 and 11\xa0years who are not able to participate in a group parent training programme and whose child:\n\nhas been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or\n\nhas oppositional defiant disorder or conduct disorder or\n\nis in contact with the criminal justice system because of antisocial behaviour.\n\nIndividual parent training programmes should involve both parents if this is possible and in the best interests of the child or young person, and should:\n\nbe based on a social learning model using modelling, rehearsal and feedback to improve parenting skills\n\ntypically consist of 8 to 10\xa0meetings of 60 to 90\xa0minutes' duration\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\n## Parent and child training programmes for children with complex needs\n\nOffer individual parent and child training programmes to children and young people aged between 3 and 11\xa0years if their problems are severe and complex and they:\n\nhave been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or\n\nhave oppositional defiant disorder or conduct disorder or\n\nare in contact with the criminal justice system because of antisocial behaviour.\n\nIndividual parent and child training programmes should involve both parents, foster carers or guardians if this is possible and in the best interests of the child or young person, and should:\n\nbe based on a social learning model using modelling, rehearsal and feedback to improve parenting skills\n\nconsist of up to 10\xa0meetings of 60\xa0minutes' duration\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\n## Foster carer/guardian training programmes\n\nOffer a group foster carer/guardian training programme to foster carers and guardians of children and young people aged between 3 and 11\xa0years who:\n\nhave been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or\n\nhave oppositional defiant disorder or conduct disorder or\n\nare in contact with the criminal justice system because of antisocial behaviour.\n\nGroup foster carer or guardian training programmes should involve both of the foster carers or guardians if this is possible and in the best interests of the child or young person, and should:\n\nmodify the intervention to take account of the care setting in which the child is living\n\ntypically have between 8 and 12\xa0foster carers or guardians in a group\n\nbe based on a social learning model using modelling, rehearsal and feedback to improve parenting skills\n\ntypically consist of between 12 and 16 meetings of 90 to 120\xa0minutes' duration\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\nOffer an individual foster carer/guardian training programme to the foster carers or guardians of children and young people aged between 3 and 11\xa0years who are not able to participate in a group programme and whose child:\n\nhas been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or\n\nhas oppositional defiant disorder or conduct disorder or\n\nis in contact with the criminal justice system because of antisocial behaviour.\n\nIndividual foster carer/guardian training programmes should involve both of the foster carers if this is possible and in the best interests of the child or young person, and should:\n\nmodify the intervention to take account of the care setting in which the child is living\n\nbe based on a social learning model using modelling, rehearsal and feedback to improve parenting skills\n\nconsist of up to 10\xa0meetings of 60\xa0minutes' duration\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\n## Child-focused programmes\n\nOffer group social and cognitive problem-solving programmes to children and young people aged between 9 and 14\xa0years who:\n\nhave been identified as being at high risk of developing oppositional defiant disorder or conduct disorder or\n\nhave oppositional defiant disorder or conduct disorder or\n\nare in contact with the criminal justice system because of antisocial behaviour.\n\nGroup social and cognitive problem-solving programmes should be adapted to the children's or young people's developmental level and should:\n\nbe based on a cognitive–behavioural problem-solving model\n\nuse modelling, rehearsal and feedback to improve skills\n\ntypically consist of 10 to 18\xa0weekly meetings of 2\xa0hours' duration\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\n## Multimodal interventions\n\nOffer multimodal interventions, for example, multisystemic therapy, to children and young people aged between 11 and 17\xa0years for the treatment of conduct disorder.\n\nMultimodal interventions should involve the child or young person and their parents and carers and should:\n\nhave an explicit and supportive family focus\n\nbe based on a social learning model with interventions provided at individual, family, school, criminal justice and community levels\n\nbe provided by specially trained case managers\n\ntypically consist of 3 to 4\xa0meetings per week over a 3- to 5‑month period\n\nadhere to a developer's manual and employ all of the necessary materials to ensure consistent implementation of the programme (the manual should have been positively evaluated in a randomised controlled trial).\n\n# Pharmacological interventions\n\nDo not offer pharmacological interventions for the routine management of behavioural problems in children and young people with oppositional defiant disorder or conduct disorder.\n\nOffer methylphenidate or atomoxetine, within their licensed indications, for the management of ADHD in children and young people with oppositional defiant disorder or conduct disorder, in line with NICE's guideline on attention deficit hyperactivity disorder.\n\nConsider risperidone for the short-term management of severely aggressive behaviour in young people with a conduct disorder who have problems with explosive anger and severe emotional dysregulation and who have not responded to psychosocial interventions.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines.\n\nProvide young people and their parents or carers with age-appropriate information and discuss the likely benefits and possible side effects of risperidone including:\n\nmetabolic (including weight gain and diabetes)\n\nextrapyramidal (including akathisia, dyskinesia and dystonia)\n\ncardiovascular (including prolonging the QT interval)\n\nhormonal (including increasing plasma prolactin)\n\nother (including unpleasant subjective experiences).In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines.\n\nRisperidone should be started by an appropriately qualified healthcare professional with expertise in conduct disorders and should be based on a comprehensive assessment and diagnosis. The healthcare professional should undertake and record the following baseline investigations:\n\nweight and height (both plotted on a growth chart)\n\nwaist and hip measurements\n\npulse and blood pressure\n\nfasting blood glucose or glycosylated haemoglobin (HbA1c)\n\nblood lipid and prolactin levels\n\nassessment of any movement disorders\n\nassessment of nutritional status, diet and level of physical activity.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines.\n\nTreatment with risperidone should be carefully evaluated, and include the following:\n\nRecord the indications and expected benefits and risks, and the expected time for a change in symptoms and appearance of side effects.\n\nAt the start of treatment give a dose at the lower end of the licensed range and slowly titrate upwards within the dose range given in the British national formulary for children (BNFC) or the summary of product characteristics (SPC).\n\nJustify and record reasons for dosages above the range given in the BNFC or SPC.\n\nMonitor and record systematically throughout treatment, but especially during titration:\n\n\n\nefficacy, including changes in symptoms and behaviour\n\nthe emergence of movement disorders\n\nweight and height (weekly)\n\nfasting blood glucose or HbA1c\n\nblood lipid and prolactin levels\n\nadherence to medication\n\nphysical health, including warning parents or carers and the young person about symptoms and signs of neuroleptic malignant syndrome.\n\n\n\nRecord the rationale for continuing or stopping treatment and the effects of these decisions.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines.\n\nReview the effects of risperidone after 3 to 4\xa0weeks and discontinue it if there is no indication of a clinically important response at 6\xa0weeks.In March 2013, this was an off-label use of some preparations of risperidone in young people, and of all preparations of risperidone in children under 5. See NICE's information on prescribing medicines.\n\n# Organisation and delivery of care\n\n## Improving access to services\n\nHealth and social care professionals, managers and commissioners should collaborate with colleagues in educational settings to develop local care pathways that promote access to services for children and young people with a conduct disorder and their parents and carers by:\n\nsupporting the integrated delivery of services across all care settings\n\nhaving clear and explicit criteria for entry to the service\n\nfocusing on entry and not exclusion criteria\n\nhaving multiple means (including self-referral) of access to the service\n\nproviding multiple points of access that facilitate links with the wider care system, including educational and social care services and the community in which the service is located.\n\nProvide information about the services and interventions that constitute the local care pathway, including the:\n\nrange and nature of the interventions provided\n\nsettings in which services are delivered\n\nprocesses by which a child or young person moves through the pathway\n\nmeans by which progress and outcomes are assessed\n\ndelivery of care in related health and social care services.\n\nWhen providing information about local care pathways for children and young people with a conduct disorder and their parents and carers:\n\ntake into account the person's knowledge and understanding of conduct disorders and their care and treatment\n\nensure that such information is appropriate to the communities using the pathway.\n\nProvide all information about services in a range of languages and formats (visual, verbal and aural) and ensure that it is available in a range of settings throughout the whole community to which the service is responsible.\n\nHealth and social care professionals, managers and commissioners should collaborate with colleagues in educational settings to develop local care pathways that promote access for a range of groups at risk of under-utilising services, including:\n\ngirls and young women\n\nblack and minority ethnic groups\n\npeople with a coexisting condition (such as ADHD or autism).\n\nSupport access to services and increase the uptake of interventions by:\n\nensuring systems are in place to provide for the overall coordination and continuity of care\n\ndesignating a professional to oversee the whole period of care (for example, a staff member in a CAMHS or social care setting).\n\nSupport access to services and increase the uptake of interventions by providing services for children and young people with a conduct disorder and their parents and carers, in a variety of settings. Use an assessment of local needs as a basis for the structure and distribution of services, which should typically include delivery of:\n\nassessment and interventions outside normal working hours\n\nassessment and interventions in the person's home or other residential settings\n\nspecialist assessment and interventions in accessible community-based settings (for example, community centres, schools and colleges and social centres) and if appropriate, in conjunction with staff from those settings\n\nboth generalist and specialist assessment and intervention services in primary care settings.\n\nHealth and social care professionals, managers and commissioners should collaborate with colleagues in educational settings to look at a range of services to support access to and uptake of services. These could include:\n\ncrèche facilities\n\nassistance with travel\n\nadvocacy services.\n\n## Developing local care pathways\n\nLocal care pathways should be developed to promote implementation of key principles of good care. Pathways should be:\n\nnegotiable, workable and understandable for children and young people with a conduct disorder and their parents and carers as well as professionals\n\naccessible and acceptable to all people in need of the services served by the pathway\n\nresponsive to the needs of children and young people with a conduct disorder and their parents and carers\n\nintegrated so that there are no barriers to movement between different levels of the pathway\n\nfocused on outcomes (including measures of quality, service user experience and harm).\n\nResponsibility for the development, management and evaluation of local care pathways should lie with a designated leadership team, which should include health and social care professionals, managers and commissioners. The leadership team should work in collaboration with colleagues in educational settings and take particular responsibility for:\n\ndeveloping clear policy and protocols for the operation of the pathway\n\nproviding training and support on the operation of the pathway\n\nauditing and reviewing the performance of the pathway.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that promote a model of service delivery that:\n\nhas clear and explicit criteria for the thresholds determining access to and movement between the different levels of the pathway\n\ndoes not use single criteria such as symptom severity or functional impairment to determine movement within the pathway\n\nmonitors progress and outcomes to ensure the most effective interventions are delivered.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that promote a range of evidence-based interventions in the pathway and support children and young people with a conduct disorder and their parents and carers in their choice of interventions.\n\nAll staff should ensure effective engagement with parents and carers, if appropriate, to:\n\ninform and improve the care of the child or young person with a conduct disorder\n\nmeet the needs of parents and carers.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that promote the active engagement of all populations served by the pathway. Pathways should:\n\noffer prompt assessments and interventions that are appropriately adapted to the cultural, gender, age and communication needs of children and young people with a conduct disorder and their parents and carers\n\nkeep to a minimum the number of assessments needed to access interventions.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that respond promptly and effectively to the changing needs of all populations served by the pathways. Pathways should have in place:\n\nclear and agreed goals for the services offered to children and young people with a conduct disorder and their parents and carers\n\nrobust and effective means for measuring and evaluating the outcomes associated with the agreed goals\n\nclear and agreed mechanisms for responding promptly to changes in individual needs.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that provide an integrated programme of care across all care settings. Pathways should:\n\nminimise the need for transition between different services or providers\n\nallow services to be built around the pathway and not the pathway around the services\n\nestablish clear links (including access and entry points) to other care pathways (including those for physical healthcare needs)\n\nhave designated staff who are responsible for the coordination of people's engagement with the pathway.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to ensure effective communication about the functioning of the local care pathway. There should be protocols for:\n\nsharing information with children and young people with a conduct disorder, and their parents and carers, about their care\n\nsharing and communicating information about the care of children and young people with other professionals (including GPs)\n\ncommunicating information between the services provided within the pathway\n\ncommunicating information to services outside the pathway.\n\nHealth and social care professionals, managers and commissioners should work with colleagues in educational settings to design local care pathways that have robust systems for outcome measurement in place, which should be used to inform all involved in a pathway about its effectiveness. This should include providing:\n\nindividual routine outcome measurement systems\n\neffective electronic systems for the routine reporting and aggregation of outcome measures\n\neffective systems for the audit and review of the overall clinical and cost effectiveness of the pathway.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# Parent training programmes for children aged 12\xa0years and over with a conduct disorder\n\nWhat is the effectiveness of parent training programmes for conduct disorders in children and young people aged 12\xa0years and over?\n\n## Why this is important\n\nThe evidence for parent training programmes is well established for children with conduct disorders aged 11\xa0years and younger, with well-developed models for the delivery of care. In contrast there is little evidence for these programmes in older children despite the recognition that parenting problems continue to play a part in the development and maintenance of conduct disorders.\n\nThis question should be answered using a randomised controlled trial (RCT) design reporting short- and medium-term outcomes, including cost effectiveness, over at least 18\xa0months. Attention should be paid to the adaptation of parent training programmes to older children, and to training and supervision of staff delivering the programmes to ensure robust and generalisable results. The outcomes and acceptability of the intervention should be rated by parents, teachers and independent observers. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators of response should also be investigated."}	https://www.nice.org.uk/guidance/cg158	This guideline covers recognising and managing antisocial behaviour and conduct disorders in children and young people aged under 19. It aims to improve care by identifying children and young people who are at risk and when interventions can prevent conduct disorders from developing. The guideline also makes recommendations on communication, to help professionals build relationships with children and young people and involve them in their own care.
1571c43a97e95e06f4fa62199b8d15099049541a	nice	Alcohol-use disorders: diagnosis and management of physical complications	Alcohol-use disorders: diagnosis and management of physical complications This guideline covers care for adults and young people (aged 10 years and older) with physical health problems that are completely or partly caused by an alcohol-use disorder. It aims to improve the health of people with alcohol-use disorders by providing recommendations on managing acute alcohol withdrawal and treating alcohol-related conditions. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Acute alcohol withdrawal ## Admission to hospital For people in acute alcohol withdrawal with, or who are assessed to be at high risk of developing, alcohol withdrawal seizures or delirium tremens, offer admission to hospital for medically assisted alcohol withdrawal. For young people under 16 years who are in acute alcohol withdrawal, offer admission to hospital for physical and psychosocial assessment, in addition to medically assisted alcohol withdrawal. For certain vulnerable people who are in acute alcohol withdrawal (for example, those who are frail, have cognitive impairment or multiple comorbidities, lack social support, have learning difficulties or are 16 or 17 years), consider a lower threshold for admission to hospital for medically assisted alcohol withdrawal. For people who are alcohol dependent but not admitted to hospital, offer advice to avoid a sudden reduction in alcohol intake and information about how to contact local alcohol support services. Note that a sudden reduction in alcohol intake can result in severe withdrawal in dependent drinkers. ## Assessment and monitoring Healthcare professionals who care for people in acute alcohol withdrawal should be skilled in the assessment and monitoring of withdrawal symptoms and signs. Follow locally specified protocols to assess and monitor patients in acute alcohol withdrawal. Consider using a tool (such as the Clinical Institute Withdrawal Assessment – Alcohol, revised scale) as an adjunct to clinical judgement. People in acute alcohol withdrawal should be assessed immediately on admission to hospital by a healthcare professional skilled in the management of alcohol withdrawal. ## Treatment for acute alcohol withdrawal Offer pharmacotherapy to treat the symptoms of acute alcohol withdrawal as follows: Consider offering a benzodiazepine or carbamazepine. Follow the MHRA safety advice on antiepileptic drugs in pregnancy. Clomethiazole may be offered as an alternative to a benzodiazepine or carbamazepine. However, it should be used with caution, in inpatient settings only and according to the summary of product characteristics.In April 2017, this was an off-label use of some benzodiazepines (alprazolam, clobazam and lorazepam) and carbamazepine. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for cautions in specific populations for all medicines for acute alcohol withdrawal. People with decompensated liver disease who are being treated for acute alcohol withdrawal should be offered advice from a healthcare professional experienced in the management of patients with liver disease. Offer information about how to contact local alcohol support services to people who are being treated for acute alcohol withdrawal. Follow a symptom-triggered regimen for drug treatment for people in acute alcohol withdrawal who are: in hospital or in other settings where 24‑hour assessment and monitoring are available. ## Management of delirium tremens In people with delirium tremens, offer oral lorazepam as first-line treatment. If symptoms persist or oral medication is declined, offer parenteral lorazepam or haloperidol.In April 2017, this was an off-label use of lorazepam and haloperidol. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for cautions in specific populations. If delirium tremens develops in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen. ## Management of alcohol withdrawal seizures In people with alcohol withdrawal seizures, consider offering a quick-acting benzodiazepine (such as lorazepam) to reduce the likelihood of further seizures.In April 2017, this was an off-label use of lorazepam. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for cautions in specific populations. If alcohol withdrawal seizures develop in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen. Do not offer phenytoin to treat alcohol withdrawal seizures. # Wernicke's encephalopathy Offer thiamine to people at high risk of developing, or with suspected, Wernicke's encephalopathy. Thiamine should be given in doses toward the upper end of the 'British national formulary' range. It should be given orally or parenterally as described in recommendations 1.2.1.2 to 1.2.1.4. Offer prophylactic oral thiamine to harmful or dependent drinkers: if they are malnourished or at risk of malnourishment or if they have decompensated liver disease or if they are in acute withdrawal or before and during a planned medically assisted alcohol withdrawal. Offer prophylactic parenteral thiamine followed by oral thiamine to harmful or dependent drinkers: if they are malnourished or at risk of malnourishment or if they have decompensated liver diseaseand in addition they attend an emergency department or are admitted to hospital with an acute illness or injury. Offer parenteral thiamine to people with suspected Wernicke's encephalopathy. Maintain a high level of suspicion for the possibility of Wernicke's encephalopathy, particularly if the person is intoxicated. Parenteral treatment should be given for a minimum of 5 days, unless Wernicke's encephalopathy is excluded. Oral thiamine treatment should follow parenteral therapy. # Alcohol-related liver disease For information on diagnosing, monitoring and manging complications of cirrhosis, see NICE's guideline on cirrhosis in over 16s: assessment and management. ## Assessment and diagnosis of alcohol-related liver disease Exclude alternative causes of liver disease in people with a history of harmful or hazardous drinking who have abnormal liver blood test results. Refer people to a specialist experienced in the management of alcohol-related liver disease to confirm a clinical diagnosis of alcohol-related liver disease. Consider liver biopsy for the investigation of alcohol-related liver disease. When considering liver biopsy for the investigation of alcohol-related liver disease: take into account the small but definite risks of morbidity and mortality discuss the benefits and risks with the patient and ensure informed consent is obtained. In people with suspected acute alcohol-related hepatitis, consider a liver biopsy to confirm the diagnosis if the hepatitis is severe enough to require corticosteroid treatment. ## Referral for consideration of liver transplantation Refer patients with decompensated liver disease to be considered for assessment for liver transplantation if they: still have decompensated liver disease after best management and 3 months' abstinence from alcohol and are otherwise suitable candidates for liver transplantation. ## Corticosteroid treatment for alcohol-related hepatitis Offer corticosteroid treatment to people with severe alcohol-related hepatitis and a discriminant function of 32 or more, only after: effectively treating any active infection or gastrointestinal bleeding that may be present controlling any renal impairment discussing the potential benefits and risks with the person and their family members or carers (as appropriate), explaining that corticosteroid treatment: has been shown to improve survival in the short term (1 month) has not been shown to improve survival over a longer term (3 months to 1 year) has been shown to increase the risk of serious infections within the first 3 months of starting treatment.In April 2017, this was an off-label use of prednisolone. See NICE's information on prescribing medicines. ## Nutritional support for alcohol-related hepatitis Assess the nutritional requirements of people with acute alcohol-related hepatitis. Offer nutritional support if needed and consider using nasogastric tube feeding (see the NICE guideline on nutrition support for adults: oral nutrition support, enteral tube feeding and parenteral nutrition). # Alcohol-related pancreatitis ## Diagnosis of chronic alcohol-related pancreatitis To inform a diagnosis of chronic alcohol-related pancreatitis use a combination of: the person's symptoms an imaging modality to determine pancreatic structure and tests of pancreatic exocrine and endocrine function. Use computed tomography as the first-line imaging modality for the diagnosis of chronic alcohol‑related pancreatitis in people with a history and symptoms suggestive of chronic alcohol‑related pancreatitis. ## Treatment options for painful chronic alcohol-related pancreatitis Refer people with pain from chronic alcohol-related pancreatitis to a specialist centre for multidisciplinary assessment. Consider surgery (open or minimally invasive) as first-line treatment in adults with painful chronic pancreatitis that is causing obstruction of the main pancreatic duct. Offer coeliac axis block, splanchnicectomy or surgery to people with poorly controlled pain from small-duct (non-obstructive) chronic alcohol-related pancreatitis. ## Prophylactic antibiotics for acute alcohol-related pancreatitis Do not offer prophylactic antimicrobials to people with acute pancreatitis. ## Nutritional support for acute alcohol-related pancreatitis Ensure that people with acute pancreatitis are not made 'nil‑by‑mouth' and do not have food withheld unless there is a clear reason for this (for example, vomiting). Offer enteral nutrition to anyone with severe or moderately severe acute pancreatitis. Start within 72 hours of presentation and aim to meet their nutritional requirements as soon as possible. Offer anyone with severe or moderately severe acute pancreatitis parenteral nutrition only if enteral nutrition has failed or is contraindicated. ## Enzyme supplementation for chronic alcohol-related pancreatitis Offer pancreatic enzyme supplements to people with chronic alcohol-related pancreatitis who have symptoms of steatorrhoea or poor nutritional status due to exocrine pancreatic insufficiency. Do not prescribe pancreatic enzyme supplements to people with chronic alcohol-related pancreatitis if pain is their only symptom. # Terms used in this guideline ## Acute alcohol withdrawal The physical and psychological symptoms that people can experience when they suddenly reduce the amount of alcohol they drink if they have previously been drinking excessively for prolonged periods of time. ## Alcohol dependence A cluster of behavioural, cognitive and physiological factors that typically include a strong desire to drink alcohol and difficulties in controlling its use. Someone who is alcohol-dependent may persist in drinking, despite harmful consequences. They will also give alcohol a higher priority than other activities and obligations. For further information, please refer to: 'Diagnostic and statistical manual of mental disorders' (DSM‑IV) (American Psychiatric Association 2000) and 'International statistical classification of diseases and related health problems – 10th revision' (ICD‑10) (World Health Organization 2007). ## Alcohol-related hepatitis Alcoholic hepatitis. ## Coeliac axis block Pain relief by nerve block of the coeliac plexus. ## CIWA–Ar scale The Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA–Ar) scale is a validated 10‑item assessment tool that can be used to quantify the severity of the alcohol withdrawal syndrome, and to monitor and medicate patients throughout withdrawal. See Sullivan et al. (1989) Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA–Ar). British Journal of Addiction 84:1353-1357. ## Decompensated liver disease Liver disease complicated by jaundice, ascites, variceal bleeding or hepatic encephalopathy. ## Discriminant function Maddrey's discriminant function (DF) was described to predict prognosis in alcohol-related hepatitis and identify patients suitable for treatment with steroids. It is 4.6 × + bilirubin in mg/dl. To calculate the DF using bilirubin in micromol/l divide the bilirubin value by 17. ## Harmful drinking (high-risk drinking) A pattern of alcohol consumption that is causing mental or physical damage (ICD‑10, DSM‑V). Consumption (units per week): Drinking 35 units a week or more for women. Drinking 50 units a week or more for men. ## Hazardous drinking (increasing risk drinking) A pattern of alcohol consumption that increases someone's risk of harm. Some would limit this definition to the physical or mental health consequences (as in harmful use). Others would include the social consequences. The term is currently used by the World Health Organization to describe this pattern of alcohol consumption. It is not a diagnostic term. Consumption (units per week): Drinking more than 14 units a week, but less than 35 units a week for women. Drinking more than 14 units a week, but less than 50 units for men. ## Malnourishment A state of nutrition in which a deficiency of energy, protein and/or other nutrients causes measurable adverse effects on tissue/body form, composition, function or clinical outcome. ## Medically assisted alcohol withdrawal The deliberate withdrawal from alcohol by a dependent drinker under the supervision of medical staff. Prescribed medication may be needed to relieve the symptoms. It can be carried out at home, in the community or in a hospital or other inpatient facility. ## Splanchnicectomy Surgical division of the splanchnic nerves and coeliac ganglion. ## Symptom-triggered regimen Treatment tailored to the person's individual needs, which are determined by the severity of withdrawal signs and symptoms. The patient is regularly assessed and monitored, either using clinical experience and questioning alone or with the help of a designated questionnaire such as the CIWA–Ar. Drug treatment is provided if the patient needs it and treatment is withheld if there are no symptoms of withdrawal.# Context In the UK, it is estimated that 24% of adults drink in a hazardous or harmful way (NHS Digital Statistics on alcohol: England, 2009) For definitions of harmful and hazardous drinking see terms used in this guideline. Levels of self-reported hazardous and harmful drinking are lowest in the central and eastern regions of England (21 to 24% of men and 10 to 14% of women). They are highest in the North East, North West and Yorkshire and Humber (26 to 28% of men, 16 to 18% of women; North West Public Health Observatory, 2007). Hazardous and harmful drinking are commonly encountered among hospital attendees; approximately 20% of patients admitted to hospital for illnesses unrelated to alcohol are drinking at potentially hazardous levels (Royal College of Physicians (2001) Alcohol – can the NHS afford it?). Continued hazardous and harmful drinking can result in alcohol dependence. An abrupt reduction in alcohol intake in a person who has been drinking excessively for a prolonged period of time may result in the development of an alcohol withdrawal syndrome. In addition, persistent drinking at hazardous and harmful levels can result in damage to almost every organ or system of the body. This guideline covers key areas in the investigation and management of the following alcohol-related conditions in adults and young people (aged 10 years and older): acute alcohol withdrawal, including seizures and delirium tremens Wernicke's encephalopathy liver disease acute and chronic pancreatitis. It does not specifically look at women who are pregnant, children younger than 10 years, or people with physical or mental health conditions caused by alcohol use, other than those listed above. In the current update, we reviewed the evidence and updated the recommendation on corticosteroid treatment for people with severe alcoholic hepatitis.# Recommendations for research In 2010, the guideline committee made the following recommendations for research. The committee's full set of recommendations for research is detailed in the full guideline. # Admission to hospital for acute alcohol withdrawal What is the clinical and cost effectiveness of admitting people who attend hospital in mild or moderate acute alcohol withdrawal for unplanned medically assisted alcohol withdrawal compared with no admission and a planned medically assisted alcohol withdrawal with regard to the outcome of long-term abstinence? ## Why this is important People presenting at a hospital who are at risk of or have alcohol withdrawal seizures or delirium tremens need admission for medical management. People with milder withdrawal are not usually admitted, but given advice and provided with information regarding local outpatient alcohol addiction services. One of the concerns with this model is that the opportunity for intervention may be lost and that many of these people may never contact addiction services. Given that abstinence is the goal, it may be that admission for these people maximises the likelihood of achieving this goal. The concerns with admission are that it is costly, the patients may not be motivated and there has been no opportunity for psychological input prior to the medically assisted withdrawal from alcohol. The research should aim to compare the two models of treatment with regard to the primary goal of abstinence. Health economic analysis should aim to determine the cost effectiveness of each approach. # Dosing regimens for acute alcohol withdrawal What are the safety and efficacy of symptom-triggered, fixed-dosing and front‑loading regimens for the management of acute alcohol withdrawal? ## Why this is important Traditionally, acute alcohol withdrawal has been managed by administering medication, typically benzodiazepines, according to a predetermined tapered-dosing schedule over a specified number of days (with the option for additional doses for breakthrough symptoms). This is called fixed‑dosing. In contrast, medication can be administered in response to a person's individual signs and symptoms (symptom‑triggered) or by giving an initial 'loading' dose (front-loading) in conjunction with a symptom‑triggered or 'as required' regimen. The safety and efficacy of symptom-triggered or front-loading regimens in comparison to the 'traditional' fixed-dose regimen needs to be established in patients admitted to acute hospital settings who undergo unplanned acute alcohol withdrawal. Staff and patients' experiences in conjunction with objective measures of acute alcohol withdrawal need to be collected. # Drugs for the management of alcohol withdrawal What is the efficacy and cost effectiveness of clomethiazole compared with chlordiazepoxide or carbamazepine or benzodiazepines for the treatment of acute alcohol withdrawal with regard to the outcomes of withdrawal severity, risk of seizures, risk of delirium tremens, length of treatment and patient satisfaction? ## Why this is important Clomethiazole has powerful, short-acting, sedative, tranquilising and anticonvulsant properties which are mediated through an indirect effect on gamma-aminobutyric acid (GABA) receptors in the brain. It has fallen out of favour in many units for the management of acute alcohol withdrawal because of reports of dependence and concerns regarding over-sedation. These have been problems in the outpatient use of clomethiazole, but it has now been restricted to the inpatient setting, where clomethiazole may be of great value. There are limited studies comparing clomethiazole with other agents. As such, an appropriately powered study comparing clomethiazole to chlordiazepoxide or carbamazepine or benzodiazepines with regard to the outcomes described above would help to define the role of this potentially very useful drug. # Assessment and monitoring What is the clinical and cost effectiveness of interventions delivered in an acute hospital setting by an alcohol specialist nurse compared with those managed through acute hospital setting with no input from a specialist nurse? ## Why this is important Alcohol-related problems are an important public health problem in the UK. Many patients present to acute services and are managed according to local pharmacotherapeutic regimens. Coordination of the management of the acute withdrawal episode with the long-term management of the patient can be complex. Prevention of Wernicke's encephalopathy, assessment for liver and extra-hepatic disease, therapies targetting alcohol addiction and the long-term management of the patient's physical, mental and social wellbeing are all components of the care. It is considered that better management during the hospital admission may lead to better outcomes with regard to long-term abstinence and health. Studies investigating the impact of an alcohol specialist nurse on these outcomes are required. # Wernicke's encephalopathy What is the clinical and cost effectiveness of the use of parenteral versus oral thiamine in preventing the first onset of Wernicke's encephalopathy in people undergoing medically assisted alcohol withdrawal? ## Why this is important Wernicke's encephalopathy has a devastating effect on the sufferer and can occur when people are withdrawing from alcohol. It is thought to be caused by a lack of thiamine due to poor diet and/or absorption at a time of increased requirement for the vitamin (for cerebral functions in particular), although little is known about the mechanisms involved. There is some theoretical and trial evidence to suggest that parenteral replacement elevates blood levels more quickly than oral replacement, however it is not known if this is clinically significant, and there is no convincing clinical evidence to suggest which route and dose of thiamine is most effective at preventing Wernicke's encephalopathy. This is important as parenteral dosing uses additional resources, is unpleasant for the patient and has a very small risk of anaphylaxis. Having a placebo arm is probably not acceptable, given the risks of significant brain damage.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Acute alcohol withdrawal\n\n## Admission to hospital\n\nFor people in acute alcohol withdrawal with, or who are assessed to be at high risk of developing, alcohol withdrawal seizures or delirium tremens, offer admission to hospital for medically assisted alcohol withdrawal. \n\nFor young people under 16\xa0years who are in acute alcohol withdrawal, offer admission to hospital for physical and psychosocial assessment, in addition to medically assisted alcohol withdrawal. \n\nFor certain vulnerable people who are in acute alcohol withdrawal (for example, those who are frail, have cognitive impairment or multiple comorbidities, lack social support, have learning difficulties or are 16 or 17\xa0years), consider a lower threshold for admission to hospital for medically assisted alcohol withdrawal. \n\nFor people who are alcohol dependent but not admitted to hospital, offer advice to avoid a sudden reduction in alcohol intake and information about how to contact local alcohol support services. Note that a sudden reduction in alcohol intake can result in severe withdrawal in dependent drinkers. \n\n## Assessment and monitoring\n\nHealthcare professionals who care for people in acute alcohol withdrawal should be skilled in the assessment and monitoring of withdrawal symptoms and signs. \n\nFollow locally specified protocols to assess and monitor patients in acute alcohol withdrawal. Consider using a tool (such as the Clinical Institute Withdrawal Assessment – Alcohol, revised [CIWA–Ar] scale) as an adjunct to clinical judgement. \n\nPeople in acute alcohol withdrawal should be assessed immediately on admission to hospital by a healthcare professional skilled in the management of alcohol withdrawal. \n\n## Treatment for acute alcohol withdrawal\n\nOffer pharmacotherapy to treat the symptoms of acute alcohol withdrawal as follows:\n\nConsider offering a benzodiazepine or carbamazepine. Follow the MHRA safety advice on antiepileptic drugs in pregnancy.\n\nClomethiazole may be offered as an alternative to a benzodiazepine or carbamazepine. However, it should be used with caution, in inpatient settings only and according to the summary of product characteristics.In April 2017, this was an off-label use of some benzodiazepines (alprazolam, clobazam and lorazepam) and carbamazepine. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for cautions in specific populations for all medicines for acute alcohol withdrawal. [2010, amended 2021]\n\nPeople with decompensated liver disease who are being treated for acute alcohol withdrawal should be offered advice from a healthcare professional experienced in the management of patients with liver disease. \n\nOffer information about how to contact local alcohol support services to people who are being treated for acute alcohol withdrawal. \n\nFollow a symptom-triggered regimen for drug treatment for people in acute alcohol withdrawal who are:\n\nin hospital or\n\nin other settings where 24‑hour assessment and monitoring are available. \n\n## Management of delirium tremens\n\nIn people with delirium tremens, offer oral lorazepam as first-line treatment. If symptoms persist or oral medication is declined, offer parenteral lorazepam or haloperidol.In April 2017, this was an off-label use of lorazepam and haloperidol. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for cautions in specific populations. [2010, amended 2017]\n\nIf delirium tremens develops in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen. \n\n## Management of alcohol withdrawal seizures\n\nIn people with alcohol withdrawal seizures, consider offering a quick-acting benzodiazepine (such as lorazepam) to reduce the likelihood of further seizures.In April 2017, this was an off-label use of lorazepam. See NICE's information on prescribing medicines. Refer to the summary of product characteristics for cautions in specific populations. \n\nIf alcohol withdrawal seizures develop in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen. \n\nDo not offer phenytoin to treat alcohol withdrawal seizures. \n\n# Wernicke's encephalopathy\n\nOffer thiamine to people at high risk of developing, or with suspected, Wernicke's encephalopathy. Thiamine should be given in doses toward the upper end of the 'British national formulary' range. It should be given orally or parenterally as described in recommendations 1.2.1.2 to 1.2.1.4. \n\nOffer prophylactic oral thiamine to harmful or dependent drinkers:\n\nif they are malnourished or at risk of malnourishment or\n\nif they have decompensated liver disease or\n\nif they are in acute withdrawal or\n\nbefore and during a planned medically assisted alcohol withdrawal. \n\nOffer prophylactic parenteral thiamine followed by oral thiamine to harmful or dependent drinkers:\n\nif they are malnourished or at risk of malnourishment or\n\nif they have decompensated liver diseaseand in addition\n\nthey attend an emergency department or\n\nare admitted to hospital with an acute illness or injury. \n\nOffer parenteral thiamine to people with suspected Wernicke's encephalopathy. Maintain a high level of suspicion for the possibility of Wernicke's encephalopathy, particularly if the person is intoxicated. Parenteral treatment should be given for a minimum of 5\xa0days, unless Wernicke's encephalopathy is excluded. Oral thiamine treatment should follow parenteral therapy. \n\n# Alcohol-related liver disease\n\nFor information on diagnosing, monitoring and manging complications of cirrhosis, see NICE's guideline on cirrhosis in over 16s: assessment and management.\n\n## Assessment and diagnosis of alcohol-related liver disease\n\nExclude alternative causes of liver disease in people with a history of harmful or hazardous drinking who have abnormal liver blood test results. \n\nRefer people to a specialist experienced in the management of alcohol-related liver disease to confirm a clinical diagnosis of alcohol-related liver disease. \n\nConsider liver biopsy for the investigation of alcohol-related liver disease. \n\nWhen considering liver biopsy for the investigation of alcohol-related liver disease:\n\ntake into account the small but definite risks of morbidity and mortality\n\ndiscuss the benefits and risks with the patient and\n\nensure informed consent is obtained. \n\nIn people with suspected acute alcohol-related hepatitis, consider a liver biopsy to confirm the diagnosis if the hepatitis is severe enough to require corticosteroid treatment. \n\n## Referral for consideration of liver transplantation\n\nRefer patients with decompensated liver disease to be considered for assessment for liver transplantation if they:\n\nstill have decompensated liver disease after best management and 3\xa0months' abstinence from alcohol and\n\nare otherwise suitable candidates for liver transplantation. [2010, amended 2017]\n\n## Corticosteroid treatment for alcohol-related hepatitis\n\nOffer corticosteroid treatment to people with severe alcohol-related hepatitis and a discriminant function of 32 or more, only after:\n\neffectively treating any active infection or gastrointestinal bleeding that may be present\n\ncontrolling any renal impairment\n\ndiscussing the potential benefits and risks with the person and their family members or carers (as appropriate), explaining that corticosteroid treatment:\n\n\n\nhas been shown to improve survival in the short term (1\xa0month)\n\nhas not been shown to improve survival over a longer term (3\xa0months to 1\xa0year)\n\nhas been shown to increase the risk of serious infections within the first 3\xa0months of starting treatment.In April 2017, this was an off-label use of prednisolone. See NICE's information on prescribing medicines. \n\n\n\n## Nutritional support for alcohol-related hepatitis\n\nAssess the nutritional requirements of people with acute alcohol-related hepatitis. Offer nutritional support if needed and consider using nasogastric tube feeding (see the NICE guideline on nutrition support for adults: oral nutrition support, enteral tube feeding and parenteral nutrition). \n\n# Alcohol-related pancreatitis\n\n## Diagnosis of chronic alcohol-related pancreatitis\n\nTo inform a diagnosis of chronic alcohol-related pancreatitis use a combination of:\n\nthe person's symptoms\n\nan imaging modality to determine pancreatic structure and\n\ntests of pancreatic exocrine and endocrine function. \n\nUse computed tomography as the first-line imaging modality for the diagnosis of chronic alcohol‑related pancreatitis in people with a history and symptoms suggestive of chronic alcohol‑related pancreatitis. \n\n## Treatment options for painful chronic alcohol-related pancreatitis\n\nRefer people with pain from chronic alcohol-related pancreatitis to a specialist centre for multidisciplinary assessment. \n\nConsider surgery (open or minimally invasive) as first-line treatment in adults with painful chronic pancreatitis that is causing obstruction of the main pancreatic duct. \n\nOffer coeliac axis block, splanchnicectomy or surgery to people with poorly controlled pain from small-duct (non-obstructive) chronic alcohol-related pancreatitis. \n\n## Prophylactic antibiotics for acute alcohol-related pancreatitis\n\nDo not offer prophylactic antimicrobials to people with acute pancreatitis. \n\n## Nutritional support for acute alcohol-related pancreatitis\n\nEnsure that people with acute pancreatitis are not made 'nil‑by‑mouth' and do not have food withheld unless there is a clear reason for this (for example, vomiting). \n\nOffer enteral nutrition to anyone with severe or moderately severe acute pancreatitis. Start within 72 hours of presentation and aim to meet their nutritional requirements as soon as possible. \n\nOffer anyone with severe or moderately severe acute pancreatitis parenteral nutrition only if enteral nutrition has failed or is contraindicated. \n\n## Enzyme supplementation for chronic alcohol-related pancreatitis\n\nOffer pancreatic enzyme supplements to people with chronic alcohol-related pancreatitis who have symptoms of steatorrhoea or poor nutritional status due to exocrine pancreatic insufficiency. \n\nDo not prescribe pancreatic enzyme supplements to people with chronic alcohol-related pancreatitis if pain is their only symptom. \n\n# Terms used in this guideline\n\n## Acute alcohol withdrawal\n\nThe physical and psychological symptoms that people can experience when they suddenly reduce the amount of alcohol they drink if they have previously been drinking excessively for prolonged periods of time.\n\n## Alcohol dependence\n\nA cluster of behavioural, cognitive and physiological factors that typically include a strong desire to drink alcohol and difficulties in controlling its use. Someone who is alcohol-dependent may persist in drinking, despite harmful consequences. They will also give alcohol a higher priority than other activities and obligations. For further information, please refer to: 'Diagnostic and statistical manual of mental disorders' (DSM‑IV) (American Psychiatric Association 2000) and 'International statistical classification of diseases and related health problems – 10th revision' (ICD‑10) (World Health Organization 2007).\n\n## Alcohol-related hepatitis\n\nAlcoholic hepatitis.\n\n## Coeliac axis block\n\nPain relief by nerve block of the coeliac plexus.\n\n## CIWA–Ar scale\n\nThe Clinical Institute Withdrawal Assessment – Alcohol, revised (CIWA–Ar) scale is a validated 10‑item assessment tool that can be used to quantify the severity of the alcohol withdrawal syndrome, and to monitor and medicate patients throughout withdrawal. See Sullivan et al. (1989) Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA–Ar). British Journal of Addiction 84:1353-1357.\n\n## Decompensated liver disease\n\nLiver disease complicated by jaundice, ascites, variceal bleeding or hepatic encephalopathy.\n\n## Discriminant function\n\nMaddrey's discriminant function (DF) was described to predict prognosis in alcohol-related hepatitis and identify patients suitable for treatment with steroids. It is 4.6\xa0×\xa0[prothrombin time − control time (seconds)] + bilirubin in mg/dl. To calculate the DF using bilirubin in micromol/l divide the bilirubin value by 17.\n\n## Harmful drinking (high-risk drinking)\n\nA pattern of alcohol consumption that is causing mental or physical damage (ICD‑10, DSM‑V).\n\nConsumption (units per week): Drinking 35 units a week or more for women. Drinking 50 units a week or more for men.\n\n## Hazardous drinking (increasing risk drinking)\n\nA pattern of alcohol consumption that increases someone's risk of harm. Some would limit this definition to the physical or mental health consequences (as in harmful use). Others would include the social consequences. The term is currently used by the World Health Organization to describe this pattern of alcohol consumption. It is not a diagnostic term.\n\nConsumption (units per week): Drinking more than 14 units a week, but less than 35 units a week for women. Drinking more than 14 units a week, but less than 50 units for men.\n\n## Malnourishment\n\nA state of nutrition in which a deficiency of energy, protein and/or other nutrients causes measurable adverse effects on tissue/body form, composition, function or clinical outcome.\n\n## Medically assisted alcohol withdrawal\n\nThe deliberate withdrawal from alcohol by a dependent drinker under the supervision of medical staff. Prescribed medication may be needed to relieve the symptoms. It can be carried out at home, in the community or in a hospital or other inpatient facility.\n\n## Splanchnicectomy\n\nSurgical division of the splanchnic nerves and coeliac ganglion.\n\n## Symptom-triggered regimen\n\nTreatment tailored to the person's individual needs, which are determined by the severity of withdrawal signs and symptoms. The patient is regularly assessed and monitored, either using clinical experience and questioning alone or with the help of a designated questionnaire such as the CIWA–Ar. Drug treatment is provided if the patient needs it and treatment is withheld if there are no symptoms of withdrawal.", 'Context': "In the UK, it is estimated that 24% of adults drink in a hazardous or harmful way (NHS Digital Statistics on alcohol: England, 2009) For definitions of harmful and hazardous drinking see terms used in this guideline. Levels of self-reported hazardous and harmful drinking are lowest in the central and eastern regions of England (21 to 24% of men and 10 to 14% of women). They are highest in the North East, North West and Yorkshire and Humber (26 to 28% of men, 16 to 18% of women; North West Public Health Observatory, 2007). Hazardous and harmful drinking are commonly encountered among hospital attendees; approximately 20% of patients admitted to hospital for illnesses unrelated to alcohol are drinking at potentially hazardous levels (Royal College of Physicians (2001) Alcohol – can the NHS afford it?).\n\nContinued hazardous and harmful drinking can result in alcohol dependence. An abrupt reduction in alcohol intake in a person who has been drinking excessively for a prolonged period of time may result in the development of an alcohol withdrawal syndrome. In addition, persistent drinking at hazardous and harmful levels can result in damage to almost every organ or system of the body.\n\nThis guideline covers key areas in the investigation and management of the following alcohol-related conditions in adults and young people (aged 10\xa0years and older):\n\nacute alcohol withdrawal, including seizures and delirium tremens\n\nWernicke's encephalopathy\n\nliver disease\n\nacute and chronic pancreatitis.\n\nIt does not specifically look at women who are pregnant, children younger than 10\xa0years, or people with physical or mental health conditions caused by alcohol use, other than those listed above.\n\nIn the current update, we reviewed the evidence and updated the recommendation on corticosteroid treatment for people with severe alcoholic hepatitis.", 'Recommendations for research': "In 2010, the guideline committee made the following recommendations for research. The committee's full set of recommendations for research is detailed in the full guideline.\n\n# Admission to hospital for acute alcohol withdrawal\n\nWhat is the clinical and cost effectiveness of admitting people who attend hospital in mild or moderate acute alcohol withdrawal for unplanned medically assisted alcohol withdrawal compared with no admission and a planned medically assisted alcohol withdrawal with regard to the outcome of long-term abstinence?\n\n## Why this is important\n\nPeople presenting at a hospital who are at risk of or have alcohol withdrawal seizures or delirium tremens need admission for medical management. People with milder withdrawal are not usually admitted, but given advice and provided with information regarding local outpatient alcohol addiction services. One of the concerns with this model is that the opportunity for intervention may be lost and that many of these people may never contact addiction services. Given that abstinence is the goal, it may be that admission for these people maximises the likelihood of achieving this goal. The concerns with admission are that it is costly, the patients may not be motivated and there has been no opportunity for psychological input prior to the medically assisted withdrawal from alcohol.\n\nThe research should aim to compare the two models of treatment with regard to the primary goal of abstinence. Health economic analysis should aim to determine the cost effectiveness of each approach. \n\n# Dosing regimens for acute alcohol withdrawal\n\nWhat are the safety and efficacy of symptom-triggered, fixed-dosing and front‑loading regimens for the management of acute alcohol withdrawal?\n\n## Why this is important\n\nTraditionally, acute alcohol withdrawal has been managed by administering medication, typically benzodiazepines, according to a predetermined tapered-dosing schedule over a specified number of days (with the option for additional doses for breakthrough symptoms). This is called fixed‑dosing. In contrast, medication can be administered in response to a person's individual signs and symptoms (symptom‑triggered) or by giving an initial 'loading' dose (front-loading) in conjunction with a symptom‑triggered or 'as required' regimen.\n\nThe safety and efficacy of symptom-triggered or front-loading regimens in comparison to the 'traditional' fixed-dose regimen needs to be established in patients admitted to acute hospital settings who undergo unplanned acute alcohol withdrawal. Staff and patients' experiences in conjunction with objective measures of acute alcohol withdrawal need to be collected. \n\n# Drugs for the management of alcohol withdrawal\n\nWhat is the efficacy and cost effectiveness of clomethiazole compared with chlordiazepoxide or carbamazepine or benzodiazepines for the treatment of acute alcohol withdrawal with regard to the outcomes of withdrawal severity, risk of seizures, risk of delirium tremens, length of treatment and patient satisfaction?\n\n## Why this is important\n\nClomethiazole has powerful, short-acting, sedative, tranquilising and anticonvulsant properties which are mediated through an indirect effect on gamma-aminobutyric acid (GABA) receptors in the brain. It has fallen out of favour in many units for the management of acute alcohol withdrawal because of reports of dependence and concerns regarding over-sedation. These have been problems in the outpatient use of clomethiazole, but it has now been restricted to the inpatient setting, where clomethiazole may be of great value.\n\nThere are limited studies comparing clomethiazole with other agents. As such, an appropriately powered study comparing clomethiazole to chlordiazepoxide or carbamazepine or benzodiazepines with regard to the outcomes described above would help to define the role of this potentially very useful drug. \n\n# Assessment and monitoring\n\nWhat is the clinical and cost effectiveness of interventions delivered in an acute hospital setting by an alcohol specialist nurse compared with those managed through acute hospital setting with no input from a specialist nurse?\n\n## Why this is important\n\nAlcohol-related problems are an important public health problem in the UK. Many patients present to acute services and are managed according to local pharmacotherapeutic regimens. Coordination of the management of the acute withdrawal episode with the long-term management of the patient can be complex. Prevention of Wernicke's encephalopathy, assessment for liver and extra-hepatic disease, therapies targetting alcohol addiction and the long-term management of the patient's physical, mental and social wellbeing are all components of the care. It is considered that better management during the hospital admission may lead to better outcomes with regard to long-term abstinence and health. Studies investigating the impact of an alcohol specialist nurse on these outcomes are required. \n\n# Wernicke's encephalopathy\n\nWhat is the clinical and cost effectiveness of the use of parenteral versus oral thiamine in preventing the first onset of Wernicke's encephalopathy in people undergoing medically assisted alcohol withdrawal?\n\n## Why this is important\n\nWernicke's encephalopathy has a devastating effect on the sufferer and can occur when people are withdrawing from alcohol. It is thought to be caused by a lack of thiamine due to poor diet and/or absorption at a time of increased requirement for the vitamin (for cerebral functions in particular), although little is known about the mechanisms involved. There is some theoretical and trial evidence to suggest that parenteral replacement elevates blood levels more quickly than oral replacement, however it is not known if this is clinically significant, and there is no convincing clinical evidence to suggest which route and dose of thiamine is most effective at preventing Wernicke's encephalopathy. This is important as parenteral dosing uses additional resources, is unpleasant for the patient and has a very small risk of anaphylaxis. Having a placebo arm is probably not acceptable, given the risks of significant brain damage. "}	https://www.nice.org.uk/guidance/cg100	This guideline covers care for adults and young people (aged 10 years and older) with physical health problems that are completely or partly caused by an alcohol-use disorder. It aims to improve the health of people with alcohol-use disorders by providing recommendations on managing acute alcohol withdrawal and treating alcohol-related conditions.
2f3d723a376c9a0283d7fb4cefde9567d9d68afe	nice	Sexually transmitted infections: condom distribution schemes	Sexually transmitted infections: condom distribution schemes This guideline covers condom distribution schemes. The aim is to reduce the risk of sexually transmitted infections (STIs). In addition, these schemes can provide a good introduction to broader sexual and reproductive health services, especially for younger people, and help prevent unplanned pregnancies. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. These recommendations should be read together with relevant NICE guidance on sexual health and contraception (see the NICE topic page on sexual health). # Targeting services Provide a range of condom distribution schemes (also known as condom schemes) to meet the needs of different local populations, based on needs assessment, consultation and sexually transmitted infection (STI) rates. Target those most at risk. Include multicomponent schemes, single component schemes (free condoms) and cost-price sales schemes. Provide condom schemes as part of existing services that are likely to be used by those most at risk. This could include services provided by the voluntary sector (such as advice projects and youth projects), school health services and primary healthcare (including GP surgeries and community pharmacies). Ensure links exist between condom schemes and local sexual and reproductive health services. For example, consider: Providing condoms with information about local sexual health services. Displaying posters and providing leaflets advertising local sexual health services where condoms are available. Publicise condom schemes to people most at risk of getting an STI. For example: Put posters and leaflets in places used by those most at risk. Advertise on geospatial social networking apps (used to find local sexual partners) or websites (such as the NHS condom locator) and social media. For a short explanation of why the committee made these recommendations, see the committee discussion on targeting services. Full details of the evidence and the committee's discussion are in the evidence reviews. # Multicomponent schemes for young people in health, education, youth and outreach settings ## Service organisation Provide tailored multicomponent condom schemes in preference to other types of condom scheme for young people aged up to 16 and others for whom there is a duty of care. Consider extending tailored multicomponent condom schemes to include all young people up to the age of 25. Integrate these schemes into broader services for young people, for example, as part of young people's sexual and reproductive health services (see the NICE guideline on contraceptive services for under 25s). Offer pathways into other services including: sexual and reproductive health, alcohol and drug, mental health and partner violence services, as needed. Ensure services: meet the Department of Health's You're Welcome criteria for young-person-friendly services are confidential are sited in settings accessible to young people for example, in health, education, youth and outreach settings and in a range of geographical areas are accessible by public transport are available at convenient times for young people (for example, after school, college or university and at weekends). Ensure the safety of young people by: Assessing the competence of those under 16, and others for whom there is a duty of care, before providing them with condoms. Being alert to signs of child sexual exploitation or abuse, including intimate partner violence. See the British Association for Sexual Health and HIV (BASHH) and Brook's Spotting the signs of child sexual exploitation (CSE) proforma and the NICE guideline on child maltreatment. Agreeing with the young person how they will use the scheme. This should take into account their age and circumstances and include an agreement that after a specified number of visits they will discuss their relationships and condom use again. Consider providing a range of condom types (for example, latex-free) and sizes, female condoms and dental dams. Include lubricant as well as condoms if they need or want it. ## Information and advice Tailor information and advice according to the young person's needs and circumstances, including their sexual identity and whether or not they are having sex or are in a relationship. Discuss the effect that alcohol and drugs can have on decision-making and their ability to consent. Teach young people to use condoms effectively and safely (using education, information and demonstrations) before providing them. Provide information about emergency contraception and post-exposure prophylaxis so that young people know what to do and where to go in the event of a condom failure. For a short explanation of why the committee made these recommendations, see the committee discussion on multicomponent schemes for young people in education, youth and outreach settings . Full details of the evidence and the committee's discussion are in the evidence reviews. # Single component schemes ## Free condoms Consider distributing free condoms (with lubricant) to people at most risk of STIs through: Commercial venues (including sex-on-premises venues), public sex environments and other places where people are at more risk of getting an STI. Local businesses that people most at risk of STIs may use, for example, some community pharmacies. Voluntary and community organisations that work with those at most risk, for example, sexual health charities. Other settings, such as universities and further education settings. Provide information next to supplies of condoms (the information should be in line with the NICE guidelines on behaviour change: general approaches and behaviour change: individual approaches). This could include information about: sexual and reproductive health reliable sources of further information (for example, NHS Choices) -ther condom schemes (including multicomponent schemes) local sexual health services, including HIV testing services what to do in the event of a condom failure. Ensure supporting information is sensitive to the environment where it is displayed, for example in terms of language and the images used. ## Cost-price sales schemes Sell cost-price condoms to the wider population using websites run by existing health and wellbeing services, or larger-scale online condom sales schemes. Provide information about using condoms and about sexual and reproductive health at the point of sale (see recommendation 1.3.2). For a short explanation of why the committee made these recommendations, see the committee discussion on single component schemes. Full details of the evidence and the committee's discussion are in the evidence reviews. # Terms used in this guideline This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary. ## Condom distribution schemes Mainly referred to as 'condom schemes' in this guideline. The term refers to all schemes that provide free or cost-price condoms, female condoms and dental dams, with or without lubricant. This includes schemes that also offer advice, information or support. ## Cost-price sales schemes These schemes provide cost-price condoms and, if appropriate, lubricant. They include community schemes that provide cost-price condoms to sex workers and online services. ## Multicomponent schemes These schemes distribute free condoms with or without lubricant, together with training, information or other support. ## Single component schemes These schemes provide or distribute free condoms and if appropriate, lubricant. This includes online services for specific groups or areas of the country, and distribution schemes in public places.# Committee discussion Evidence statement numbers are given in square brackets. For an explanation of the evidence statement numbering, see the section on evidence reviews. # Background This guideline supplements existing NICE guidance on contraceptive services. The committee agreed that although the focus of the guideline is on sexually transmitted infections (STIs), condom distribution schemes may lead to wider benefits, such as preventing unplanned pregnancies or getting young people involved with health services. It agreed that people should be advised to use condoms to reduce the risk of STIs in addition to their chosen method of birth control. The committee noted that there is often a substantial overlap between condom schemes that just provide or sell condoms and multicomponent schemes that provide additional training, advice, information or support. For example, a multicomponent scheme for young people may also sell cost-price condoms to other groups. The committee did not examine evidence about condom schemes in prisons or other detention centres because these were excluded from the scope. The committee noted that NICE's guideline on physical health of people in prison addresses this. # Overview of the effectiveness evidence The committee expressed its concern about the quality of the evidence on condom schemes in the UK. Much evidence dated from the 1990s and most was from the US (little was identified from the UK). In many cases, key statistics and intervention details are missing from the papers. Limited evidence was available on how the components of schemes influenced effectiveness or cost effectiveness. No evidence was identified on the effectiveness and cost effectiveness of the C‑Card scheme, which is commonly used with young people in the UK. Most of the evidence that was available focused on condom schemes for HIV prevention, whereas current UK schemes focus on preventing a broad range of STIs and unwanted pregnancies . The committee did not make any recommendation based on ES8, which compared sexual risk taking after different types of condom provision, because there were no statistically significant differences that could inform or enhance a recommendation. The committee discussed a paper submitted during the consultation process. It had not been published in a peer-reviewed publication and did not meet the inclusion criteria for the review. It claimed that some condom schemes increased teenage pregnancy rates in the US during the 1990s (The incidental fertility effects of school condom distribution programs Buckles and Hungerman 2016). The committee noted that, because there were extensive methodological issues with the paper, no clear conclusions could be drawn. ## Outcomes Most included studies reported intermediate outcomes, such as intention to use condoms, condom use at last intercourse or attitudinal measures. Few reported STI outcomes – those that did were poor quality studies. The committee was aware that the focus of this guideline was condom provision to prevent STIs and that avoiding pregnancy was outside the scope. But it was also clear that increasing condom use would help avoid some pregnancies. Indeed, many of the proxy measures mentioned are as relevant to preventing pregnancy as to STI prevention. The costs of these avoided pregnancies were included in the economic analysis. In addition, the review database was checked to ensure that no studies with pregnancy outcomes alone had been overlooked and the committee was confident that a body of evidence had not been missed. The committee was aware of a recently published meta-analysis indicating that: 'interventions increasing the availability of, or accessibility to, condoms were shown to be efficacious in increasing condom use behaviours and that condom schemes provide an efficacious means of HIV/STI prevention'. Although most papers in the meta-analysis did not meet the inclusion criteria for this guideline (for example, two-thirds were in Africa or Asia) the committee was reassured that this review supported its conclusions. Efficacy of structural-level condom distribution interventions: a meta-analysis of U.S. and international studies (Charania MR, Crepaz N, Guenther-Gray C et al. 2011) ## Unintended consequences The included studies clearly showed that condom schemes do not increase levels of sexual activity among young people, nor do they reduce the age at which young people become sexually active . ## Key gaps in the evidence The committee was clear that an understanding of behaviour change must underpin condom schemes, but there was no specific evidence on the techniques used to deliver any of the evaluated schemes. The committee agreed that schemes should be delivered in line with the NICE guideline on behaviour change: general approaches, behaviour change: individual approaches and patient experience in adult NHS services. The committee discussed the importance of collecting data from UK-based condom schemes. An expert told the committee that one of the largest sources of evidence could be existing C‑Card schemes. Many of these undertake regular, extensive monitoring and evaluation of their programmes, as recommended in the C‑Card guidance . The committee agreed that a standardised approach to assessing the effectiveness of local schemes would be extremely beneficial and enable a national evidence synthesis to explore the effectiveness of C‑Card schemes in STI prevention. It agreed this should be strongly reflected in the research recommendations. The committee discussed the possibility that online services could address some equity issues for people in rural areas. But the evidence was poor so the committee made a research recommendation on this. Some GP surgeries provide condoms as part of their reproductive health role, but the committee questioned whether they would want to get involved in condom schemes aimed specifically at preventing STIs. Stakeholder comments reassured them that GPs might be interested in delivering such schemes. The committee agreed that this approach could be particularly useful for GP practices used by those most at risk, for example, in universities. But because there was little evidence, the committee made a research recommendation on this. # Targeting services The discussion below explains how we made the recommendations 1.1.1 to 1.1.4. The committee agreed that people are most at risk of STIs if they are involved in higher rates of risky sex (for example, they may have multiple partners or frequently change partners). There may be more people involved in such activities in some groups than others, but this does not mean that everyone in the group is necessarily at high risk. For example, men who have sex with men are the highest risk group for STIs and HIV, but this does not mean that every person in that group is at high risk. The committee agreed that a person's behaviour was the key determinant of their risk, so recommendation 1.1.1 refers to 'those most at risk'. The committee discussed the importance of integrating condom schemes with broader services, not just sexual and reproductive health services but, for example, general practice, young people's services, education, school nursing and pharmacies. It recognised that areas needed to plan their own mix of the different types of condom scheme recommended in the guideline based on local need. The committee discussed evidence that a small media campaign had been effective in raising awareness of syphilis and condom use. Members agreed that advertising and publicity were a key component of effective condom schemes . ## Cost effectiveness The committee heard expert testimony on the cost effectiveness of condom schemes. This showed that they are most cost effective and sustainable if they target people at most risk of STIs and are embedded into existing services. It was also told that: "Commissioning is currently taking place within the context of a challenging economic climate. Local authority budgets, in particular, are reducing, which results in less funding available for prevention work … for condom and lube schemes." The expert noted that commissioners need to work collaboratively and commission services for communities of people who share a common interest, belief or other characteristic, not just communities linked by geographical area. Another expert told the committee that in recent years some schemes have been commissioned to cover multiple local authority areas. Examples include the Come Correct scheme in London, which is funded by more than 20 local authorities. This enables local areas to buy into a pre-designed scheme and potentially benefit from economies of scale . ## Inequalities The committee recognised that targeting schemes at different population groups or geographical areas could lead to inequalities (for example, people living outside cities may not have access to city-based services). It also noted the lack of evidence of effectiveness for some groups, for example, people with learning disabilities. For this reason, the committee kept its recommendations as broad as possible. It also agreed that, although the evidence for selling condoms at cost price was lacking, it could help offset some of the potential inequalities generated by targeted schemes. It agreed that web-based postal systems, in particular, might help to overcome inequalities related to geographical isolation or stigma . But, based on the economic modelling, these schemes would need to be very low cost. # Multicomponent schemes for young people in education, youth and outreach settings The discussion below explains how we made recommendations 1.2.1 to 1.2.11 The committee was aware that young people under 16 need to be assessed as competent to consent to sexual intercourse before providing them with condoms. Either they should have parental permission or they should demonstrate that they can understand and appraise the nature and implications of condom use. This includes understanding the risks of not using them, and alternative courses of action. As a result, the committee agreed that if there are concerns about a young person's competency to consent, multicomponent schemes are more appropriate than single component schemes, even though they are much more costly. The committee was aware that multicomponent schemes also provide information and training (both in terms of education and hands-on training or demonstration) so 'condom naive' young people can take responsibility for using them effectively. But it was unclear from the evidence exactly what mix of components made multicomponent schemes more or less effective, so the committee was unable to make firm recommendations about their exact content . No evidence of effectiveness was identified for the C‑Card scheme, the most common multicomponent scheme in the UK. The committee agreed this is a key gap because most of these schemes provide condoms to young people up to the age of 25 – and because young people aged 16 to 25 have one of the highest rates of STIs. It also agreed that, in lieu of this evidence, the Brook and Public Health England, C-Card best practice guidance is helpful. On balance, members agreed that multicomponent condom schemes should consider providing their service to young people up to the age of 25 . ## Cost effectiveness The economic analysis used a model scheme that provided education, condoms (using a credit card type C‑Card) and telephone counselling, because these are common elements. Effectiveness data came from a multicomponent scheme for school students (aged 17) who were 1.23 times more likely to use a condom than students in a school without a scheme. It cost £0.48 per person per year, calculated from cost data from 4 UK C‑Card schemes. This included costs for: condoms and lubricants, staff time for training and administration, website, advertising and the C‑Card. STIs included in the model were chlamydia, gonorrhoea, HIV and syphilis. STI diagnosis rates were used to judge the initial prevalence of these STIs. STI incidence in the model was influenced by initial prevalence, transmission rates, sexual activity levels and condom failure rates, as well as condom use. The incidence of each STI was associated with a quality-adjusted life year (QALY) loss and a cost. For a target population aged 13 to 18, the model showed a condom distribution scheme prevented 1,373 STIs. This led to savings on STI-related costs of £758,947. Each person gained 17 QALYs. The scheme cost £1,538,499 and the incremental cost effectiveness ratio (ICER) of using condom schemes to prevent STIs only was £45,856. The committee was clear that increasing condom use would also help avoid some pregnancies, so an economic analysis was conducted on preventing pregnancies for a population aged 14 to 18. This used an economic model from the NICE guideline on contraceptive services for under 25s. The model assumed that all pregnancies in this age group were unintended and that increased condom use would either delay or prevent pregnancy, as well as preventing STIs. The committee noted that for a population of 100,000 people aged 14 to 18, increasing condom use by 22% would lead to pregnancy-related savings of over £11 million. This would make condom schemes highly cost saving. Analysis conducted for a target population aged 13 to 25, considering the effect of condom schemes on STIs only, resulted in an ICER of £17,411. Condom schemes were more cost effective for this broader age group because the rates of both sexual activity and STI prevalence were higher. In this age group, an analysis of the effect of increasing HIV prevalence to 0.19% (the UK average) showed that this would make the condom scheme cost saving. So it would be more effective and cost less than not providing a scheme. A scenario analysis considered that training provided by multicomponent schemes may reduce condom breakage. This reduced the ICER to £14,469, potentially demonstrating the importance of including training in condom schemes. The committee noted a threshold analysis in which effectiveness (relative risk of condom use) and cost per person in the target population were varied. This suggested that schemes can be cost effective even without considering pregnancy effects, as long as costs and condom use effects can be balanced. If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits. Additionally, the committee heard that the use of static models and short time horizons are likely to have underestimated the cost effectiveness of schemes. # Single component schemes The discussion below explains how we made recommendations 1.3.1 to 1.3.5. The committee discussed the challenges of making sure condoms are available to the widest possible audience, while ensuring schemes are cost effective by targeting populations most at risk of an STI. It also discussed the transition for young people from multicomponent to single component schemes. The committee was aware that young people under 16 might also use single component schemes. It agreed that there was no way to prevent this. But it was clear that multicomponent schemes are the best option for them and for anyone over 16 for whom there is a duty of care (for example, if they have special educational needs or disabilities). It agreed that providing condoms freely to people most at risk of STIs is important, although it is better if this takes place in the context of broader information provision or education, especially for young people. One expert told the committee that: …free condoms and lube within locations (including gay bars, clubs and saunas) should be maintained. It is appropriate to provide free condoms and lubricant targeted at gay, bisexual and other men who have sex with men, due to them shouldering a disproportionate burden of HIV and other STIs. Furthermore, condoms and lube available within bars, clubs, saunas and other settings provide important visibility, helping to increase social norms of condom and lube usage. Ensuring that they are free reduces one of the barriers for people accessing condoms and lube, cost. This is particularly important given the fact that addressing social determinants is an important aspect of HIV prevention. The committee noted the lack of published evidence about the effectiveness of single component condom schemes, but it also noted the range and flexibility of these schemes. In addition, it noted that the cost effectiveness evidence for them was compelling. As a result, the committee did recommend these schemes but, because of the lack of published evidence, could only make this a 'consider' recommendation. ## Cost effectiveness The committee noted that specific cost and effectiveness data were not available for condom schemes aimed at adults most at risk of STIs. Cost effectiveness analysis was conducted for 2 groups that include people most at risk of HIV: men who have sex with men, and black Africans. This showed that distributing free condoms to people at most risk is highly cost effective or cost saving, even with high scheme costs and relatively small effects. That is because, among people most at risk of an STI, a small increase in condom usage can avert numerous HIV cases, saving £100,000 and 4.5 QALYs per case . For groups of men who have sex with men, in populations with a low HIV prevalence (using diagnosis rates, average 0.05%), the committee noted schemes would be cost effective or cost saving with a cost per person per year up to: £5 if they increased condom use by 4% £10 if they increased it by 6% £15 if they increased it by 8%. For populations with a medium to high HIV prevalence (average 5 to 9%), schemes costing up to £15 per person per year would be cost effective or cost saving if condom use increased by 2% . If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits. The committee noted economic evidence supporting large-scale condom distribution among black Africans. It noted that for black African populations with a low HIV prevalence (average 1.46% for men and 3.84% for women), schemes that increased condom use by at least 8% would be cost effective or cost saving if the cost per person per year was less than £15. With medium HIV prevalence (average 1.79% for men and 4.55% for women), schemes would be cost effective or cost saving at up to: £5 per person per year if they increased condom use by 2% £10 if they increased it by 4% £15 if they increased it by 6% . If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits. # Cost-price sales schemes The committee noted that cost-price sales schemes may encourage more of the general population to use condoms, and it may be possible to deliver these at a low cost. This could help people who might not be regarded as most at risk to get low price condoms and so help offset any potential differential impact resulting from this guideline. ## Cost effectiveness The committee agreed that programmes selling condoms at cost or reduced price, particularly large-scale programmes such as a national web-based scheme, could be cost effective. They would have the added advantage of diminishing some of the potential inequalities in service provision as a result of specific targeting of condom schemes – possibly reaching people who would not otherwise be able to access schemes. This was particularly felt to be the case for web-based postal schemes . The committee considered the cost effectiveness of condom schemes for the general population. It noted that when using diagnosis rates for HIV prevalence, condom schemes would have to increase condom use by 20% and cost less than £0.20 per person per year. It noted that any reduction in unplanned pregnancies would increase the cost effectiveness of schemes. In an analysis that increased HIV prevalence to an average of 0.19%, schemes that cost £5 per person would be cost effective if they increased condom use by more than 50%. The committee discussed the fact that ICERs are higher for the general population because of the relatively low prevalence of STIs, and that schemes targeting those most at risk would be more cost effective. In an analysis that increased HIV prevalence to 0.4%, condom schemes costing up to £2 per person per year would be cost effective if they increased condom use by 10%. Those costing £5 would be cost effective if they increased use by 24%. If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits. If cost-price sales schemes can recover any administrative costs, through charging for condoms and postage and packaging, they could be cost‑neutral. # Evidence reviews Details of the evidence discussed are in evidence reviews, reports and papers from experts in the area. The evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from. Evidence statement (ES) number 1 indicates that the linked statement is numbered 1 in the evidence review. EP1 indicates that expert paper 'C card distribution scheme' is linked to a recommendation. EP2 indicates that expert paper 'LGBT Foundation condom & lube distribution scheme' is linked to a recommendation. EA indicates that the recommendation is supported by the economic analysis 'A model to evaluate the cost effectiveness of condom distribution (CD) schemes'. If a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1.1.1: EA; EP1; IDE Recommendation 1.1.2: EA; EP1; IDE Recommendation 1.1.3: ES6; EP1 Recommendation 1.1.4: ES6; EP1, EP2 Recommendation 1.2.1: ES1, ES2, ES3, ES4 Recommendation 1.2.2: EA; IDE Recommendation 1.2.3: EA; IDE Recommendation 1.2.4: IDE Recommendation 1.2.5: ES1, ES2, ES3, ES4; EP1; IDE Recommendation 1.2.6: ES1, ES2, ES3, ES4; EP1; IDE Recommendation 1.2.7: EP1, EP2; IDE Recommendation 1.2.8: ES1, ES2, ES3, ES4; EP1; IDE Recommendation 1.2.9: IDE Recommendation 1.2.10: ES2, ES3, ES10; IDE Recommendation 1.2.11: IDE Recommendation 1.3.1: EA; EP2; IDE Recommendation 1.3.2: EA; EP2; IDE Recommendation 1.3.3: EP2; IDE Recommendation 1.3.4: EA; ES7; IDE Recommendation 1.3.5: EP2; IDE# Recommendations for research The guideline committee has made the following recommendations for research. # What measures would make up an effective, standardised approach to evaluation of condom distribution schemes? How can we develop a standardised framework to evaluate condom schemes and what would be included in that evaluation? ## Why this is important Hundreds of condom schemes in the UK are collecting data on usage. But the focus is on the number of condoms distributed and number of users. UK-specific evidence on the effectiveness and cost effectiveness of schemes, using standardised frameworks for data collection and evaluation, would support outcome-based commissioning. It would also allow comparison of the effectiveness and cost effectiveness of different models of condom provision and support local learning. High level area or national datasets would enable more rigorous analysis of the effectiveness and cost effectiveness of different types of scheme. # How can the effectiveness and cost effectiveness of condom schemes in the UK be improved for people at most risk of STIs? How can we ensure the effectiveness and cost effectiveness of the C‑Card and other UK-based condom schemes for preventing sexually transmitted infections (STIs) and unintended pregnancies among groups at high risk? What are the essential components of an effective scheme? ## Why this is important We did not identify any UK-based comparative studies on condom schemes. Information about the essential components needed and how these schemes can be tailored for, and targeted at, different population groups is needed. In addition, information is needed on their impact on STI rates. Based on such data, more effective and cost effective condom schemes can be introduced. # What behaviour change techniques are most effective as part of a condom distribution scheme? What combinations of behaviour change techniques can be used to help condom schemes increase condom use among different high risk groups? ## Why this is important Many evaluations have been published on behavioural interventions to increase condom use. But the effectiveness of these interventions in the context of condom schemes has not been measured. In addition, many of these studies examined 'intention to use' condoms rather than actual use. Using an established taxonomy of behaviour change techniques to identify the most effective combinations could increase the effectiveness of schemes. # How can digital technologies be used to increase access to, and uptake of, condom schemes? Can digital technologies such as web-based schemes increase access to, and uptake of, schemes among people who live in areas without a face-to-face condom scheme or who would prefer to remain anonymous? ## Why this is important There is a potential equality issue inherent in providing targeted condom schemes. Increasing access for broader at-risk populations (for example, in rural areas) would help to offset the potential differential effects of these schemes. # Can GP practices deliver effective and cost effective condom schemes to reduce STIs? Can condom schemes be effective and cost effective in GP practices to reduce STIs? Can they be delivered in ways that are acceptable to GPs and other practice staff? In addition, how can the impact of such schemes be maximised? ## Why this is important Many GPs are interested in delivering condom schemes, and this could have a number of benefits. For example, the UK network of GP practices could improve delivery in rural areas and to other populations with poor access to services or who do not use existing services. Conversely, some people might be reluctant to get free condoms from their local GP.# Context In 2015 there were approximately 435,000 new diagnoses of sexually transmitted infections (STIs) in England. Most were among heterosexual people under 25 and men who have sex with men (Sexually transmitted infections and chlamydia screening in England: 2015 Public Health England). In the UK as a whole, 6,095 people were diagnosed with HIV in 2015 (National HIV surveillance data tables Public Health England). Over half of these were men who have sex with men (3,320). In the heterosexual population a disproportionate number of diagnoses were among black Africans. Condoms can protect against many STIs including HIV, chlamydia and gonorrhoea. They offer less protection against STIs transmitted by skin-to-skin contact, such as genital herpes and warts. In the UK in 2011, the cost of treating STIs (excluding HIV) was estimated at £620 million (Unprotected nation Family Planning Association). Cost can be a major barrier to condom use, particularly for poorer people (Barriers to condom use Sakar 2008). Social norms and religious and cultural beliefs can also prevent people from using them because of stigma or embarrassment. Some condom schemes only provide free or cost-price condoms. Others combine this with information or support. The C‑Card scheme is probably the most widespread UK scheme. Local authorities commission these and define who is eligible. Typically they focus on people aged 13 to 24 (see Brook and Public Health England's C-Card condom distribution schemes). This guideline will help local authorities and the NHS reduce STIs, a key objective in Department of Health's. A framework for sexual health improvement in England. Local authorities are responsible for commissioning and delivering all community and pharmacy contraceptive services. See Public Health England's, Making it work: a guide to whole system commissioning for sexual health, reproductive health and HIV. NHS England commissions contraception schemes provided as an additional service under the GP contract, and sexual health services in prisons.# Glossary # Black Africans The term 'black African' includes anyone who identifies themselves as black African, whether they are migrants from Africa, African descendants or African nationals. # Competence In this guideline, competence refers to an assessment of whether a young person has maturity and understanding to make decisions and provide consent. This is sometimes called 'Gillick competence' and may be applied through 'Fraser guidelines' (see section 6 of Brook and Public Health England's C-Card condom distribution schemes). # Dental dam A thin, square piece of rubber that is placed over the labia or anus during oral-vaginal or oral-anal intercourse. # Post-exposure prophylaxis (PEP) A month-long course of drugs that can prevent HIV infection after the virus has entered a person's body. The sooner PEP is started, the more likely it is to work. A course of PEP needs to start within 72 hours of exposure otherwise it is unlikely to work. # Public sex environments Public areas where people go for consensual sexual contact (both same sex and opposite sex). # Sex-on-premises venues This term is used for commercial venues, as opposed to public spaces and parks, where men who have sex with men can meet and have sexual relations on site. A similar term, 'on-premises club', is used by heterosexual swingers to describe a sex club where non-commercial sexual activity takes place. For a glossary of public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThese recommendations should be read together with relevant NICE guidance on sexual health and contraception (see the\xa0NICE topic page on sexual health).\n\n# Targeting services\n\nProvide a range of condom distribution schemes (also known as condom schemes) to meet the needs of different local populations, based on needs assessment, consultation and sexually transmitted infection (STI) rates. Target those most at risk. Include multicomponent schemes, single component schemes (free condoms) and cost-price sales schemes.\n\nProvide condom schemes as part of existing services that are likely to be used by those most at risk. This could include services provided by the voluntary sector (such as advice projects and youth projects), school health services and primary healthcare (including GP surgeries and community pharmacies).\n\nEnsure links exist between condom schemes and local sexual and reproductive health services. For example, consider:\n\nProviding condoms with information about local sexual health services.\n\nDisplaying posters and providing leaflets advertising local sexual health services where condoms are available.\n\nPublicise condom schemes to people most at risk of getting an STI. For example:\n\nPut posters and leaflets in places used by those most at risk.\n\nAdvertise on geospatial social networking apps (used to find local sexual partners) or websites (such as the NHS condom locator) and social media.\n\nFor a short explanation of why the committee made these recommendations, see the committee discussion on targeting services.\n\nFull details of the evidence and the committee's discussion are in the evidence reviews.\n\n# Multicomponent schemes for young people in health, education, youth and outreach settings\n\n## Service organisation\n\nProvide tailored multicomponent condom schemes in preference to other types of condom scheme for young people aged up to 16 and others for whom there is a duty of care.\n\nConsider extending tailored multicomponent condom schemes to include all young people up to the age of 25.\n\nIntegrate these schemes into broader services for young people, for example, as part of young people's sexual and reproductive health services (see the NICE guideline on contraceptive services for under 25s).\n\nOffer pathways into other services including: sexual and reproductive health, alcohol and drug, mental health and partner violence services, as needed.\n\nEnsure services:\n\nmeet the Department of Health's You're Welcome criteria for young-person-friendly services\n\nare confidential\n\nare sited in settings accessible to young people for example, in health, education, youth and outreach settings and in a range of geographical areas\n\nare accessible by public transport\n\nare available at convenient times for young people (for example, after school, college or university and at weekends).\n\nEnsure the safety of young people by:\n\nAssessing the competence of those under 16, and others for whom there is a duty of care, before providing them with condoms.\n\nBeing alert to signs of child sexual exploitation or abuse, including intimate partner violence. See the British Association for Sexual Health and HIV (BASHH) and Brook's Spotting the signs of child sexual exploitation (CSE) proforma and the NICE guideline on child maltreatment.\n\nAgreeing with the young person how they will use the scheme. This should take into account their age and circumstances and include an agreement that after a specified number of visits they will discuss their relationships and condom use again.\n\nConsider providing a range of condom types (for example, latex-free) and sizes, female condoms and dental dams. Include lubricant as well as condoms if they need or want it.\n\n## Information and advice\n\nTailor information and advice according to the young person's needs and circumstances, including their sexual identity and whether or not they are having sex or are in a relationship.\n\nDiscuss the effect that alcohol and drugs can have on decision-making and their ability to consent.\n\nTeach young people to use condoms effectively and safely (using education, information and demonstrations) before providing them.\n\nProvide information about emergency contraception and post-exposure prophylaxis so that young people know what to do and where to go in the event of a condom failure.\n\nFor a short explanation of why the committee made these recommendations, see the committee discussion on multicomponent schemes for young people in education, youth and outreach settings .\n\nFull details of the evidence and the committee's discussion are in the evidence reviews.\n\n# Single component schemes\n\n## Free condoms\n\nConsider distributing free condoms (with lubricant) to people at most risk of STIs through:\n\nCommercial venues (including sex-on-premises venues), public sex environments and other places where people are at more risk of getting an STI.\n\nLocal businesses that people most at risk of STIs may use, for example, some community pharmacies.\n\nVoluntary and community organisations that work with those at most risk, for example, sexual health charities.\n\nOther settings, such as universities and further education settings.\n\nProvide information next to supplies of condoms (the information should be in line with the NICE guidelines on behaviour change: general approaches and behaviour change: individual approaches). This could include information about:\n\nsexual and reproductive health\n\nreliable sources of further information (for example, NHS Choices)\n\nother condom schemes (including multicomponent schemes)\n\nlocal sexual health services, including HIV testing services\n\nwhat to do in the event of a condom failure.\n\nEnsure supporting information is sensitive to the environment where it is displayed, for example in terms of language and the images used.\n\n## Cost-price sales schemes\n\nSell cost-price condoms to the wider population using websites run by existing health and wellbeing services, or larger-scale online condom sales schemes.\n\nProvide information about using condoms and about sexual and reproductive health at the point of sale (see recommendation 1.3.2).\n\nFor a short explanation of why the committee made these recommendations, see the committee discussion on single component schemes.\n\nFull details of the evidence and the committee's discussion are in the evidence reviews.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.\n\n## Condom distribution schemes\n\nMainly referred to as 'condom schemes' in this guideline. The term refers to all schemes that provide free or cost-price condoms, female condoms and dental dams, with or without lubricant. This includes schemes that also offer advice, information or support.\n\n## Cost-price sales schemes\n\nThese schemes provide cost-price condoms and, if appropriate, lubricant. They include community schemes that provide cost-price condoms to sex workers and online services.\n\n## Multicomponent schemes\n\nThese schemes distribute free condoms with or without lubricant, together with training, information or other support.\n\n## Single component schemes\n\nThese schemes provide or distribute free condoms and if appropriate, lubricant. This includes online services for specific groups or areas of the country, and distribution schemes in public places.", 'Committee discussion': 'Evidence statement numbers are given in square brackets. For an explanation of the evidence statement numbering, see the section on evidence reviews.\n\n# Background\n\nThis guideline supplements existing NICE guidance on contraceptive services. The committee agreed that although the focus of the guideline is on sexually transmitted infections (STIs), condom distribution schemes may lead to wider benefits, such as preventing unplanned pregnancies or getting young people involved with health services. It agreed that people should be advised to use condoms to reduce the risk of STIs in addition to their chosen method of birth control.\n\nThe committee noted that there is often a substantial overlap between condom schemes that just provide or sell condoms and multicomponent schemes that provide additional training, advice, information or support. For example, a multicomponent scheme for young people may also sell cost-price condoms to other groups.\n\nThe committee did not examine evidence about condom schemes in prisons or other detention centres because these were excluded from the scope. The committee noted that NICE\'s guideline on physical health of people in prison addresses this.\n\n# Overview of the effectiveness evidence\n\nThe committee expressed its concern about the quality of the evidence on condom schemes in the UK. Much evidence dated from the 1990s and most was from the US (little was identified from the UK). In many cases, key statistics and intervention details are missing from the papers. Limited evidence was available on how the components of schemes influenced effectiveness or cost effectiveness. No evidence was identified on the effectiveness and cost effectiveness of the C‑Card scheme, which is commonly used with young people in the UK.\n\nMost of the evidence that was available focused on condom schemes for HIV prevention, whereas current UK schemes focus on preventing a broad range of STIs and unwanted pregnancies [ES1, ES2, ES3, ES4, ES5, ES6, ES7, ES8].\n\nThe committee did not make any recommendation based on ES8, which compared sexual risk taking after different types of condom provision, because there were no statistically significant differences that could inform or enhance a recommendation.\n\nThe committee discussed a paper submitted during the consultation process. It had not been published in a peer-reviewed publication and did not meet the inclusion criteria for the review. It claimed that some condom schemes increased teenage pregnancy rates in the US during the 1990s (The incidental fertility effects of school condom distribution programs Buckles and Hungerman 2016). The committee noted that, because there were extensive methodological issues with the paper, no clear conclusions could be drawn.\n\n## Outcomes\n\nMost included studies reported intermediate outcomes, such as intention to use condoms, condom use at last intercourse or attitudinal measures. Few reported STI outcomes – those that did were poor quality studies.\n\nThe committee was aware that the focus of this guideline was condom provision to prevent STIs and that avoiding pregnancy was outside the scope. But it was also clear that increasing condom use would help avoid some pregnancies. Indeed, many of the proxy measures mentioned are as relevant to preventing pregnancy as to STI prevention.\n\nThe costs of these avoided pregnancies were included in the economic analysis. In addition, the review database was checked to ensure that no studies with pregnancy outcomes alone had been overlooked and the committee was confident that a body of evidence had not been missed.\n\nThe committee was aware of a recently published meta-analysis indicating that: \'interventions increasing the availability of, or accessibility to, condoms were shown to be efficacious in increasing condom use behaviours and that condom schemes provide an efficacious means of HIV/STI prevention\'. Although most papers in the meta-analysis did not meet the inclusion criteria for this guideline (for example, two-thirds were in Africa or Asia) the committee was reassured that this review supported its conclusions.\n\nEfficacy of structural-level condom distribution interventions: a meta-analysis of U.S. and international studies (Charania MR, Crepaz N, Guenther-Gray C et al. 2011)\n\n## Unintended consequences\n\nThe included studies clearly showed that condom schemes do not increase levels of sexual activity among young people, nor do they reduce the age at which young people become sexually active [ES1, ES5].\n\n## Key gaps in the evidence\n\nThe committee was clear that an understanding of behaviour change must underpin condom schemes, but there was no specific evidence on the techniques used to deliver any of the evaluated schemes. The committee agreed that schemes should be delivered in line with the NICE guideline on behaviour change: general approaches, behaviour change: individual approaches and patient experience in adult NHS services.\n\nThe committee discussed the importance of collecting data from UK-based condom schemes. An expert told the committee that one of the largest sources of evidence could be existing C‑Card schemes. Many of these undertake regular, extensive monitoring and evaluation of their programmes, as recommended in the C‑Card guidance [EP1].\n\nThe committee agreed that a standardised approach to assessing the effectiveness of local schemes would be extremely beneficial and enable a national evidence synthesis to explore the effectiveness of C‑Card schemes in STI prevention. It agreed this should be strongly reflected in the research recommendations.\n\nThe committee discussed the possibility that online services could address some equity issues for people in rural areas. But the evidence was poor so the committee made a research recommendation on this.\n\nSome GP surgeries provide condoms as part of their reproductive health role, but the committee questioned whether they would want to get involved in condom schemes aimed specifically at preventing STIs. Stakeholder comments reassured them that GPs might be interested in delivering such schemes. The committee agreed that this approach could be particularly useful for GP practices used by those most at risk, for example, in universities. But because there was little evidence, the committee made a research recommendation on this.\n\n# Targeting services\n\nThe discussion below explains how we made the recommendations 1.1.1 to 1.1.4.\n\nThe committee agreed that people are most at risk of STIs if they are involved in higher rates of risky sex (for example, they may have multiple partners or frequently change partners). There may be more people involved in such activities in some groups than others, but this does not mean that everyone in the group is necessarily at high risk. For example, men who have sex with men are the highest risk group for STIs and HIV, but this does not mean that every person in that group is at high risk.\n\nThe committee agreed that a person\'s behaviour was the key determinant of their risk, so recommendation 1.1.1 refers to \'those most at risk\'.\n\nThe committee discussed the importance of integrating condom schemes with broader services, not just sexual and reproductive health services but, for example, general practice, young people\'s services, education, school nursing and pharmacies. It recognised that areas needed to plan their own mix of the different types of condom scheme recommended in the guideline based on local need.\n\nThe committee discussed evidence that a small media campaign had been effective in raising awareness of syphilis and condom use. Members agreed that advertising and publicity were a key component of effective condom schemes [ES6, EP1, EP2].\n\n## Cost effectiveness\n\nThe committee heard expert testimony on the cost effectiveness of condom schemes. This showed that they are most cost effective and sustainable if they target people at most risk of STIs and are embedded into existing services. It was also told that: "Commissioning is currently taking place within the context of a challenging economic climate. Local authority budgets, in particular, are reducing, which results in less funding available for prevention work … [such as] for condom and lube schemes."\n\nThe expert noted that commissioners need to work collaboratively and commission services for communities of people who share a common interest, belief or other characteristic, not just communities linked by geographical area. Another expert told the committee that in recent years some schemes have been commissioned to cover multiple local authority areas. Examples include the Come Correct scheme in London, which is funded by more than 20 local authorities. This enables local areas to buy into a pre-designed scheme and potentially benefit from economies of scale [ES10, EA, EP1, EP2].\n\n## Inequalities\n\nThe committee recognised that targeting schemes at different population groups or geographical areas could lead to inequalities (for example, people living outside cities may not have access to city-based services). It also noted the lack of evidence of effectiveness for some groups, for example, people with learning disabilities. For this reason, the committee kept its recommendations as broad as possible.\n\nIt also agreed that, although the evidence for selling condoms at cost price was lacking, it could help offset some of the potential inequalities generated by targeted schemes. It agreed that web-based postal systems, in particular, might help to overcome inequalities related to geographical isolation or stigma [ES7]. But, based on the economic modelling, these schemes would need to be very low cost.\n\n# Multicomponent schemes for young people in education, youth and outreach settings\n\nThe discussion below explains how we made recommendations 1.2.1 to 1.2.11\n\nThe committee was aware that young people under 16 need to be assessed as competent to consent to sexual intercourse before providing them with condoms. Either they should have parental permission or they should demonstrate that they can understand and appraise the nature and implications of condom use. This includes understanding the risks of not using them, and alternative courses of action. As a result, the committee agreed that if there are concerns about a young person\'s competency to consent, multicomponent schemes are more appropriate than single component schemes, even though they are much more costly.\n\nThe committee was aware that multicomponent schemes also provide information and training (both in terms of education and hands-on training or demonstration) so \'condom naive\' young people can take responsibility for using them effectively. But it was unclear from the evidence exactly what mix of components made multicomponent schemes more or less effective, so the committee was unable to make firm recommendations about their exact content [ES1, ES2, ES3].\n\nNo evidence of effectiveness was identified for the C‑Card scheme, the most common multicomponent scheme in the UK. The committee agreed this is a key gap because most of these schemes provide condoms to young people up to the age of 25 – and because young people aged 16 to 25 have one of the highest rates of STIs. It also agreed that, in lieu of this evidence, the Brook and Public Health England, C-Card best practice guidance is helpful.\n\nOn balance, members agreed that multicomponent condom schemes should consider providing their service to young people up to the age of 25 [EP1].\n\n## Cost effectiveness\n\nThe economic analysis used a model scheme that provided education, condoms (using a credit card type C‑Card) and telephone counselling, because these are common elements. Effectiveness data came from a multicomponent scheme for school students (aged\xa017) who were 1.23\xa0times more likely to use a condom than students in a school without a scheme. It cost £0.48 per person per year, calculated from cost data from 4 UK C‑Card schemes. This included costs for: condoms and lubricants, staff time for training and administration, website, advertising and the C‑Card.\n\nSTIs included in the model were chlamydia, gonorrhoea, HIV and syphilis. STI diagnosis rates were used to judge the initial prevalence of these STIs. STI incidence in the model was influenced by initial prevalence, transmission rates, sexual activity levels and condom failure rates, as well as condom use. The incidence of each STI was associated with a quality-adjusted life year (QALY) loss and a cost.\n\nFor a target population aged 13 to 18, the model showed a condom distribution scheme prevented 1,373\xa0STIs. This led to savings on STI-related costs of £758,947. Each person gained 17\xa0QALYs. The scheme cost £1,538,499 and the incremental cost effectiveness ratio (ICER) of using condom schemes to prevent STIs only was £45,856.\n\nThe committee was clear that increasing condom use would also help avoid some pregnancies, so an economic analysis was conducted on preventing pregnancies for a population aged 14 to 18. This used an economic model from the NICE guideline on contraceptive services for under 25s. The model assumed that all pregnancies in this age group were unintended and that increased condom use would either delay or prevent pregnancy, as well as preventing STIs.\n\nThe committee noted that for a population of 100,000\xa0people aged 14 to 18, increasing condom use by 22% would lead to pregnancy-related savings of over £11\xa0million. This would make condom schemes highly cost saving.\n\nAnalysis conducted for a target population aged 13 to 25, considering the effect of condom schemes on STIs only, resulted in an ICER of £17,411. Condom schemes were more cost effective for this broader age group because the rates of both sexual activity and STI prevalence were higher. In this age group, an analysis of the effect of increasing HIV prevalence to 0.19% (the UK average) showed that this would make the condom scheme cost saving. So it would be more effective and cost less than not providing a scheme. A scenario analysis considered that training provided by multicomponent schemes may reduce condom breakage. This reduced the ICER to £14,469, potentially demonstrating the importance of including training in condom schemes.\n\nThe committee noted a threshold analysis in which effectiveness (relative risk of condom use) and cost per person in the target population were varied. This suggested that schemes can be cost effective even without considering pregnancy effects, as long as costs and condom use effects can be balanced. If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits.\n\nAdditionally, the committee heard that the use of static models and short time horizons are likely to have underestimated the cost effectiveness of schemes.\n\n# Single component schemes\n\nThe discussion below explains how we made recommendations 1.3.1 to 1.3.5.\n\nThe committee discussed the challenges of making sure condoms are available to the widest possible audience, while ensuring schemes are cost effective by targeting populations most at risk of an STI. It also discussed the transition for young people from multicomponent to single component schemes.\n\nThe committee was aware that young people under\xa016 might also use single component schemes. It agreed that there was no way to prevent this. But it was clear that multicomponent schemes are the best option for them and for anyone over\xa016 for whom there is a duty of care (for example, if they have special educational needs or disabilities).\n\nIt agreed that providing condoms freely to people most at risk of STIs is important, although it is better if this takes place in the context of broader information provision or education, especially for young people. One expert told the committee that:\n\n…free condoms and lube within locations (including gay bars, clubs and saunas) should be maintained. It is appropriate to provide free condoms and lubricant targeted at gay, bisexual and other men who have sex with men, due to them shouldering a disproportionate burden of HIV and other STIs.\n\nFurthermore, condoms and lube available within bars, clubs, saunas and other settings provide important visibility, helping to increase social norms of condom and lube usage.\n\nEnsuring that they are free reduces one of the barriers for people accessing condoms and lube, [that is] cost. This is particularly important given the fact that addressing social determinants is an important aspect of HIV prevention.\n\nThe committee noted the lack of published evidence about the effectiveness of single component condom schemes, but it also noted the range and flexibility of these schemes. In addition, it noted that the cost effectiveness evidence for them was compelling. As a result, the committee did recommend these schemes but, because of the lack of published evidence, could only make this a \'consider\' recommendation.\n\n## Cost effectiveness\n\nThe committee noted that specific cost and effectiveness data were not available for condom schemes aimed at adults most at risk of STIs. Cost effectiveness analysis was conducted for 2\xa0groups that include people most at risk of HIV: men who have sex with men, and black Africans. This showed that distributing free condoms to people at most risk is highly cost effective or cost saving, even with high scheme costs and relatively small effects. That is because, among people most at risk of an STI, a small increase in condom usage can avert numerous HIV cases, saving £100,000 and 4.5\xa0QALYs per case [EA].\n\nFor groups of men who have sex with men, in populations with a low HIV prevalence (using diagnosis rates, average\xa00.05%), the committee noted schemes would be cost effective or cost saving with a cost per person per year up to:\n\n£5 if they increased condom use by 4%\n\n£10 if they increased it by 6%\n\n£15 if they increased it by 8%.\n\nFor populations with a medium to high HIV prevalence (average 5 to 9%), schemes costing up to £15 per person per year would be cost effective or cost saving if condom use increased by 2% [EA]. If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits.\n\nThe committee noted economic evidence supporting large-scale condom distribution among black Africans. It noted that for black African populations with a low HIV prevalence (average 1.46% for men and 3.84% for women), schemes that increased condom use by at least 8% would be cost effective or cost saving if the cost per person per year was less than £15. With medium HIV prevalence (average 1.79% for men and 4.55% for women), schemes would be cost effective or cost saving at up to:\n\n£5 per person per year if they increased condom use by 2%\n\n£10 if they increased it by 4%\n\n£15 if they increased it by 6% [ES9; EA].\n\nIf a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits.\n\n# Cost-price sales schemes\n\nThe committee noted that cost-price sales schemes may encourage more of the general population to use condoms, and it may be possible to deliver these at a low cost. This could help people who might not be regarded as most at risk to get low price condoms and so help offset any potential differential impact resulting from this guideline.\n\n## Cost effectiveness\n\nThe committee agreed that programmes selling condoms at cost or reduced price, particularly large-scale programmes such as a national web-based scheme, could be cost effective. They would have the added advantage of diminishing some of the potential inequalities in service provision as a result of specific targeting of condom schemes – possibly reaching people who would not otherwise be able to access schemes. This was particularly felt to be the case for web-based postal schemes [ES7].\n\nThe committee considered the cost effectiveness of condom schemes for the general population. It noted that when using diagnosis rates for HIV prevalence, condom schemes would have to increase condom use by 20% and cost less than £0.20 per person per year. It noted that any reduction in unplanned pregnancies would increase the cost effectiveness of schemes.\n\nIn an analysis that increased HIV prevalence to an average of 0.19%, schemes that cost £5 per person would be cost effective if they increased condom use by more than 50%.\n\nThe committee discussed the fact that ICERs are higher for the general population because of the relatively low prevalence of STIs, and that schemes targeting those most at risk would be more cost effective.\n\nIn an analysis that increased HIV prevalence to 0.4%, condom schemes costing up to £2 per person per year would be cost effective if they increased condom use by 10%. Those costing £5 would be cost effective if they increased use by 24%. If a scheme did not achieve any change in condom use it would not be cost effective because it would accrue the cost for no health benefits.\n\nIf cost-price sales schemes can recover any administrative costs, through charging for condoms and postage and packaging, they could be cost‑neutral.\n\n# Evidence reviews\n\nDetails of the evidence discussed are in evidence reviews, reports and papers from experts in the area.\n\nThe evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement (ES) number\xa01 indicates that the linked statement is numbered 1 in the evidence review. EP1 indicates that expert paper \'C card distribution scheme\' is linked to a recommendation. EP2 indicates that expert paper \'LGBT Foundation condom & lube distribution scheme\' is linked to a recommendation. EA indicates that the recommendation is supported by the economic analysis \'A model to evaluate the cost effectiveness of condom distribution (CD) schemes\'.\n\nIf a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1.1.1: EA; EP1; IDE\n\nRecommendation 1.1.2: EA; EP1; IDE\n\nRecommendation 1.1.3: ES6; EP1\n\nRecommendation 1.1.4: ES6; EP1, EP2\n\nRecommendation 1.2.1: ES1, ES2, ES3, ES4\n\nRecommendation 1.2.2: EA; IDE\n\nRecommendation 1.2.3: EA; IDE\n\nRecommendation 1.2.4: IDE\n\nRecommendation 1.2.5: ES1, ES2, ES3, ES4; EP1; IDE\n\nRecommendation 1.2.6: ES1, ES2, ES3, ES4; EP1; IDE\n\nRecommendation 1.2.7: EP1, EP2; IDE\n\nRecommendation 1.2.8: ES1, ES2, ES3, ES4; EP1; IDE\n\nRecommendation 1.2.9: IDE\n\nRecommendation 1.2.10: ES2, ES3, ES10; IDE\n\nRecommendation 1.2.11: IDE\n\nRecommendation 1.3.1: EA; EP2; IDE\n\nRecommendation 1.3.2: EA; EP2; IDE\n\nRecommendation 1.3.3: EP2; IDE\n\nRecommendation 1.3.4: EA; ES7; IDE\n\nRecommendation 1.3.5: EP2; IDE', 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# What measures would make up an effective, standardised approach to evaluation of condom distribution schemes?\n\nHow can we develop a standardised framework to evaluate condom schemes and what would be included in that evaluation?\n\n## Why this is important\n\nHundreds of condom schemes in the UK are collecting data on usage. But the focus is on the number of condoms distributed and number of users. UK-specific evidence on the effectiveness and cost effectiveness of schemes, using standardised frameworks for data collection and evaluation, would support outcome-based commissioning. It would also allow comparison of the effectiveness and cost effectiveness of different models of condom provision and support local learning. High level area or national datasets would enable more rigorous analysis of the effectiveness and cost effectiveness of different types of scheme.\n\n# How can the effectiveness and cost effectiveness of condom schemes in the UK be improved for people at most risk of STIs?\n\nHow can we ensure the effectiveness and cost effectiveness of the C‑Card and other UK-based condom schemes for preventing sexually transmitted infections (STIs) and unintended pregnancies among groups at high risk? What are the essential components of an effective scheme?\n\n## Why this is important\n\nWe did not identify any UK-based comparative studies on condom schemes. Information about the essential components needed and how these schemes can be tailored for, and targeted at, different population groups is needed. In addition, information is needed on their impact on STI rates. Based on such data, more effective and cost effective condom schemes can be introduced.\n\n# What behaviour change techniques are most effective as part of a condom distribution scheme?\n\nWhat combinations of behaviour change techniques can be used to help condom schemes increase condom use among different high risk groups?\n\n## Why this is important\n\nMany evaluations have been published on behavioural interventions to increase condom use. But the effectiveness of these interventions in the context of condom schemes has not been measured. In addition, many of these studies examined 'intention to use' condoms rather than actual use. Using an established taxonomy of behaviour change techniques to identify the most effective combinations could increase the effectiveness of schemes.\n\n# How can digital technologies be used to increase access to, and uptake of, condom schemes?\n\nCan digital technologies such as web-based schemes increase access to, and uptake of, schemes among people who live in areas without a face-to-face condom scheme or who would prefer to remain anonymous?\n\n## Why this is important\n\nThere is a potential equality issue inherent in providing targeted condom schemes. Increasing access for broader at-risk populations (for example, in rural areas) would help to offset the potential differential effects of these schemes.\n\n# Can GP practices deliver effective and cost effective condom schemes to reduce STIs?\n\nCan condom schemes be effective and cost effective in GP practices to reduce STIs? Can they be delivered in ways that are acceptable to GPs and other practice staff? In addition, how can the impact of such schemes be maximised?\n\n## Why this is important\n\nMany GPs are interested in delivering condom schemes, and this could have a number of benefits. For example, the UK network of GP practices could improve delivery in rural areas and to other populations with poor access to services or who do not use existing services. Conversely, some people might be reluctant to get free condoms from their local GP.", 'Context': "In 2015 there were approximately 435,000 new diagnoses of sexually transmitted infections (STIs) in England. Most were among heterosexual people under 25 and men who have sex with men (Sexually transmitted infections and chlamydia screening in England: 2015 Public Health England). In the UK as a whole, 6,095 people were diagnosed with HIV in 2015 (National HIV surveillance data tables Public Health England). Over half of these were men who have sex with men (3,320). In the heterosexual population a disproportionate number of diagnoses were among black Africans.\n\nCondoms can protect against many STIs including HIV, chlamydia and gonorrhoea. They offer less protection against STIs transmitted by skin-to-skin contact, such as genital herpes and warts. In the UK in 2011, the cost of treating STIs (excluding HIV) was estimated at £620\xa0million (Unprotected nation Family Planning Association).\n\nCost can be a major barrier to condom use, particularly for poorer people (Barriers to condom use Sakar 2008). Social norms and religious and cultural beliefs can also prevent people from using them because of stigma or embarrassment.\n\nSome condom schemes only provide free or cost-price condoms. Others combine this with information or support. The C‑Card scheme is probably the most widespread UK scheme. Local authorities commission these and define who is eligible. Typically they focus on people aged 13 to 24 (see Brook and Public Health England's C-Card condom distribution schemes).\n\nThis guideline will help local authorities and the NHS reduce STIs, a key objective in Department of Health's. A framework for sexual health improvement in England.\n\nLocal authorities are responsible for commissioning and delivering all community and pharmacy contraceptive services. See Public Health England's, Making it work: a guide to whole system commissioning for sexual health, reproductive health and HIV. NHS England commissions contraception schemes provided as an additional service under the GP contract, and sexual health services in prisons.", 'Glossary': "# Black Africans\n\nThe term 'black African' includes anyone who identifies themselves as black African, whether they are migrants from Africa, African descendants or African nationals.\n\n# Competence\n\nIn this guideline, competence refers to an assessment of whether a young person has maturity and understanding to make decisions and provide consent. This is sometimes called 'Gillick competence' and may be applied through 'Fraser guidelines' (see section 6 of Brook and Public Health England's C-Card condom distribution schemes).\n\n# Dental dam\n\nA thin, square piece of rubber that is placed over the labia or anus during oral-vaginal or oral-anal intercourse.\n\n# Post-exposure prophylaxis (PEP)\n\nA month-long course of drugs that can prevent HIV infection after the virus has entered a person's body. The sooner PEP is started, the more likely it is to work. A course of PEP needs to start within 72\xa0hours of exposure otherwise it is unlikely to work.\n\n# Public sex environments\n\nPublic areas where people go for consensual sexual contact (both same sex and opposite sex).\n\n# Sex-on-premises venues\n\nThis term is used for commercial venues, as opposed to public spaces and parks, where men who have sex with men can meet and have sexual relations on site. A similar term, 'on-premises club', is used by heterosexual swingers to describe a sex club where non-commercial sexual activity takes place.\n\nFor a glossary of public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster."}	https://www.nice.org.uk/guidance/ng68	This guideline covers condom distribution schemes. The aim is to reduce the risk of sexually transmitted infections (STIs). In addition, these schemes can provide a good introduction to broader sexual and reproductive health services, especially for younger people, and help prevent unplanned pregnancies.
21244786d7e77e0d4ee753c0670792cc894a550f	nice	Minimally invasive sacroiliac joint fusion surgery for chronic sacroiliac pain	Minimally invasive sacroiliac joint fusion surgery for chronic sacroiliac pain Evidence-based recommendations on minimally invasive sacroiliac joint fusion surgery for chronic sacroiliac pain in adults. This involves fixing the sacrum to the ilium using 2 or 3 metal implants. # Recommendations Current evidence on the safety and efficacy of minimally invasive sacroiliac (SI) joint fusion surgery for chronic SI pain is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Patients having this procedure should have a confirmed diagnosis of unilateral or bilateral SI joint dysfunction due to degenerative sacroiliitis or SI joint disruption. This technically challenging procedure should only be done by surgeons who regularly use image-guided surgery for implant placement. The surgeons should also have had specific training and expertise in minimally invasive SI joint fusion surgery for chronic SI pain.# Indications and current treatments Chronic pain in the lower back triggered from the sacroiliac (SI) joint occurs in 15% to 30% of patients with low back pain. The causes of SI joint pain include degenerative sacroiliitis, osteoarthritis, SI joint disruptions from trauma or pregnancy, problems after lumbar spinal fixation techniques, anatomical abnormalities such as scoliosis, infection, gout, tumour or idiopathic causes. Conservative treatments for SI joint pain include analgesics, non-steroidal anti-inflammatory drugs, physiotherapy, manipulative therapy, intra-articular SI joint corticosteroid injections, periarticular injections, botulinum toxin injections and radiofrequency denervation. Surgical treatment is considered for persistent chronic symptoms that are unresponsive to conservative treatment. Surgical techniques include open SI joint fusion surgery or minimally invasive SI joint fusion using percutaneous implants to stabilise the joint and treat joint pain.# The procedure Minimally invasive surgical fusion of the sacroiliac (SI) joint is done with the patient under general or spinal anaesthesia and in a prone position. Fluoroscopic guidance is used. Using a lateral transarticular approach, the SI joint is accessed laterally through a small incision made in the buttock to reach the ilium. A pin is passed through the ilium across the SI joint into the centre of the sacrum, avoiding the neural foramen. A drill is then used to create a pathway through the ilium to the sacrum. An implant is inserted (with the lateral portion of the implant sitting in the ilium and the medial end in the sacrum), spanning the SI joint. Typically, 3 implants are used. Treatment of both SI joints can be done at the same time, or in staged procedures. After surgery, patients are advised to make a gradual return to full weight bearing over several weeks, using a walker for assistance, and then have physiotherapy.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. In a randomised controlled trial (RCT) of 148 patients with sacroiliac (SI) joint dysfunction comparing minimally invasive SI joint fusion (n=102) with non-surgical management (NSM, n=46), success rates at 6 months were higher in the minimally invasive SI joint fusion group (81% versus 26% ; Bayesian posterior probability of superiority >0.9999). (Success was defined as a composite of pain reduction from baseline visual analogue scale pain score by at least 20 mm, absence of device-related serious adverse events or neurological worsening, and absence of surgical re-intervention.) In a prospective case series of 172 patients, intention-to-treat success rate was 80% (119/149) at 24 months (Bayesian posterior probability of superiority >0.9999). In a systematic review of SI joint fusion in 430 patients, in those who had minimally invasive SI joint fusion (n=299), radiographically confirmed fusion rates (determined by CT or plain radiograph) were 13% to 100% (in 4 out of 9 studies) at a mean follow-up of 21 months. In the prospective case series of 172 patients, CT scan at 1‑year follow-up showed 97% bone adherence to at least 2 implants on both the iliac and sacral sides, with moderate rates of bone growth across the SI joint. In the RCT of 148 patients, in the SI joint fusion group (n=102), mean joint pain (measured using a 0–100 VAS) improved from 82.3 at baseline to 30.4 at 6‑month follow-up (p<0.001), 28.3 at 12‑month follow-up (p<0.001) and 26.7 at the 24‑month follow-up (p<0.001). In the NSM group, mean SI joint pain improved from 82.2 at baseline to 70.3 at 6 months (p=0.001). Similarly, in the SI joint fusion group, mean Oswestry Disability Index (ODI) decreased from 57.2 at baseline to 29.9 at 6 months (p<0.001), 28.1 at 12 months (p<0.001) and 28.7 at 24 months (p<0.001). In the NSM group, mean ODI decreased from 56.0 at baseline to 51.6 at 6 months (p=0.06). There were clinically important improvements from baseline (VAS more than 20.0 points; ODI more than 15.0 points) and sustained clinical benefit (VAS more than 25.0 or less than 35.0 points; ODI more than 18.8 points) in the SI joint fusion group compared with patients in the NSM group. In a systematic review and meta-analysis of 432 patients on minimally invasive SI joint fusion using a lateral transarticular approach, the random effects meta-analysis (RMA) mean pain score decreased from a baseline of 8.1 (95% confidence interval 7.8 to 8.4) to 2.8 (95% CI 2.4 to 3.2) at 6 months, 2.7 (95% CI 2.1 to 3.3) at 12 months and 2.0 (95% CI 1.4 to 2.5) at 24 months. ODI decreased from an RMA mean score of 56.6 (95% CI 51.0 to 61.5) at baseline, 30.3 (95% CI 22.5 to 38.0) at 6 months and 25.1 (95% CI 12.3 to 37.9) at 12 months. In an RCT of 103 patients, SI joint function ratings (measured using the active straight leg raise test on a scale of 0 to 6) decreased statistically significantly more (p<0.0001) in the SI joint fusion group (from 4.0 to 2.0) than in the conservative management group (from 3.8 to 3.7). The proportion of patients who could raise the leg with no difficulty at 6 months was 71% in the SI joint fusion group and 32% in conservative management group (p=0.0002). In the systematic review and meta-analysis of 432 patients, improvements in quality of life (measured on the SF‑36 physical component score ) were consistent in 2 studies of triangular implants; scores increased from 30.2 and 30.7 at baseline to 42.8 and 37.0 at 6 months respectively. In the RCT of 148 patients, in the SI joint fusion group (n=102), quality of life (measured with an EQ‑5D time trade‑off index utility of current health) improved from 0.44 at baseline to 0.72 at 6‑month follow-up (p<0.001), 0.74 at 12‑month follow-up (p<0.001) and 0.72 at the 24‑month follow-up (p<0.001). The mean change was only 0.05 points in the NSM group at 6 months (p=0.17). For patients who crossed over (n=35), the change was small at 6 months (0.02; p=0.66) but, after crossover, improved from 0.47 at 6 months to 0.73 at 12 months (0.26 point increase, p<0.001). In those who did not cross over (n=11), the change from 6 months to 12 months was small (p=0.008). Quality of life (measured using SF‑36) showed that mean 6‑month changes in PCS and mental health component summary scores (MCS) were statistically significant (p<0.001) in the fusion group compared with the NSM group. Patients who crossed over from NSM after 6 months had larger improvements in PCS and MCS scores compared with those who did not cross over. In the systematic review of SI joint fusion of 430 patients, clinical and patient satisfaction with surgery (determined by subjective questionnaires and judged by patients' stated satisfaction with surgery) ranged from 56% to 100% in 299 patients (from 9 studies) who had minimally invasive SI joint fusion, at a mean follow-up of 21 months. In the RCT of 103 patients, satisfaction levels were higher at 3 and 6 months in the SI joint fusion group compared with the conservative management group (p<0.0001 by proportional odds logistic regression). The proportion of patients reporting that they would have the procedure again was also higher in the SI joint fusion group (p=0.0001). The specialist advisers listed key efficacy outcomes as improvement in pain and function, and reduced length of hospital stay. Eight commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. The overall complication rate was 4% (204/5,319) in a prospective database analysis of post-marketing complaints for patients having minimally invasive sacroiliac (SI) joint fusion for degenerative sacroiliitis and SI joint disruption. Pain was the most commonly reported event (2% ), followed by nerve impingement in less than 1% (n=48) and recurrent SI joint pain in less than 1% (n=43). The overall complication rate was 13% (57/432) in a systematic review and meta-analysis of 432 patients from 12 cohort studies on minimally invasive SI joint fusion using a lateral transarticular approach. The most common events were surgical wound problems (4%, 17/432), trochanteric bursitis (2%, 8/432), facet pain (less than 1%, 3/432), recurrent SI pain (less than 1%, 3/432), toe and foot numbness (less than 1%, 2/432), and nerve root impingement needing revision in 2% (9/432) patients. In a systematic review on SI joint fusion including 430 patients, for those having minimally invasive SI joint fusion (n=299 in 9 studies), complications reported were new-onset facet joint pain, trochanteric bursitis, deep wound infections, new onset of low back or buttock pain, worsening knee or leg pain, superficial cellulitis, radiculopathy, large haematomas, vascular necrosis of the hip, piriformis syndrome, implant penetration into the sacral neural foramen, peripheral neuropathy, a non-displaced fracture, pulmonary embolism and deep vein thrombosis. The device-related adverse event rate was 1% (75/5,319) in the prospective database analysis of post-marketing complaints. These were related to issues with binding, bending or breakage of the Steinmann pin (n=43), pin advancement difficulties (n=14), radiographic halo (n=13) and device migration (n=4). In a randomised controlled trial (RCT) of 148 patients, device-related events were reported in 3% (3/102) in the SI joint fusion group at 6‑month follow-up. Two events (1 implant-related impingement on a sacral nerve causing pain and needing immediate revision and 1 hairline ilium fracture adjacent to implant causing pain resolved after revision surgery) were definitely related to the device and 1 event (SI joint pain because of suboptimal placement of implants, which needed revision surgery) was deemed probably related to the device. The procedure-related adverse event rate was 2% (108/5,319) in the prospective database analysis of post-marketing complaints. Improper implant placement was reported in 1% (n=72) of patients. Improper device length was reported in less than 1% (n=36) of patients, with most implants deemed to be too short (n=30). In the RCT of 148 patients, 19% (19/102) of the events were probably or definitely related to the SI joint fusion and 11% (5/46) of the events were related to non-surgical management (NSM) at 6‑month follow-up. Events related to surgical procedure included neuropathic symptoms (n=1), postoperative medical problems (n=4; urinary retention, nausea/vomiting, atrial fibrillation), SI joint pain or trochanteric bursitis (n=7), surgical wound problems (n=5), iliac fracture (n=1) and asymptomatic physical examination findings (n=1). With NSM, 3 patients reported SI joint pain after treatment; 1 had flushing and shortness of breath after SI joint injection and 1 had worsening SI joint pain related to physiotherapy. The revision rate was 2% (9/432) in the systematic review and meta-analysis of 432 patients. Reoperation rate ranged from 0% to 17% (mean 6%) in the 299 patients who had minimally invasive SI joint fusion surgery in the systematic review of 430 patients (in 9 studies; mean follow-up of 21 months). In the prospective database analysis of post-marketing complaints, the reoperation rate was 2% (n=96/5,319) at a median follow-up of 4 months. Revisions were typically done in the early postoperative period (median 19 days) for treatment of a symptomatic wrongly positioned implant (less than 1%, n=46), or to correct an improperly sized implant in an asymptomatic patient (less than 1%, n=10). Revisions in the late postoperative period were done (at a median of 297 days) to treat symptom recurrence (n=34) or for continued pain of undetermined aetiology (n=6). Revision outcomes and management in these patients were not reported. Postoperative infection rate was 4% (n=19) at 6 months in a retrospective analysis of 469 patients treated by minimally invasive SI joint fusion. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: non-union and implant loosening, which would be similar to pseudoarthrosis. They considered that the following were theoretical adverse events: residual pain and injury to L5 or sacral nerve roots by wrong positioning of the screw (implant). Eight commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information For related NICE guidance, see the NICE website. Patient commentaries supported use of the procedure. They were largely positive and many patients described having pain relief. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2414-1	{'Recommendations': 'Current evidence on the safety and efficacy of minimally invasive sacroiliac (SI) joint fusion surgery for chronic SI pain is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatients having this procedure should have a confirmed diagnosis of unilateral or bilateral SI joint dysfunction due to degenerative sacroiliitis or SI joint disruption.\n\nThis technically challenging procedure should only be done by surgeons who regularly use image-guided surgery for implant placement. The surgeons should also have had specific training and expertise in minimally invasive SI joint fusion surgery for chronic SI pain.', 'Indications and current treatments': 'Chronic pain in the lower back triggered from the sacroiliac (SI) joint occurs in 15% to 30% of patients with low back pain. The causes of SI joint pain include degenerative sacroiliitis, osteoarthritis, SI joint disruptions from trauma or pregnancy, problems after lumbar spinal fixation techniques, anatomical abnormalities such as scoliosis, infection, gout, tumour or idiopathic causes.\n\nConservative treatments for SI joint pain include analgesics, non-steroidal anti-inflammatory drugs, physiotherapy, manipulative therapy, intra-articular SI joint corticosteroid injections, periarticular injections, botulinum toxin injections and radiofrequency denervation. Surgical treatment is considered for persistent chronic symptoms that are unresponsive to conservative treatment. Surgical techniques include open SI joint fusion surgery or minimally invasive SI joint fusion using percutaneous implants to stabilise the joint and treat joint pain.', 'The procedure': 'Minimally invasive surgical fusion of the sacroiliac (SI) joint is done with the patient under general or spinal anaesthesia and in a prone position. Fluoroscopic guidance is used. Using a lateral transarticular approach, the SI joint is accessed laterally through a small incision made in the buttock to reach the ilium. A pin is passed through the ilium across the SI joint into the centre of the sacrum, avoiding the neural foramen. A drill is then used to create a pathway through the ilium to the sacrum. An implant is inserted (with the lateral portion of the implant sitting in the ilium and the medial end in the sacrum), spanning the SI joint. Typically, 3\xa0implants are used.\n\nTreatment of both SI joints can be done at the same time, or in staged procedures. After surgery, patients are advised to make a gradual return to full weight bearing over several weeks, using a walker for assistance, and then have physiotherapy.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nIn a randomised controlled trial (RCT) of 148\xa0patients with sacroiliac (SI) joint dysfunction comparing minimally invasive SI joint fusion (n=102) with non-surgical management (NSM, n=46), success rates at 6\xa0months were higher in the minimally invasive SI joint fusion group (81% [83/102] versus 26% [12/46]; Bayesian posterior probability of superiority >0.9999). (Success was defined as a composite of pain reduction from baseline visual analogue scale [VAS] pain score by at least 20\xa0mm, absence of device-related serious adverse events or neurological worsening, and absence of surgical re-intervention.) In a prospective case series of 172\xa0patients, intention-to-treat success rate was 80% (119/149) at 24\xa0months (Bayesian posterior probability of superiority >0.9999).\n\nIn a systematic review of SI joint fusion in 430\xa0patients, in those who had minimally invasive SI joint fusion (n=299), radiographically confirmed fusion rates (determined by CT or plain radiograph) were 13% to 100% (in 4\xa0out of 9\xa0studies) at a mean follow-up of 21\xa0months. In the prospective case series of 172\xa0patients, CT scan at 1‑year follow-up showed 97% bone adherence to at least 2\xa0implants on both the iliac and sacral sides, with moderate rates of bone growth across the SI joint.\n\nIn the RCT of 148\xa0patients, in the SI joint fusion group (n=102), mean joint pain (measured using a 0–100\xa0VAS) improved from 82.3 at baseline to 30.4 at 6‑month follow-up (p<0.001), 28.3 at 12‑month follow-up (p<0.001) and 26.7 at the 24‑month follow-up (p<0.001). In the NSM group, mean SI joint pain improved from 82.2 at baseline to 70.3 at 6\xa0months (p=0.001). Similarly, in the SI joint fusion group, mean Oswestry Disability Index (ODI) decreased from 57.2 at baseline to 29.9 at 6\xa0months (p<0.001), 28.1 at 12\xa0months (p<0.001) and 28.7 at 24\xa0months (p<0.001). In the NSM group, mean ODI decreased from 56.0 at baseline to 51.6 at 6\xa0months (p=0.06). There were clinically important improvements from baseline (VAS more than 20.0\xa0points; ODI more than 15.0\xa0points) and sustained clinical benefit (VAS more than 25.0\xa0or less than 35.0\xa0points; ODI more than 18.8\xa0points) in the SI joint fusion group compared with patients in the NSM group.\n\nIn a systematic review and meta-analysis of 432\xa0patients on minimally invasive SI joint fusion using a lateral transarticular approach, the random effects meta-analysis (RMA) mean pain score decreased from a baseline of 8.1 (95% confidence interval [CI] 7.8 to 8.4) to 2.8 (95% CI 2.4 to 3.2) at 6\xa0months, 2.7 (95%\xa0CI 2.1 to 3.3) at 12\xa0months and 2.0 (95%\xa0CI 1.4 to 2.5) at 24\xa0months. ODI decreased from an RMA mean score of 56.6 (95%\xa0CI 51.0 to 61.5) at baseline, 30.3 (95%\xa0CI 22.5 to 38.0) at 6\xa0months and 25.1 (95%\xa0CI 12.3 to 37.9) at 12\xa0months.\n\nIn an RCT of 103\xa0patients, SI joint function ratings (measured using the active straight leg raise test on a scale of 0\xa0to\xa06) decreased statistically significantly more (p<0.0001) in the SI joint fusion group (from 4.0 to 2.0) than in the conservative management group (from 3.8 to 3.7). The proportion of patients who could raise the leg with no difficulty at 6\xa0months was 71% in the SI joint fusion group and 32% in conservative management group (p=0.0002).\n\nIn the systematic review and meta-analysis of 432\xa0patients, improvements in quality of life (measured on the SF‑36 physical component score [PCS]) were consistent in 2\xa0studies of triangular implants; scores increased from 30.2 and 30.7 at baseline to 42.8 and 37.0 at 6\xa0months respectively. In the RCT of 148\xa0patients, in the SI joint fusion group (n=102), quality of life (measured with an EQ‑5D time trade‑off index utility of current health) improved from 0.44 at baseline to 0.72 at 6‑month follow-up (p<0.001), 0.74 at 12‑month follow-up (p<0.001) and 0.72 at the 24‑month follow-up (p<0.001). The mean change was only 0.05\xa0points in the NSM group at 6\xa0months (p=0.17). For patients who crossed over (n=35), the change was small at 6\xa0months (0.02; p=0.66) but, after crossover, improved from 0.47 at 6\xa0months to 0.73 at 12\xa0months (0.26\xa0point increase, p<0.001). In those who did not cross over (n=11), the change from 6\xa0months to 12\xa0months was small (p=0.008). Quality of life (measured using SF‑36) showed that mean 6‑month changes in PCS and mental health component summary scores (MCS) were statistically significant (p<0.001) in the fusion group compared with the NSM group. Patients who crossed over from NSM after 6\xa0months had larger improvements in PCS and MCS scores compared with those who did not cross over.\n\nIn the systematic review of SI joint fusion of 430\xa0patients, clinical and patient satisfaction with surgery (determined by subjective questionnaires and judged by patients' stated satisfaction with surgery) ranged from 56% to 100% in 299\xa0patients (from 9\xa0studies) who had minimally invasive SI joint fusion, at a mean follow-up of 21\xa0months. In the RCT of 103\xa0patients, satisfaction levels were higher at 3\xa0and 6\xa0months in the SI joint fusion group compared with the conservative management group (p<0.0001 by proportional odds logistic regression). The proportion of patients reporting that they would have the procedure again was also higher in the SI joint fusion group (p=0.0001).\n\nThe specialist advisers listed key efficacy outcomes as improvement in pain and function, and reduced length of hospital stay.\n\nEight commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nThe overall complication rate was 4% (204/5,319) in a prospective database analysis of post-marketing complaints for patients having minimally invasive sacroiliac (SI) joint fusion for degenerative sacroiliitis and SI joint disruption. Pain was the most commonly reported event (2% [119/5,319]), followed by nerve impingement in less than 1% (n=48) and recurrent SI joint pain in less than 1%\xa0(n=43).\n\nThe overall complication rate was 13% (57/432) in a systematic review and meta-analysis of 432\xa0patients from 12\xa0cohort studies on minimally invasive SI joint fusion using a lateral transarticular approach. The most common events were surgical wound problems (4%, 17/432), trochanteric bursitis (2%, 8/432), facet pain (less than 1%, 3/432), recurrent SI pain (less than 1%, 3/432), toe and foot numbness (less than 1%, 2/432), and nerve root impingement needing revision in 2% (9/432) patients. In a systematic review on SI joint fusion including 430\xa0patients, for those having minimally invasive SI joint fusion (n=299 in 9\xa0studies), complications reported were new-onset facet joint pain, trochanteric bursitis, deep wound infections, new onset of low back or buttock pain, worsening knee or leg pain, superficial cellulitis, radiculopathy, large haematomas, vascular necrosis of the hip, piriformis syndrome, implant penetration into the sacral neural foramen, peripheral neuropathy, a non-displaced fracture, pulmonary embolism and deep vein thrombosis.\n\nThe device-related adverse event rate was 1% (75/5,319) in the prospective database analysis of post-marketing complaints. These were related to issues with binding, bending or breakage of the Steinmann pin (n=43), pin advancement difficulties (n=14), radiographic halo (n=13) and device migration (n=4). In a randomised controlled trial (RCT) of 148\xa0patients, device-related events were reported in 3% (3/102) in the SI joint fusion group at 6‑month follow-up. Two events (1\xa0implant-related impingement on a sacral nerve causing pain and needing immediate revision and 1\xa0hairline ilium fracture adjacent to implant causing pain resolved after revision surgery) were definitely related to the device and 1\xa0event (SI joint pain because of suboptimal placement of implants, which needed revision surgery) was deemed probably related to the device.\n\nThe procedure-related adverse event rate was 2% (108/5,319) in the prospective database analysis of post-marketing complaints. Improper implant placement was reported in 1% (n=72) of patients. Improper device length was reported in less than 1% (n=36) of patients, with most implants deemed to be too short (n=30). In the RCT of 148\xa0patients, 19% (19/102) of the events were probably or definitely related to the SI joint fusion and 11% (5/46) of the events were related to non-surgical management (NSM) at 6‑month follow-up. Events related to surgical procedure included neuropathic symptoms (n=1), postoperative medical problems (n=4; urinary retention, nausea/vomiting, atrial fibrillation), SI joint pain or trochanteric bursitis (n=7), surgical wound problems (n=5), iliac fracture (n=1) and asymptomatic physical examination findings (n=1). With NSM, 3\xa0patients reported SI joint pain after treatment; 1\xa0had flushing and shortness of breath after SI joint injection and 1\xa0had worsening SI joint pain related to physiotherapy.\n\nThe revision rate was 2% (9/432) in the systematic review and meta-analysis of 432\xa0patients. Reoperation rate ranged from 0% to 17% (mean 6%) in the 299\xa0patients who had minimally invasive SI joint fusion surgery in the systematic review of 430\xa0patients (in 9\xa0studies; mean follow-up of 21\xa0months). In the prospective database analysis of post-marketing complaints, the reoperation rate was 2% (n=96/5,319) at a median follow-up of 4\xa0months. Revisions were typically done in the early postoperative period (median 19\xa0days) for treatment of a symptomatic wrongly positioned implant (less than 1%, n=46), or to correct an improperly sized implant in an asymptomatic patient (less than 1%, n=10). Revisions in the late postoperative period were done (at a median of 297\xa0days) to treat symptom recurrence (n=34) or for continued pain of undetermined aetiology (n=6). Revision outcomes and management in these patients were not reported.\n\nPostoperative infection rate was 4% (n=19) at 6\xa0months in a retrospective analysis of 469\xa0patients treated by minimally invasive SI joint fusion.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: non-union and implant loosening, which would be similar to pseudoarthrosis. They considered that the following were theoretical adverse events: residual pain and injury to L5 or sacral nerve roots by wrong positioning of the screw (implant).\n\nEight commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentaries supported use of the procedure. They were largely positive and many patients described having pain relief.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2414-1'}	https://www.nice.org.uk/guidance/ipg578	Evidence-based recommendations on minimally invasive sacroiliac joint fusion surgery for chronic sacroiliac pain in adults. This involves fixing the sacrum to the ilium using 2 or 3 metal implants.
b7875982de1d654c30a03241654bb984a1aff397	nice	Irritable bowel syndrome in adults: diagnosis and management	Irritable bowel syndrome in adults: diagnosis and management This guideline covers diagnosing and managing irritable bowel syndrome (IBS) in people aged 18 and over. It details how to accurately diagnose IBS, and aims to improve the quality of life for adults with IBS by promoting effective management using dietary and lifestyle advice, pharmacological therapy and referral for psychological interventions. # Introduction Irritable bowel syndrome (IBS) is a chronic, relapsing and often life‑long disorder. It is characterised by the presence of abdominal pain or discomfort, which may be associated with defaecation and/or accompanied by a change in bowel habit. Symptoms may include disordered defaecation (constipation or diarrhoea or both) and abdominal distension, usually referred to as bloating. Symptoms sometimes overlap with other gastrointestinal disorders such as non‑ulcer dyspepsia or coeliac disease. People with IBS present to primary care with a wide range of symptoms, some of which they may be reluctant to disclose without sensitive questioning. People with IBS present with varying symptom profiles, most commonly 'diarrhoea predominant', 'constipation predominant' or alternating symptom profiles. IBS most often affects people between the ages of 20 and 30 years and is twice as common in women as in men. Prevalence in the general population is estimated to be between 10% and 20%. Recent trends indicate that there is also a significant prevalence of IBS in older people. IBS diagnosis should be a consideration when an older person presents with unexplained abdominal symptoms. Key aspects of this guideline include establishing a diagnosis; referral into secondary care only after identification of 'red flags' (symptoms and/or features that may be caused by another condition that needs investigation); providing lifestyle advice; drug and psychological interventions; and referral and follow‑up. The guideline refers to NICE's guideline on suspected cancer: recognition and referral in relation to appropriate referral to secondary care. The main aims of this guideline are to: provide positive diagnostic criteria for people presenting with symptoms suggestive of IBS provide guidance on clinical and cost‑effective management of IBS in primary care determine clinical indications for referral to IBS services, taking into account cost effectiveness. # Recommendations about medicines The guideline will assume that prescribers will use a medicine's summary of product characteristics to inform decisions made with individual patients. This guideline recommends some medicines for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Use of medicines outside their licensed indications ('off‑label use') are noted in the recommendations.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Diagnosis and management of irritable bowel syndrome (IBS) can be frustrating, both for people presenting with IBS symptoms and for clinicians. Both parties need to understand the limitations of current knowledge about IBS and to recognise the chronic nature of the condition. # Diagnosis of IBS Confirming a diagnosis of IBS is a crucial part of this guideline. The primary aim should be to establish the person's symptom profile, with abdominal pain or discomfort being a key symptom. It is also necessary to establish the quantity and quality of the pain or discomfort, and to identify its site (which can be anywhere in the abdomen) and whether this varies. This distinguishes IBS from cancer‑related pain, which typically has a fixed site. When establishing bowel habit, showing people the Bristol Stool Form Scale (see appendix I of the full guideline) may help them with description, particularly when determining quality and quantity of stool. People presenting with IBS symptoms commonly report incomplete evacuation/rectal hypersensitivity, as well as urgency, which is increased in diarrhoea‑predominant IBS. About 20% of people experiencing faecal incontinence disclose their incontinence only if asked. People who present with symptoms of IBS should be asked open questions to establish the presence of such symptoms (for example, 'tell me about how your symptoms affect aspects of your daily life, such as leaving the house'). Healthcare professionals should be sensitive to the cultural, ethnic and communication needs of people for whom English is not a first language or who may have cognitive and/or behavioural problems or disabilities. These factors should be taken into consideration to facilitate effective consultation. ## Initial assessment Healthcare professionals should consider assessment for IBS if the person reports having had any of the following symptoms for at least 6 months: Abdominal pain or discomfort Bloating Change in bowel habit. All people presenting with possible IBS symptoms should be assessed and clinically examined for the following 'red flag' indicators and should be referred to secondary care for further investigation if any are present: signs and symptoms of cancer in line with the NICE guideline on suspected cancer: recognition and referral inflammatory markers for inflammatory bowel disease. This recommendation has been withdrawn. A diagnosis of IBS should be considered only if the person has abdominal pain or discomfort that is either relieved by defaecation or associated with altered bowel frequency or stool form. This should be accompanied by at least 2 of the following 4 symptoms: altered stool passage (straining, urgency, incomplete evacuation) abdominal bloating (more common in women than men), distension, tension or hardness symptoms made worse by eating passage of mucus. Other features such as lethargy, nausea, backache and bladder symptoms are common in people with IBS, and may be used to support the diagnosis. ## Diagnostic tests In people who meet the IBS diagnostic criteria, the following tests should be undertaken to exclude other diagnoses: full blood count (FBC) erythrocyte sedimentation rate (ESR) or plasma viscosity c‑reactive protein (CRP) antibody testing for coeliac disease (endomysial antibodies or tissue transglutaminase ). The following tests are not necessary to confirm diagnosis in people who meet the IBS diagnostic criteria: ultrasound rigid or flexible sigmoidoscopy colonoscopy; barium enema thyroid function test faecal ova and parasite test faecal occult blood hydrogen breath test (for lactose intolerance and bacterial overgrowth). # Clinical management of IBS ## Dietary and lifestyle advice People with IBS should be given information that explains the importance of self‑help in effectively managing their IBS. This should include information on general lifestyle, physical activity, diet and symptom‑targeted medication. Healthcare professionals should encourage people with IBS to identify and make the most of their available leisure time and to create relaxation time. Healthcare professionals should assess the physical activity levels of people with IBS, ideally using the General Practice Physical Activity Questionnaire (GPPAQ; see appendix J of the full guideline). People with low activity levels should be given brief advice and counselling to encourage them to increase their activity levels. Diet and nutrition should be assessed for people with IBS and the following general advice given. Have regular meals and take time to eat. Avoid missing meals or leaving long gaps between eating. Drink at least 8 cups of fluid per day, especially water or other non‑caffeinated drinks, for example herbal teas. Restrict tea and coffee to 3 cups per day. Reduce intake of alcohol and fizzy drinks. It may be helpful to limit intake of high‑fibre food (such as wholemeal or high‑fibre flour and breads, cereals high in bran, and whole grains such as brown rice). Reduce intake of 'resistant starch' (starch that resists digestion in the small intestine and reaches the colon intact), which is often found in processed or re‑cooked foods. Limit fresh fruit to 3 portions per day (a portion should be approximately 80 g). People with diarrhoea should avoid sorbitol, an artificial sweetener found in sugar‑free sweets (including chewing gum) and drinks, and in some diabetic and slimming products. People with wind and bloating may find it helpful to eat oats (such as oat‑based breakfast cereal or porridge) and linseeds (up to 1 tablespoon per day). Healthcare professionals should review the fibre intake of people with IBS, adjusting (usually reducing) it while monitoring the effect on symptoms. People with IBS should be discouraged from eating insoluble fibre (for example, bran). If an increase in dietary fibre is advised, it should be soluble fibre such as ispaghula powder or foods high in soluble fibre (for example, oats). People with IBS who choose to try probiotics should be advised to take the product for at least 4 weeks while monitoring the effect. Probiotics should be taken at the dose recommended by the manufacturer. Healthcare professionals should discourage the use of aloe vera in the treatment of IBS. If a person's IBS symptoms persist while following general lifestyle and dietary advice, offer advice on further dietary management. Such advice should: include single food avoidance and exclusion diets (for example, a low FODMAP diet) -nly be given by a healthcare professional with expertise in dietary management. ## Pharmacological therapy Decisions about pharmacological management should be based on the nature and severity of symptoms. The recommendations made below assume that the choice of single or combination medication is determined by the predominant symptom(s). Healthcare professionals should consider prescribing antispasmodic agents for people with IBS. These should be taken as required, alongside dietary and lifestyle advice. Laxatives should be considered for the treatment of constipation in people with IBS, but people should be discouraged from taking lactulose. Consider linaclotide for people with IBS only if: -ptimal or maximum tolerated doses of previous laxatives from different classes have not helped and they have had constipation for at least 12 months. Follow up people taking linaclotide after 3 months. Loperamide should be the first choice of antimotility agent for diarrhoea in people with IBS. People with IBS should be advised how to adjust their doses of laxative or antimotility agent according to the clinical response. The dose should be titrated according to stool consistency, with the aim of achieving a soft, well‑formed stool (corresponding to Bristol Stool Form Scale type 4). Consider tricyclic antidepressants (TCAs) as second‑line treatment for people with IBS if laxatives, loperamide or antispasmodics have not helped. Start treatment at a low dose (5 mg to 10 mg equivalent of amitriptyline), taken once at night, and review regularly. Increase the dose if needed, but not usually beyond 30 mg. At the time of publication (February 2015), TCAs and selective serotonin reuptake inhibitors (SSRIs) did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Consider SSRIs for people with IBS only if TCAs are ineffective. At the time of publication (February 2015), TCAs and SSRIs did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Take into account the possible side effects when offering TCAs or SSRIs to people with IBS. Follow up people taking either of these drugs for the first time at low doses for the treatment of pain or discomfort in IBS after 4 weeks and then every 6 to 12 months. At the time of publication (February 2015), TCAs and SSRIs did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. For guidance on safe prescribing of antidepressants (such as TCAs and SSRIs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. ## Psychological interventions Referral for psychological interventions (cognitive behavioural therapy , hypnotherapy and/or psychological therapy) should be considered for people with IBS who do not respond to pharmacological treatments after 12 months and who develop a continuing symptom profile (described as refractory IBS). ## Complementary and alternative medicine (CAM) The use of acupuncture should not be encouraged for the treatment of IBS. The use of reflexology should not be encouraged for the treatment of IBS. ## Follow-up Follow‑up should be agreed between the healthcare professional and the person with IBS, based on the response of the person's symptoms to interventions. This should form part of the annual patient review. The emergence of any 'red flag' symptoms during management and follow‑up should prompt further investigation and/or referral to secondary care. # Recommendations for research In 2008, the guideline development group made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. As part of the 2015 update, the committee made 3 additional recommendations for research on the clinical and cost effectiveness of a low FODMAP diet, low‑dose tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in primary care, and computerised CBT and mindfulness therapy. These can be found in the addendum. # Low-dose antidepressants Are low‑dose TCAs, SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) effective as first‑line treatment for irritable bowel syndrome (IBS), and which is the most effective and safe option? ## Why this is important Reviews have shown that TCAs and SSRIs have each been compared with placebo in the treatment of IBS, but not at low doses. In practice, TCAs are used at higher doses, and concordance with treatment is poor because of side effects. The Guideline Development Group clinicians believe that at low doses (5 mg to 10 mg equivalent of amitriptyline), TCAs could be the treatment of choice for IBS, but there is a lack of evidence to support this. A newer type of antidepressant, SNRIs, may also be useful in the treatment of IBS‑associated pain. A large randomised trial is proposed, comparing an SSRI, a TCA and an SNRI with placebo. Participants should be adults with a positive diagnosis of IBS, stratified by type of IBS and randomised to treatments. The type of IBS is defined by the predominant bowel symptom: diarrhoea, constipation or alternating symptoms. The primary outcome should be global improvement in IBS symptoms. Health‑related quality of life should also be measured, and adverse effects recorded. Study outcomes should be assessed 12, 26 and 52 weeks after the start of therapy. # Psychological interventions Are the psychological interventions CBT, hypnotherapy and psychological therapy all equally effective in the management of IBS symptoms, either as first‑line therapies in primary care, or in the treatment of people with IBS that is refractory to other treatments? ## Why this is important Reviews show some evidence of effect when comparing psychological interventions with a control group, with the greatest effect shown in people who have refractory IBS. Many trials are small in size. Certain psychological interventions – namely, CBT, hypnotherapy and psychological therapy – are thought to be useful in helping people with IBS to cope with their symptoms, but it is unclear at what stage these should be given, including whether they should be used as first‑line therapies in primary care. A large randomised trial is proposed, comparing CBT, hypnotherapy and psychological therapy (in particular, psychodynamic interpersonal therapy). Participants should be adults with a positive diagnosis of IBS, and they should be stratified into those with and without refractory IBS and then randomised to treatments. The primary outcome should be global improvement in IBS symptoms. Health‑related quality of life should also be measured, and adverse effects recorded. Study outcomes should be assessed 12, 26 and 52 weeks after the start of therapy. # Refractory IBS What factors contribute to refractory IBS? ## Why this is important Most people with IBS experience symptoms that are relatively short‑lived or that only trouble them on an intermittent basis. Some people, however, develop chronic and severe symptoms that are difficult to treat. There are relatively few prospective studies that have investigated this problem. A large, prospective, population‑based cohort study is proposed, which would evaluate people in the community with IBS symptoms according to measures of bowel symptomatology, physical symptom profile, psychological symptoms, childhood adversity, psychiatric history, social supports, quality of life and other relevant potential predictors. Participants would be re‑evaluated 12 and 24 months later using similar measures. Baseline variables would be used to predict chronicity of symptoms, quality of life and healthcare utilisation at 12 and 24 months. # Relaxation and biofeedback What is the effect of relaxation and biofeedback therapies on IBS symptoms and patient‑related outcomes? ## Why this is important Reviews of biofeedback and relaxation therapies suggest a positive effect on the control of IBS symptoms, but evidence is limited and not sufficient to make recommendations. Patient representation in the Guideline Development Group supports this view, from a personal and anecdotal perspective. Recent developments in computer‑aided biofeedback methods merit investigation. A large randomised trial is proposed to compare relaxation therapy, computer‑aided biofeedback therapy and attention control in primary care. Participants should be adults with a positive diagnosis of IBS, and they should be stratified into those with and without refractory IBS and then randomised to treatments. The primary outcome should be global improvement in IBS symptoms. Health‑related quality of life should also be measured, and adverse effects recorded. Study outcomes should be assessed 12, 26 and 52 weeks after the start of therapy. Qualitative data should be generated relating to how people with IBS perceive their condition. # Herbal medicines Are Chinese and non‑Chinese herbal medicines safe and effective as first‑line therapy in the treatment of IBS, and which is the most effective and safe option? ## Why this is important Reviews of herbal medicines suggest a positive effect on the control of IBS symptoms, but evidence is limited and not sufficient to make recommendations (8 comparisons from the 6 trials provide heterogeneous data, which are very difficult to interpret). A large randomised placebo‑controlled trial is proposed, comparing Chinese and non‑Chinese herbal medicines (both single and multiple compounds) that are available in the UK as standard preparations. Participants should be adults with a positive diagnosis of IBS, and they should be stratified by type of IBS and then randomised to treatments. The primary outcome should be global improvement in IBS symptoms, with symptom scores recorded using a validated scale. Health‑related quality of life should also be measured, and adverse events recorded. Study outcomes should be assessed 12, 26 and 52 weeks post‑intervention.	{'Introduction': "Irritable bowel syndrome (IBS) is a chronic, relapsing and often life‑long disorder. It is characterised by the presence of abdominal pain or discomfort, which may be associated with defaecation and/or accompanied by a change in bowel habit. Symptoms may include disordered defaecation (constipation or diarrhoea or both) and abdominal distension, usually referred to as bloating. Symptoms sometimes overlap with other gastrointestinal disorders such as non‑ulcer dyspepsia or coeliac disease. People with IBS present to primary care with a wide range of symptoms, some of which they may be reluctant to disclose without sensitive questioning.\n\nPeople with IBS present with varying symptom profiles, most commonly 'diarrhoea predominant', 'constipation predominant' or alternating symptom profiles. IBS most often affects people between the ages of 20\xa0and 30\xa0years and is twice as common in women as in men. Prevalence in the general population is estimated to be between 10% and 20%. Recent trends indicate that there is also a significant prevalence of IBS in older people. IBS diagnosis should be a consideration when an older person presents with unexplained abdominal symptoms.\n\nKey aspects of this guideline include establishing a diagnosis; referral into secondary care only after identification of 'red flags' (symptoms and/or features that may be caused by another condition that needs investigation); providing lifestyle advice; drug and psychological interventions; and referral and follow‑up. The guideline refers to NICE's guideline on suspected cancer: recognition and referral in relation to appropriate referral to secondary care.\n\nThe main aims of this guideline are to:\n\nprovide positive diagnostic criteria for people presenting with symptoms suggestive of IBS\n\nprovide guidance on clinical and cost‑effective management of IBS in primary care\n\ndetermine clinical indications for referral to IBS services, taking into account cost effectiveness.\n\n# Recommendations about medicines\n\nThe guideline will assume that prescribers will use a medicine's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some medicines for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Use of medicines outside their licensed indications ('off‑label use') are noted in the recommendations.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nDiagnosis and management of irritable bowel syndrome (IBS) can be frustrating, both for people presenting with IBS symptoms and for clinicians. Both parties need to understand the limitations of current knowledge about IBS and to recognise the chronic nature of the condition.\n\n# Diagnosis of IBS\n\nConfirming a diagnosis of IBS is a crucial part of this guideline. The primary aim should be to establish the person's symptom profile, with abdominal pain or discomfort being a key symptom. It is also necessary to establish the quantity and quality of the pain or discomfort, and to identify its site (which can be anywhere in the abdomen) and whether this varies. This distinguishes IBS from cancer‑related pain, which typically has a fixed site.\n\nWhen establishing bowel habit, showing people the Bristol Stool Form Scale (see appendix\xa0I of the full guideline) may help them with description, particularly when determining quality and quantity of stool. People presenting with IBS symptoms commonly report incomplete evacuation/rectal hypersensitivity, as well as urgency, which is increased in diarrhoea‑predominant IBS. About 20% of people experiencing faecal incontinence disclose their incontinence only if asked. People who present with symptoms of IBS should be asked open questions to establish the presence of such symptoms (for example, 'tell me about how your symptoms affect aspects of your daily life, such as leaving the house'). Healthcare professionals should be sensitive to the cultural, ethnic and communication needs of people for whom English is not a first language or who may have cognitive and/or behavioural problems or disabilities. These factors should be taken into consideration to facilitate effective consultation.\n\n## Initial assessment\n\nHealthcare professionals should consider assessment for IBS if the person reports having had any of the following symptoms for at least 6\xa0months:\n\nAbdominal pain or discomfort\n\nBloating\n\nChange in bowel habit. \n\nAll people presenting with possible IBS symptoms should be assessed and clinically examined for the following 'red flag' indicators and should be referred to secondary care for further investigation if any are present:\n\nsigns and symptoms of cancer in line with the NICE guideline on suspected cancer: recognition and referral\n\ninflammatory markers for inflammatory bowel disease. \n\nThis recommendation has been withdrawn. \n\nA diagnosis of IBS should be considered only if the person has abdominal pain or discomfort that is either relieved by defaecation or associated with altered bowel frequency or stool form. This should be accompanied by at least 2 of the following 4 symptoms:\n\naltered stool passage (straining, urgency, incomplete evacuation)\n\nabdominal bloating (more common in women than men), distension, tension or hardness\n\nsymptoms made worse by eating\n\npassage of mucus. Other features such as lethargy, nausea, backache and bladder symptoms are common in people with IBS, and may be used to support the diagnosis. \n\n## Diagnostic tests\n\nIn people who meet the IBS diagnostic criteria, the following tests should be undertaken to exclude other diagnoses:\n\nfull blood count (FBC)\n\nerythrocyte sedimentation rate (ESR) or plasma viscosity\n\nc‑reactive protein (CRP)\n\nantibody testing for coeliac disease (endomysial antibodies [EMA] or tissue transglutaminase [TTG]). \n\nThe following tests are not necessary to confirm diagnosis in people who meet the IBS diagnostic criteria:\n\nultrasound\n\nrigid or flexible sigmoidoscopy\n\ncolonoscopy; barium enema\n\nthyroid function test\n\nfaecal ova and parasite test\n\nfaecal occult blood\n\nhydrogen breath test (for lactose intolerance and bacterial overgrowth). \n\n# Clinical management of IBS\n\n## Dietary and lifestyle advice\n\nPeople with IBS should be given information that explains the importance of self‑help in effectively managing their IBS. This should include information on general lifestyle, physical activity, diet and symptom‑targeted medication. \n\nHealthcare professionals should encourage people with IBS to identify and make the most of their available leisure time and to create relaxation time. \n\nHealthcare professionals should assess the physical activity levels of people with IBS, ideally using the General Practice Physical Activity Questionnaire (GPPAQ; see appendix\xa0J of the full guideline). People with low activity levels should be given brief advice and counselling to encourage them to increase their activity levels. \n\nDiet and nutrition should be assessed for people with IBS and the following general advice given.\n\nHave regular meals and take time to eat.\n\nAvoid missing meals or leaving long gaps between eating.\n\nDrink at least 8\xa0cups of fluid per day, especially water or other non‑caffeinated drinks, for example herbal teas.\n\nRestrict tea and coffee to 3\xa0cups per day.\n\nReduce intake of alcohol and fizzy drinks.\n\nIt may be helpful to limit intake of high‑fibre food (such as wholemeal or high‑fibre flour and breads, cereals high in bran, and whole grains such as brown rice).\n\nReduce intake of 'resistant starch' (starch that resists digestion in the small intestine and reaches the colon intact), which is often found in processed or re‑cooked foods.\n\nLimit fresh fruit to 3\xa0portions per day (a portion should be approximately 80\xa0g).\n\nPeople with diarrhoea should avoid sorbitol, an artificial sweetener found in sugar‑free sweets (including chewing gum) and drinks, and in some diabetic and slimming products.\n\nPeople with wind and bloating may find it helpful to eat oats (such as oat‑based breakfast cereal or porridge) and linseeds (up to 1\xa0tablespoon per day). \n\nHealthcare professionals should review the fibre intake of people with IBS, adjusting (usually reducing) it while monitoring the effect on symptoms. People with IBS should be discouraged from eating insoluble fibre (for example, bran). If an increase in dietary fibre is advised, it should be soluble fibre such as ispaghula powder or foods high in soluble fibre (for example, oats). \n\nPeople with IBS who choose to try probiotics should be advised to take the product for at least 4\xa0weeks while monitoring the effect. Probiotics should be taken at the dose recommended by the manufacturer. \n\nHealthcare professionals should discourage the use of aloe vera in the treatment of IBS. \n\nIf a person's IBS symptoms persist while following general lifestyle and dietary advice, offer advice on further dietary management. Such advice should:\n\ninclude single food avoidance and exclusion diets (for example, a low FODMAP [fermentable oligosaccharides, disaccharides, monosaccharides and polyols] diet)\n\nonly be given by a healthcare professional with expertise in dietary management. [new 2015]\n\n## Pharmacological therapy\n\nDecisions about pharmacological management should be based on the nature and severity of symptoms. The recommendations made below assume that the choice of single or combination medication is determined by the predominant symptom(s).\n\nHealthcare professionals should consider prescribing antispasmodic agents for people with IBS. These should be taken as required, alongside dietary and lifestyle advice. \n\nLaxatives should be considered for the treatment of constipation in people with IBS, but people should be discouraged from taking lactulose. \n\nConsider linaclotide for people with IBS only if:\n\noptimal or maximum tolerated doses of previous laxatives from different classes have not helped and\n\nthey have had constipation for at least 12\xa0months. Follow up people taking linaclotide after 3\xa0months. [new 2015]\n\nLoperamide should be the first choice of antimotility agent for diarrhoea in people with IBS. \n\nPeople with IBS should be advised how to adjust their doses of laxative or antimotility agent according to the clinical response. The dose should be titrated according to stool consistency, with the aim of achieving a soft, well‑formed stool (corresponding to Bristol Stool Form Scale type\xa04). \n\nConsider tricyclic antidepressants (TCAs) as second‑line treatment for people with IBS if laxatives, loperamide or antispasmodics have not helped. Start treatment at a low dose (5\xa0mg\xa0to 10\xa0mg equivalent of amitriptyline), taken once at night, and review regularly. Increase the dose if needed, but not usually beyond 30\xa0mg. At the time of publication (February\xa02015), TCAs and selective serotonin reuptake inhibitors (SSRIs) did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. \n\nConsider SSRIs for people with IBS only if TCAs are ineffective. At the time of publication (February\xa02015), TCAs and SSRIs did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. \n\nTake into account the possible side effects when offering TCAs or SSRIs to people with IBS. Follow up people taking either of these drugs for the first time at low doses for the treatment of pain or discomfort in IBS after 4\xa0weeks and then every 6\xa0to 12\xa0months. At the time of publication (February\xa02015), TCAs and SSRIs did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. For guidance on safe prescribing of antidepressants (such as TCAs and SSRIs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. \n\n## Psychological interventions\n\nReferral for psychological interventions (cognitive behavioural therapy [CBT], hypnotherapy and/or psychological therapy) should be considered for people with IBS who do not respond to pharmacological treatments after 12\xa0months and who develop a continuing symptom profile (described as refractory IBS). \n\n## Complementary and alternative medicine (CAM)\n\nThe use of acupuncture should not be encouraged for the treatment of IBS. \n\nThe use of reflexology should not be encouraged for the treatment of IBS. \n\n## Follow-up\n\nFollow‑up should be agreed between the healthcare professional and the person with IBS, based on the response of the person's symptoms to interventions. This should form part of the annual patient review. The emergence of any 'red flag' symptoms during management and follow‑up should prompt further investigation and/or referral to secondary care. ", 'Recommendations for research': 'In 2008, the guideline development group made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\nAs part of the 2015 update, the committee made 3\xa0additional recommendations for research on the clinical and cost effectiveness of a low FODMAP diet, low‑dose tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in primary care, and computerised CBT and mindfulness therapy. These can be found in the addendum.\n\n# Low-dose antidepressants\n\nAre low‑dose TCAs, SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) effective as first‑line treatment for irritable bowel syndrome (IBS), and which is the most effective and safe option?\n\n## Why this is important\n\nReviews have shown that TCAs and SSRIs have each been compared with placebo in the treatment of IBS, but not at low doses. In practice, TCAs are used at higher doses, and concordance with treatment is poor because of side effects. The Guideline Development Group clinicians believe that at low doses (5\xa0mg\xa0to 10\xa0mg equivalent of amitriptyline), TCAs could be the treatment of choice for IBS, but there is a lack of evidence to support this. A newer type of antidepressant, SNRIs, may also be useful in the treatment of IBS‑associated pain. A large randomised trial is proposed, comparing an SSRI, a TCA and an SNRI with placebo. Participants should be adults with a positive diagnosis of IBS, stratified by type of IBS and randomised to treatments. The type of IBS is defined by the predominant bowel symptom: diarrhoea, constipation or alternating symptoms. The primary outcome should be global improvement in IBS symptoms. Health‑related quality of life should also be measured, and adverse effects recorded. Study outcomes should be assessed 12, 26 and 52\xa0weeks after the start of therapy.\n\n# Psychological interventions\n\nAre the psychological interventions CBT, hypnotherapy and psychological therapy all equally effective in the management of IBS symptoms, either as first‑line therapies in primary care, or in the treatment of people with IBS that is refractory to other treatments?\n\n## Why this is important\n\nReviews show some evidence of effect when comparing psychological interventions with a control group, with the greatest effect shown in people who have refractory IBS. Many trials are small in size. Certain psychological interventions – namely, CBT, hypnotherapy and psychological therapy – are thought to be useful in helping people with IBS to cope with their symptoms, but it is unclear at what stage these should be given, including whether they should be used as first‑line therapies in primary care. A large randomised trial is proposed, comparing CBT, hypnotherapy and psychological therapy (in particular, psychodynamic interpersonal therapy). Participants should be adults with a positive diagnosis of IBS, and they should be stratified into those with and without refractory IBS and then randomised to treatments. The primary outcome should be global improvement in IBS symptoms. Health‑related quality of life should also be measured, and adverse effects recorded. Study outcomes should be assessed 12, 26 and 52\xa0weeks after the start of therapy.\n\n# Refractory IBS\n\nWhat factors contribute to refractory IBS?\n\n## Why this is important\n\nMost people with IBS experience symptoms that are relatively short‑lived or that only trouble them on an intermittent basis. Some people, however, develop chronic and severe symptoms that are difficult to treat. There are relatively few prospective studies that have investigated this problem.\n\nA large, prospective, population‑based cohort study is proposed, which would evaluate people in the community with IBS symptoms according to measures of bowel symptomatology, physical symptom profile, psychological symptoms, childhood adversity, psychiatric history, social supports, quality of life and other relevant potential predictors. Participants would be re‑evaluated 12\xa0and 24\xa0months later using similar measures. Baseline variables would be used to predict chronicity of symptoms, quality of life and healthcare utilisation at 12\xa0and 24\xa0months.\n\n# Relaxation and biofeedback\n\nWhat is the effect of relaxation and biofeedback therapies on IBS symptoms and patient‑related outcomes?\n\n## Why this is important\n\nReviews of biofeedback and relaxation therapies suggest a positive effect on the control of IBS symptoms, but evidence is limited and not sufficient to make recommendations. Patient representation in the Guideline Development Group supports this view, from a personal and anecdotal perspective.\n\nRecent developments in computer‑aided biofeedback methods merit investigation. A large randomised trial is proposed to compare relaxation therapy, computer‑aided biofeedback therapy and attention control in primary care. Participants should be adults with a positive diagnosis of IBS, and they should be stratified into those with and without refractory IBS and then randomised to treatments. The primary outcome should be global improvement in IBS symptoms. Health‑related quality of life should also be measured, and adverse effects recorded. Study outcomes should be assessed 12, 26 and 52\xa0weeks after the start of therapy. Qualitative data should be generated relating to how people with IBS perceive their condition.\n\n# Herbal medicines\n\nAre Chinese and non‑Chinese herbal medicines safe and effective as first‑line therapy in the treatment of IBS, and which is the most effective and safe option?\n\n## Why this is important\n\nReviews of herbal medicines suggest a positive effect on the control of IBS symptoms, but evidence is limited and not sufficient to make recommendations (8\xa0comparisons from the 6\xa0trials provide heterogeneous data, which are very difficult to interpret). A large randomised placebo‑controlled trial is proposed, comparing Chinese and non‑Chinese herbal medicines (both single and multiple compounds) that are available in the UK as standard preparations. Participants should be adults with a positive diagnosis of IBS, and they should be stratified by type of IBS and then randomised to treatments. The primary outcome should be global improvement in IBS symptoms, with symptom scores recorded using a validated scale. Health‑related quality of life should also be measured, and adverse events recorded. Study outcomes should be assessed 12, 26 and 52\xa0weeks post‑intervention.'}	https://www.nice.org.uk/guidance/cg61	This guideline covers diagnosing and managing irritable bowel syndrome (IBS) in people aged 18 and over. It details how to accurately diagnose IBS, and aims to improve the quality of life for adults with IBS by promoting effective management using dietary and lifestyle advice, pharmacological therapy and referral for psychological interventions.
d9696bdbc70065632d5c28ce0877966acf3ef0a7	nice	Managing medicines for adults receiving social care in the community	Managing medicines for adults receiving social care in the community This guideline covers medicines support for adults (aged 18 and over) who are receiving social care in the community. It aims to ensure that people who receive social care are supported to take and look after their medicines effectively and safely at home. It gives advice on assessing if people need help with managing their medicines, who should provide medicines support and how health and social care staff should work together. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The recommendations in this guideline assume that the responsibilities for providing medicines support have been agreed between the relevant NHS and local authority commissioners. The term 'medicines support' is defined as any support that enables a person to manage their medicines. This varies for different people depending on their specific needs. The guideline aims to ensure that medicines are managed safely and effectively for all adults receiving social care in the community. People living in residential or nursing care homes are covered by NICE's guideline on managing medicines in care homes. Before any medicines support is provided by a social care provider, commissioning and contractual arrangements need to be discussed, agreed and recorded as part of the local care planning process. This is to ensure that it is clear who is responsible and accountable for the decisions being made, and which providers will deliver each aspect of medicines support. The person or organisation responsible for implementing a recommendation is clearly stated, except when it is not possible to specify. This will be for commissioners and providers to consider and determine locally. # Governance for managing medicines safely and effectively Health and social care commissioners and providers should review their local governance arrangements to ensure that it is clear who is accountable and responsible for providing medicines support. When social care providers have responsibilities for medicines support, they should have a documented medicines policy based on current legislation and best available evidence. The content of this policy will depend on the responsibilities of the social care provider, but it is likely to include processes for: assessing a person's medicines support needs supporting people to take their medicines, including 'when required', time-sensitive and over-the-counter medicines joint working with other health and social care providers sharing information about a person's medicines ensuring that records are accurate and up to date managing concerns about medicines, including medicines-related safeguarding incidents giving medicines to people without their knowledge (covert administration) -rdering and supplying medicines transporting, storing and disposing of medicines medicines‑related staff training and assessment of competency. # Assessing and reviewing a person's medicines support needs Many people want to actively participate in their own care. Enabling and supporting people to manage their medicines is an essential part of this, with help from family members or carers if needed. The term 'medicines support' is defined as any support that enables a person to manage their medicines. This varies for different people depending on their specific needs. Assess a person's medicines support needs as part of the overall assessment of their needs and preferences for care and treatment. Do not take responsibility for managing a person's medicines unless the overall assessment indicates the need to do so, and this has been agreed as part of local governance arrangements. Ensure that people assessing a person's medicines support needs (for example, social workers) have the necessary knowledge, skills and experience. Engage with the person (and their family members or carers if this has been agreed with the person) when assessing a person's medicines support needs. Focus on how the person can be supported to manage their own medicines, taking into account: the person's needs and preferences, including their social, cultural, emotional, religious and spiritual needs the person's expectations for confidentiality and advance care planning the person's understanding of why they are taking their medicines what they are able to do and what support is needed, for example, reading medicine labels, using inhalers or applying creams how they currently manage their medicines, for example, how they order, store and take their medicines whether they have any problems taking their medicines, particularly if they are taking multiple medicines whether they have nutritional and hydration needs, including the need for nutritional supplements or parenteral nutrition who to contact about their medicines (ideally the person themselves, if they choose to and are able to, or a family member, carer or care coordinator) the time and resources likely to be needed. Record the discussions and decisions about the person's medicines support needs. If the person needs medicines support include the following information in the provider's care plan: the person's needs and preferences the person's expectations for confidentiality and advance care planning how consent for decisions about medicines will be sought details of who to contact about their medicines (the person or a named contact) what support is needed for each medicine how the medicines support will be given who will be responsible for providing medicines support, particularly when it is agreed that more than one care provider is involved when the medicines support will be reviewed, for example, after 6 weeks. Review a person's medicines support to check whether it is meeting their needs and preferences. This should be carried out at the time specified in the provider's care plan or sooner if there are changes in the person's circumstances, such as: changes to their medicines regimen a concern is raised a hospital admission a life event, such as a bereavement. # Joint working between health and social care Joint working enables people to receive integrated, person-centred support. Health professionals working in primary and secondary care have an important role in advising and supporting care workers and other social care practitioners. Social care providers should notify a person's general practice and supplying pharmacy when starting to provide medicines support, including details of who to contact about their medicines (the person or a named contact). General practices should record details of the person's medicines support and who to contact about their medicines (the person or a named contact) in their medical record, when notified that a person is receiving medicines support from a social care provider. Social care practitioners should seek advice about medicines from people with specialist experience, such as the prescriber, a pharmacist or another health professional, when it is needed. Health professionals should provide ongoing advice and support about a person's medicines and check if any changes or extra support may be helpful, for example, by checking if: the person's medicines regimen can be simplified information about time-sensitive medicines has been shared any medicines can be stopped the formulation of a medicine can be changed support can be provided for problems with medicines adherence a review of the person's medicines may be needed. When specific skills are needed to give a medicine (for example, using a percutaneous endoscopic gastrostomy tube), health professionals should only delegate the task of giving the medicine to a care worker when: there is local agreement between health and social care that this support will be provided by a care worker the person (or their family member or carer if they have lasting power of attorney) has given their consent the responsibilities of each person are agreed and recorded the care worker is trained and assessed as competent (see also the section on training and competency). Health professionals should continue to monitor and evaluate the safety and effectiveness of a person's medicines when medicines support is provided by a care worker. # Sharing information about a person's medicines It is important that information about medicines is shared with the person and their family members or carers, and between health and social care practitioners, to support high‑quality care. Take into account the 5 rules set out in the Health and Social Care Information Centre's guide to confidentiality in health and social care (2013) when sharing information. See the NICE guideline on medicines optimisation for guidance on medicines‑related communication and medicines reconciliation when a person is transferred from one care setting to another. When social care providers have responsibilities for medicines support, they should have robust processes for communicating and sharing information about a person's medicines that take account of the person's expectations for confidentiality. This includes communication with: the person and their family members or carers care workers and other social care practitioners health professionals, for example, the person's GP or supplying pharmacist -ther agencies, for example, when care is shared or the person moves between care settings. If a person has cognitive decline or fluctuating mental capacity, ensure that the person and their family members or carers are actively involved in discussions and decision‑making. Record the person's views and preferences to help make decisions in the person's best interest if they lack capacity to make decisions in the future. Follow the advice in the NICE guideline on medicines optimisation on sharing information about medicines when a person is transferred from one care setting to another. Prescribers should communicate changes to a person's medicines (for example, when stopping or starting a medicine) by: informing the person or their named contact and providing written instructions of the change or issuing a new prescription and informing the person's supplying pharmacy, if this is needed and agreed with the person and/or their family members or carers. When changes to a person's medicines need to be made verbally to avoid delays in treatment (for example, by telephone, video link or online), prescribers should give written confirmation as soon as possible. Written confirmation should be sent by an agreed method, for example, a secure fax or secure email. When social care providers have responsibilities for medicines support, they should have robust processes for handling changes to a person's medicines received verbally from a prescriber, including: recording details of the requested change (including who requested the change, the date and time of the request, and who received the request) reading back the information that has been recorded to the prescriber requesting the change to confirm it is correct (including spelling the name of the medicine) asking the prescriber requesting the change to repeat the request to someone else (for example, to the person and/or a family member or carer) whenever possible. # Ensuring that records are accurate and up to date Poor record keeping can put people receiving medicines support and care workers at risk. Social care providers are required by law (The Health and Social Care Act 2008 Regulations 2014) to securely maintain accurate and up-to-date records about medicines for each person receiving medicines support. When social care providers have responsibilities for medicines support, they should have robust processes for recording a person's current medicines. These should ensure that records are: accurate and kept up to date accessible, in line with the person's expectations for confidentiality. Care workers must record the medicines support given to a person for each individual medicine on every occasion, in line with Regulation 17 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014. This includes details of all support for prescribed and over-the-counter medicines, such as: reminding a person to take their medicine giving the person their medicine recording whether the person has taken or declined their medicine (see also recommendation 1.6.4 on raising concerns). Care workers should use a medicines administration record to record any medicines support that they give to a person. This should ideally be a printed record provided by the supplying pharmacist, dispensing doctor or social care provider (if they have the resources to produce them) (see also recommendation 1.9.10 on supplying medicines administration records). When social care providers have responsibilities for medicines support, they should have robust processes to ensure that medicines administration records are accurate and up to date. For example, changes should only be made and checked by people who are trained and assessed as competent to do so (see also the section on training and competency). Ensure that medicines administration records include: the person's name, date of birth and any other available person‑specific identifiers, such as the person's NHS number the name, formulation and strength of the medicine(s) how often or the time the medicine should be taken how the medicine is taken or used (route of administration) the name of the person's GP practice any stop or review date any additional information, such as specific instructions for giving a medicine and any known drug allergies. When a family member or carer gives a medicine (for example, during a day out), agree with the person and/or their family member or carer how this will be recorded. Include this information in the provider's care plan. # Managing concerns about medicines Medicines use can be complex, particularly when people have several long-term conditions and are taking multiple medicines. Enabling people to raise any concerns about their medicines and managing medicines-related problems effectively when they happen are important to minimise harm and guide future care. When social care providers have responsibilities for medicines support, they must have robust processes for medicines-related safeguarding incidents, in line with Regulation 13 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014. For guidance on ensuring safety and safeguarding people using home care services, see the NICE guideline on home care. When social care providers have responsibilities for medicines support, they should have robust processes for identifying, reporting, reviewing and learning from medicines-related problems. These processes should support a person-centred, 'fair blame' culture that actively encourages people and/or their family members or carers and care workers to report their concerns. Social care commissioners and providers should review their medicines‑related problems over a period of time to identify and address any trends that may have led to incidents. They should share this learning with: people working in the organisation people receiving medicines support, their family members and carers people working in related services, for example, GPs, supplying pharmacies and community health providers. Care workers should raise any concerns about a person's medicines with the social care provider. These concerns may include: the person declining to take their medicine medicines not being taken in accordance with the prescriber's instructions possible adverse effects (including falls after changes to medicines; see the NICE guideline on falls in older people) the person stockpiling their medicines medication errors or near misses possible misuse or diversion of medicines the person's mental capacity to make decisions about their medicines changes to the person's physical or mental health. Care workers and other social care practitioners should advise people and/or their family members or carers to seek advice from a health professional (for example, the prescriber or a pharmacist) if they have clinical questions about medicines. Health and social care practitioners should encourage and support people and/or their family members or carers to raise any concerns about their medicines. They should explain how to seek help or make a complaint, including who to complain to and the role of advocacy services (if needed), and record this information in the provider's care plan. Health and social care providers should ensure that people and/or their family members or carers, and care workers know how to report adverse effects of medicines, including using the Medicines and Healthcare products Regulatory Agency's yellow card scheme. # Supporting people to take their medicines Supporting people to take their medicines may involve helping people to take their medicines themselves (self-administration) or giving people their medicines (administration). For guidance on self-management of medicines, see the recommendations on self-management plans in the NICE guideline on medicines optimisation. Social care providers should have robust processes for care workers who are supporting people to take their medicines, including: the 6 rights (R's) of administration: right person right medicine right route right dose right time person's right to decline what to do if the person is having a meal or sleeping what to do if the person is going to be away for a short time, for example, visiting family how to give specific formulations of medicines, for example, patches, creams, inhalers, eye drops and liquids using the correct equipment, for example, oral syringes for small doses of liquid medicines giving time-sensitive or 'when required' medicines what to do if the person has declining or fluctuating mental capacity. Care workers should only provide the medicines support that has been agreed and documented in the provider's care plan. Prescribers, supplying pharmacists and dispensing doctors should provide clear written directions on the prescription and dispensing label on how each prescribed medicine should be taken or given, including: for time‑sensitive medicines: what the medicine is for what dose should be taken what time the dose should be taken, as agreed with the person for 'when required' medicines: what the medicine is for what dose should be taken (avoiding variable doses unless the person or their family member or carer can direct the care worker) the minimum time between doses the maximum number of doses to be given (for example, in a 24‑hour period). Social care providers should record any additional information to help manage time‑sensitive and 'when required' medicines in the provider's care plan. Care workers should only give a medicine to a person if: there is authorisation and clear instructions to give the medicine, for example, on the dispensing label of a prescribed medicine and the 6 R's of administration have been met (see also recommendation 1.7.1) and they have been trained and assessed as competent to give the medicine (see also the section on training and competency). Before supporting a person to take a dose of their medicine, care workers should ask the person if they have already taken the dose and check the written records to ensure that the dose has not already been given. Care workers should ask the person if they are ready to take their medicine, before removing it from its packaging, unless this has been agreed and it is recorded in the provider's care plan. Care workers should give medicines directly from the container they are supplied in. They should not leave doses out for a person to take later unless this has been agreed with the person after a risk assessment and it is recorded in the provider's care plan. When a person declines to take a medicine, care workers should consider waiting a short while before offering it again. They should ask about other factors that may cause the person to decline their medicine, such as being in pain or discomfort (see also recommendations 1.6.4 and 1.6.5 on raising concerns or seeking advice). Supplying pharmacists and dispensing doctors must supply a patient information leaflet for each medicine supplied, in line with The Human Medicines Regulations 2012. This includes medicines supplied in monitored dosage systems. Social care providers should ensure that an up-to-date patient information leaflet for each prescribed medicine is kept in the person's home. This includes medicines supplied in monitored dosage systems. Social care providers should ensure that care workers are able to prioritise their visits for people who need support with time-sensitive medicines. # Giving medicines to people without their knowledge (covert administration) Covert administration of medicines is when medicines are given in a disguised form without the knowledge or consent of the person receiving them. Ensure that covert administration of medicines only takes place in accordance with the requirements of the Mental Capacity Act 2005 and good practice frameworks (Mental Capacity Act 2005: Code of Practice) to protect both the person and care workers. Care workers must not give, or make the decision to give, medicines by covert administration, unless there is clear authorisation and instructions to do this in the provider's care plan, in line with the Mental Capacity Act 2005. Ensure that the process for covert administration clearly defines who should be involved in, and responsible for, decision-making, including: assessing a person's mental capacity to make a specific decision about their medicines seeking advice from the prescriber about other options, for example, whether the medicine could be stopped holding a best interests meeting to agree whether giving medicines covertly is in the person's best interests recording any decisions and who was involved in decision-making agreeing where records of the decision are kept and who has access planning how medicines will be given covertly, for example, by seeking advice from a pharmacist providing authorisation and clear instructions for care workers in the provider's care plan ensuring care workers are trained and assessed as competent to give the medicine covertly (see also the section on training and competency) when the decision to give medicines covertly will be reviewed. # Ordering and supplying medicines Responsibility for ordering medicines usually stays with the person and/or their family members or carers. However, if it has been agreed that a social care provider is responsible, effective medicines management systems need to be in place. Social care providers should agree with the person and/or their family members or carers who will be responsible for ordering medicines, and record this information in the provider's care plan. This should be the person, if they agree and are able to, with support from family members, carers or care workers (if needed). When social care providers are responsible for ordering a person's medicines they must ensure that the correct amounts of the medicines are available when required, in line with Regulation 12 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014. When social care providers are responsible for ordering a person's medicines they should not delegate this task to the supplying pharmacist (or another provider), unless this has been requested and agreed with the person and/or their family members or carers. When social care providers are responsible for ordering a person's medicines they should ensure that care workers: have enough time allocated for checking which medicines are needed, ordering medicines and checking that the correct medicines have been supplied are trained and assessed as competent to do so (see also the section on training and competency). When ordering a person's medicines, care workers should: record when medicines have been ordered, including the name, strength and quantity of the medicine record when medicines have been supplied check for any discrepancies between the medicines ordered and those supplied. Social care providers should ensure that care workers know what action to take if a discrepancy is noted between the medicines ordered and those supplied. Supplying pharmacists and dispensing doctors should supply medicines in their original packaging. They must make reasonable adjustments to the supplied packaging to help the person manage their medicines (for example, childproof tops), in line with the Equality Act 2010. Consider using a monitored dosage system only when an assessment by a health professional (for example, a pharmacist) has been carried out, in line with the Equality Act 2010, and a specific need has been identified to support medicines adherence. Take account of the person's needs and preferences, and involve the person and/or their family members or carers and the social care provider in decision‑making. Supplying pharmacists and dispensing doctors should provide a description of the appearance of each individual medicine supplied in a monitored dosage system. Supplying pharmacists and dispensing doctors should consider supplying printed medicines administration records for a person receiving medicines support from a social care provider (see also recommendation 1.5.3 on record keeping). When social care providers have responsibilities for medicines support, they should have robust processes for managing over‑the‑counter medicines that are requested by a person, including: seeking advice from a pharmacist or another health professional ensuring that the person understands and accepts any risk associated with taking the medicine what information needs to be recorded, for example, the name, strength and quantity of the medicine. # Transporting, storing and disposing of medicines Responsibility for transporting, storing and disposing of medicines usually stays with the person and/or their family members or carers. However, if it has been agreed that a social care provider is responsible, effective medicines management systems need to be in place. Agree with the person and/or their family members or carers who will be responsible for transporting medicines to or from the person's home. If a social care provider is involved, carry out a risk assessment of transport arrangements. Agree with the person how their medicines should be stored and disposed of. Encourage the person to take responsibility for this, if they agree and are able to, with support from family members, carers or care workers (if needed). Record this information in the provider's care plan. When a person is assessed to be at risk because of unsecured access to their medicines, social care providers should agree with the person and/or their family members or carers whether secure home storage is needed, for example, in a lockable cupboard. When social care providers are responsible for storing a person's medicines, they should have robust processes to ensure there is safe access to medicines, particularly for controlled drugs (for more information see NICE's guideline on controlled drugs). These should include: identifying who should have authorised access to the medicines seeking advice from a health professional about how to store medicines safely, if needed ensuring there is a safe storage place or cupboard for storing medicines, including those supplied in monitored dosage systems assessing the need for secure storage, for example, in a lockable cupboard identifying the need for fridge storage reviewing storage needs, for example, if the person has declining or fluctuating mental capacity. When social care providers are responsible for disposing of any unwanted, damaged, out-of-date or part-used medicines, they must have robust processes, in line with The Controlled Waste (England and Wales) Regulations 2012. These should include: -btaining agreement from the person (or their family member or carer) how the medicines will be disposed of, usually by returning them to a pharmacy for disposal any special considerations, for example, for disposal of controlled drugs, needles and syringes what information needs to be recorded, for example, the name and quantity of medicine, the name of the person returning the medicine, the date returned and the name of the pharmacy. # Training and competency Appropriate training, support and competency assessment for managing medicines is essential to ensure the safety, quality and consistency of care. When social care providers are responsible for medicines support, they should have robust processes for medicines‑related training and competency assessment for care workers, to ensure that they: receive appropriate training and support have the necessary knowledge and skills are assessed as competent to give the medicines support being asked of them, including assessment through direct observation have an annual review of their knowledge, skills and competencies. Follow the advice on recruiting, training and supporting home care workers in NICE's guideline on home care. # Terms used in this guideline ## Advance care planning A voluntary process of discussion about what care a person would or would not want in the future, if they were unable to make decisions because of illness or a lack of mental capacity to consent. The person may also choose to involve their family members or friends in discussions. ## Carer The term 'carer' is used to define an informal, unpaid carer only (see also 'care worker'). ## Care worker A person who is employed to provide care and support to people in their own home. This includes home care workers, personal assistants (who are directly employed by people who use services) and other support workers. Note that a person's own home includes extra care housing, Shared Lives Scheme (formerly Adult Placement Scheme) living arrangements, sheltered housing (such as supported housing or specialist accommodation), supported living and temporary accommodation (such as for people who are homeless). ## Fair blame culture In health and social care, this enables open and honest reporting of mistakes that are treated as an opportunity to learn to improve care. ## Health and social care practitioners The wider health and social care team of health professionals and social care practitioners. Health professionals include, but are not limited to, GPs, pharmacists, hospital consultants, community nurses, specialist nurses and mental health professionals. Social care practitioners include, but are not limited to, care workers, case managers, care coordinators and social workers. When specific recommendations are made for a particular group, this is specified in the recommendation. ## Medicine All prescription and non-prescription (over-the-counter) healthcare treatments, such as oral medicines, topical medicines, inhaled products, injections, wound care products, appliances and vaccines. ## Medicines-related problems Medicines-related problem include: potentially avoidable medicines-related hospital admissions prescribing errors dispensing errors administration errors (for example, missed or delayed doses, inappropriate or incorrect administration) monitoring errors (for example, inadequate review or follow-up, incomplete or inaccurate documentation) adverse events, incident reporting and significant events near misses (a prevented medicines-related patient safety incident which could have led to patient harm) deliberate withholding of medicines or deliberate attempt to harm restraint or covert administration that has been used inappropriately misuse, such as missing or diverted medicines -ther unintended or unexpected incidents that were specifically related to medicines use, which could have, or did, lead to harm (including death). ## Medicines support Any support that enables a person to manage their medicines. This varies for different people depending on their specific needs. ## Mental capacity The ability of a person to make a decision about their own care, including: decisions that affect daily life (for example, when to get up, what to wear or whether to go to the doctor when feeling ill, and more serious or significant decisions) decisions that may have legal consequences for them or others (for example, agreeing to have medical treatment, buying goods or making a will). The Mental Capacity Act 2005 defines a lack of mental capacity as when 'a person lacks capacity in relation to a matter if at the material time he is unable to make a decision for himself in relation to the matter because of an impairment of, or a disturbance in the functioning of, the mind or brain'. Health professionals should follow the Department of Health's advice on consent. If a person does not have capacity to make decisions, health and social care practitioners should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards. ## Monitored dosage system A system for packing medicines, for example, by putting medicines for each time of day in separate blisters or compartments in a box. ## Original packaging The packaging in which the medicine is supplied by the supplying pharmacy. This could be a manufacturers packaging or pharmacy supplied packaging after larger amounts of medicines have been decanted for individual patient use. ## Parenteral nutrition Providing nutrients intravenously. ## Provider's care plan A written plan that sets out the care and support that providers and the person have agreed will be put in place, following a local authority assessment. It includes details of both personal care and practical support. ## Social care provider A provider organisation, registered with the Care Quality Commission to provide community adult care services, which directly employs care workers to provide personal care and support in a person's home. ## Time-sensitive medicine A medicine that needs to be given or taken at a specific time, where a delay in receiving the dose or omission of the dose may lead to serious patient harm, for example, insulin injections for diabetes or specific medicines for Parkinson's disease. For other health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are: the adequate provision of education and training for care workers and other support staff the provision and appropriate use of medicines administration records. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context This guideline has been developed to help ensure that adults who receive social care in the community get the support they need to manage their medicines safely and effectively. Social care in the community is defined as care and support in their own home for adults who: the local authority has to discharge a duty or responsibility under either the Care Act 2014 or the Mental Health Act 1983 receive any social care component of an NHS continuing care package self-fund their own care and support. Note that a person's own home includes extra care housing, Shared Lives Scheme (formerly Adult Placement Scheme) living arrangements, sheltered housing (such as supported housing or specialist accommodation), supported living and temporary accommodation (such as for people who are homeless). An increasing number of people need social care and support in the community, which may include help with managing their medicines, as reported in the Department of Health's policy on health and social care integration (2013). People receiving social care in the community may be at a greater risk of medicines-related problems. For example, if they have multiple long-term conditions (multimorbidity) or are taking multiple medicines (polypharmacy). Family members, carers and care workers often help people to take and look after their medicines, for example, by ordering prescription medicines or reminding a person to take their medicines. Care workers who are responsible for providing medicines support have limited supervision by health professionals. There is variation in staff training and low pay, which leads to a high turnover of staff (32% of care workers leave within 12 months; 56% within 2 years). This can result in a lack of continuity of care and inflexibility in changing care arrangements (Commissioning home care for older people. Social Care Institute for Excellence, 2014). This guideline focuses on adults (aged 18 and over) and considers how to assess their medicines support needs, with an emphasis on enabling and supporting people to manage their own medicines as much as possible, when they are able to do so. It covers how support should be planned and delivered, with health and social care providers sharing accurate and up-to-date information, and working together to deliver high-quality care. This guideline also addresses the medicines management systems and processes that need to be in place so that people receive the medicines they need in a safe and effective way. This includes ensuring that care workers receive support and training to provide medicines support for the people that they care for, and know how and when to get help and advice. Finally, the guideline encourages a person-centred, 'fair blame' culture where people, their family members, carers and care workers can raise concerns about medicines, and social care providers have robust governance arrangements to help keep people safe in line with Regulation 13 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014. The following legislation and regulations relating to this guideline have been published by the UK Government, although this is not intended to be a comprehensive list: The Care Act 2014 Health and Social Care Act 2008 (Regulated Activities) Regulations 2014 Health and Social Care Act 2012 The Controlled Waste (England and Wales) Regulations 2012 Care Quality Commission (Registration) Regulations 2009 Health and Social Care Act 2008 Mental Capacity Act 2005 Data Protection Act 1998 Equality Act 2010 The Human Medicines Regulations 2012 The Misuse of Drugs (Safe Custody) Regulations 1973 Misuse of Drugs Act 1971.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations in this guideline assume that the responsibilities for providing medicines support have been agreed between the relevant NHS and local authority commissioners. The term 'medicines support' is defined as any support that enables a person to manage their medicines. This varies for different people depending on their specific needs. The guideline aims to ensure that medicines are managed safely and effectively for all adults receiving social care in the community. People living in residential or nursing care homes are covered by NICE's guideline on managing medicines in care homes.\n\nBefore any medicines support is provided by a social care provider, commissioning and contractual arrangements need to be discussed, agreed and recorded as part of the local care planning process. This is to ensure that it is clear who is responsible and accountable for the decisions being made, and which providers will deliver each aspect of medicines support.\n\nThe person or organisation responsible for implementing a recommendation is clearly stated, except when it is not possible to specify. This will be for commissioners and providers to consider and determine locally.\n\n# Governance for managing medicines safely and effectively\n\nHealth and social care commissioners and providers should review their local governance arrangements to ensure that it is clear who is accountable and responsible for providing medicines support.\n\nWhen social care providers have responsibilities for medicines support, they should have a documented medicines policy based on current legislation and best available evidence. The content of this policy will depend on the responsibilities of the social care provider, but it is likely to include processes for:\n\nassessing a person's medicines support needs\n\nsupporting people to take their medicines, including 'when required', time-sensitive and over-the-counter medicines\n\njoint working with other health and social care providers\n\nsharing information about a person's medicines\n\nensuring that records are accurate and up to date\n\nmanaging concerns about medicines, including medicines-related safeguarding incidents\n\ngiving medicines to people without their knowledge (covert administration)\n\nordering and supplying medicines\n\ntransporting, storing and disposing of medicines\n\nmedicines‑related staff training and assessment of competency.\n\n# Assessing and reviewing a person's medicines support needs\n\nMany people want to actively participate in their own care. Enabling and supporting people to manage their medicines is an essential part of this, with help from family members or carers if needed. The term 'medicines support' is defined as any support that enables a person to manage their medicines. This varies for different people depending on their specific needs.\n\nAssess a person's medicines support needs as part of the overall assessment of their needs and preferences for care and treatment.\n\nDo not take responsibility for managing a person's medicines unless the overall assessment indicates the need to do so, and this has been agreed as part of local governance arrangements.\n\nEnsure that people assessing a person's medicines support needs (for example, social workers) have the necessary knowledge, skills and experience.\n\nEngage with the person (and their family members or carers if this has been agreed with the person) when assessing a person's medicines support needs. Focus on how the person can be supported to manage their own medicines, taking into account:\n\nthe person's needs and preferences, including their social, cultural, emotional, religious and spiritual needs\n\nthe person's expectations for confidentiality and advance care planning\n\nthe person's understanding of why they are taking their medicines\n\nwhat they are able to do and what support is needed, for example, reading medicine labels, using inhalers or applying creams\n\nhow they currently manage their medicines, for example, how they order, store and take their medicines\n\nwhether they have any problems taking their medicines, particularly if they are taking multiple medicines\n\nwhether they have nutritional and hydration needs, including the need for nutritional supplements or parenteral nutrition\n\nwho to contact about their medicines (ideally the person themselves, if they choose to and are able to, or a family member, carer or care coordinator)\n\nthe time and resources likely to be needed.\n\nRecord the discussions and decisions about the person's medicines support needs. If the person needs medicines support include the following information in the provider's care plan:\n\nthe person's needs and preferences\n\nthe person's expectations for confidentiality and advance care planning\n\nhow consent for decisions about medicines will be sought\n\ndetails of who to contact about their medicines (the person or a named contact)\n\nwhat support is needed for each medicine\n\nhow the medicines support will be given\n\nwho will be responsible for providing medicines support, particularly when it is agreed that more than one care provider is involved\n\nwhen the medicines support will be reviewed, for example, after 6\xa0weeks.\n\nReview a person's medicines support to check whether it is meeting their needs and preferences. This should be carried out at the time specified in the provider's care plan or sooner if there are changes in the person's circumstances, such as:\n\nchanges to their medicines regimen\n\na concern is raised\n\na hospital admission\n\na life event, such as a bereavement.\n\n# Joint working between health and social care\n\nJoint working enables people to receive integrated, person-centred support. Health professionals working in primary and secondary care have an important role in advising and supporting care workers and other social care practitioners.\n\nSocial care providers should notify a person's general practice and supplying pharmacy when starting to provide medicines support, including details of who to contact about their medicines (the person or a named contact).\n\nGeneral practices should record details of the person's medicines support and who to contact about their medicines (the person or a named contact) in their medical record, when notified that a person is receiving medicines support from a social care provider.\n\nSocial care practitioners should seek advice about medicines from people with specialist experience, such as the prescriber, a pharmacist or another health professional, when it is needed.\n\nHealth professionals should provide ongoing advice and support about a person's medicines and check if any changes or extra support may be helpful, for example, by checking if:\n\nthe person's medicines regimen can be simplified\n\ninformation about time-sensitive medicines has been shared\n\nany medicines can be stopped\n\nthe formulation of a medicine can be changed\n\nsupport can be provided for problems with medicines adherence\n\na review of the person's medicines may be needed.\n\nWhen specific skills are needed to give a medicine (for example, using a percutaneous endoscopic gastrostomy [PEG] tube), health professionals should only delegate the task of giving the medicine to a care worker when:\n\nthere is local agreement between health and social care that this support will be provided by a care worker\n\nthe person (or their family member or carer if they have lasting power of attorney) has given their consent\n\nthe responsibilities of each person are agreed and recorded\n\nthe care worker is trained and assessed as competent (see also the section on training and competency).\n\nHealth professionals should continue to monitor and evaluate the safety and effectiveness of a person's medicines when medicines support is provided by a care worker.\n\n# Sharing information about a person's medicines\n\nIt is important that information about medicines is shared with the person and their family members or carers, and between health and social care practitioners, to support high‑quality care. Take into account the 5 rules set out in the Health and Social Care Information Centre's guide to confidentiality in health and social care (2013) when sharing information.\n\nSee the NICE guideline on medicines optimisation for guidance on medicines‑related communication and medicines reconciliation when a person is transferred from one care setting to another.\n\nWhen social care providers have responsibilities for medicines support, they should have robust processes for communicating and sharing information about a person's medicines that take account of the person's expectations for confidentiality. This includes communication with:\n\nthe person and their family members or carers\n\ncare workers and other social care practitioners\n\nhealth professionals, for example, the person's GP or supplying pharmacist\n\nother agencies, for example, when care is shared or the person moves between care settings.\n\nIf a person has cognitive decline or fluctuating mental capacity, ensure that the person and their family members or carers are actively involved in discussions and decision‑making. Record the person's views and preferences to help make decisions in the person's best interest if they lack capacity to make decisions in the future.\n\nFollow the advice in the NICE guideline on medicines optimisation on sharing information about medicines when a person is transferred from one care setting to another.\n\nPrescribers should communicate changes to a person's medicines (for example, when stopping or starting a medicine) by:\n\ninforming the person or their named contact and\n\nproviding written instructions of the change or issuing a new prescription and\n\ninforming the person's supplying pharmacy, if this is needed and agreed with the person and/or their family members or carers.\n\nWhen changes to a person's medicines need to be made verbally to avoid delays in treatment (for example, by telephone, video link or online), prescribers should give written confirmation as soon as possible. Written confirmation should be sent by an agreed method, for example, a secure fax or secure email.\n\nWhen social care providers have responsibilities for medicines support, they should have robust processes for handling changes to a person's medicines received verbally from a prescriber, including:\n\nrecording details of the requested change (including who requested the change, the date and time of the request, and who received the request)\n\nreading back the information that has been recorded to the prescriber requesting the change to confirm it is correct (including spelling the name of the medicine)\n\nasking the prescriber requesting the change to repeat the request to someone else (for example, to the person and/or a family member or carer) whenever possible.\n\n# Ensuring that records are accurate and up to date\n\nPoor record keeping can put people receiving medicines support and care workers at risk. Social care providers are required by law (The Health and Social Care Act 2008 [Regulated Activities] Regulations 2014) to securely maintain accurate and up-to-date records about medicines for each person receiving medicines support.\n\nWhen social care providers have responsibilities for medicines support, they should have robust processes for recording a person's current medicines. These should ensure that records are:\n\naccurate and kept up to date\n\naccessible, in line with the person's expectations for confidentiality.\n\nCare workers must record the medicines support given to a person for each individual medicine on every occasion, in line with Regulation 17 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014. This includes details of all support for prescribed and over-the-counter medicines, such as:\n\nreminding a person to take their medicine\n\ngiving the person their medicine\n\nrecording whether the person has taken or declined their medicine (see also recommendation 1.6.4 on raising concerns).\n\nCare workers should use a medicines administration record to record any medicines support that they give to a person. This should ideally be a printed record provided by the supplying pharmacist, dispensing doctor or social care provider (if they have the resources to produce them) (see also recommendation 1.9.10 on supplying medicines administration records).\n\nWhen social care providers have responsibilities for medicines support, they should have robust processes to ensure that medicines administration records are accurate and up to date. For example, changes should only be made and checked by people who are trained and assessed as competent to do so (see also the section on training and competency).\n\nEnsure that medicines administration records include:\n\nthe person's name, date of birth and any other available person‑specific identifiers, such as the person's NHS number\n\nthe name, formulation and strength of the medicine(s)\n\nhow often or the time the medicine should be taken\n\nhow the medicine is taken or used (route of administration)\n\nthe name of the person's GP practice\n\nany stop or review date\n\nany additional information, such as specific instructions for giving a medicine and any known drug allergies.\n\nWhen a family member or carer gives a medicine (for example, during a day out), agree with the person and/or their family member or carer how this will be recorded. Include this information in the provider's care plan.\n\n# Managing concerns about medicines\n\nMedicines use can be complex, particularly when people have several long-term conditions and are taking multiple medicines. Enabling people to raise any concerns about their medicines and managing medicines-related problems effectively when they happen are important to minimise harm and guide future care.\n\nWhen social care providers have responsibilities for medicines support, they must have robust processes for medicines-related safeguarding incidents, in line with Regulation 13 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014. For guidance on ensuring safety and safeguarding people using home care services, see the NICE guideline on home care.\n\nWhen social care providers have responsibilities for medicines support, they should have robust processes for identifying, reporting, reviewing and learning from medicines-related problems. These processes should support a person-centred, 'fair blame' culture that actively encourages people and/or their family members or carers and care workers to report their concerns.\n\nSocial care commissioners and providers should review their medicines‑related problems over a period of time to identify and address any trends that may have led to incidents. They should share this learning with:\n\npeople working in the organisation\n\npeople receiving medicines support, their family members and carers\n\npeople working in related services, for example, GPs, supplying pharmacies and community health providers.\n\nCare workers should raise any concerns about a person's medicines with the social care provider. These concerns may include:\n\nthe person declining to take their medicine\n\nmedicines not being taken in accordance with the prescriber's instructions\n\npossible adverse effects (including falls after changes to medicines; see the NICE guideline on falls in older people)\n\nthe person stockpiling their medicines\n\nmedication errors or near misses\n\npossible misuse or diversion of medicines\n\nthe person's mental capacity to make decisions about their medicines\n\nchanges to the person's physical or mental health.\n\nCare workers and other social care practitioners should advise people and/or their family members or carers to seek advice from a health professional (for example, the prescriber or a pharmacist) if they have clinical questions about medicines.\n\nHealth and social care practitioners should encourage and support people and/or their family members or carers to raise any concerns about their medicines. They should explain how to seek help or make a complaint, including who to complain to and the role of advocacy services (if needed), and record this information in the provider's care plan.\n\nHealth and social care providers should ensure that people and/or their family members or carers, and care workers know how to report adverse effects of medicines, including using the Medicines and Healthcare products Regulatory Agency's yellow card scheme.\n\n# Supporting people to take their medicines\n\nSupporting people to take their medicines may involve helping people to take their medicines themselves (self-administration) or giving people their medicines (administration).\n\nFor guidance on self-management of medicines, see the recommendations on self-management plans in the NICE guideline on medicines optimisation.\n\nSocial care providers should have robust processes for care workers who are supporting people to take their medicines, including:\n\nthe 6 rights (R's) of administration:\n\n\n\nright person\n\nright medicine\n\nright route\n\nright dose\n\nright time\n\nperson's right to decline\n\n\n\nwhat to do if the person is having a meal or sleeping\n\nwhat to do if the person is going to be away for a short time, for example, visiting family\n\nhow to give specific formulations of medicines, for example, patches, creams, inhalers, eye drops and liquids\n\nusing the correct equipment, for example, oral syringes for small doses of liquid medicines\n\ngiving time-sensitive or 'when required' medicines\n\nwhat to do if the person has declining or fluctuating mental capacity.\n\nCare workers should only provide the medicines support that has been agreed and documented in the provider's care plan.\n\nPrescribers, supplying pharmacists and dispensing doctors should provide clear written directions on the prescription and dispensing label on how each prescribed medicine should be taken or given, including:\n\nfor time‑sensitive medicines:\n\n\n\nwhat the medicine is for\n\nwhat dose should be taken\n\nwhat time the dose should be taken, as agreed with the person\n\n\n\nfor 'when required' medicines:\n\n\n\nwhat the medicine is for\n\nwhat dose should be taken (avoiding variable doses unless the person or their family member or carer can direct the care worker)\n\nthe minimum time between doses\n\n\n\nthe maximum number of doses to be given (for example, in a 24‑hour period).\n\nSocial care providers should record any additional information to help manage time‑sensitive and 'when required' medicines in the provider's care plan.\n\nCare workers should only give a medicine to a person if:\n\nthere is authorisation and clear instructions to give the medicine, for example, on the dispensing label of a prescribed medicine and\n\nthe 6 R's of administration have been met (see also recommendation 1.7.1) and\n\nthey have been trained and assessed as competent to give the medicine (see also the section on training and competency).\n\nBefore supporting a person to take a dose of their medicine, care workers should ask the person if they have already taken the dose and check the written records to ensure that the dose has not already been given.\n\nCare workers should ask the person if they are ready to take their medicine, before removing it from its packaging, unless this has been agreed and it is recorded in the provider's care plan.\n\nCare workers should give medicines directly from the container they are supplied in. They should not leave doses out for a person to take later unless this has been agreed with the person after a risk assessment and it is recorded in the provider's care plan.\n\nWhen a person declines to take a medicine, care workers should consider waiting a short while before offering it again. They should ask about other factors that may cause the person to decline their medicine, such as being in pain or discomfort (see also recommendations 1.6.4 and 1.6.5 on raising concerns or seeking advice).\n\nSupplying pharmacists and dispensing doctors must supply a patient information leaflet for each medicine supplied, in line with The Human Medicines Regulations 2012. This includes medicines supplied in monitored dosage systems.\n\nSocial care providers should ensure that an up-to-date patient information leaflet for each prescribed medicine is kept in the person's home. This includes medicines supplied in monitored dosage systems.\n\nSocial care providers should ensure that care workers are able to prioritise their visits for people who need support with time-sensitive medicines.\n\n# Giving medicines to people without their knowledge (covert administration)\n\nCovert administration of medicines is when medicines are given in a disguised form without the knowledge or consent of the person receiving them.\n\nEnsure that covert administration of medicines only takes place in accordance with the requirements of the Mental Capacity Act 2005 and good practice frameworks (Mental Capacity Act 2005: Code of Practice) to protect both the person and care workers.\n\nCare workers must not give, or make the decision to give, medicines by covert administration, unless there is clear authorisation and instructions to do this in the provider's care plan, in line with the Mental Capacity Act 2005.\n\nEnsure that the process for covert administration clearly defines who should be involved in, and responsible for, decision-making, including:\n\nassessing a person's mental capacity to make a specific decision about their medicines\n\nseeking advice from the prescriber about other options, for example, whether the medicine could be stopped\n\nholding a best interests meeting to agree whether giving medicines covertly is in the person's best interests\n\nrecording any decisions and who was involved in decision-making\n\nagreeing where records of the decision are kept and who has access\n\nplanning how medicines will be given covertly, for example, by seeking advice from a pharmacist\n\nproviding authorisation and clear instructions for care workers in the provider's care plan\n\nensuring care workers are trained and assessed as competent to give the medicine covertly (see also the section on training and competency)\n\nwhen the decision to give medicines covertly will be reviewed.\n\n# Ordering and supplying medicines\n\nResponsibility for ordering medicines usually stays with the person and/or their family members or carers. However, if it has been agreed that a social care provider is responsible, effective medicines management systems need to be in place.\n\nSocial care providers should agree with the person and/or their family members or carers who will be responsible for ordering medicines, and record this information in the provider's care plan. This should be the person, if they agree and are able to, with support from family members, carers or care workers (if needed).\n\nWhen social care providers are responsible for ordering a person's medicines they must ensure that the correct amounts of the medicines are available when required, in line with Regulation 12 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014.\n\nWhen social care providers are responsible for ordering a person's medicines they should not delegate this task to the supplying pharmacist (or another provider), unless this has been requested and agreed with the person and/or their family members or carers.\n\nWhen social care providers are responsible for ordering a person's medicines they should ensure that care workers:\n\nhave enough time allocated for checking which medicines are needed, ordering medicines and checking that the correct medicines have been supplied\n\nare trained and assessed as competent to do so (see also the section on training and competency).\n\nWhen ordering a person's medicines, care workers should:\n\nrecord when medicines have been ordered, including the name, strength and quantity of the medicine\n\nrecord when medicines have been supplied\n\ncheck for any discrepancies between the medicines ordered and those supplied.\n\nSocial care providers should ensure that care workers know what action to take if a discrepancy is noted between the medicines ordered and those supplied.\n\nSupplying pharmacists and dispensing doctors should supply medicines in their original packaging. They must make reasonable adjustments to the supplied packaging to help the person manage their medicines (for example, childproof tops), in line with the Equality Act 2010.\n\nConsider using a monitored dosage system only when an assessment by a health professional (for example, a pharmacist) has been carried out, in line with the Equality Act 2010, and a specific need has been identified to support medicines adherence. Take account of the person's needs and preferences, and involve the person and/or their family members or carers and the social care provider in decision‑making.\n\nSupplying pharmacists and dispensing doctors should provide a description of the appearance of each individual medicine supplied in a monitored dosage system.\n\nSupplying pharmacists and dispensing doctors should consider supplying printed medicines administration records for a person receiving medicines support from a social care provider (see also recommendation 1.5.3 on record keeping).\n\nWhen social care providers have responsibilities for medicines support, they should have robust processes for managing over‑the‑counter medicines that are requested by a person, including:\n\nseeking advice from a pharmacist or another health professional\n\nensuring that the person understands and accepts any risk associated with taking the medicine\n\nwhat information needs to be recorded, for example, the name, strength and quantity of the medicine.\n\n# Transporting, storing and disposing of medicines\n\nResponsibility for transporting, storing and disposing of medicines usually stays with the person and/or their family members or carers. However, if it has been agreed that a social care provider is responsible, effective medicines management systems need to be in place.\n\nAgree with the person and/or their family members or carers who will be responsible for transporting medicines to or from the person's home. If a social care provider is involved, carry out a risk assessment of transport arrangements.\n\nAgree with the person how their medicines should be stored and disposed of. Encourage the person to take responsibility for this, if they agree and are able to, with support from family members, carers or care workers (if needed). Record this information in the provider's care plan.\n\nWhen a person is assessed to be at risk because of unsecured access to their medicines, social care providers should agree with the person and/or their family members or carers whether secure home storage is needed, for example, in a lockable cupboard.\n\nWhen social care providers are responsible for storing a person's medicines, they should have robust processes to ensure there is safe access to medicines, particularly for controlled drugs (for more information see NICE's guideline on controlled drugs). These should include:\n\nidentifying who should have authorised access to the medicines\n\nseeking advice from a health professional about how to store medicines safely, if needed\n\nensuring there is a safe storage place or cupboard for storing medicines, including those supplied in monitored dosage systems\n\nassessing the need for secure storage, for example, in a lockable cupboard\n\nidentifying the need for fridge storage\n\nreviewing storage needs, for example, if the person has declining or fluctuating mental capacity.\n\nWhen social care providers are responsible for disposing of any unwanted, damaged, out-of-date or part-used medicines, they must have robust processes, in line with The Controlled Waste (England and Wales) Regulations 2012. These should include:\n\nobtaining agreement from the person (or their family member or carer)\n\nhow the medicines will be disposed of, usually by returning them to a pharmacy for disposal\n\nany special considerations, for example, for disposal of controlled drugs, needles and syringes\n\nwhat information needs to be recorded, for example, the name and quantity of medicine, the name of the person returning the medicine, the date returned and the name of the pharmacy.\n\n# Training and competency\n\nAppropriate training, support and competency assessment for managing medicines is essential to ensure the safety, quality and consistency of care.\n\nWhen social care providers are responsible for medicines support, they should have robust processes for medicines‑related training and competency assessment for care workers, to ensure that they:\n\nreceive appropriate training and support\n\nhave the necessary knowledge and skills\n\nare assessed as competent to give the medicines support being asked of them, including assessment through direct observation\n\nhave an annual review of their knowledge, skills and competencies.\n\nFollow the advice on recruiting, training and supporting home care workers in NICE's guideline on home care.\n\n# Terms used in this guideline\n\n## Advance care planning\n\nA voluntary process of discussion about what care a person would or would not want in the future, if they were unable to make decisions because of illness or a lack of mental capacity to consent. The person may also choose to involve their family members or friends in discussions.\n\n## Carer\n\nThe term 'carer' is used to define an informal, unpaid carer only (see also 'care worker').\n\n## Care worker\n\nA person who is employed to provide care and support to people in their own home. This includes home care workers, personal assistants (who are directly employed by people who use services) and other support workers. Note that a person's own home includes extra care housing, Shared Lives Scheme (formerly Adult Placement Scheme) living arrangements, sheltered housing (such as supported housing or specialist accommodation), supported living and temporary accommodation (such as for people who are homeless).\n\n## Fair blame culture\n\nIn health and social care, this enables open and honest reporting of mistakes that are treated as an opportunity to learn to improve care.\n\n## Health and social care practitioners\n\nThe wider health and social care team of health professionals and social care practitioners. Health professionals include, but are not limited to, GPs, pharmacists, hospital consultants, community nurses, specialist nurses and mental health professionals. Social care practitioners include, but are not limited to, care workers, case managers, care coordinators and social workers. When specific recommendations are made for a particular group, this is specified in the recommendation.\n\n## Medicine\n\nAll prescription and non-prescription (over-the-counter) healthcare treatments, such as oral medicines, topical medicines, inhaled products, injections, wound care products, appliances and vaccines.\n\n## Medicines-related problems\n\nMedicines-related problem include:\n\npotentially avoidable medicines-related hospital admissions\n\nprescribing errors\n\ndispensing errors\n\nadministration errors (for example, missed or delayed doses, inappropriate or incorrect administration)\n\nmonitoring errors (for example, inadequate review or follow-up, incomplete or inaccurate documentation)\n\nadverse events, incident reporting and significant events\n\nnear misses (a prevented medicines-related patient safety incident which could have led to patient harm)\n\ndeliberate withholding of medicines or deliberate attempt to harm\n\nrestraint or covert administration that has been used inappropriately\n\nmisuse, such as missing or diverted medicines\n\nother unintended or unexpected incidents that were specifically related to medicines use, which could have, or did, lead to harm (including death).\n\n## Medicines support\n\nAny support that enables a person to manage their medicines. This varies for different people depending on their specific needs.\n\n## Mental capacity\n\nThe ability of a person to make a decision about their own care, including:\n\ndecisions that affect daily life (for example, when to get up, what to wear or whether to go to the doctor when feeling ill, and more serious or significant decisions)\n\ndecisions that may have legal consequences for them or others (for example, agreeing to have medical treatment, buying goods or making a will).\n\nThe Mental Capacity Act 2005 defines a lack of mental capacity as when 'a person lacks capacity in relation to a matter if at the material time he is unable to make a decision for himself in relation to the matter because of an impairment of, or a disturbance in the functioning of, the mind or brain'.\n\nHealth professionals should follow the Department of Health's advice on consent. If a person does not have capacity to make decisions, health and social care practitioners should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards.\n\n## Monitored dosage system\n\nA system for packing medicines, for example, by putting medicines for each time of day in separate blisters or compartments in a box.\n\n## Original packaging\n\nThe packaging in which the medicine is supplied by the supplying pharmacy. This could be a manufacturers packaging or pharmacy supplied packaging after larger amounts of medicines have been decanted for individual patient use.\n\n## Parenteral nutrition\n\nProviding nutrients intravenously.\n\n## Provider's care plan\n\nA written plan that sets out the care and support that providers and the person have agreed will be put in place, following a local authority assessment. It includes details of both personal care and practical support.\n\n## Social care provider\n\nA provider organisation, registered with the Care Quality Commission to provide community adult care services, which directly employs care workers to provide personal care and support in a person's home.\n\n## Time-sensitive medicine\n\nA medicine that needs to be given or taken at a specific time, where a delay in receiving the dose or omission of the dose may lead to serious patient harm, for example, insulin injections for diabetes or specific medicines for Parkinson's disease.\n\nFor other health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nthe adequate provision of education and training for care workers and other support staff\n\nthe provision and appropriate use of medicines administration records.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "This guideline has been developed to help ensure that adults who receive social care in the community get the support they need to manage their medicines safely and effectively. Social care in the community is defined as care and support in their own home for adults who:\n\nthe local authority has to discharge a duty or responsibility under either the Care Act 2014 or the Mental Health Act 1983\n\nreceive any social care component of an NHS continuing care package\n\nself-fund their own care and support.\n\nNote that a person's own home includes extra care housing, Shared Lives Scheme (formerly Adult Placement Scheme) living arrangements, sheltered housing (such as supported housing or specialist accommodation), supported living and temporary accommodation (such as for people who are homeless).\n\nAn increasing number of people need social care and support in the community, which may include help with managing their medicines, as reported in the Department of Health's policy on health and social care integration (2013).\n\nPeople receiving social care in the community may be at a greater risk of medicines-related problems. For example, if they have multiple long-term conditions (multimorbidity) or are taking multiple medicines (polypharmacy). Family members, carers and care workers often help people to take and look after their medicines, for example, by ordering prescription medicines or reminding a person to take their medicines.\n\nCare workers who are responsible for providing medicines support have limited supervision by health professionals. There is variation in staff training and low pay, which leads to a high turnover of staff (32% of care workers leave within 12\xa0months; 56% within 2\xa0years). This can result in a lack of continuity of care and inflexibility in changing care arrangements (Commissioning home care for older people. Social Care Institute for Excellence, 2014).\n\nThis guideline focuses on adults (aged 18 and over) and considers how to assess their medicines support needs, with an emphasis on enabling and supporting people to manage their own medicines as much as possible, when they are able to do so. It covers how support should be planned and delivered, with health and social care providers sharing accurate and up-to-date information, and working together to deliver high-quality care.\n\nThis guideline also addresses the medicines management systems and processes that need to be in place so that people receive the medicines they need in a safe and effective way. This includes ensuring that care workers receive support and training to provide medicines support for the people that they care for, and know how and when to get help and advice.\n\nFinally, the guideline encourages a person-centred, 'fair blame' culture where people, their family members, carers and care workers can raise concerns about medicines, and social care providers have robust governance arrangements to help keep people safe in line with Regulation 13 of The Health and Social Care Act 2008 (Regulated Activities) Regulations 2014.\n\nThe following legislation and regulations relating to this guideline have been published by the UK Government, although this is not intended to be a comprehensive list:\n\nThe Care Act 2014\n\nHealth and Social Care Act 2008 (Regulated Activities) Regulations 2014\n\nHealth and Social Care Act 2012\n\nThe Controlled Waste (England and Wales) Regulations 2012\n\nCare Quality Commission (Registration) Regulations 2009\n\nHealth and Social Care Act 2008\n\nMental Capacity Act 2005\n\nData Protection Act 1998\n\nEquality Act 2010\n\nThe Human Medicines Regulations 2012\n\nThe Misuse of Drugs (Safe Custody) Regulations 1973\n\nMisuse of Drugs Act 1971."}	https://www.nice.org.uk/guidance/ng67	This guideline covers medicines support for adults (aged 18 and over) who are receiving social care in the community. It aims to ensure that people who receive social care are supported to take and look after their medicines effectively and safely at home. It gives advice on assessing if people need help with managing their medicines, who should provide medicines support and how health and social care staff should work together.
9b23e984690faddbdd3071eb28ad2961642a42dc	nice	Panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer (terminated appraisal)	Panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer (terminated appraisal) NICE is unable to recommend panitumumab with 5‑fluorouracil, folinic acid and irinotecan (FOLFIRI) for previously treated metastatic colorectal cancer in adults because no evidence submission was received from the manufacturer or sponsor of the technology. # Background The manufacturer of panitumumab (Amgen) was invited to submit evidence for this single technology appraisal of panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer. In July 2011, Amgen informed NICE that it would not be making an evidence submission. Amgen stated that, taking into account approaches previously used by NICE to appraising drugs for the treatment of colorectal cancer, there was not sufficient evidence to robustly estimate the cost effectiveness of panitumumab for this indication. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer. If, after doing this, organisations still wish to consider panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable. NICE will review the position if the company decides that it wants to make a full submission. ISBN: 978-1-4731-2442-4	{'Background': 'The manufacturer of panitumumab (Amgen) was invited to submit evidence for this single technology appraisal of panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer.\n\nIn July 2011, Amgen informed NICE that it would not be making an evidence submission. Amgen stated that, taking into account approaches previously used by NICE to appraising drugs for the treatment of colorectal cancer, there was not sufficient evidence to robustly estimate the cost effectiveness of panitumumab for this indication.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer. If, after doing this, organisations still wish to consider panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable.\n\nNICE will review the position if the company decides that it wants to make a full submission.\n\nISBN: 978-1-4731-2442-4'}	https://www.nice.org.uk/guidance/ta240	NICE is unable to recommend panitumumab with 5‑fluorouracil, folinic acid and irinotecan (FOLFIRI) for previously treated metastatic colorectal cancer in adults because no evidence submission was received from the manufacturer or sponsor of the technology.
4370d9bd7ff433eee97f0254786e94a4d271a853	nice	Alectinib for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer (terminated appraisal)	Alectinib for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer (terminated appraisal) NICE is unable to make a recommendation about the use in the NHS of alectinib for anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer previously treated with crizotinib because no evidence submission was received from Roche. We will review this decision if the company decides to make a submission. # Background Roche was invited to submit evidence for this single technology appraisal for alectinib in June 2016. The company informed NICE that it would be difficult to demonstrate the cost effectiveness of alectinib in people who have had crizotinib. This is because the evidence base is a single arm, phase II clinical trial and the assessment of relative effectiveness would have to be based on naive indirect comparisons. Given this insufficient evidence and the availability of an alternative option, ceritinib, recently recommended by NICE, the company will not be submitting evidence for this appraisal. The company stated that the evidence emerging from a trial directly comparing alectinib with crizotinib suggests that the value of alectinib to the NHS will be shown in people with untreated disease. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of alectinib for previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer. If, after doing this, organisations still wish to consider alectinib for previously treated ALK-positive advanced non-small-cell lung cancer, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable. NICE will review the position if the company decides that it wants to make a full submission. ISBN: 978-1-4731-2418-9	{'Background': 'Roche was invited to submit evidence for this single technology appraisal for alectinib in June 2016.\n\nThe company informed NICE that it would be difficult to demonstrate the cost effectiveness of alectinib in people who have had crizotinib. This is because the evidence base is a single arm, phase\xa0II clinical trial and the assessment of relative effectiveness would have to be based on naive indirect comparisons. Given this insufficient evidence and the availability of an alternative option, ceritinib, recently recommended by NICE, the company will not be submitting evidence for this appraisal.\n\nThe company stated that the evidence emerging from a trial directly comparing alectinib with crizotinib suggests that the value of alectinib to the NHS will be shown in people with untreated disease.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of alectinib for previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer. If, after doing this, organisations still wish to consider alectinib for previously treated ALK-positive advanced non-small-cell lung cancer, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable.\n\nNICE will review the position if the company decides that it wants to make a full submission.\n\nISBN: 978-1-4731-2418-9'}	https://www.nice.org.uk/guidance/ta438	NICE is unable to make a recommendation about the use in the NHS of alectinib for anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer previously treated with crizotinib because no evidence submission was received from Roche. We will review this decision if the company decides to make a submission.
dda991efb006ed39da2026da125b50012f38a4fa	nice	Patient group directions	Patient group directions This guideline covers good practice for developing, authorising, using and updating patient group directions. It also offers advice on deciding whether a patient group direction is needed. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Considering the need for a patient group direction Provide the majority of clinical care involving supplying and/or administering medicines on an individual, patient-specific basis. Reserve patient group directions (PGDs) for limited situations in which this offers an advantage for patient care, without compromising patient safety, and where there are clear governance arrangements and accountability. Explore all the available options for supplying and/or administering medicines in a specific clinical situation. Consider whether 1 option or a range of options is appropriate. Use the NHS Specialist Pharmacy Service PGD resources to consider whether a PGD is necessary. Do not use PGDs for medicines when exemptions in legislation allow their supply and/or administration without the need for a PGD. Consider investing in the training of additional non-medical prescribers to enable redesign of services if necessary, as part of a wider development or review of local medicines policy. PGDs must be used only by named and authorised registered health professionals who can legally supply and/or administer medicines using a PGD (see recommendation 1.4.9) in line with the Human Medicines Regulations 2012. PGDs must only include medicines with a UK marketing authorisation, in line with the Human Medicines Regulations 2012. Ensure that off-label use of a licensed medicine is included in a PGD only when clearly justified by best clinical practice. Clearly state that the medicine is being used outside the terms of the marketing authorisation on the PGD. Consider informing the patient or their carer that the use is off-label, in line with General Medical Council guidance on prescribing unlicensed medicines. Ensure that a black triangle medicine is included in a PGD only when clearly justified by best clinical practice. Clearly indicate the black triangle status on the PGD. Ensure that a controlled drug is included in a PGD only when legally permitted and clearly justified by best clinical practice. Do not jeopardise local and national strategies to combat antimicrobial resistance and healthcare‑associated infections. Ensure that an antimicrobial is included in a PGD only when: clinically essential and clearly justified by best practice guidance a local specialist in microbiology has agreed that a PGD is needed and this is clearly documented (see recommendation 1.3.2) use of the PGD is monitored and reviewed regularly (see recommendation 1.6.4 and recommendation 1.8.5). Do not include a medicine needing frequent dosage adjustments or frequent or complex monitoring in a PGD (for example, anticoagulants or insulin). Do not make dose adjustments to a medicine supplied under a PGD when the medicine is already in the patient's possession. Carefully consider the risks and benefits of including more than 1 medicine in a PGD on a case-by-case basis. Ensure all legal requirements are met for each medicine in line with the Human Medicines Regulations 2012. Do not use PGDs for managing long-term conditions, such as hypertension or diabetes, or when uncertainty remains about the differential diagnosis. # Obtaining agreement to develop a patient group direction Establish a robust and transparent process for obtaining the agreement of the authorising body before proceeding to develop a PGD. Ensure that relevant information is clear and easily accessible. Ensure that a multidisciplinary PGD approval group, with a locally defined mix of members, reviews proposals to develop PGDs. Define the roles and responsibilities of members and consider their training and competency needs. Ensure that governance arrangements for the PGD approval group are firmly established, with clear lines of accountability and the delegated authority of the authorising body. This should include: agreeing and documenting terms of reference declaring any conflicts of interests setting the agenda of meetings and taking minutes or notes prioritising PGD proposals establishing reporting arrangements engaging stakeholders, such as clinical groups and patients and the public liaising with commissioning and finance. Ensure that the following information is included in proposal documentation for seeking agreement to develop a PGD: the title of the PGD details of the proposer and other individual people who would be involved in developing and authorising the PGD details of the organisation delivering the service (if this organisation is not the authorising body) the setting where the PGD would be used the condition to be treated, considering patient inclusion and/or exclusion criteria benefits to patient care potential risks to patient safety details of medicine(s) to be supplied and/or administered, including dosage, quantity, formulation and strength, route and frequency of administration, duration of treatment and whether it is included in the local formulary health professional groups who would work under the PGD, including training and competency needs current and/or future service provisions for supplying and/or administering the medicine(s), including its position within the care pathway evidence to support the proposal resources needed to deliver the service a timescale for developing the PGD. Establish a robust and transparent decision-making process that clearly defines standard criteria for reviewing proposals to develop a PGD. Ensure that: all legal requirements have been met robust local processes and clear governance arrangements are in place the risks and benefits of all options for supplying and/or administering the medicine(s) have been explored the PGD will deliver effective patient care that is appropriate in a pre-defined clinical situation, without compromising patient safety the views of stakeholders, such as clinical groups, patients and the public, and the provider or commissioning organisation have been considered appropriate registered health professionals are available to use the PGD, and training and competency needs are addressed people who are developing, authorising, monitoring, reviewing and updating the PGD are identified, and training and competency needs are addressed the need for appropriately labelled packs and safe storage can be met adequate resources, such as finance, training, medicines procurement and diagnostic equipment are available for service delivery adequate resources are available to ensure that processes are followed within any locally agreed timeframe decisions are aligned with local clinical commissioning frameworks. Record decisions to accept or reject the proposal, including the rationale for the decision. Communicate the decision by writing to the person who submitted the proposal, within a locally agreed timeframe. Ensure that the decision is communicated to other appropriate stakeholders. Establish and publish a robust and transparent process for appeals of decisions made by the PGD approval group. Clearly define the acceptable grounds and timescale for appeals. # Developing patient group directions Ensure that a named lead author has responsibility for developing a PGD, supported by a locally determined multidisciplinary PGD working group. Include a doctor (or dentist), pharmacist and representative of any other professional group(s) using the PGD. Define their roles and responsibilities, and consider their training and competency needs. Liaise with a local specialist in microbiology when developing a PGD that includes an antimicrobial (see recommendation 1.1.10). Seek views on draft PGDs and agree final draft PGDs with relevant stakeholders, including clinicians and local medicines decision-making groups. All legally required information must be included in a PGD in line with the Human Medicines Regulations 2012. Use a standard template to ensure that the format is consistent across the organisation. Ensure PGDs are consistent with the relevant summary of product characteristics, unless the medicine is being used off-label or relevant national guidance is being followed (see recommendation 1.1.7). Use the best available evidence, such as NICE guidance and other sources of high-quality information when developing PGDs. Include key references in an appendix to the PGD. # Authorising patient group directions PGDs must be authorised only by an appropriate authorising body in line with the Human Medicines Regulations 2012. Address barriers that may delay authorising PGDs, such as lack of clear leadership, ownership and understanding of legislation and governance arrangements. At an early stage, identify the appropriate senior doctor (or dentist) and senior pharmacist who will sign the PGD, in line with the Human Medicines Regulations 2012. Define the roles and responsibilities of these people and consider their training and competency needs. When acting as a doctor, dentist or pharmacist signatory, establish that the clinical and pharmaceutical content is accurate and supported by the best available evidence. At an early stage, identify the appropriate person who will sign the PGD as a representative of any professional group(s) practising under the PGD. Consider their training and competency needs. At an early stage, identify the appropriate person, such as the clinical governance or patient safety lead, who has designated responsibility for signing PGDs on behalf of the authorising body, in line with the Human Medicines Regulations 2012. Define the roles and responsibilities of this person and consider their training and competency needs. When signing a PGD on behalf of an authorising body, establish that: local processes and governance arrangements have been followed all legal requirements have been met. Assess local needs and develop a communications plan to support the dissemination of PGDs. Identify an appropriate person who is responsible for ensuring that this occurs. For each PGD, the provider organisation should: identify a senior, responsible person from within the service (if the provider is not the authorising body, this responsibility would require a formal agreement between the commissioner and provider) to authorise named, registered health professionals to practise under the PGD (see recommendation 1.1.5) ensure that authorised health professionals have signed the appropriate documentation (see recommendation 1.5.2). Publish final signed versions of PGDs on an intranet. When a PGD is developed and authorised by a commissioning organisation for use across multiple provider organisations, ensure that it is adopted for use within each provider organisation. # Using patient group directions When supplying and/or administering a medicine under a PGD, health professionals should follow local organisational policies and act within their code(s) of professional conduct and local governance arrangements (see recommendations 1.8.1 and 1.8.2). Before practising under a PGD, health professionals should ensure that they: have undertaken the necessary initial training and continuing professional development have been assessed as competent and authorised to practise by the provider organisation (see recommendation 1.4.9) have signed the appropriate documentation (see recommendation 1.4.9) are using a copy of the most recent and in date final signed version of the PGD (see recommendation 1.4.10) have read and understand the context and content of the PGD. When practising under a PGD, health professionals should: not delegate their responsibility ensure that they can determine that the patient meets the inclusion criteria as set out in the PGD ensure that they can determine that no exclusion criteria apply discuss alternative options for treating the patient's condition, when appropriate assess each individual patient's circumstances and preferences recognise when signposting or referral to another health professional or service is needed, as specified in the PGD understand relevant information about the medicine(s) included in the PGD, such as: how to administer the medicine how the medicine acts within the body dosage calculations potential adverse effects and how to manage them drug interactions, precautions and contraindications storage requirements, including maintenance of the 'cold chain' follow-up arrangements be able to advise the patient or their carer about the medicine(s), as appropriate. When supplying a medicine(s), provide an appropriately labelled pack. Health professionals (other than pharmacists or dispensing doctors) should not split packs. Ensure that the patient receives a manufacturer's patient information leaflet with each medicine. Identify whether patients supplied with a medicine(s) under a PGD are exempt from NHS prescription charges. The appropriate prescription charge(s) must be collected from patients who are not exempt, in line with the National Health Service (Charges for Drugs and Appliances) Amendment (No. 2) Regulations 2000. Document the following information about the clinical assessment and supply and/or administration of the medicine(s): date and time of supply and/or administration patient details, such as name, date of birth, allergies, previous adverse events and how the patient met the criteria of the PGD details of medicine, such as name, strength, dose, frequency, quantity, route and site (if by injection) of administration (record the batch number and expiry date for vaccines, blood-derived products and other medicines if recommended by relevant national guidance) a statement that supply or administration is by using a PGD name and signature (which may be an electronic signature) of the health professional supplying or administering the medicine relevant information that was provided to the patient or their carer whether patient consent to treatment was obtained, in line with the Department of Health's advice on consent (2009). # Reviewing and updating patient group directions Establish and manage a structured work programme for reviewing, updating and reauthorising PGDs. Ensure that sufficient resources are available to deliver the work programme. Ensure that a named lead author has responsibility for reviewing and updating the PGD, supported by a locally determined multidisciplinary PGD working group. Include a doctor (or dentist), pharmacist and representative of any other professional group(s) using the PGD. Define their roles and responsibilities and consider their training and competency needs (see recommendation 1.3.1). When reviewing the PGD, conduct an appropriate literature search to identify new evidence. Ensure that this evidence is evaluated to assess its relevance and validity. When reviewing the PGD, determine whether the PGD remains the most appropriate option to deliver the service. This should be informed by local monitoring and evaluations, frequency of use of the PGD, views of health professionals working under the PGD and views of relevant stakeholders, such as patients or their carers. Determine the expiry date for an individual PGD on a case-by-case basis, with patient safety paramount. Ensure that this date does not exceed 3 years from the date the PGD was authorised. Ensure that an updated PGD is reauthorised, in line with the Human Medicines Regulations 2012 (see recommendations 1.4.3 to 1.4.7). When a PGD is updated, ensure all relevant documentation is also updated, including the record and signatures of health professionals authorised to practise under the PGD (see recommendation 1.8.6). Ensure that an updated PGD is communicated and disseminated effectively to all relevant stakeholders (see recommendations 1.4.8 and 1.4.10). Establish a robust and transparent process for the unscheduled review and updating of a PGD, when the need for this has been identified. This should include responding to: changes in legislation important new evidence or guidance that changes the PGD, such as new NICE guidance new information on drug safety changes in the summary of product characteristics changes to the local formulary. # Training and competency Identify the senior person in each profession who is responsible for ensuring that only fully competent, qualified and trained health professionals use PGDs. Identify gaps in competency and establish a comprehensive and appropriate training programme for all people involved in considering the need for, developing, authorising, using and updating PGDs. Ensure that adequate educational materials are available to enable individual people and organisations to deliver safe and effective services in which PGDs are used. Consider collaborating with other organisations and sharing existing educational materials to ensure a comprehensive approach. Ensure that training and re-training of health professionals using PGDs incorporates a post-training assessment of competency. # Organisational governance For each PGD, the commissioning and provider organisation(s) should collaborate to firmly establish local governance arrangements with clear lines of responsibility and accountability. Develop or review the organisational PGD policy and associated procedures to ensure that robust and transparent processes are documented. Ensure that the PGD policy is publicly available. Ensure that a designated person has overall organisational responsibility for PGDs. Ensure that patient safety incidents relating to PGD use are reported, collated and reviewed by the appropriate organisations in a planned programme, in line with national patient safety reporting systems. Agree and undertake a planned programme of monitoring and evaluation of PGD use within the service. Ensure that appropriate organisational records are maintained, stored securely and archived, in line with relevant legislation and the Department of Health and Social Care's code of practice on records management. These records should include: patient safety incidents, such as medication errors, near misses and suspected adverse events terms of reference and minutes or notes of the PGD approval group a list of all PGDs in use within the organisation, including their review date and expiry date master authorised copies of PGDs expired versions of PGDs members of the PGD working group signatures of people signing a PGD a list of named, registered health professionals authorised to practise under each PGD used within the service training records results of monitoring and evaluation. # Terms used in the guideline ## Appropriately labelled pack In most cases, the pack to be issued under a PGD will need to be labelled to reflect the dose exactly as authorised in the PGD, as if it were being dispensed against a prescription. Separate requirements exist for prescription-only medicines (POMs) and for pharmacy (P) and general sales list (GSL) medicines. In practice, medicines supplied for use under a PGD are often in packs that are pre-labelled by a licensed manufacturing unit. These labels include all the standard labelling requirements, leaving a space on the pack for the patient's name, date of dispensing and address of the supplying service to be added at the time of supply. This is sometimes known as over-labelling. ## Authorising body An organisation listed in the Human Medicines Regulations 2012 (and subsequent amendments) that is legally able to authorise a PGD. The commissioning and/or provider organisation may be an authorising body. In the NHS in England, these organisations are: clinical commissioning groups (CCGs) local authorities NHS trusts or NHS foundation trusts NHS England Public Health England. ## Black triangle medicine Black triangle medicines are licensed medicines that are intensively monitored and subject to special reporting arrangements for adverse events. ## Commissioning organisation/commissioner The organisation with which a contract or agreement for the provision of a service that may require the prescribing, supply or administration of medicines has been made. ## Off-label use Using a UK licensed medicine outside the terms of its marketing authorisation, such as outside defined indications, doses or routes of administration. For example, when amitriptyline, licensed for the treatment of depression, is used for neuropathic pain. ## Organisations Unless stated otherwise, use of the term 'organisation' includes authorising bodies and any other organisations (both NHS and non-NHS) who are considering the need for, developing, authorising, using and updating PGDs to provide public-funded services. ## Patient group direction (PGD) Defined in Health Service Circular (HSC 2000/026) as 'Written instructions for the supply or administration of medicines to groups of patients who may not be individually identified before presentation for treatment'. ## Patient safety incident Any unintended or unexpected incident that could have or did lead to harm for 1 or more patients receiving healthcare. This includes clinical errors, medication errors, adverse events and near misses. ## PGD approval group A locally determined multidisciplinary group that considers proposals to develop a PGD to deliver a service. This group may also be involved at other stages of the process, depending on local arrangements. For example, the group may approve a final draft of the PGD before it is submitted for authorisation. The term 'PGD approval group' is used for the purpose of this guidance, but other names for the group may be used locally. The group may be an existing local medicines decision-making group, such as the drug and therapeutics committee, or subgroup. ## PGD working group A locally determined multidisciplinary group established for each individual PGD. The PGD working group is responsible for developing the PGD and its subsequent review and updating. The term 'PGD working group' is used for the purpose of this guideline, but other names for the group may be used locally. ## Provider organisation/provider The organisation responsible for providing the commissioned service, which may require the prescribing, supply or administration of medicines. This may be an NHS organisation or a non-NHS organisation providing public-funded service. ## Public-funded service A service commissioned by the NHS or local authority that may be provided by an NHS organisation or a non-NHS organisation, such as: independent organisations, for example, independent hospitals independent contractors, for example, community pharmacies voluntary and charitable agencies, for example, hospices.# Context This guideline provides good practice recommendations for the systems and processes used when commissioners and providers of public‑funded services are considering the need for, developing, authorising, using and updating patient group directions (PGDs). It also covers governance arrangements to ensure that patients receive safe and appropriate care, and timely access to medicines, in line with legislation. The guideline incorporates medicines legislation and takes into account the range of organisations providing public-funded services. This includes NHS organisations, local authorities (in England), and any public-funded services provided by non-NHS organisations, such as: independent organisations (for example, independent hospitals) independent contractors (for example, community pharmacies) voluntary and charitable agencies (for example, hospices). Legislation establishing PGDs was introduced in 2000, and the Health Service Circular (HSC 2000/026) provided additional guidance. The current legislation for PGDs is included in The Human Medicines Regulations 2012, which came into force in August 2012. This legislation was amended in April 2013 to reflect changes to NHS organisational structures in England, as a result of the Health and Social Care Act 2012 (see The National Treatment Agency and the Health and Social Care Act 2012 Order 2013). PGDs provide a legal framework that allows the supply and/or administration of a specified medicine(s), by named, authorised, registered health professionals, to a pre-defined group of patients needing prophylaxis or treatment for a condition described in the PGD, without the need for a prescription or an instruction from a prescriber. A PGD is defined in Health Service Circular (HSC 2000/026) as: 'Written instructions for the supply or administration of medicines to groups of patients who may not be individually identified before presentation for treatment.' This definition should not be interpreted as indicating that the patient should not be identified. Patients may or may not be known to the service provider. The Health Service Circular (HSC 2000/026) states that 'the majority of clinical care should be provided on an individual, patient-specific basis'. Supplying and/or administering medicines under PGDs should be reserved for situations in which this offers an advantage for patient care without compromising patient safety, and there are clear governance arrangements and accountability. Using a PGD is not a form of prescribing.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Considering the need for a patient group direction\n\nProvide the majority of clinical care involving supplying and/or administering medicines on an individual, patient-specific basis. Reserve patient group directions (PGDs) for limited situations in which this offers an advantage for patient care, without compromising patient safety, and where there are clear governance arrangements and accountability.\n\nExplore all the available options for supplying and/or administering medicines in a specific clinical situation. Consider whether 1 option or a range of options is appropriate.\n\nUse the NHS Specialist Pharmacy Service PGD resources to consider whether a PGD is necessary. Do not use PGDs for medicines when exemptions in legislation allow their supply and/or administration without the need for a PGD.\n\nConsider investing in the training of additional non-medical prescribers to enable redesign of services if necessary, as part of a wider development or review of local medicines policy.\n\nPGDs must be used only by named and authorised registered health professionals who can legally supply and/or administer medicines using a PGD (see recommendation 1.4.9) in line with the Human Medicines Regulations 2012.\n\nPGDs must only include medicines with a UK marketing authorisation, in line with the Human Medicines Regulations 2012.\n\nEnsure that off-label use of a licensed medicine is included in a PGD only when clearly justified by best clinical practice. Clearly state that the medicine is being used outside the terms of the marketing authorisation on the PGD. Consider informing the patient or their carer that the use is off-label, in line with General Medical Council guidance on prescribing unlicensed medicines.\n\nEnsure that a black triangle medicine is included in a PGD only when clearly justified by best clinical practice. Clearly indicate the black triangle status on the PGD.\n\nEnsure that a controlled drug is included in a PGD only when legally permitted and clearly justified by best clinical practice.\n\nDo not jeopardise local and national strategies to combat antimicrobial resistance and healthcare‑associated infections. Ensure that an antimicrobial is included in a PGD only when:\n\nclinically essential and clearly justified by best practice guidance\n\na local specialist in microbiology has agreed that a PGD is needed and this is clearly documented (see recommendation 1.3.2)\n\nuse of the PGD is monitored and reviewed regularly (see recommendation 1.6.4 and recommendation 1.8.5).\n\nDo not include a medicine needing frequent dosage adjustments or frequent or complex monitoring in a PGD (for example, anticoagulants or insulin).\n\nDo not make dose adjustments to a medicine supplied under a PGD when the medicine is already in the patient's possession.\n\nCarefully consider the risks and benefits of including more than 1\xa0medicine in a PGD on a case-by-case basis. Ensure all legal requirements are met for each medicine in line with the Human Medicines Regulations 2012.\n\nDo not use PGDs for managing long-term conditions, such as hypertension or diabetes, or when uncertainty remains about the differential diagnosis.\n\n# Obtaining agreement to develop a patient group direction\n\nEstablish a robust and transparent process for obtaining the agreement of the authorising body before proceeding to develop a PGD. Ensure that relevant information is clear and easily accessible.\n\nEnsure that a multidisciplinary PGD approval group, with a locally defined mix of members, reviews proposals to develop PGDs. Define the roles and responsibilities of members and consider their training and competency needs.\n\nEnsure that governance arrangements for the PGD approval group are firmly established, with clear lines of accountability and the delegated authority of the authorising body. This should include:\n\nagreeing and documenting terms of reference\n\ndeclaring any conflicts of interests\n\nsetting the agenda of meetings and taking minutes or notes\n\nprioritising PGD proposals\n\nestablishing reporting arrangements\n\nengaging stakeholders, such as clinical groups and patients and the public\n\nliaising with commissioning and finance.\n\nEnsure that the following information is included in proposal documentation for seeking agreement to develop a PGD:\n\nthe title of the PGD\n\ndetails of the proposer and other individual people who would be involved in developing and authorising the PGD\n\ndetails of the organisation delivering the service (if this organisation is not the authorising body)\n\nthe setting where the PGD would be used\n\nthe condition to be treated, considering patient inclusion and/or exclusion criteria\n\nbenefits to patient care\n\npotential risks to patient safety\n\ndetails of medicine(s) to be supplied and/or administered, including dosage, quantity, formulation and strength, route and frequency of administration, duration of treatment and whether it is included in the local formulary\n\nhealth professional groups who would work under the PGD, including training and competency needs\n\ncurrent and/or future service provisions for supplying and/or administering the medicine(s), including its position within the care pathway\n\nevidence to support the proposal\n\nresources needed to deliver the service\n\na timescale for developing the PGD.\n\nEstablish a robust and transparent decision-making process that clearly defines standard criteria for reviewing proposals to develop a PGD. Ensure that:\n\nall legal requirements have been met\n\nrobust local processes and clear governance arrangements are in place\n\nthe risks and benefits of all options for supplying and/or administering the medicine(s) have been explored\n\nthe PGD will deliver effective patient care that is appropriate in a pre-defined clinical situation, without compromising patient safety\n\nthe views of stakeholders, such as clinical groups, patients and the public, and the provider or commissioning organisation have been considered\n\nappropriate registered health professionals are available to use the PGD, and training and competency needs are addressed\n\npeople who are developing, authorising, monitoring, reviewing and updating the PGD are identified, and training and competency needs are addressed\n\nthe need for appropriately labelled packs and safe storage can be met\n\nadequate resources, such as finance, training, medicines procurement and diagnostic equipment are available for service delivery\n\nadequate resources are available to ensure that processes are followed within any locally agreed timeframe\n\ndecisions are aligned with local clinical commissioning frameworks.\n\nRecord decisions to accept or reject the proposal, including the rationale for the decision. Communicate the decision by writing to the person who submitted the proposal, within a locally agreed timeframe. Ensure that the decision is communicated to other appropriate stakeholders.\n\nEstablish and publish a robust and transparent process for appeals of decisions made by the PGD approval group. Clearly define the acceptable grounds and timescale for appeals.\n\n# Developing patient group directions\n\nEnsure that a named lead author has responsibility for developing a PGD, supported by a locally determined multidisciplinary PGD working group. Include a doctor (or dentist), pharmacist and representative of any other professional group(s) using the PGD. Define their roles and responsibilities, and consider their training and competency needs.\n\nLiaise with a local specialist in microbiology when developing a PGD that includes an antimicrobial (see recommendation 1.1.10).\n\nSeek views on draft PGDs and agree final draft PGDs with relevant stakeholders, including clinicians and local medicines decision-making groups.\n\nAll legally required information must be included in a PGD in line with the Human Medicines Regulations 2012. Use a standard template to ensure that the format is consistent across the organisation.\n\nEnsure PGDs are consistent with the relevant summary of product characteristics, unless the medicine is being used off-label or relevant national guidance is being followed (see recommendation 1.1.7).\n\nUse the best available evidence, such as NICE guidance and other sources of high-quality information when developing PGDs. Include key references in an appendix to the PGD.\n\n# Authorising patient group directions\n\nPGDs must be authorised only by an appropriate authorising body in line with the Human Medicines Regulations 2012.\n\nAddress barriers that may delay authorising PGDs, such as lack of clear leadership, ownership and understanding of legislation and governance arrangements.\n\nAt an early stage, identify the appropriate senior doctor (or dentist) and senior pharmacist who will sign the PGD, in line with the Human Medicines Regulations 2012. Define the roles and responsibilities of these people and consider their training and competency needs.\n\nWhen acting as a doctor, dentist or pharmacist signatory, establish that the clinical and pharmaceutical content is accurate and supported by the best available evidence.\n\nAt an early stage, identify the appropriate person who will sign the PGD as a representative of any professional group(s) practising under the PGD. Consider their training and competency needs.\n\nAt an early stage, identify the appropriate person, such as the clinical governance or patient safety lead, who has designated responsibility for signing PGDs on behalf of the authorising body, in line with the Human Medicines Regulations 2012. Define the roles and responsibilities of this person and consider their training and competency needs.\n\nWhen signing a PGD on behalf of an authorising body, establish that:\n\nlocal processes and governance arrangements have been followed\n\nall legal requirements have been met.\n\nAssess local needs and develop a communications plan to support the dissemination of PGDs. Identify an appropriate person who is responsible for ensuring that this occurs.\n\nFor each PGD, the provider organisation should:\n\nidentify a senior, responsible person from within the service (if the provider is not the authorising body, this responsibility would require a formal agreement between the commissioner and provider) to authorise named, registered health professionals to practise under the PGD (see recommendation 1.1.5)\n\nensure that authorised health professionals have signed the appropriate documentation (see recommendation 1.5.2).\n\nPublish final signed versions of PGDs on an intranet.\n\nWhen a PGD is developed and authorised by a commissioning organisation for use across multiple provider organisations, ensure that it is adopted for use within each provider organisation.\n\n# Using patient group directions\n\nWhen supplying and/or administering a medicine under a PGD, health professionals should follow local organisational policies and act within their code(s) of professional conduct and local governance arrangements (see recommendations 1.8.1 and 1.8.2).\n\nBefore practising under a PGD, health professionals should ensure that they:\n\nhave undertaken the necessary initial training and continuing professional development\n\nhave been assessed as competent and authorised to practise by the provider organisation (see recommendation 1.4.9)\n\nhave signed the appropriate documentation (see recommendation 1.4.9)\n\nare using a copy of the most recent and in date final signed version of the PGD (see recommendation 1.4.10)\n\nhave read and understand the context and content of the PGD.\n\nWhen practising under a PGD, health professionals should:\n\nnot delegate their responsibility\n\nensure that they can determine that the patient meets the inclusion criteria as set out in the PGD\n\nensure that they can determine that no exclusion criteria apply\n\ndiscuss alternative options for treating the patient's condition, when appropriate\n\nassess each individual patient's circumstances and preferences\n\nrecognise when signposting or referral to another health professional or service is needed, as specified in the PGD\n\nunderstand relevant information about the medicine(s) included in the PGD, such as:\n\n\n\nhow to administer the medicine\n\nhow the medicine acts within the body\n\ndosage calculations\n\npotential adverse effects and how to manage them\n\ndrug interactions, precautions and contraindications\n\nstorage requirements, including maintenance of the 'cold chain'\n\nfollow-up arrangements\n\n\n\nbe able to advise the patient or their carer about the medicine(s), as appropriate.\n\nWhen supplying a medicine(s), provide an appropriately labelled pack. Health professionals (other than pharmacists or dispensing doctors) should not split packs.\n\nEnsure that the patient receives a manufacturer's patient information leaflet with each medicine.\n\nIdentify whether patients supplied with a medicine(s) under a PGD are exempt from NHS prescription charges. The appropriate prescription charge(s) must be collected from patients who are not exempt, in line with the National Health Service (Charges for Drugs and Appliances) Amendment (No. 2) Regulations 2000.\n\nDocument the following information about the clinical assessment and supply and/or administration of the medicine(s):\n\ndate and time of supply and/or administration\n\npatient details, such as name, date of birth, allergies, previous adverse events and how the patient met the criteria of the PGD\n\ndetails of medicine, such as name, strength, dose, frequency, quantity, route and site (if by injection) of administration (record the batch number and expiry date for vaccines, blood-derived products and other medicines if recommended by relevant national guidance)\n\na statement that supply or administration is by using a PGD\n\nname and signature (which may be an electronic signature) of the health professional supplying or administering the medicine\n\nrelevant information that was provided to the patient or their carer\n\nwhether patient consent to treatment was obtained, in line with the Department of Health's advice on consent (2009).\n\n# Reviewing and updating patient group directions\n\nEstablish and manage a structured work programme for reviewing, updating and reauthorising PGDs. Ensure that sufficient resources are available to deliver the work programme.\n\nEnsure that a named lead author has responsibility for reviewing and updating the PGD, supported by a locally determined multidisciplinary PGD working group. Include a doctor (or dentist), pharmacist and representative of any other professional group(s) using the PGD. Define their roles and responsibilities and consider their training and competency needs (see recommendation\xa01.3.1).\n\nWhen reviewing the PGD, conduct an appropriate literature search to identify new evidence. Ensure that this evidence is evaluated to assess its relevance and validity.\n\nWhen reviewing the PGD, determine whether the PGD remains the most appropriate option to deliver the service. This should be informed by local monitoring and evaluations, frequency of use of the PGD, views of health professionals working under the PGD and views of relevant stakeholders, such as patients or their carers.\n\nDetermine the expiry date for an individual PGD on a case-by-case basis, with patient safety paramount. Ensure that this date does not exceed 3\xa0years from the date the PGD was authorised.\n\nEnsure that an updated PGD is reauthorised, in line with the Human Medicines Regulations 2012 (see recommendations 1.4.3 to 1.4.7).\n\nWhen a PGD is updated, ensure all relevant documentation is also updated, including the record and signatures of health professionals authorised to practise under the PGD (see recommendation 1.8.6).\n\nEnsure that an updated PGD is communicated and disseminated effectively to all relevant stakeholders (see recommendations 1.4.8 and 1.4.10).\n\nEstablish a robust and transparent process for the unscheduled review and updating of a PGD, when the need for this has been identified. This should include responding to:\n\nchanges in legislation\n\nimportant new evidence or guidance that changes the PGD, such as new NICE guidance\n\nnew information on drug safety\n\nchanges in the summary of product characteristics\n\nchanges to the local formulary.\n\n# Training and competency\n\nIdentify the senior person in each profession who is responsible for ensuring that only fully competent, qualified and trained health professionals use PGDs.\n\nIdentify gaps in competency and establish a comprehensive and appropriate training programme for all people involved in considering the need for, developing, authorising, using and updating PGDs.\n\nEnsure that adequate educational materials are available to enable individual people and organisations to deliver safe and effective services in which PGDs are used.\n\nConsider collaborating with other organisations and sharing existing educational materials to ensure a comprehensive approach.\n\nEnsure that training and re-training of health professionals using PGDs incorporates a post-training assessment of competency.\n\n# Organisational governance\n\nFor each PGD, the commissioning and provider organisation(s) should collaborate to firmly establish local governance arrangements with clear lines of responsibility and accountability.\n\nDevelop or review the organisational PGD policy and associated procedures to ensure that robust and transparent processes are documented. Ensure that the PGD policy is publicly available.\n\nEnsure that a designated person has overall organisational responsibility for PGDs.\n\nEnsure that patient safety incidents relating to PGD use are reported, collated and reviewed by the appropriate organisations in a planned programme, in line with national patient safety reporting systems.\n\nAgree and undertake a planned programme of monitoring and evaluation of PGD use within the service.\n\nEnsure that appropriate organisational records are maintained, stored securely and archived, in line with relevant legislation and the Department of Health and Social Care's code of practice on records management. These records should include:\n\npatient safety incidents, such as medication errors, near misses and suspected adverse events\n\nterms of reference and minutes or notes of the PGD approval group\n\na list of all PGDs in use within the organisation, including their review date and expiry date\n\nmaster authorised copies of PGDs\n\nexpired versions of PGDs\n\nmembers of the PGD working group\n\nsignatures of people signing a PGD\n\na list of named, registered health professionals authorised to practise under each PGD used within the service\n\ntraining records\n\nresults of monitoring and evaluation.\n\n# Terms used in the guideline\n\n## Appropriately labelled pack\n\nIn most cases, the pack to be issued under a PGD will need to be labelled to reflect the dose exactly as authorised in the PGD, as if it were being dispensed against a prescription. Separate requirements exist for prescription-only medicines (POMs) and for pharmacy (P) and general sales list (GSL) medicines. In practice, medicines supplied for use under a PGD are often in packs that are pre-labelled by a licensed manufacturing unit. These labels include all the standard labelling requirements, leaving a space on the pack for the patient's name, date of dispensing and address of the supplying service to be added at the time of supply. This is sometimes known as over-labelling.\n\n## Authorising body\n\nAn organisation listed in the Human Medicines Regulations 2012 (and subsequent amendments) that is legally able to authorise a PGD. The commissioning and/or provider organisation may be an authorising body.\n\nIn the NHS in England, these organisations are:\n\nclinical commissioning groups (CCGs)\n\nlocal authorities\n\nNHS trusts or NHS foundation trusts\n\nNHS England\n\nPublic Health England.\n\n## Black triangle medicine\n\nBlack triangle medicines are licensed medicines that are intensively monitored and subject to special reporting arrangements for adverse events.\n\n## Commissioning organisation/commissioner\n\nThe organisation with which a contract or agreement for the provision of a service that may require the prescribing, supply or administration of medicines has been made.\n\n## Off-label use\n\nUsing a UK licensed medicine outside the terms of its marketing authorisation, such as outside defined indications, doses or routes of administration. For example, when amitriptyline, licensed for the treatment of depression, is used for neuropathic pain.\n\n## Organisations\n\nUnless stated otherwise, use of the term 'organisation' includes authorising bodies and any other organisations (both NHS and non-NHS) who are considering the need for, developing, authorising, using and updating PGDs to provide public-funded services.\n\n## Patient group direction (PGD)\n\nDefined in Health Service Circular (HSC 2000/026) as 'Written instructions for the supply or administration of medicines to groups of patients who may not be individually identified before presentation for treatment'.\n\n## Patient safety incident\n\nAny unintended or unexpected incident that could have or did lead to harm for 1 or more patients receiving healthcare. This includes clinical errors, medication errors, adverse events and near misses.\n\n## PGD approval group\n\nA locally determined multidisciplinary group that considers proposals to develop a PGD to deliver a service. This group may also be involved at other stages of the process, depending on local arrangements. For example, the group may approve a final draft of the PGD before it is submitted for authorisation. The term 'PGD approval group' is used for the purpose of this guidance, but other names for the group may be used locally. The group may be an existing local medicines decision-making group, such as the drug and therapeutics committee, or subgroup.\n\n## PGD working group\n\nA locally determined multidisciplinary group established for each individual PGD. The PGD working group is responsible for developing the PGD and its subsequent review and updating. The term 'PGD working group' is used for the purpose of this guideline, but other names for the group may be used locally.\n\n## Provider organisation/provider\n\nThe organisation responsible for providing the commissioned service, which may require the prescribing, supply or administration of medicines. This may be an NHS organisation or a non-NHS organisation providing public-funded service.\n\n## Public-funded service\n\nA service commissioned by the NHS or local authority that may be provided by an NHS organisation or a non-NHS organisation, such as:\n\nindependent organisations, for example, independent hospitals\n\nindependent contractors, for example, community pharmacies\n\nvoluntary and charitable agencies, for example, hospices.", 'Context': "This guideline provides good practice recommendations for the systems and processes used when commissioners and providers of public‑funded services are considering the need for, developing, authorising, using and updating patient group directions (PGDs). It also covers governance arrangements to ensure that patients receive safe and appropriate care, and timely access to medicines, in line with legislation.\n\nThe guideline incorporates medicines legislation and takes into account the range of organisations providing public-funded services. This includes NHS organisations, local authorities (in England), and any public-funded services provided by non-NHS organisations, such as:\n\nindependent organisations (for example, independent hospitals)\n\nindependent contractors (for example, community pharmacies)\n\nvoluntary and charitable agencies (for example, hospices).\n\nLegislation establishing PGDs was introduced in 2000, and the Health Service Circular (HSC 2000/026) provided additional guidance. The current legislation for PGDs is included in The Human Medicines Regulations 2012, which came into force in August 2012. This legislation was amended in April 2013 to reflect changes to NHS organisational structures in England, as a result of the Health and Social Care Act 2012 (see The National Treatment Agency [Abolition] and the Health and Social Care Act 2012 [Consequential, Transitional and Saving Provisions] Order 2013).\n\nPGDs provide a legal framework that allows the supply and/or administration of a specified medicine(s), by named, authorised, registered health professionals, to a pre-defined group of patients needing prophylaxis or treatment for a condition described in the PGD, without the need for a prescription or an instruction from a prescriber.\n\nA PGD is defined in Health Service Circular (HSC 2000/026) as: 'Written instructions for the supply or administration of medicines to groups of patients who may not be individually identified before presentation for treatment.' This definition should not be interpreted as indicating that the patient should not be identified. Patients may or may not be known to the service provider.\n\nThe Health Service Circular (HSC 2000/026) states that 'the majority of clinical care should be provided on an individual, patient-specific basis'. Supplying and/or administering medicines under PGDs should be reserved for situations in which this offers an advantage for patient care without compromising patient safety, and there are clear governance arrangements and accountability. Using a PGD is not a form of prescribing."}	https://www.nice.org.uk/guidance/mpg2	This guideline covers good practice for developing, authorising, using and updating patient group directions. It also offers advice on deciding whether a patient group direction is needed.
f05dc0e5ee19fb314207159108245b97e5dea9cf	nice	Elotuzumab for previously treated multiple myeloma (terminated appraisal)	Elotuzumab for previously treated multiple myeloma (terminated appraisal) NICE was unable to make a recommendation about the use in the NHS of elotuzumab for previously treated multiple myeloma because no evidence submission was received from Bristol–Myers Squibb, but will review this decision if the company decides to make a submission. # Background Bristol–Myers Squibb was invited to submit evidence for this single technology appraisal for elotuzumab in December 2015. Elotuzumab is used in combination with lenalidomide and dexamethasone. The ELOQUENT-2 clinical trial showed a favourable efficacy and safety profile of this regimen compared with lenalidomide plus dexamethasone. The company was unable to show that the additional survival benefit or the improvements in quality of life associated with this combination were sufficient to warrant the increased cost to the NHS of funding all 3 drugs, as determined by the NICE cost-effectiveness threshold. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of elotuzumab for previously treated multiple myeloma. If, after doing this, organisations still wish to consider elotuzumab for previously treated multiple myeloma, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable. NICE will review the position at any point if the company indicates that it wishes to make a full submission. ISBN: 978-1-4731-2420-2	{'Background': 'Bristol–Myers Squibb was invited to submit evidence for this single technology appraisal for elotuzumab in December 2015.\n\nElotuzumab is used in combination with lenalidomide and dexamethasone. The ELOQUENT-2 clinical trial showed a favourable efficacy and safety profile of this regimen compared with lenalidomide plus dexamethasone.\n\nThe company was unable to show that the additional survival benefit or the improvements in quality of life associated with this combination were sufficient to warrant the increased cost to the NHS of funding all 3\xa0drugs, as determined by the NICE cost-effectiveness threshold.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of elotuzumab for previously treated multiple myeloma. If, after doing this, organisations still wish to consider elotuzumab for previously treated multiple myeloma, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable.\n\nNICE will review the position at any point if the company indicates that it wishes to make a full submission.\n\nISBN: 978-1-4731-2420-2'}	https://www.nice.org.uk/guidance/ta434	NICE was unable to make a recommendation about the use in the NHS of elotuzumab for previously treated multiple myeloma because no evidence submission was received from Bristol–Myers Squibb, but will review this decision if the company decides to make a submission.
1ddd9b4a3e6639219fa8354267b363c047766e45	nice	Extraurethral (non-circumferential) retropubic adjustable compression devices for stress urinary incontinence in women	Extraurethral (non-circumferential) retropubic adjustable compression devices for stress urinary incontinence in women Evidence-based recommendations on extraurethral (non-circumferential) retropubic adjustable compression devices for stress urinary incontinence in women. This involves putting 2 small balloons on either side of the tube that carries urine from the bladder to support it and reduce leaks. # Recommendations Current evidence on the safety and efficacy of extraurethral (non-circumferential) retropubic adjustable compression devices for stress urinary incontinence in women is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wishing to insert extraurethral retropubic adjustable compression devices for stress urinary incontinence in women should: Inform the clinical governance leads in their trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having extraurethral retropubic adjustable compression devices for stress urinary incontinence (see section 7.3). All adverse events involving any medical devices used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency. Further research into this procedure should include detailed safety outcomes, long-term results and patient-reported outcome measures. NICE may update the guidance on publication of further evidence.# Indications and current treatments Stress urinary incontinence is the involuntary leakage of urine during exercise or certain movements such as coughing, sneezing and laughing. In women, it is most commonly associated with previous pregnancy, with or without recognised obstetric trauma. Previous urogynaecological surgery may also result in stress urinary incontinence. A NICE guideline on urinary incontinence and pelvic organ prolapse in women describes recommendations for the management of urinary incontinence in women. Conventional treatment is conservative, and includes lifestyle changes such as weight loss and pelvic floor muscle training. Surgery is considered if these conservative measures do not help. Different types of surgery may be used including intramural bulking procedures, insertion of a synthetic tension-free vaginal tape, insertion of a transobturator tape or other sling procedures, and colposuspension. When previous surgery has failed, insertion of an artificial urinary sphincter may be needed.# The procedure Extraurethral (non-circumferential) retropubic adjustable compression device insertion aims to prevent stress urinary incontinence by increasing urethral resistance and providing support to the bladder neck. With the patient under local, regional or general anaesthesia, an incision is made in the perineum. Specially designed introducers are used to insert 2 small silicone balloons. Under radiological guidance the balloons are positioned on either side of the urethra, close to the bladder neck. The balloons are filled with a mixture of water and radiocontrast medium to enable the positioning to be confirmed. Each balloon is then attached to a subcutaneous port sited in the labia major. These ports can be used to add or remove fluid to the balloon postoperatively, thereby achieving the best balance between voiding and leakage.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. In a systematic review of 8 studies, the mean number of pads used per day reduced from a range of 4.1 to 5.4 at baseline to a range of 1.1 to 1.2 at 2‑year follow‑up. In a case series of 57 patients (also included in the systematic review), there was a statistically significant decrease in the mean number of pads used per day from 5.6 (±2.3) at baseline (n=57) to 0.4 (±0.8) at 72‑month follow‑up (n=29; p<0.001). In a case series of 52 patients, 14% (7/52) of patients were fully continent and 25% (13/52) of patients reported more than 80% improvement at last follow‑up (median 10.5 months); 19% (10/52) of patients were still having successive balloon inflations. In the case series of 57 patients, 62% of patients reported that they were fully continent at last follow‑up (mean 72 months), 30% reported improvement of more than 50%, and 8% of patients reported no change or improvement of less than 50%. In a case series of 41 patients, 44% of patients were fully continent, 15% reported significant improvement, 29% reported slight improvement and 12% reported no change at last follow‑up (mean 25 months). In a case series of 162 patients (also included in the systematic review), 51% and 76% of patients were fully continent (<2 g on a provocative pad test) at 1‑ and 5‑year follow‑up respectively. The mean provocative pad weight decreased for 85% (107/126) of patients, with a mean improvement from 49.6 g to 11.2 g (p<0.001) at 1‑year follow‑up. In the case series of 162 patients, the mean Incontinence Quality of Life (IQOL) score improved from 36.8 at baseline to 71.1 at 1‑year and 74.3 at 5‑year follow‑up (p value not reported). In the same study, the mean Urogenital Distress Inventory (UDI) score improved from 60 at baseline to 37 at 1‑year and 51 at 5‑year follow‑up. In the case series of 57 patients, there was a statistically significant improvement in the mean IQOL score from 27.2 at baseline to 65.9 at 1‑year and 78.6 at 72‑month follow‑up (p<0.001 for both). In the case series of 57 patients, there was a statistically significant increase in the mean Valsalva leak point pressure from 51 cmH2O at baseline to 86 cmH2O at 12‑month follow‑up (n=30; p<0.01). The mean urethral closure pressure increased from 47 cmH2O at baseline to 51 cmH2O at 12‑month follow‑up (n=30; p=not significant). In the case series of 41 patients, explantation because of non-response was done in 15% (6/41) of patients. The specialist advisers listed key efficacy outcomes as cure or improvement in urinary incontinence as measured by subjective outcome measures (validated questionnaires), and objective measures (pad tests and urodynamics).# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. Intraoperative urethral or bladder perforation was reported in 3% to 17% of patients in a systematic review of 8 studies. Haematoma within 30 days of the procedure (first implantation) was reported in 1 patient in a case series of 52 patients; this was treated by deflation of the balloons. Urethral erosion was reported in 2% to 15% of patients and cutaneous erosion of the port was reported in 3% to 8% of patients, during the first year of follow‑up, in the systematic review of 8 studies. Balloon migration during the first year was reported in 7% to 18% of patients in the same study and balloon dysfunction during the first year was reported in 0.6% to 6% of patients. Device infection during the first year was reported in 0.6% to 9% of patients in the systematic review of 8 studies. Urinary tract infection was reported in 2% of patients in a case series of 162 patients. Dysuria or acute urinary retention was reported in 2% to 7% of patients in the systematic review of 8 studies. De novo urgency during the first year of follow‑up was reported in 11% of patients in 1 study included in the systematic review of 8 studies. The device was explanted in 18% (28/153) of patients during the first year of follow‑up in the case series of 162 patients. Of these, 50% (14/28) were reimplanted within 12 months. Reasons for explantation included port erosion, balloon migration, balloon erosion, worsening incontinence, pain, device failure, infection and port migration. Balloons were removed in 21% (12/57) of patients (3 bilateral and 9 unilateral) in a case series of 57 patients. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not describe any anecdotal adverse events. They considered that the following were theoretical adverse events: urethrovaginal fistula formation, urethral stricture, vaginal erosion, pelvic or genital pain, dyspareunia, development of overactive bladder, and urethral stenosis. One adviser noted that the procedure may make established techniques (as a secondary procedure) more technically difficult.# Further information For related NICE guidance, see the NICE website. Patient commentary was not sought, because it was not possible to identify any patients who had treatment with by this procedure in the UK. This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion). # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2389-2	{'Recommendations': "Current evidence on the safety and efficacy of extraurethral (non-circumferential) retropubic adjustable compression devices for stress urinary incontinence in women is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to insert extraurethral retropubic adjustable compression devices for stress urinary incontinence in women should:\n\nInform the clinical governance leads in their trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having extraurethral retropubic adjustable compression devices for stress urinary incontinence (see section\xa07.3).\n\nAll adverse events involving any medical devices used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nFurther research into this procedure should include detailed safety outcomes, long-term results and patient-reported outcome measures. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Stress urinary incontinence is the involuntary leakage of urine during exercise or certain movements such as coughing, sneezing and laughing. In women, it is most commonly associated with previous pregnancy, with or without recognised obstetric trauma. Previous urogynaecological surgery may also result in stress urinary incontinence.\n\nA NICE guideline on urinary incontinence and pelvic organ prolapse in women describes recommendations for the management of urinary incontinence in women. Conventional treatment is conservative, and includes lifestyle changes such as weight loss and pelvic floor muscle training. Surgery is considered if these conservative measures do not help. Different types of surgery may be used including intramural bulking procedures, insertion of a synthetic tension-free vaginal tape, insertion of a transobturator tape or other sling procedures, and colposuspension. When previous surgery has failed, insertion of an artificial urinary sphincter may be needed.', 'The procedure': 'Extraurethral (non-circumferential) retropubic adjustable compression device insertion aims to prevent stress urinary incontinence by increasing urethral resistance and providing support to the bladder neck.\n\nWith the patient under local, regional or general anaesthesia, an incision is made in the perineum. Specially designed introducers are used to insert 2\xa0small silicone balloons. Under radiological guidance the balloons are positioned on either side of the urethra, close to the bladder neck. The balloons are filled with a mixture of water and radiocontrast medium to enable the positioning to be confirmed. Each balloon is then attached to a subcutaneous port sited in the labia major. These ports can be used to add or remove fluid to the balloon postoperatively, thereby achieving the best balance between voiding and leakage.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nIn a systematic review of 8\xa0studies, the mean number of pads used per day reduced from a range of 4.1 to 5.4 at baseline to a range of 1.1 to 1.2 at 2‑year follow‑up. In a case series of 57\xa0patients (also included in the systematic review), there was a statistically significant decrease in the mean number of pads used per day from 5.6\xa0(±2.3) at baseline (n=57) to 0.4\xa0(±0.8) at 72‑month follow‑up (n=29; p<0.001).\n\nIn a case series of 52\xa0patients, 14% (7/52) of patients were fully continent and 25% (13/52) of patients reported more than 80% improvement at last follow‑up (median 10.5\xa0months); 19% (10/52) of patients were still having successive balloon inflations. In the case series of 57\xa0patients, 62% of patients reported that they were fully continent at last follow‑up (mean 72\xa0months), 30% reported improvement of more than 50%, and 8% of patients reported no change or improvement of less than 50%. In a case series of 41\xa0patients, 44% of patients were fully continent, 15% reported significant improvement, 29% reported slight improvement and 12% reported no change at last follow‑up (mean 25\xa0months).\n\nIn a case series of 162\xa0patients (also included in the systematic review), 51% and 76% of patients were fully continent (<2\xa0g on a provocative pad test) at 1‑ and 5‑year follow‑up respectively. The mean provocative pad weight decreased for 85% (107/126) of patients, with a mean improvement from 49.6\xa0g to 11.2\xa0g (p<0.001) at 1‑year follow‑up.\n\nIn the case series of 162\xa0patients, the mean Incontinence Quality of Life (IQOL) score improved from 36.8 at baseline to 71.1 at 1‑year and 74.3 at 5‑year follow‑up (p\xa0value not reported). In the same study, the mean Urogenital Distress Inventory (UDI) score improved from 60 at baseline to 37 at 1‑year and 51 at 5‑year follow‑up. In the case series of 57\xa0patients, there was a statistically significant improvement in the mean IQOL score from 27.2 at baseline to 65.9 at 1‑year and 78.6 at 72‑month follow‑up (p<0.001 for both).\n\nIn the case series of 57\xa0patients, there was a statistically significant increase in the mean Valsalva leak point pressure from 51\xa0cmH2O at baseline to 86\xa0cmH2O at 12‑month follow‑up (n=30; p<0.01). The mean urethral closure pressure increased from 47\xa0cmH2O at baseline to 51\xa0cmH2O at 12‑month follow‑up (n=30; p=not significant).\n\nIn the case series of 41\xa0patients, explantation because of non-response was done in 15% (6/41) of patients.\n\nThe specialist advisers listed key efficacy outcomes as cure or improvement in urinary incontinence as measured by subjective outcome measures (validated questionnaires), and objective measures (pad tests and urodynamics).', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nIntraoperative urethral or bladder perforation was reported in 3% to 17% of patients in a systematic review of 8\xa0studies. Haematoma within 30\xa0days of the procedure (first implantation) was reported in 1\xa0patient in a case series of 52\xa0patients; this was treated by deflation of the balloons.\n\nUrethral erosion was reported in 2% to 15% of patients and cutaneous erosion of the port was reported in 3% to 8% of patients, during the first year of follow‑up, in the systematic review of 8\xa0studies. Balloon migration during the first year was reported in 7% to 18% of patients in the same study and balloon dysfunction during the first year was reported in 0.6% to 6% of patients.\n\nDevice infection during the first year was reported in 0.6% to 9% of patients in the systematic review of 8\xa0studies. Urinary tract infection was reported in 2% of patients in a case series of 162\xa0patients.\n\nDysuria or acute urinary retention was reported in 2% to 7% of patients in the systematic review of 8\xa0studies. De novo urgency during the first year of follow‑up was reported in 11% of patients in 1\xa0study included in the systematic review of 8\xa0studies.\n\nThe device was explanted in 18% (28/153) of patients during the first year of follow‑up in the case series of 162\xa0patients. Of these, 50% (14/28) were reimplanted within 12\xa0months. Reasons for explantation included port erosion, balloon migration, balloon erosion, worsening incontinence, pain, device failure, infection and port migration. Balloons were removed in 21% (12/57) of patients (3\xa0bilateral and 9\xa0unilateral) in a case series of 57\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not describe any anecdotal adverse events. They considered that the following were theoretical adverse events: urethrovaginal fistula formation, urethral stricture, vaginal erosion, pelvic or genital pain, dyspareunia, development of overactive bladder, and urethral stenosis. One\xa0adviser noted that the procedure may make established techniques (as a secondary procedure) more technically difficult.', 'Further information': "For related NICE guidance, see the NICE website.\n\nPatient commentary was not sought, because it was not possible to identify any patients who had treatment with by this procedure in the UK.\n\nThis guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2389-2"}	https://www.nice.org.uk/guidance/ipg576	Evidence-based recommendations on extraurethral (non-circumferential) retropubic adjustable compression devices for stress urinary incontinence in women. This involves putting 2 small balloons on either side of the tube that carries urine from the bladder to support it and reduce leaks.
56facd4ca7da2816010e1fb6f6971f84091fa07c	nice	Sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse	Sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse Evidence-based recommendations on sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse. This involves attaching mesh from the top of the vagina to the base of the spine to support the pelvic organs after the womb has been removed. # Recommendations Current evidence on the safety and efficacy of sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wishing to do sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse should: Inform the clinical governance leads in their trusts. During the consent process, ensure that patients understand the uncertainty about the procedure's safety, including mesh erosion (for example, into the vagina) and the risk of recurrence, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Patient selection and treatment should only be done by specialists with experience in managing pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training in the procedure. Clinicians should enter details about all patients having sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse onto an appropriate registry (for example, the British Society of Urogynaecology database). All adverse events involving the medical device used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency. NICE may update the guidance on publication of further evidence.# Indications and current treatments Uterine prolapse is when the uterus descends from its usual position, into and sometimes through, the vagina. It can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function. Current treatment options include pelvic floor muscle training, use of pessaries and surgery. Different surgical procedures can be used, including hysterectomy, infracoccygeal sacropexy, uterine suspension sling (including sacrohysteropexy) and uterine or vault suspension (without sling). Some of these procedures involve the use of mesh, to provide additional support.# The procedure Sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse is done with the patient under general anaesthesia. An open or laparoscopic abdominal approach is used after the hysterectomy. Mesh is attached to the apex of the vagina and may also be attached to the anterior or posterior vaginal wall, to prevent future vaginal vault prolapse. This procedure can be combined with surgery for stress urinary incontinence such as colposuspension or suburethral sling placement. Several different types of synthetic and biological mesh are available, which vary in structure and in their physical properties, such as absorbability.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. A non-randomised study, included in a systematic review of 311 women with uterine prolapse, compared 36 women treated by mesh sacrohysteropexy with 39 women treated by hysterectomy with concomitant sacrocolpopexy. There was no objective failure (defined as prolapse at less than 6 cm above the hymen) in either group. This was at a mean follow‑up of 51 months. In the same non-randomised study included in the systematic review of 311 women, none of the 75 women needed a further operation for recurrent or de novo prolapse at a mean follow‑up of 51 months. In a prospective case series of 67 women treated by sacrocolpopexy with concomitant total abdominal hysterectomy, recurrent stage 2 rectocele without any cystoceles or vault prolapse occurred in 8% (4/64) of women at a median follow‑up of 27 months. A retrospective comparative study of 182 women with uterovaginal prolapse compared 123 women treated by total vaginal hysterectomy with concomitant laparoscopic sacrocolpopexy (TVH+LSC) with 59 women treated by laparoscopic supracervical hysterectomy with concomitant laparoscopic sacrocolpopexy (LSCH+LSC). There was no difference in anatomical success (defined as no prolapse at or beyond the hymen and no apical prolapse beyond the mid-vagina; TVH+LSC 94% versus LSCH+LSC 93%, p=0.8) or subjective success (defined as the absence of bulge symptoms and overall Patient Global Impression of Improvement‑I response of 'very much better' or 'much better'; TVH+LSC 91% versus LSCH+LSC 81%, p=0.3) between the 2 groups. In the prospective case series of 67 women treated by sacrocolpopexy with concomitant total abdominal hysterectomy, 93% (60/64) of women reported satisfaction with the procedure at a median follow‑up of 27 months. Mean pelvic floor distress inventory scores improved from 50 to 10 (p=0.001). The specialist advisers considered key efficacy outcomes as patient satisfaction, correction of prolapse and reduction of a bulge. Six commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. # Mesh erosion ## Abdominal sacrocolpopexy with concomitant hysterectomy The risk of mesh erosion varied across 4 studies on abdominal sacrocolpopexy with concomitant hysterectomy to repair uterine prolapse included in a systematic review. Mesh erosion was reported in 4% (1/23) of women treated by hysterectomy with concomitant sacrocolpopexy in a randomised controlled trial of 47 women available as a conference abstract (mean follow‑up 33 months). In a non-randomised comparative study of 75 women, mesh erosion occurred in 8% (3/39) of women treated by hysterectomy with concomitant sacrocolpopexy and in no women (0/36) in the sacrohysteropexy group (mean follow‑up 51 months); all women with mesh erosion needed further surgery. In another non-randomised comparative study of 88 women, erosion rates of 11% (8/76) were reported in women treated by total hysterectomy with concomitant sacrocolpopexy and in 4% (1/28) of women treated by supracervical hysterectomy with concomitant sacrocolpopexy (median follow‑up 4 months); 4 of the 8 women with mesh erosion needed further surgery. In a case series of 324 women, 7% (7/101) of women reported mesh erosion after hysterectomy with concomitant sacrocolpopexy at a median follow‑up of 8.4 months (range 1.4 to 13 months). In a retrospective non-randomised comparative study of 179 women, mesh erosion was reported in 6.5% (5/74) of women in the hysterectomy with concomitant sacrocolpopexy group, in 5.9% (3/51) of women in the sacrohysteropexy group and in 7.4% (4/54) of women in the sacrocolpopexy group with previous hysterectomy at a mean follow‑up 57 months. The time to mesh erosion ranged from 2 to 66 months. Four erosions were asymptomatic and 5 presented with vaginal bleeding, associated with dyspareunia in 2 women and infection in 3 women. In all women, surgery was needed to remove the mesh because conservative management did not work. In a case-control study of 336 women treated by abdominal sacrocolpopexy (ASC n=43, control n=147) or vaginal mesh procedure (VMP n=41, control n=105) with concomitant hysterectomy, concomitant hysterectomy was associated with mesh extrusion among women who had ASC (odds ratio , 3.18; 95% confidence interval 1.27 to 7.93, p=0.01) and VMP (OR 3.72, 95% CI 1.20 to 11.54, p=0.02). In a retrospective non-randomised comparative study of 292 women treated by ASC (74 with concomitant hysterectomy, 218 with previous hysterectomy), the rates of mesh exposure were lower in women with previous hysterectomy (mesh erosion 53% versus no erosion 76% , p=0.03) at a median follow‑up of 42 months. Also, the study found that concomitant hysterectomy (mesh erosion 47% versus no erosion 24% , p=0.03) or 3 or more additional procedures (mesh erosion 32% versus no erosion 11% , p=0.02) increased the risk of mesh exposure. ## Robotic assisted sacrocolpopexy with concomitant hysterectomy Mesh erosion rate after robotic assisted sacrocolpopexy (RASC) with a concomitant hysterectomy or RASC alone was not significantly different (2.7% versus 5.1% ; p=0.50) in a retrospective non-randomised comparative study of 230 women at 6‑week follow‑up. The 2.7% (3/79) of mesh exposures in the hysterectomy group were associated with total hysterectomy and none with supracervical hysterectomy (n=33), this difference was not significant (p=0.50). In another retrospective non-randomised comparative study, there was a mesh exposure rate of 14% (8/57) in the combined RASC with total hysterectomy group compared with 0% (0/45) in the RASC with supracervical hysterectomy group (p<0.01) at 3‑month follow‑up. All erosions occurred at the vaginal apex. ## Laparoscopic sacrocolpopexy with concomitant hysterectomy Mesh erosion rates were higher in women having conventional laparoscopic sacrocolpopexy (LSC) with concomitant total vaginal hysterectomy (TVH) compared with both robotic or conventional sacrocolpopexy after hysterectomy (23% versus 5% ; p=0.003) and robotic LSC with supracervical hysterectomy (23% versus 5% ; p=0.984) in a retrospective cohort study of 188 women (mean follow‑up of 20 weeks). In multivariate regression analysis, the odds ratio of erosion for TVH done at the same time as sacrocolpopexy was 5.67 (95% CI 1.88 to 17.10; p=0.002) compared with sacrocolpopexy with concomitant hysterectomy. Mesh exposure was more common when the vaginal cuff was opened, either in the course of hysterectomy or during vaginal attachment of mesh in women with a previous hysterectomy (4.9% versus 0.5% ; relative risk 9.0; p=0.012) in a retrospective non-randomised comparative study of 390 women at a median follow‑up 26 weeks. In women who had a concomitant hysterectomy, a higher mesh exposure rate was seen in open-cuff hysterectomy (TVH or laparoscopically assisted vaginal hysterectomy ) compared with supracervical hysterectomy (4.9% versus 0% , p=0.032). Mesh exposure was more common when the mesh was sutured laparoscopically compared with transvaginally in women treated by open-cuff hysterectomy (14.3% versus 2.7% ; relative risk, 5.4; p=0.013). There was no difference in exposure rates between TVH and LAVH groups (6.8% versus 4% ; p=0.469).The rate of mesh complications was not significantly different among women who had TVH with LSC compared with women who had laparoscopic supracervical hysterectomy (LSCH) with LSC (1.6% versus 1.7% ; p=1.0) in a retrospective non-randomised comparative study of 182 women with a median prospective follow‑up of 9 months. Extrusion of permanent suture was more common in women treated by LSCH with LSC compared with women treated by TVH with LSC (5.6% versus 0.6% ; relative risk, 8.8; p=0.010) in a retrospective cohort study of 390 women. Most of these extrusions were asymptomatic and were managed non-surgically. The rate of suture erosion was not significantly different among women who had TVH with LSC compared with women who had LSCH with LSC (1% versus 2%; p=1.0) in the retrospective non-randomised comparative study of 182 women with a median prospective follow‑up of 9 months. ## Other complications Wound infection was reported in 8% (3/39) of women treated by hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75 women included in the systematic review. The presence of granulation tissue was not significantly different among women who had TVH with LSC compared with women who had LSCH with LSC (10% versus 7%; p=0.6) in the retrospective non-randomised comparative study of 182 women with a median prospective follow‑up of 9 months. This was treated in the operating room. Peri-vesical haematoma was reported in 5% (2/36) of women treated by sacrohysteropexy and 10% (4/39) of women who had hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75 women included in the systematic review. The time of occurrence and further details were not reported. Incisional hernia was reported in 5% (2/36) of women treated by sacrohysteropexy and 2% (1/39) of women who had hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75 women included in the systematic review. Severe abdominal pain because of bowel obstruction was reported in 1 patient in the LSCH+LSC group (n=59) in the non-randomised comparative study of 182 women. This was managed by small bowel resection and re-anastomosis of the bowel. The patient recovered completely and there was no evidence of mesh exposure. Voiding dysfunction was reported in 11% (4/36) of women treated by sacrohysteropexy and 2% (1/39) of women who had hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75 women included in the systematic review. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: osteomyelitis because of vagina being opened and inserting mesh. Six commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2395-3	{'Recommendations': "Current evidence on the safety and efficacy of sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse should:\n\nInform the clinical governance leads in their trusts.\n\nDuring the consent process, ensure that patients understand the uncertainty about the procedure's safety, including mesh erosion (for example, into the vagina) and the risk of recurrence, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nPatient selection and treatment should only be done by specialists with experience in managing pelvic organ prolapse and urinary incontinence in women. All clinicians doing this procedure should have specific up-to-date training in the procedure.\n\nClinicians should enter details about all patients having sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse onto an appropriate registry (for example, the British Society of Urogynaecology database). All adverse events involving the medical device used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nNICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Uterine prolapse is when the uterus descends from its usual position, into and sometimes through, the vagina. It can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function.\n\nCurrent treatment options include pelvic floor muscle training, use of pessaries and surgery. Different surgical procedures can be used, including hysterectomy, infracoccygeal sacropexy, uterine suspension sling (including sacrohysteropexy) and uterine or vault suspension (without sling). Some of these procedures involve the use of mesh, to provide additional support.', 'The procedure': 'Sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse is done with the patient under general anaesthesia. An open or laparoscopic abdominal approach is used after the hysterectomy. Mesh is attached to the apex of the vagina and may also be attached to the anterior or posterior vaginal wall, to prevent future vaginal vault prolapse.\n\nThis procedure can be combined with surgery for stress urinary incontinence such as colposuspension or suburethral sling placement. Several different types of synthetic and biological mesh are available, which vary in structure and in their physical properties, such as absorbability.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nA non-randomised study, included in a systematic review of 311\xa0women with uterine prolapse, compared 36\xa0women treated by mesh sacrohysteropexy with 39\xa0women treated by hysterectomy with concomitant sacrocolpopexy. There was no objective failure (defined as prolapse at less than 6\xa0cm above the hymen) in either group. This was at a mean follow‑up of 51\xa0months.\n\nIn the same non-randomised study included in the systematic review of 311\xa0women, none of the 75\xa0women needed a further operation for recurrent or de novo prolapse at a mean follow‑up of 51\xa0months. In a prospective case series of 67\xa0women treated by sacrocolpopexy with concomitant total abdominal hysterectomy, recurrent stage\xa02 rectocele without any cystoceles or vault prolapse occurred in 8% (4/64) of women at a median follow‑up of 27\xa0months. A retrospective comparative study of 182\xa0women with uterovaginal prolapse compared 123\xa0women treated by total vaginal hysterectomy with concomitant laparoscopic sacrocolpopexy (TVH+LSC) with 59\xa0women treated by laparoscopic supracervical hysterectomy with concomitant laparoscopic sacrocolpopexy (LSCH+LSC). There was no difference in anatomical success (defined as no prolapse at or beyond the hymen and no apical prolapse beyond the mid-vagina; TVH+LSC 94% versus LSCH+LSC 93%, p=0.8) or subjective success (defined as the absence of bulge symptoms and overall Patient Global Impression of Improvement‑I response of 'very much better' or 'much better'; TVH+LSC 91% versus LSCH+LSC 81%, p=0.3) between the 2\xa0groups.\n\nIn the prospective case series of 67\xa0women treated by sacrocolpopexy with concomitant total abdominal hysterectomy, 93% (60/64) of women reported satisfaction with the procedure at a median follow‑up of 27\xa0months. Mean pelvic floor distress inventory scores improved from 50\xa0to 10\xa0(p=0.001).\n\nThe specialist advisers considered key efficacy outcomes as patient satisfaction, correction of prolapse and reduction of a bulge.\n\nSix commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\n# Mesh erosion\n\n## Abdominal sacrocolpopexy with concomitant hysterectomy\n\nThe risk of mesh erosion varied across 4\xa0studies on abdominal sacrocolpopexy with concomitant hysterectomy to repair uterine prolapse included in a systematic review.\n\nMesh erosion was reported in 4% (1/23) of women treated by hysterectomy with concomitant sacrocolpopexy in a randomised controlled trial of 47\xa0women available as a conference abstract (mean follow‑up 33\xa0months).\n\nIn a non-randomised comparative study of 75\xa0women, mesh erosion occurred in 8% (3/39) of women treated by hysterectomy with concomitant sacrocolpopexy and in no women (0/36) in the sacrohysteropexy group (mean follow‑up 51\xa0months); all women with mesh erosion needed further surgery.\n\nIn another non-randomised comparative study of 88\xa0women, erosion rates of 11% (8/76) were reported in women treated by total hysterectomy with concomitant sacrocolpopexy and in 4% (1/28) of women treated by supracervical hysterectomy with concomitant sacrocolpopexy (median follow‑up 4\xa0months); 4\xa0of the 8\xa0women with mesh erosion needed further surgery.\n\nIn a case series of 324\xa0women, 7% (7/101) of women reported mesh erosion after hysterectomy with concomitant sacrocolpopexy at a median follow‑up of 8.4\xa0months (range 1.4\xa0to 13\xa0months).\n\nIn a retrospective non-randomised comparative study of 179\xa0women, mesh erosion was reported in 6.5% (5/74) of women in the hysterectomy with concomitant sacrocolpopexy group, in 5.9% (3/51) of women in the sacrohysteropexy group and in 7.4% (4/54) of women in the sacrocolpopexy group with previous hysterectomy at a mean follow‑up 57\xa0months. The time to mesh erosion ranged from 2\xa0to 66\xa0months. Four erosions were asymptomatic and 5\xa0presented with vaginal bleeding, associated with dyspareunia in 2\xa0women and infection in 3\xa0women. In all women, surgery was needed to remove the mesh because conservative management did not work.\n\nIn a case-control study of 336\xa0women treated by abdominal sacrocolpopexy (ASC n=43, control n=147) or vaginal mesh procedure (VMP n=41, control n=105) with concomitant hysterectomy, concomitant hysterectomy was associated with mesh extrusion among women who had ASC (odds ratio [OR], 3.18; 95% confidence interval [CI] 1.27 to 7.93, p=0.01) and VMP (OR 3.72, 95% CI 1.20 to 11.54, p=0.02).\n\nIn a retrospective non-randomised comparative study of 292\xa0women treated by ASC (74\xa0with concomitant hysterectomy, 218\xa0with previous hysterectomy), the rates of mesh exposure were lower in women with previous hysterectomy (mesh erosion 53% [10/19] versus no erosion 76% [208/273], p=0.03) at a median follow‑up of 42\xa0months. Also, the study found that concomitant hysterectomy (mesh erosion 47% [9/19] versus no erosion 24% [65/273], p=0.03) or 3\xa0or more additional procedures (mesh erosion 32% [6/19] versus no erosion 11% [31/273], p=0.02) increased the risk of mesh exposure.\n\n## Robotic assisted sacrocolpopexy with concomitant hysterectomy\n\nMesh erosion rate after robotic assisted sacrocolpopexy (RASC) with a concomitant hysterectomy or RASC alone was not significantly different (2.7% [3/112] versus 5.1% [6/118]; p=0.50) in a retrospective non-randomised comparative study of 230\xa0women at 6‑week follow‑up. The 2.7% (3/79) of mesh exposures in the hysterectomy group were associated with total hysterectomy and none with supracervical hysterectomy (n=33), this difference was not significant (p=0.50). In another retrospective non-randomised comparative study, there was a mesh exposure rate of 14% (8/57) in the combined RASC with total hysterectomy group compared with 0% (0/45) in the RASC with supracervical hysterectomy group (p<0.01) at 3‑month follow‑up. All erosions occurred at the vaginal apex.\n\n## Laparoscopic sacrocolpopexy with concomitant hysterectomy\n\nMesh erosion rates were higher in women having conventional laparoscopic sacrocolpopexy (LSC) with concomitant total vaginal hysterectomy (TVH) compared with both robotic or conventional sacrocolpopexy after hysterectomy (23% [13/57] versus 5% [5/110]; p=0.003) and robotic LSC with supracervical hysterectomy (23% [13/57] versus 5% [1/21]; p=0.984) in a retrospective cohort study of 188\xa0women (mean follow‑up of 20\xa0weeks). In multivariate regression analysis, the odds ratio of erosion for TVH done at the same time as sacrocolpopexy was 5.67 (95% CI 1.88 to 17.10; p=0.002) compared with sacrocolpopexy with concomitant hysterectomy.\n\nMesh exposure was more common when the vaginal cuff was opened, either in the course of hysterectomy or during vaginal attachment of mesh in women with a previous hysterectomy (4.9% [10/205] versus 0.5% [1/185]; relative risk [RR] 9.0; p=0.012) in a retrospective non-randomised comparative study of 390\xa0women at a median follow‑up 26\xa0weeks. In women who had a concomitant hysterectomy, a higher mesh exposure rate was seen in open-cuff hysterectomy (TVH or laparoscopically assisted vaginal hysterectomy [LAVH]) compared with supracervical hysterectomy (4.9% [9/185] versus 0% [0/92], p=0.032). Mesh exposure was more common when the mesh was sutured laparoscopically compared with transvaginally in women treated by open-cuff hysterectomy (14.3% [5/35] versus 2.7% [4/150]; relative risk, 5.4; p=0.013). There was no difference in exposure rates between TVH and LAVH groups (6.8% [4/59] versus 4% [5/126]; p=0.469).The rate of mesh complications was not significantly different among women who had TVH with LSC compared with women who had laparoscopic supracervical hysterectomy (LSCH) with LSC (1.6% [2/123] versus 1.7% [1/59]; p=1.0) in a retrospective non-randomised comparative study of 182\xa0women with a median prospective follow‑up of 9\xa0months.\n\nExtrusion of permanent suture was more common in women treated by LSCH with LSC compared with women treated by TVH with LSC (5.6% [13/233] versus 0.6% [1/157]; relative risk, 8.8; p=0.010) in a retrospective cohort study of 390\xa0women. Most of these extrusions were asymptomatic and were managed non-surgically. The rate of suture erosion was not significantly different among women who had TVH with LSC compared with women who had LSCH with LSC (1% versus 2%; p=1.0) in the retrospective non-randomised comparative study of 182\xa0women with a median prospective follow‑up of 9\xa0months.\n\n## Other complications\n\nWound infection was reported in 8% (3/39) of women treated by hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75\xa0women included in the systematic review.\n\nThe presence of granulation tissue was not significantly different among women who had TVH with LSC compared with women who had LSCH with LSC (10% versus 7%; p=0.6) in the retrospective non-randomised comparative study of 182\xa0women with a median prospective follow‑up of 9\xa0months. This was treated in the operating room.\n\nPeri-vesical haematoma was reported in 5% (2/36) of women treated by sacrohysteropexy and 10% (4/39) of women who had hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75\xa0women included in the systematic review. The time of occurrence and further details were not reported.\n\nIncisional hernia was reported in 5% (2/36) of women treated by sacrohysteropexy and 2% (1/39) of women who had hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75\xa0women included in the systematic review.\n\nSevere abdominal pain because of bowel obstruction was reported in 1\xa0patient in the LSCH+LSC group (n=59) in the non-randomised comparative study of 182\xa0women. This was managed by small bowel resection and re-anastomosis of the bowel. The patient recovered completely and there was no evidence of mesh exposure.\n\nVoiding dysfunction was reported in 11% (4/36) of women treated by sacrohysteropexy and 2% (1/39) of women who had hysterectomy with concomitant sacrocolpopexy in the non-randomised comparative study of 75\xa0women included in the systematic review.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: osteomyelitis because of vagina being opened and inserting mesh.\n\nSix commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2395-3'}	https://www.nice.org.uk/guidance/ipg577	Evidence-based recommendations on sacrocolpopexy with hysterectomy using mesh to repair uterine prolapse. This involves attaching mesh from the top of the vagina to the base of the spine to support the pelvic organs after the womb has been removed.
a95a23f940326a94d2a1083cd20ce9aa8c357f6f	nice	Tenofovir alafenamide for treating chronic hepatitis B (terminated appraisal)	Tenofovir alafenamide for treating chronic hepatitis B (terminated appraisal) NICE was unable to make a recommendation about the use in the NHS of tenofovir alafenamide for treating chronic hepatitis B because no evidence submission was received from Gilead, but will review this decision if the company decides to make a submission. # Background Gilead was invited to submit evidence for this single technology appraisal for tenofovir alafenamide in May 2016. Gilead has advised NICE that the particular population that would have the greatest need for tenofovir alafenamide cannot be differentiated from the broader population without additional data. Gilead therefore did not make a submission to NICE. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of tenofovir alafenamide for treating chronic hepatitis B. If, after doing this, organisations still wish to consider tenofovir alafenamide for treating chronic hepatitis B, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable. NICE will review the position at any point if the company indicates that it wishes to make a full submission. ISBN: 978-1-4731-2421-9	{'Background': 'Gilead was invited to submit evidence for this single technology appraisal for tenofovir alafenamide in May 2016.\n\nGilead has advised NICE that the particular population that would have the greatest need for tenofovir alafenamide cannot be differentiated from the broader population without additional data. Gilead therefore did not make a submission to NICE.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of tenofovir alafenamide for treating chronic hepatitis B. If, after doing this, organisations still wish to consider tenofovir alafenamide for treating chronic hepatitis\xa0B, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable.\n\nNICE will review the position at any point if the company indicates that it wishes to make a full submission.\n\nISBN: 978-1-4731-2421-9'}	https://www.nice.org.uk/guidance/ta435	NICE was unable to make a recommendation about the use in the NHS of tenofovir alafenamide for treating chronic hepatitis B because no evidence submission was received from Gilead, but will review this decision if the company decides to make a submission.
92e29265f590235d42ef44a725fb5f41256bbcf1	nice	Bevacizumab for treating EGFR mutation-positive non-small-cell lung cancer (terminated appraisal)	Bevacizumab for treating EGFR mutation-positive non-small-cell lung cancer (terminated appraisal) NICE was unable to make a recommendation about the use in the NHS of bevacizumab for treating epidermal growth factor receptor mutation-positive non-small-cell lung cancer because no evidence submission was received from Roche, but will review this decision if the company decides to make a submission. # Background Roche has informed NICE that it does not intend to pursue reimbursement for this indication and, as such, will not be making an evidence submission to NICE for this indication. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of bevacizumab for treating epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer. If, after doing this, organisations still wish to consider bevacizumab for treating EGFR mutation-positive non-small-cell lung cancer, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable. NICE will review the position at any point if the company decides that it wants to make a full submission. ISBN: 978-1-4731-2422-6	{'Background': 'Roche has informed NICE that it does not intend to pursue reimbursement for this indication and, as such, will not be making an evidence submission to NICE for this indication.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of bevacizumab for treating epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer. If, after doing this, organisations still wish to consider bevacizumab for treating EGFR mutation-positive non-small-cell lung cancer, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable.\n\nNICE will review the position at any point if the company decides that it wants to make a full submission.\n\nISBN: 978-1-4731-2422-6'}	https://www.nice.org.uk/guidance/ta436	NICE was unable to make a recommendation about the use in the NHS of bevacizumab for treating epidermal growth factor receptor mutation-positive non-small-cell lung cancer because no evidence submission was received from Roche, but will review this decision if the company decides to make a submission.
2a16a9ede50bcb6069720b9580c9cdcf8834bd0f	nice	Ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy (terminated appraisal)	Ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy (terminated appraisal) NICE was unable to make a recommendation about the use in the NHS of ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy because no evidence submission was received from Janssen-Cilag, but will review this decision if the company decides to make a submission. # Background Janssen-Cilag has informed NICE that they "…understand from the clinical community that there is no desire to use ibrutinib in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukaemia (R/R CLL). Ibrutinib will only be used as monotherapy for the treatment of R/R CLL". As such, Janssen-Cilag will not be making an evidence submission to NICE for this indication. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy. If, after doing this, organisations still wish to consider ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable. NICE will review the position at any point if the company decides that it wants to make a full submission. ISBN: 978-1-4731-2423-3	{'Background': 'Janssen-Cilag has informed NICE that they "…understand from the clinical community that there is no desire to use ibrutinib in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukaemia (R/R CLL). Ibrutinib will only be used as monotherapy for the treatment of R/R CLL". As such, Janssen-Cilag will not be making an evidence submission to NICE for this indication.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the company did not make an evidence submission when considering whether or not to recommend local use of ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy. If, after doing this, organisations still wish to consider ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy, they should follow the advice on rational local decision-making in the NHS Constitution for England and the NHS Commissioning Board and Clinical Commissioning Groups (Responsibilities and Standing Rules) Regulations 2012. This outlines the approach that should be taken when NICE guidance is unavailable.\n\nNICE will review the position at any point if the company decides that it wants to make a full submission.\n\nISBN: 978-1-4731-2423-3'}	https://www.nice.org.uk/guidance/ta437	NICE was unable to make a recommendation about the use in the NHS of ibrutinib with bendamustine and rituximab for treating relapsed or refractory chronic lymphocytic leukaemia after systemic therapy because no evidence submission was received from Janssen-Cilag, but will review this decision if the company decides to make a submission.
0064d61436664c59dd205921600181b541679c14	nice	Mental health of adults in contact with the criminal justice system	Mental health of adults in contact with the criminal justice system This guideline covers assessing, diagnosing and managing mental health problems in adults (aged 18 and over) who are in contact with the criminal justice system. It aims to improve mental health and wellbeing in this population by establishing principles for assessment and management, and promoting more coordinated care planning and service organisation across the criminal justice system. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in your care. Making decisions using NICE guidelines explains how we use words to show the strength of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Using this guideline together with other NICE guidelines Use this guideline with the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services to improve the experience of care for people with mental health problems including those with neurodevelopmental disorders. Use this guideline with any NICE guidelines on specific mental health problems. Take into account: the nature and severity of any mental health problem the presence of a learning disability or any acquired cognitive impairment -ther communication difficulties (for example, language, literacy, information processing or sensory deficit) the nature of any coexisting mental health problems (including substance misuse) limitations on prescribing and administering medicine (for example, in-possession medicine) or the timing of the delivery of interventions in certain settings (for example, prison) the development of trust in an environment where health and care staff may be held in suspicion any cultural and ethnic differences in beliefs about mental health problems any differences in presentation of mental health problems the setting in which the assessment or treatment takes place. Obtain, evaluate and integrate all available and reliable information about the person when assessing or treating people in contact with the criminal justice system. For example: person escort record (PER) pre-sentence report all medical records custody reports Assessment, Care in Custody and Teamwork (ACCT) document reports from other relevant services, including liaison and diversion, substance misuse services, social service or housing services and youth offending services Offender Assessment System (OASys) or other assessment tools.Take into account how up to date the information is and how it was gathered. # Principles of assessment Work with a family member, partner, carer, advocate or legal representative when possible in order to get relevant information and support the person, help explain the outcome of assessment and help them make informed decisions about their care. Take into account: the person's wishes the nature and quality of family relationships, including any safeguarding issues any statutory or legal considerations that may limit family and carer involvement the requirements of the Care Act 2014. Carry out assessments: in a suitable environment that is safe and private in an engaging, empathic and non-judgemental manner. When assessing a person, make reasonable adjustments to the assessment that take into account any suspected neurodevelopmental disorders (including learning disabilities), cognitive impairments, or physical health problems or disabilities. Seek advice or involve specialists if needed. # Identification and assessment throughout the care pathway Be vigilant for the possibility of unidentified or emerging mental health problems in people in contact with the criminal justice system, and review available records for any indications of a mental health problem. Ensure all staff working in criminal justice settings are aware of the potential impact on a person's mental health of being in contact with the criminal justice system. ## First-stage health assessment at reception into prison Recommendations 1.3.3 to 1.3.5 cover what happens when a person first arrives into prison, and are taken from the NICE guideline on physical health of people in prison. They refer to the first-stage health assessment, which is a combined physical and mental health assessment. A second-stage mental health assessment in prison should normally be done within 7 days. There is also a downloadable version of the first stage health assessment table as shown in table 1. At first reception into prison, a healthcare professional (or trained healthcare assistant under the supervision of a registered nurse) should carry out a health assessment for every person. Do this before the person is allocated to their cell. As part of the assessment, identify: any issues that may affect the person's immediate health and safety before the second-stage health assessment priority health needs to be addressed at the next clinical opportunity. Ensure continuity of care for people transferring from one custodial setting to another (including court, the receiving prison or during escort periods) by, for example: accessing relevant information from the patient clinical record, prisoner escort record and cell sharing risk assessment checking medicines and any outstanding medical appointments. The first-stage health assessment should include the questions and actions in table 1. It should cover: physical health alcohol use substance misuse mental health self-harm and suicide risk. ## Table 1 Questions for first-stage prison health assessment Topic questions Actions Prison sentence . Has the person committed murder, manslaughter or another offence with a long sentence? Yes: refer the person for mental health assessment by the prison mental health in-reach team if necessary. No: record no action needed. Prescribed medicines . Is the person taking any prescribed medicines (for example, insulin) or over-the-counter medicines (such as creams or drops)? If so: what are they what are they for how do they take them? Yes: document any current medicines being taken and generate a medicine chart. Refer the person to the prescriber for appropriate medicines to be prescribed, to ensure continuity of medicines. If medicines are being taken, ensure that the next dose has been provided (see recommendations 1.7.10 and 1.7.11 in the NICE guideline on physical health of people in prison). Let the person know that medicines reconciliation will take place before the second-stage health assessment. No: record no action needed. Physical injuries . Has the person received any physical injuries over the past few days, and if so: what were they how were they treated? Yes: assess severity of injury, any treatment received and record any significant head, abdominal injuries or fractures. Document any bruises or lacerations observed on a body map. In very severe cases, or after GP assessment, the person may need to be transferred to an external hospital. Liaise with prison staff to transfer the person to the hospital emergency department by ambulance. If the person has made any allegations of assault, record negative observations as well (for example, 'no physical evidence of injury'). No: record no action needed. Other health conditions . Does the person have any of the following: allergies, asthma, diabetes, epilepsy or history of seizures chest pain, heart disease chronic obstructive pulmonary disease tuberculosis, sickle cell disease hepatitis B or C virus, HIV, other sexually transmitted infections learning disabilities neurodevelopmental disorders physical disabilities? Ask about each condition listed. Yes: make short notes on any details of the person's condition or management. For example, 'Asthma – on Ventolin 1 puff daily'. Make appointments with relevant clinics or specialist nurses if specific needs have been identified. No: record no action needed. . Are there any other health problems the person is aware of that have not been reported? Yes: record the details and check with the person that no other physical health complaint has been overlooked. No: record no action needed. . Are there any other concerns about the person's health? Yes: make a note of any other concerns about physical health. This should include any health-related observations about the person's physical appearance (for example, weight, pallor, jaundice, gait or frailty). Refer the person to the GP or relevant clinic. No: note 'Nil'. Additional questions for women . Does the woman have reason to think she is pregnant, or would she like a pregnancy test? If the woman is pregnant, refer to the GP and midwife. If there is reason to think the woman is pregnant, or would like a pregnancy test: provide a pregnancy test. Record the outcome. If positive, make an appointment for the woman to see the GP and midwife. No: record response. Living arrangements, mobility and diet . Does the person need help to live independently? Yes: note any needs. Liaise with the prison disability lead in reception about: the location of the person's cell further disability assessments the prison may need to carry out. No: record response. . Do they use any equipment or aids (for example, walking stick, hearing aid, glasses, dentures, continence aids or stoma)? Yes: remind prison staff that all special equipment and aids the person uses should follow them from reception to their cell. No: record response. . Do they need a special medical diet? Yes: confirm the need for a special medical diet. Note the medical diet the person needs and send a request to catering. Refer to appropriate clinic for ongoing monitoring. No: record response. Past or future medical appointments . Has the person seen a doctor or other healthcare professional in the past few months? If so, what was this for? Yes: note details of any recent medical contact. Arrange a contact letter to get further information from the person's doctor or specialist clinic. Note any ongoing treatment the person needs and make appointments with relevant clinics, specialist nurses, GP or other healthcare staff. No: record no action needed. . Does the person have any outstanding medical appointments? If so, who are they with, and when? Yes: note future appointment dates. Ask healthcare administrative staff to manage these appointments or arrange for new dates and referral letters to be sent if the person's current hospital is out of the local area. No: record no action needed. Alcohol and substance misuse . Does the person drink alcohol, and if so: how much do they normally drink? how much did they drink in the week before coming into custody? Urgently refer the person to the GP or an alternative suitable healthcare professional if: they drink more than 15 units of alcohol daily or they are showing signs of withdrawal or they have been given medication for withdrawal in police or court cells. No: record response. . Has the person used street drugs in the last month? If so, how frequently? When did they last use: heroin methadone benzodiazepines amphetamine cocaine or crack novel psychoactive substances cannabis anabolic steroids performance and image enhancing drugs? Yes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. Take into account whether: they have taken drugs intravenously they have a positive urine test for drugs their answers suggest that they use drugs more than once a week they have been given medication for withdrawal in police or court cells. If the person has used intravenous drugs, check them for injection sites. Refer them to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. No: record response. Problematic use of prescription medicines . Has the person used prescription or over-the-counter medicines in the past month: that were not prescribed or recommended for them or for purposes or at doses that were not prescribed? If so, what was the medicine and how did they use it (frequency and dose)? Yes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. No: record response. Mental health . Has the person ever seen a healthcare professional or service about a mental health problem (including a psychiatrist, GP, psychologist, counsellor, community mental health services, alcohol or substance misuse services or learning disability services)? If so, who did they see and what was the nature of the problem? Yes: refer the person for a mental health assessment if they have previously seen a mental health professional in any service setting. No: record response. . Has the person ever been admitted to a psychiatric hospital, and if so: when was their most recent discharge what is the name of the hospital what is the name of their consultant? Yes: refer the person for a mental health assessment. No: record response. . Has the person ever been prescribed medicine for any mental health problems? If so: what was the medicine when did they receive it when did they take the last dose what is the current dose (if they are still taking it) when did they stop taking it? Yes: refer the person for a mental health assessment if they have taken medicine for mental health problems. No: record response. Self-harm and suicide risk . Is the person: feeling hopeless or currently thinking about or planning to harm themselves or attempt suicide? Yes: refer the person for an urgent mental health assessment. Open an Assessment, Care in Custody and Teamwork (ACCT) plan if: there are serious concerns raised in response to questions about self-harm, including thoughts, intentions or plans, or observations (for example, the patient is very withdrawn or agitated) or the person has a history of previous suicide attempts. Be aware and record details of the impact of the sentence on the person, changes in legal status and first imprisonment, and the nature of the offence (for example, murder, manslaughter, offence against the person and sexual offences). No: record response. . Has the person ever tried to harm themselves, and if so: do they have a history of suicide attempts was this inside or outside prison when was the most recent incident what was the most serious incident? Yes: refer the person for a mental health assessment if they have ever tried to harm themselves. No: record response. ## Identification and assessment throughout the care pathway (including second-stage health assessment in prisons) Recommendations 1.3.6 to 1.3.8 apply both throughout the care pathway and to the second-stage health assessment in prisons. In non-prison settings, all staff should think about using the Correctional Mental Health Screen tool (see recommendation 1.3.6). Consider using the Correctional Mental Health Screen for Men (CMHS-M) or Women (CMHS-W) to identify possible mental health problems if: the person's history, presentation or behaviour suggest they may have a mental health problem the person's responses to the first-stage health assessment suggest they may have a mental health problem the person has a chronic physical health problem with associated functional impairment concerns have been raised by other agencies about the person's abilities to participate in the criminal justice process. When using the CMHS‑M or CMHS‑W with a transgender person, use the measure that is in line with their preferred gender identity. If a man scores 6 or more on the CMHS‑M, or a woman scores 4 or more on the CMHS‑W, or there is other evidence supporting the likelihood of mental health problems, practitioners should: conduct a further assessment if they are competent to perform assessments of mental health problems or refer the person to an appropriately trained professional for further assessment if they are not competent to perform such assessments themselves. ## Carrying out a mental health assessment Service providers should ensure that competent practitioners who have experience of working with people in contact with the criminal justice system with mental health problems: perform the mental health assessment coordinate the input of other professionals into the assessment when needed. If there are concerns about a person's mental capacity, practitioners should: perform a mental capacity assessment if they are competent to do this (or refer the person to a practitioner who is) consider involving an advocate to support the person. All practitioners should discuss rights to confidentiality with people and explain: what the mental health assessment is for and how the outcome of the assessment may be used how consent for sharing information with named family members, carers and other services should be sought that the assessor may have a legal or ethical duty to disclose information relating to the safety of the person or others, or to the security of the institution. All practitioners should ensure mental health assessment is a collaborative process that: involves negotiation with the person, as early as possible in the assessment process, about how information about them will be shared with others involved in their care makes the most of the contribution of everyone involved, including the person, those providing care or legal advice and family members and carers engages the person in an informed discussion of treatment, support and care options allows for the discussion of the person's concerns about the assessment process. Ensure all practitioners carrying out mental health assessments are competent to assess problems that commonly present, with an understanding of the context and setting in which they are done. They should: tailor the content, structure and pace of an assessment to the person's needs and adjust the assessment as new information emerges take into account the person's understanding of the problem have knowledge and awareness of diagnostic classification systems and their limitations appraise the reliability and validity of all available health and criminal justice systems records identify and take into account the reasons for any significant differences between the assessor's views and those of the person and other agencies involved in their care use validated tools relevant to the disorders or problems being assessed take into account the views of practitioners from other services involved in the person's care. All practitioners carrying out mental health assessment should take into account the following when conducting an assessment of suspected mental health problems for people in contact with the criminal justice system: the nature and severity of the presenting mental health problems (including cognitive functioning) and their development and history coexisting mental health problems coexisting substance misuse problems, including novel psychoactive substances coexisting physical health problems social and personal circumstances, including personal experience of trauma social care, educational and occupational needs people's strengths available support networks, and the person's capacity to make use of them previous care, support and treatment, including how the person responded to these -ffending history and how this may interact with mental health problems. When assessing people in contact with the criminal justice system all practitioners should: recognise potential barriers to accessing and engaging in interventions and methods to overcome these at the individual and service level discuss mental health problems and treatment options in a way that gives rise to hope and optimism by explaining that change is possible and attainable be aware that people may have negative expectations based on earlier experiences with mental health services, the criminal justice system, or other relevant services. All practitioners should share the outcomes of a mental health assessment, in accordance with legislation and local policies, subject to permission from the person where necessary, with: the person and, if possible, their family members or carers all staff and agencies (for example, probation service providers and secondary care mental health services) involved in the direct development and implementation of the plan -ther staff or agencies (as needed) not directly involved in the development and implementation of the plan who could support the effective implementation and delivery of the plan. ## Reviewing the mental health assessment Practitioners should review and update mental health assessments: if new information is available about the person's mental health problem if there are significant differences between the views of the person and the views of the family, carers or staff that cannot be resolved through discussion when major legal or life events occur when the person is transferred between, or out of, criminal justice services if a person experiences a significant change in care or support, for example, stopping an Assessment, Care in Custody and Teamwork (ACCT) plan if a person disengages or does not stick to their treatment plan annually, or as required by local policy such as Care Programme Approach or Care Treatment Plan. When updating mental health assessments, practitioners should consider: reviewing and ensuring demographic information is accurate reviewing psychological, social, safety, personal historical and criminological factors assessing multiple areas of need, including social and personal circumstances, physical health, occupational rehabilitation, education and previous and current care and support developing an increased understanding of the function of the offending behaviour and its relationship with mental health problems covering any areas not fully explored by the initial assessment. # Risk assessment and management Perform a risk assessment for all people in contact with the criminal justice system when a mental health problem occurs or is suspected. All practitioners should take into account the following issues in risk assessments for people in contact with the criminal justice system: risk to self, including self-harm, suicide, self-neglect, risk to own health and degree of vulnerability to exploitation or victimisation risk to others that is linked to mental health problems, including aggression, violence, exploitation and sexual offending causal and maintaining factors the likelihood, imminence and severity of the risk the impact of their social and physical environment protective factors that may reduce risk. During a risk assessment the practitioner doing the assessment should explain to the person that their behaviours may need to be monitored. This may include: external monitoring of behaviours that may indicate a risk to self or others self-monitoring of risk behaviours to help the person to identify, anticipate and prevent high-risk situations. If indicated by their risk assessment, the practitioner doing the assessment should develop a risk management plan for a person. This should: integrate with or be consistent with the mental health assessment and plan take an individualised approach to each person and recognise that risk levels may change over time set out the interventions to reduce risk at the individual, service or environmental level take into account any legal or statutory responsibilities which apply in the setting in which they are used be shared with the person (and their family members or carers if appropriate) and relevant agencies and services subject to permission from the person where necessary be reviewed regularly by those responsible for implementing the plan and adjusted if risk levels change. All practitioners should ensure that any risk management plan is: informed by the assessments and interventions in relevant NICE guidance for the relevant mental health disorders, including the NICE guidelines on self-harm in over 8s: short-term management and prevention of recurrence and self-harm in over 8s: long-term management implemented in line with agreed protocols for safeguarding vulnerable people and the provision of appropriate adults implemented in line with agreed protocols in police custody, prisoner escort services, prison, community settings and probation service providers. Ensure that the risk management plan is integrated with, and recorded in, the relevant information systems; for example, the ACCT procedure in prisons, the Offender Assessment System (OASys) and SystmOne and Multi-Agency Risk Assessment Conference (MARAC) and Multi-Agency Public Protection Arrangements (MAPPA). # Care planning Develop a mental health care plan in collaboration with the person and, when possible, their family, carers and advocates. All practitioners developing the plan should ensure it is integrated with care plans from other services, and includes: a profile of the person's needs (including physical health needs), identifying agreed goals and the means to progress towards them identification of the roles and responsibilities of those practitioners involved in delivering the care plan the implications of any mandated treatment programmes, post-release licences and transfer between institutions or agencies, in particular release from prison a clear strategy to access all identified interventions and services agreed outcome measures and timescale to evaluate and review the plan a risk management plan and a crisis plan if developed an agreed process for communicating the care plan (such as the Care Programme Approach or Care Treatment Plan) to all relevant agencies, the person, and their families and carers, subject to permission from the person where necessary. When developing or implementing a mental health care plan all practitioners should take into account: the ability of the person to take in and remember information the need to provide extra information and support to help with the understanding and implementation of the care plan the need for any adjustment to the social or physical environment the need to adjust the structure, content, duration or frequency of any intervention the need for any prompts or cognitive aids to help with delivery of the intervention. # Psychological interventions ## Delivering psychological interventions for mental health problems Refer to relevant NICE guidance for the psychological treatment of mental health problems for adults in contact with the criminal justice system, taking into account the need: to modify the delivery of psychological interventions in the criminal justice system to ensure continuity of the psychological intervention (for example, transfer between prison settings or on release from prison) for staff to be trained and competent in the interventions they are delivering for supervision for audit using routinely available outcome measures. Be aware that many people in contact with the criminal justice system (including people with a diagnosis of personality disorder) may have difficulties with: accurately interpreting and controlling emotions impulse control (for example, difficulty planning, seeking high levels of stimulation, ambivalent about consequences of their negative actions) experiencing themselves as having a lack of autonomy (for example, seeing their actions as pointless, having difficulties in setting and achieving goals) having an unstable sense of self that varies depending on context or is influenced by the people they interact with social functioning (for example, relating to, cooperating with and forming relationships with others, difficulties understanding their own and others' needs) -ccupational functioning. ## Personality disorder Providers of services should ensure staff are able to identify common features and behaviours associated with personality disorders and use these to inform the development of programmes of care. Practitioners should ensure interventions for people with a diagnosis of personality disorder or associated problems are supportive, facilitate learning and develop new behaviours and coping strategies in the following areas: problem solving emotion regulation and impulse control managing interpersonal relationships self-harm use of medicine (including reducing polypharmacy). Practitioners should be aware when delivering interventions for people with mental health problems that having a personality disorder or an associated problem may reduce the effectiveness of interventions. Think about: providing additional support adjusting the duration and intensity of psychological interventions if standard protocols have not worked delivering complex interventions in a multidisciplinary context. Practitioners should not exclude people with personality disorders from any health or social care service, or intervention for comorbid disorders, as a direct result of their diagnosis. ## Specific psychological interventions Practitioners should consider using contingency management to reduce drug misuse and promote engagement with services for people with substance misuse problems. Practitioners delivering contingency management programmes should: agree with the person the behaviour that is the target of change provide incentives in a timely and consistent manner confirm the person understands the relationship between the treatment goal and the incentive schedule make incentives reinforcing and supportive of a healthy and drug-free lifestyle. Practitioners should consider referral to a therapeutic community specifically for substance misuse for people in prison with a minimum 18-month sentence who have an established pattern of drug misuse. When setting up therapeutic community programmes in prison settings in a separate wing of a prison for people with substance misuse problems, aim to: include up to 50 prisoners in the programme provide treatment for between 12 and 18 months, made up of: twice-weekly group therapy sessions (mean group size of 8) daily (5 days only) community meeting for all wing residents daily (5 days only) social activity groups for all wing residents a once-weekly individual review meeting (20 minutes). Consider psychological interventions for paraphilias only when delivered as part of a research programme. # Pharmacological interventions Refer to relevant NICE guidance for pharmacological interventions for mental health problems in adults in contact with the criminal justice system. Take into account: risks associated with in-possession medicines administration times for medication availability of medicines in the first 48 hours of transfer to prison availability of medicines after release from prison. Refer to NICE's guidance on attention deficit hyperactivity disorder (ADHD) when prescribing pharmacological interventions for this condition. Review all medicines prescribed for sleep problems and the management of chronic pain to: establish the best course of treatment (seek specialist advice if needed) assess the risk of diversion or misuse of medicines. # Organisation of services ## Service structures and delivery Commissioners and providers of criminal justice services and healthcare services should support the development of liaison and diversion functions for police custody and the courts that provide prompt access to the following: the effective identification and recognition of mental health problems a comprehensive mental health assessment advice on immediate care and management appropriate treatment and care (including medication). Providers of criminal justice services and healthcare services should consider diverting people from standard courts to dedicated drug courts if the offence is linked to substance misuse and was non-violent. Commissioners and providers of criminal justice services and healthcare services should consider establishing joint working arrangements between healthcare, social care and police services for managing urgent and emergency mental health presentations in the community (for example, street triage). Include: joint training for police, healthcare and social care staff agreed protocols for joint working developed and reviewed by a multi-agency group agreed protocols for effective communication within and between agencies agreed referral pathways for urgent and emergency care and routine care. Commissioners and providers of criminal justice services and healthcare services should ensure effective identification, assessment, coordination and delivery of care for all people with a mental health problem in contact with the criminal justice system. This should include people who are transferring from young offender services and those on probation. In particular, ensure that: all people with a severe or complex mental health problem have a designated care coordinator during transitions between services care plans are shared and agreed between all services effective protocols are in place to support routine data sharing and, when necessary, joint plans of care between health services (including primary and secondary care services) and criminal justice agencies to reduce unnecessary assessments and promote effective interventions. # Staff training Commissioners and providers of criminal justice services and healthcare services should ensure that all staff working in the criminal justice system, who provide direct care or supervision, have a comprehensive induction, covering: the purpose of the service in which they work, and the role and availability of other related local services, including pathways for referral the roles, responsibilities and processes of criminal justice, health and social care staff legislation and local policies relevant to their role, for sharing information with others involved in the person's care protocols for dealing with mental health problems in the criminal justice system (for example, in-possession medicines, side effects, withdrawal) the importance of clear communication, including avoiding acronyms and using consistent terminology. Commissioners and providers of criminal justice services and healthcare services should educate all staff about: the stigma and discrimination associated with mental health problems and associated behaviours, such as self-harm the need to avoid judgemental attitudes the need to avoid using inappropriate terminology. Provide multidisciplinary and multi‑agency training (as part of both induction training and continuing professional development) to increase consistency, understanding of ways of working, and promotion of positive working relationships for all staff who work in the criminal justice system on: the prevalence of mental health problems in the criminal justice system, and why such problems may bring people into contact with the criminal justice system the main features of commonly occurring mental health problems seen in the criminal justice system, and the impact these may have on behaviour and compliance with rules and statutory requirements recognising and responding to mental health problems and communication problems that arise from, or are related to, physical health problems. Give all staff involved in direct care, training (as part of induction training and continuing professional development) and supervision to support them in: dealing with critical incidents, including emergency life support managing stress associated with working in the criminal justice system and how this may affect their interactions with people and their own mental health and wellbeing the recognition, assessment, treatment and management of self-harm and suicide de-escalation methods to minimise the use of restrictive interventions recognition of changes in behaviour, taking into account that these may indicate the onset of, or changes to, mental health problems knowledge of effective interventions for mental health problems developing and maintaining safe boundaries and constructive relationships delivering interventions within the constraints of the criminal justice system (for example, jail craft training, formulation skills). # Terms used in this guideline ## Assessment, Care in Custody and Teamwork (ACCT) ACCT is a prisoner-centred, flexible care-planning system which, when used effectively, can reduce risk, primarily of self-harm. The ACCT process is necessarily prescriptive and it is vital that all stages are followed in the timescales prescribed. ## Acquired cognitive impairment Any cognitive impairment that develops after birth, including traumatic brain injury, stroke, and neurodegenerative disorders such as dementia. ## Appropriate adult A person who is responsible for protecting (or 'safeguarding') the rights and welfare of a child or 'mentally vulnerable' adult who is either detained by police or is interviewed under caution voluntarily. The role was created alongside the Police and Criminal Evidence Act (PACE) 1984. ## Carer A person who provides unpaid support to someone who is ill, having trouble coping or who has disabilities. ## Contingency management A set of techniques that focus on the use of reinforcement to change certain specified behaviours. These may include promoting abstinence from drugs (for example, cocaine), reducing drug misuse (for example, illicit drug use by people receiving methadone maintenance treatment), and improving adherence to interventions that can improve physical health outcomes. ## Correctional Mental Health Screen for men (CMHS‑M) or women (CMHS‑W) This is a screening tool that measures acute mental health issues present in people in prison. Questions are answered in a yes–no format, and then rated on a Likert-scale from 1 (low risk or need) to 5 (high risk or need), depending on severity. ## In-possession medicine Medicine is said to be held in-possession if a person (usually in a prison or other secure setting) is responsible for holding and taking it themselves. ## Jail craft Learned, knowledgeable work depending on experience and fine judgements in a prison setting – often learned by new staff working in prisons through shadowing and being mentored by experienced staff. ## Liaison and diversion service This is a service that aims to identify people who have mental health problems who come into contact with the criminal justice system before they enter prison. They may be able to liaise and refer people they identify with mental health problems to local services or divert someone out of the criminal justice system, for example by arranging a Mental Health Act assessment. A liaison and diversion service may be in the form of a street triage service (see below) or they can be based in police custody suites or the court cells. ## Mental health in-reach team A secondary mental health team based in prisons to support adults in prison. The team will be part of the NHS trust for the area the prison is located. This team may consist of the same types of staff who work in community mental health teams, including community psychiatric nurses, social workers, psychologists, occupational therapists and psychiatrists. ## Multi-Agency Public Protection Arrangements (MAPPA) These arrangements are designed to protect the public, including previous victims of crime, from serious harm by sexual and violent offenders. They require the local criminal justice agencies and other bodies dealing with offenders to work together in partnership in dealing with these offenders. ## Multi-Agency Risk Assessment Conference (MARAC) This is a monthly meeting where professionals across criminal justice agencies and other bodies dealing with offenders share information on high risk cases of domestic violence and abuse and put in place a risk management plan. ## Multidisciplinary A multidisciplinary team Is a group of experts from different disciplines who each provide specific support to a person, working as a team. ## Offender Assessment System (OASys) This is a risk and needs assessment tool. It identifies and classifies offending related needs, such as a lack of accommodation, poor educational and employment skills, substance misuse, relationship problems, and problems with thinking and attitudes and the risk of harm offenders pose to themselves and others. ## Programme of care This is developed from a comprehensive assessment of a person's needs and sets out how those needs might be met, who is responsible for meeting those needs, and how the programme of care will be evaluated and reviewed. ## Street triage Schemes involving mental health professionals providing on-the-spot support to police officers who are dealing with people with possible mental health problems. ## SystmOne A clinical computer system used widely by healthcare professionals in the UK to manage electronic patient records. SystmOne is the standard system currently used in prisons in England and Wales. This guideline covers the full range of mental health problems including common mental disorders, substance misuse disorders, neurodevelopmental disorders and personality disorders.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Mental health problems are very common among people in contact with the criminal justice system, with the amount of people affected ranging from 39% in police custody up to 90% in prison. There is also evidence that certain mental disorders, like personality disorders and psychotic disorders, are more prevalent in the prison population than the general population. It has also been reported that certain groups like females, black and minority ethnic groups, people older than 50 years and people with comorbid disorders are over-represented in prisoners with mental health disorders. The underlying mechanisms between crime and mental illness are still not yet well understood. There are some suggestions that pre-existing social factors, for example homelessness, may be associated with increased offending. In other areas, such as substance misuse, the urge to use illicit drugs may drive people to commit crimes such as theft. In some cases, the links may relate to either poor adaptive functioning or the consequence of offending and contact with the criminal justice system upon mental health. Currently, NHS England is responsible for commissioning healthcare provision including mental healthcare for people in contact with the criminal justice system, with the exceptions of police and court custody. There is also a joint care pilot scheme between the criminal justice system and NHS funded by the Department of Health, with initiatives such as 'street triage' schemes. However, identifying mental health problems in police custody is complicated by the lack of training, education and a standard assessment. There is also a lack of clarity on appropriate signposting and prompt access to a mental healthcare. This guideline covers recognition, assessment, treatment and prevention of mental health problems in adults who are in contact with the criminal justice system (police and court custody, prison custody, street triage and liaison and diversion services, as well as probation service providers). Mental health problems include common mental health problems, severe mental illness, paraphilias, neurodevelopmental disorders and acquired cognitive impairment. There are recommendations on care planning and pathways, and organisation and structure of services, as well as training for health, social care and criminal justice professionals and practitioners. Although the focus of this guideline is on healthcare, the Care Act 2014 has relevance to people in the criminal justice system, in the community and in prisons. This may be of particular relevance for people with neurodevelopmental disorders, including learning disability and autistic spectrum disorders. You can also see this guideline in the NICE pathway on health of people in the criminal justice system. To find out what NICE has said on topics related to this guideline, see our web page on prisons and other secure settings and mental health and behavioural conditions. See also the guideline committee's discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee.# Recommendations for research The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline. # Psychological and pharmacological interventions for people with paraphilic disorders What is the clinical effectiveness, cost effectiveness and safety of specific psychological and pharmacological interventions both in and out of prison among people with paraphilic disorders? ## Why this is important The limited evidence for pharmacological interventions (for example, medroxyprogesterone acetate) provides no clear evidence of benefit in people with paraphilias. A randomised trial with an adequate sample size is needed to examine the effectiveness of medroxyprogesterone acetate in these populations. There is also insufficient evidence on the effectiveness of psychological interventions for people with paraphilias in the criminal justice system. An individual patient data analysis of existing large scale data sets of paedophiles who have been treated in the criminal justice system should be conducted to inform the choice of treatment and the design of any future research. Psychological interventions for paraphilias (such as sex offender treatment programme) should be tested in large randomised controlled trials in criminal justice populations. This research could have a significant impact upon updates of this guideline. Important outcomes could include: -ffending and re-offending rates mental health problems cost-effectiveness service utilisation. When designing the trials, consideration should be given to the timing, intensity and duration of interventions in the context of the criminal justice system. # Structured clinical management interventions in probation service providers What is the effectiveness of structured clinical (case) management in improving mental health outcomes using interventions within probation service providers? ## Why this is important Many people in contact with the community-based criminal justice services have significant mental health problems, in particular, personality problems and interpersonal difficulties. Evidence from studies of people with such problems in general mental health services suggests that structured organisation and delivery of mental health interventions (structured clinical management) may be of benefit in improving mental health outcomes. A programme of research is needed which would first refine and develop structured clinical management for use in the community rehabilitation companies (CRCs) and the National Probation Service (NPS) and then test this in large scale randomised control trials in both CRCs and the NPS. The comparison should be against standard CRC and NPS care. The trial should consider both clinical outcomes and cost-effectiveness. Important outcomes could include: mental health outcomes -ffending and re-offending rates service utilisation cost-effectiveness broader measures of social functioning. # Interventions for coordination and delivery of care to improve access and uptake What models for the coordination and delivery of care for people in contact with the criminal justice system provide for the most effective and efficient coordination of care and improve access and uptake of services? ## Why this is important There is low quality evidence for a range of systems for the delivery and coordination of care in the criminal justice system (for example, drug or mental health courts, and case management). However, there is clear evidence of poor engagement, uptake and retention in treatment for people with mental health problems in contact with the criminal justice system. A number of models (for example, case management and collaborative care) have shown benefit for people with common and severe mental health problems in routine healthcare settings. A programme of research and development is needed, which will first develop and test different models of care coordination for the delivery of care in small feasibility studies, and then test models that have shown promise in the feasibility studies in large scale randomised clinical trials in the criminal justice system. Important outcomes could include: improved mental health outcomes improved access and uptake of services reductions in offending and re-offending cost effectiveness. # Tools for case identification for cognitive impairment in criminal justice system populations What are the reliable and valid tools to identify cognitive impairment among people in contact with the criminal justice system (including people who have experienced physical trauma, neurodevelopmental disorders or other acquired cognitive impairment)? ## Why this is important Acquired cognitive impairment is common in criminal justice system populations and may be associated with poor social, occupational an interpersonal functioning. Also, people with acquired cognitive impairment have high risk of self-harm which is particularly prevalent in the prison population. Acquired cognitive impairment may arise as a result of, for example, traumatic brain injury, a stroke or other neurological conditions. Experts in this area have suggested that early identification of deficits, and implementation of effective management strategies, could be important in limiting the long-term impact of acquired cognitive impairment. However, there is a lack of evidence on reliable and valid case identification tools and methods. It is important that research is developed to assist staff in the criminal justice pathway to help identify people with acquired cognitive impairment and support better understanding and management of acquired cognitive impairment. # Prevalence of mental health problems What is the prevalence of mental health problems and associated social problems for those in contact with the criminal justice system? ## Why this is important It is widely recognised that the people in contact with the criminal justice system have a high prevalence of a whole range of mental health problems and associated problems including unstable housing, long-standing unemployment, a lack of supportive social networks and debt. What is not clear, however, is how the mental and social functioning of this group of people has changed since the last major epidemiological study in the late 1990s. In order to plan for the effective mental health care of people in the criminal justice system, it is important to have a greater understanding of the prevalence of mental health problems and social functioning of this group of people. There are a number of factors which have changed since the last epidemiological study; these include a larger prison population, changing patterns of substance misuse, an aging prison population, changes in probation practice and sentencing policy as well as broader changes in society such as changes in mental health care and social care practice. A series of epidemiological studies of representative criminal justice system populations should be undertaken to address the above problems. # Identification of factors associated with suicide What factors are associated with suicide attempts and completed suicides? ## Why this is important There is high prevalence of suicide attempts among people in contact with the criminal justice system. When developing interventions to prevent self-harm among these populations, it is important to identify and understand the factors related to successful suicide. A retrospective analysis of observational studies of suicidal attempts and completed suicides using suicide as a definitive and measurable outcome should be performed to identify the prognostic factors for successful prevention. ISBN: 978-1-4731-2381-6	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Using this guideline together with other NICE guidelines\n\nUse this guideline with the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services to improve the experience of care for people with mental health problems including those with neurodevelopmental disorders.\n\nUse this guideline with any NICE guidelines on specific mental health problems. Take into account:\n\nthe nature and severity of any mental health problem\n\nthe presence of a learning disability or any acquired cognitive impairment\n\nother communication difficulties (for example, language, literacy, information processing or sensory deficit)\n\nthe nature of any coexisting mental health problems (including substance misuse)\n\nlimitations on prescribing and administering medicine (for example, in-possession medicine) or the timing of the delivery of interventions in certain settings (for example, prison)\n\nthe development of trust in an environment where health and care staff may be held in suspicion\n\nany cultural and ethnic differences in beliefs about mental health problems\n\nany differences in presentation of mental health problems\n\nthe setting in which the assessment or treatment takes place.\n\nObtain, evaluate and integrate all available and reliable information about the person when assessing or treating people in contact with the criminal justice system. For example:\n\nperson escort record (PER)\n\npre-sentence report\n\nall medical records\n\ncustody reports\n\nAssessment, Care in Custody and Teamwork (ACCT) document\n\nreports from other relevant services, including liaison and diversion, substance misuse services, social service or housing services and youth offending services\n\nOffender Assessment System (OASys) or other assessment tools.Take into account how up to date the information is and how it was gathered.\n\n# Principles of assessment\n\nWork with a family member, partner, carer, advocate or legal representative when possible in order to get relevant information and support the person, help explain the outcome of assessment and help them make informed decisions about their care. Take into account:\n\nthe person's wishes\n\nthe nature and quality of family relationships, including any safeguarding issues\n\nany statutory or legal considerations that may limit family and carer involvement\n\nthe requirements of the Care Act 2014.\n\nCarry out assessments:\n\nin a suitable environment that is safe and private\n\nin an engaging, empathic and non-judgemental manner.\n\nWhen assessing a person, make reasonable adjustments to the assessment that take into account any suspected neurodevelopmental disorders (including learning disabilities), cognitive impairments, or physical health problems or disabilities. Seek advice or involve specialists if needed.\n\n# Identification and assessment throughout the care pathway\n\nBe vigilant for the possibility of unidentified or emerging mental health problems in people in contact with the criminal justice system, and review available records for any indications of a mental health problem.\n\nEnsure all staff working in criminal justice settings are aware of the potential impact on a person's mental health of being in contact with the criminal justice system.\n\n## First-stage health assessment at reception into prison\n\nRecommendations 1.3.3 to 1.3.5 cover what happens when a person first arrives into prison, and are taken from the NICE guideline on physical health of people in prison. They refer to the first-stage health assessment, which is a combined physical and mental health assessment. A second-stage mental health assessment in prison should normally be done within 7\xa0days.\n\nThere is also a downloadable version of the first stage health assessment table as shown in table\xa01.\n\nAt first reception into prison, a healthcare professional (or trained healthcare assistant under the supervision of a registered nurse) should carry out a health assessment for every person. Do this before the person is allocated to their cell. As part of the assessment, identify:\n\nany issues that may affect the person's immediate health and safety before the second-stage health assessment\n\npriority health needs to be addressed at the next clinical opportunity.\n\nEnsure continuity of care for people transferring from one custodial setting to another (including court, the receiving prison or during escort periods) by, for example:\n\naccessing relevant information from the patient clinical record, prisoner escort record and cell sharing risk assessment\n\nchecking medicines and any outstanding medical appointments.\n\nThe first-stage health assessment should include the questions and actions in table\xa01. It should cover:\n\nphysical health\n\nalcohol use\n\nsubstance misuse\n\nmental health\n\nself-harm and suicide risk.\n\n## Table 1 Questions for first-stage prison health assessment\n\nTopic questions\n\nActions\n\nPrison sentence\n\n. Has the person committed murder, manslaughter or another offence with a long sentence?\n\nYes: refer the person for mental health assessment by the prison mental health in-reach team if necessary.\n\nNo: record no action needed.\n\nPrescribed medicines\n\n. Is the person taking any prescribed medicines (for example, insulin) or over-the-counter medicines (such as creams or drops)? If so:\n\nwhat are they\n\nwhat are they for\n\nhow do they take them?\n\nYes: document any current medicines being taken and generate a medicine chart.\n\nRefer the person to the prescriber for appropriate medicines to be prescribed, to ensure continuity of medicines.\n\nIf medicines are being taken, ensure that the next dose has been provided (see recommendations 1.7.10 and 1.7.11 in the NICE guideline on physical health of people in prison).\n\nLet the person know that medicines reconciliation will take place before the second-stage health assessment.\n\nNo: record no action needed.\n\nPhysical injuries\n\n. Has the person received any physical injuries over the past few days, and if so:\n\nwhat were they\n\nhow were they treated?\n\nYes: assess severity of injury, any treatment received and record any significant head, abdominal injuries or fractures.\n\nDocument any bruises or lacerations observed on a body map.\n\nIn very severe cases, or after GP assessment, the person may need to be transferred to an external hospital. Liaise with prison staff to transfer the person to the hospital emergency department by ambulance.\n\nIf the person has made any allegations of assault, record negative observations as well (for example, 'no physical evidence of injury').\n\nNo: record no action needed.\n\nOther health conditions\n\n. Does the person have any of the following:\n\nallergies, asthma, diabetes, epilepsy or history of seizures\n\nchest pain, heart disease\n\nchronic obstructive pulmonary disease\n\ntuberculosis, sickle cell disease\n\nhepatitis B or C virus, HIV, other sexually transmitted infections\n\nlearning disabilities\n\nneurodevelopmental disorders\n\nphysical disabilities?\n\nAsk about each condition listed.\n\nYes: make short notes on any details of the person's condition or management. For example, 'Asthma – on Ventolin 1 puff daily'.\n\nMake appointments with relevant clinics or specialist nurses if specific needs have been identified.\n\nNo: record no action needed.\n\n. Are there any other health problems the person is aware of that have not been reported?\n\nYes: record the details and check with the person that no other physical health complaint has been overlooked.\n\nNo: record no action needed.\n\n. Are there any other concerns about the person's health?\n\nYes: make a note of any other concerns about physical health. This should include any health-related observations about the person's physical appearance (for example, weight, pallor, jaundice, gait or frailty).\n\nRefer the person to the GP or relevant clinic.\n\nNo: note 'Nil'.\n\nAdditional questions for women\n\n. Does the woman have reason to think she is pregnant, or would she like a pregnancy test?\n\nIf the woman is pregnant, refer to the GP and midwife.\n\nIf there is reason to think the woman is pregnant, or would like a pregnancy test: provide a pregnancy test. Record the outcome. If positive, make an appointment for the woman to see the GP and midwife.\n\nNo: record response.\n\nLiving arrangements, mobility and diet\n\n. Does the person need help to live independently?\n\nYes: note any needs. Liaise with the prison disability lead in reception about:\n\nthe location of the person's cell\n\nfurther disability assessments the prison may need to carry out.\n\nNo: record response.\n\n. Do they use any equipment or aids (for example, walking stick, hearing aid, glasses, dentures, continence aids or stoma)?\n\nYes: remind prison staff that all special equipment and aids the person uses should follow them from reception to their cell.\n\nNo: record response.\n\n. Do they need a special medical diet?\n\nYes: confirm the need for a special medical diet. Note the medical diet the person needs and send a request to catering. Refer to appropriate clinic for ongoing monitoring.\n\nNo: record response.\n\nPast or future medical appointments\n\n. Has the person seen a doctor or other healthcare professional in the past few months? If so, what was this for?\n\nYes: note details of any recent medical contact. Arrange a contact letter to get further information from the person's doctor or specialist clinic. Note any ongoing treatment the person needs and make appointments with relevant clinics, specialist nurses, GP or other healthcare staff.\n\nNo: record no action needed.\n\n. Does the person have any outstanding medical appointments? If so, who are they with, and when?\n\nYes: note future appointment dates. Ask healthcare administrative staff to manage these appointments or arrange for new dates and referral letters to be sent if the person's current hospital is out of the local area.\n\nNo: record no action needed.\n\nAlcohol and substance misuse\n\n. Does the person drink alcohol, and if so:\n\nhow much do they normally drink?\n\nhow much did they drink in the week before coming into custody?\n\nUrgently refer the person to the GP or an alternative suitable healthcare professional if:\n\nthey drink more than 15 units of alcohol daily or\n\nthey are showing signs of withdrawal or\n\nthey have been given medication for withdrawal in police or court cells.\n\nNo: record response.\n\n. Has the person used street drugs in the last month? If so, how frequently?\n\nWhen did they last use:\n\nheroin\n\nmethadone\n\nbenzodiazepines\n\namphetamine\n\ncocaine or crack\n\nnovel psychoactive substances\n\ncannabis\n\nanabolic steroids\n\nperformance and image enhancing drugs?\n\nYes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. Take into account whether:\n\nthey have taken drugs intravenously\n\nthey have a positive urine test for drugs\n\ntheir answers suggest that they use drugs more than once a week\n\nthey have been given medication for withdrawal in police or court cells.\n\nIf the person has used intravenous drugs, check them for injection sites. Refer them to substance misuse services if there are concerns about their immediate clinical management and they need immediate support.\n\nNo: record response.\n\nProblematic use of prescription medicines\n\n. Has the person used prescription or over-the-counter medicines in the past month:\n\nthat were not prescribed or recommended for them or\n\nfor purposes or at doses that were not prescribed?\n\nIf so, what was the medicine and how did they use it (frequency and dose)?\n\nYes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support.\n\nNo: record response.\n\nMental health\n\n. Has the person ever seen a healthcare professional or service about a mental health problem (including a psychiatrist, GP, psychologist, counsellor, community mental health services, alcohol or substance misuse services or learning disability services)?\n\nIf so, who did they see and what was the nature of the problem?\n\nYes: refer the person for a mental health assessment if they have previously seen a mental health professional in any service setting.\n\nNo: record response.\n\n. Has the person ever been admitted to a psychiatric hospital, and if so:\n\nwhen was their most recent discharge\n\nwhat is the name of the hospital\n\nwhat is the name of their consultant?\n\nYes: refer the person for a mental health assessment.\n\nNo: record response.\n\n. Has the person ever been prescribed medicine for any mental health problems? If so:\n\nwhat was the medicine\n\nwhen did they receive it\n\nwhen did they take the last dose\n\nwhat is the current dose (if they are still taking it)\n\nwhen did they stop taking it?\n\nYes: refer the person for a mental health assessment if they have taken medicine for mental health problems.\n\nNo: record response.\n\nSelf-harm and suicide risk\n\n. Is the person:\n\nfeeling hopeless or\n\ncurrently thinking about or planning to harm themselves or attempt suicide?\n\nYes: refer the person for an urgent mental health assessment. Open an Assessment, Care in Custody and Teamwork (ACCT) plan if:\n\nthere are serious concerns raised in response to questions about self-harm, including thoughts, intentions or plans, or observations (for example, the patient is very withdrawn or agitated) or\n\nthe person has a history of previous suicide attempts.\n\nBe aware and record details of the impact of the sentence on the person, changes in legal status and first imprisonment, and the nature of the offence (for example, murder, manslaughter, offence against the person and sexual offences).\n\nNo: record response.\n\n. Has the person ever tried to harm themselves, and if so:\n\ndo they have a history of suicide attempts\n\nwas this inside or outside prison\n\nwhen was the most recent incident\n\nwhat was the most serious incident?\n\nYes: refer the person for a mental health assessment if they have ever tried to harm themselves.\n\nNo: record response.\n\n## Identification and assessment throughout the care pathway (including second-stage health assessment in prisons)\n\nRecommendations 1.3.6 to 1.3.8 apply both throughout the care pathway and to the second-stage health assessment in prisons. In non-prison settings, all staff should think about using the Correctional Mental Health Screen tool (see recommendation 1.3.6).\n\nConsider using the Correctional Mental Health Screen for Men (CMHS-M) or Women (CMHS-W) to identify possible mental health problems if:\n\nthe person's history, presentation or behaviour suggest they may have a mental health problem\n\nthe person's responses to the first-stage health assessment suggest they may have a mental health problem\n\nthe person has a chronic physical health problem with associated functional impairment\n\nconcerns have been raised by other agencies about the person's abilities to participate in the criminal justice process.\n\nWhen using the CMHS‑M or CMHS‑W with a transgender person, use the measure that is in line with their preferred gender identity.\n\nIf a man scores 6 or more on the CMHS‑M, or a woman scores 4 or more on the CMHS‑W, or there is other evidence supporting the likelihood of mental health problems, practitioners should:\n\nconduct a further assessment if they are competent to perform assessments of mental health problems or\n\nrefer the person to an appropriately trained professional for further assessment if they are not competent to perform such assessments themselves.\n\n## Carrying out a mental health assessment\n\nService providers should ensure that competent practitioners who have experience of working with people in contact with the criminal justice system with mental health problems:\n\nperform the mental health assessment\n\ncoordinate the input of other professionals into the assessment when needed.\n\nIf there are concerns about a person's mental capacity, practitioners should:\n\nperform a mental capacity assessment if they are competent to do this (or refer the person to a practitioner who is)\n\nconsider involving an advocate to support the person.\n\nAll practitioners should discuss rights to confidentiality with people and explain:\n\nwhat the mental health assessment is for and how the outcome of the assessment may be used\n\nhow consent for sharing information with named family members, carers and other services should be sought\n\nthat the assessor may have a legal or ethical duty to disclose information relating to the safety of the person or others, or to the security of the institution.\n\nAll practitioners should ensure mental health assessment is a collaborative process that:\n\ninvolves negotiation with the person, as early as possible in the assessment process, about how information about them will be shared with others involved in their care\n\nmakes the most of the contribution of everyone involved, including the person, those providing care or legal advice and family members and carers\n\nengages the person in an informed discussion of treatment, support and care options\n\nallows for the discussion of the person's concerns about the assessment process.\n\nEnsure all practitioners carrying out mental health assessments are competent to assess problems that commonly present, with an understanding of the context and setting in which they are done. They should:\n\ntailor the content, structure and pace of an assessment to the person's needs and adjust the assessment as new information emerges\n\ntake into account the person's understanding of the problem\n\nhave knowledge and awareness of diagnostic classification systems and their limitations\n\nappraise the reliability and validity of all available health and criminal justice systems records\n\nidentify and take into account the reasons for any significant differences between the assessor's views and those of the person and other agencies involved in their care\n\nuse validated tools relevant to the disorders or problems being assessed\n\ntake into account the views of practitioners from other services involved in the person's care.\n\nAll practitioners carrying out mental health assessment should take into account the following when conducting an assessment of suspected mental health problems for people in contact with the criminal justice system:\n\nthe nature and severity of the presenting mental health problems (including cognitive functioning) and their development and history\n\ncoexisting mental health problems\n\ncoexisting substance misuse problems, including novel psychoactive substances\n\ncoexisting physical health problems\n\nsocial and personal circumstances, including personal experience of trauma\n\nsocial care, educational and occupational needs\n\npeople's strengths\n\navailable support networks, and the person's capacity to make use of them\n\nprevious care, support and treatment, including how the person responded to these\n\noffending history and how this may interact with mental health problems.\n\nWhen assessing people in contact with the criminal justice system all practitioners should:\n\nrecognise potential barriers to accessing and engaging in interventions and methods to overcome these at the individual and service level\n\ndiscuss mental health problems and treatment options in a way that gives rise to hope and optimism by explaining that change is possible and attainable\n\nbe aware that people may have negative expectations based on earlier experiences with mental health services, the criminal justice system, or other relevant services.\n\nAll practitioners should share the outcomes of a mental health assessment, in accordance with legislation and local policies, subject to permission from the person where necessary, with:\n\nthe person and, if possible, their family members or carers\n\nall staff and agencies (for example, probation service providers and secondary care mental health services) involved in the direct development and implementation of the plan\n\nother staff or agencies (as needed) not directly involved in the development and implementation of the plan who could support the effective implementation and delivery of the plan.\n\n## Reviewing the mental health assessment\n\nPractitioners should review and update mental health assessments:\n\nif new information is available about the person's mental health problem\n\nif there are significant differences between the views of the person and the views of the family, carers or staff that cannot be resolved through discussion\n\nwhen major legal or life events occur\n\nwhen the person is transferred between, or out of, criminal justice services\n\nif a person experiences a significant change in care or support, for example, stopping an Assessment, Care in Custody and Teamwork (ACCT) plan\n\nif a person disengages or does not stick to their treatment plan\n\nannually, or as required by local policy such as Care Programme Approach or Care Treatment Plan.\n\nWhen updating mental health assessments, practitioners should consider:\n\nreviewing and ensuring demographic information is accurate\n\nreviewing psychological, social, safety, personal historical and criminological factors\n\nassessing multiple areas of need, including social and personal circumstances, physical health, occupational rehabilitation, education and previous and current care and support\n\ndeveloping an increased understanding of the function of the offending behaviour and its relationship with mental health problems\n\ncovering any areas not fully explored by the initial assessment.\n\n# Risk assessment and management\n\nPerform a risk assessment for all people in contact with the criminal justice system when a mental health problem occurs or is suspected.\n\nAll practitioners should take into account the following issues in risk assessments for people in contact with the criminal justice system:\n\nrisk to self, including self-harm, suicide, self-neglect, risk to own health and degree of vulnerability to exploitation or victimisation\n\nrisk to others that is linked to mental health problems, including aggression, violence, exploitation and sexual offending\n\ncausal and maintaining factors\n\nthe likelihood, imminence and severity of the risk\n\nthe impact of their social and physical environment\n\nprotective factors that may reduce risk.\n\nDuring a risk assessment the practitioner doing the assessment should explain to the person that their behaviours may need to be monitored. This may include:\n\nexternal monitoring of behaviours that may indicate a risk to self or others\n\nself-monitoring of risk behaviours to help the person to identify, anticipate and prevent high-risk situations.\n\nIf indicated by their risk assessment, the practitioner doing the assessment should develop a risk management plan for a person. This should:\n\nintegrate with or be consistent with the mental health assessment and plan\n\ntake an individualised approach to each person and recognise that risk levels may change over time\n\nset out the interventions to reduce risk at the individual, service or environmental level\n\ntake into account any legal or statutory responsibilities which apply in the setting in which they are used\n\nbe shared with the person (and their family members or carers if appropriate) and relevant agencies and services subject to permission from the person where necessary\n\nbe reviewed regularly by those responsible for implementing the plan and adjusted if risk levels change.\n\nAll practitioners should ensure that any risk management plan is:\n\ninformed by the assessments and interventions in relevant NICE guidance for the relevant mental health disorders, including the NICE guidelines on self-harm in over 8s: short-term management and prevention of recurrence and self-harm in over 8s: long-term management\n\nimplemented in line with agreed protocols for safeguarding vulnerable people and the provision of appropriate adults\n\nimplemented in line with agreed protocols in police custody, prisoner escort services, prison, community settings and probation service providers.\n\nEnsure that the risk management plan is integrated with, and recorded in, the relevant information systems; for example, the ACCT procedure in prisons, the Offender Assessment System (OASys) and SystmOne and Multi-Agency Risk Assessment Conference (MARAC) and Multi-Agency Public Protection Arrangements (MAPPA).\n\n# Care planning\n\nDevelop a mental health care plan in collaboration with the person and, when possible, their family, carers and advocates. All practitioners developing the plan should ensure it is integrated with care plans from other services, and includes:\n\na profile of the person's needs (including physical health needs), identifying agreed goals and the means to progress towards them\n\nidentification of the roles and responsibilities of those practitioners involved in delivering the care plan\n\nthe implications of any mandated treatment programmes, post-release licences and transfer between institutions or agencies, in particular release from prison\n\na clear strategy to access all identified interventions and services\n\nagreed outcome measures and timescale to evaluate and review the plan\n\na risk management plan and a crisis plan if developed\n\nan agreed process for communicating the care plan (such as the Care Programme Approach or Care Treatment Plan) to all relevant agencies, the person, and their families and carers, subject to permission from the person where necessary.\n\nWhen developing or implementing a mental health care plan all practitioners should take into account:\n\nthe ability of the person to take in and remember information\n\nthe need to provide extra information and support to help with the understanding and implementation of the care plan\n\nthe need for any adjustment to the social or physical environment\n\nthe need to adjust the structure, content, duration or frequency of any intervention\n\nthe need for any prompts or cognitive aids to help with delivery of the intervention.\n\n# Psychological interventions\n\n## Delivering psychological interventions for mental health problems\n\nRefer to relevant NICE guidance for the psychological treatment of mental health problems for adults in contact with the criminal justice system, taking into account the need:\n\nto modify the delivery of psychological interventions in the criminal justice system\n\nto ensure continuity of the psychological intervention (for example, transfer between prison settings or on release from prison)\n\nfor staff to be trained and competent in the interventions they are delivering\n\nfor supervision\n\nfor audit using routinely available outcome measures.\n\nBe aware that many people in contact with the criminal justice system (including people with a diagnosis of personality disorder) may have difficulties with:\n\naccurately interpreting and controlling emotions\n\nimpulse control (for example, difficulty planning, seeking high levels of stimulation, ambivalent about consequences of their negative actions)\n\nexperiencing themselves as having a lack of autonomy (for example, seeing their actions as pointless, having difficulties in setting and achieving goals)\n\nhaving an unstable sense of self that varies depending on context or is influenced by the people they interact with\n\nsocial functioning (for example, relating to, cooperating with and forming relationships with others, difficulties understanding their own and others' needs)\n\noccupational functioning.\n\n## Personality disorder\n\nProviders of services should ensure staff are able to identify common features and behaviours associated with personality disorders and use these to inform the development of programmes of care.\n\nPractitioners should ensure interventions for people with a diagnosis of personality disorder or associated problems are supportive, facilitate learning and develop new behaviours and coping strategies in the following areas:\n\nproblem solving\n\nemotion regulation and impulse control\n\nmanaging interpersonal relationships\n\nself-harm\n\nuse of medicine (including reducing polypharmacy).\n\nPractitioners should be aware when delivering interventions for people with mental health problems that having a personality disorder or an associated problem may reduce the effectiveness of interventions. Think about:\n\nproviding additional support\n\nadjusting the duration and intensity of psychological interventions if standard protocols have not worked\n\ndelivering complex interventions in a multidisciplinary context.\n\nPractitioners should not exclude people with personality disorders from any health or social care service, or intervention for comorbid disorders, as a direct result of their diagnosis.\n\n## Specific psychological interventions\n\nPractitioners should consider using contingency management to reduce drug misuse and promote engagement with services for people with substance misuse problems.\n\nPractitioners delivering contingency management programmes should:\n\nagree with the person the behaviour that is the target of change\n\nprovide incentives in a timely and consistent manner\n\nconfirm the person understands the relationship between the treatment goal and the incentive schedule\n\nmake incentives reinforcing and supportive of a healthy and drug-free lifestyle.\n\nPractitioners should consider referral to a therapeutic community specifically for substance misuse for people in prison with a minimum 18-month sentence who have an established pattern of drug misuse.\n\nWhen setting up therapeutic community programmes in prison settings in a separate wing of a prison for people with substance misuse problems, aim to:\n\ninclude up to 50\xa0prisoners in the programme\n\nprovide treatment for between 12 and 18\xa0months, made up of:\n\n\n\ntwice-weekly group therapy sessions (mean group size of 8)\n\ndaily (5\xa0days only) community meeting for all wing residents\n\ndaily (5\xa0days only) social activity groups for all wing residents\n\na once-weekly individual review meeting (20\xa0minutes).\n\n\n\nConsider psychological interventions for paraphilias only when delivered as part of a research programme.\n\n# Pharmacological interventions\n\nRefer to relevant NICE guidance for pharmacological interventions for mental health problems in adults in contact with the criminal justice system. Take into account:\n\nrisks associated with in-possession medicines\n\nadministration times for medication\n\navailability of medicines in the first 48\xa0hours of transfer to prison\n\navailability of medicines after release from prison.\n\nRefer to NICE's guidance on attention deficit hyperactivity disorder (ADHD) when prescribing pharmacological interventions for this condition.\n\nReview all medicines prescribed for sleep problems and the management of chronic pain to:\n\nestablish the best course of treatment (seek specialist advice if needed)\n\nassess the risk of diversion or misuse of medicines.\n\n# Organisation of services\n\n## Service structures and delivery\n\nCommissioners and providers of criminal justice services and healthcare services should support the development of liaison and diversion functions for police custody and the courts that provide prompt access to the following:\n\nthe effective identification and recognition of mental health problems\n\na comprehensive mental health assessment\n\nadvice on immediate care and management\n\nappropriate treatment and care (including medication).\n\nProviders of criminal justice services and healthcare services should consider diverting people from standard courts to dedicated drug courts if the offence is linked to substance misuse and was non-violent.\n\nCommissioners and providers of criminal justice services and healthcare services should consider establishing joint working arrangements between healthcare, social care and police services for managing urgent and emergency mental health presentations in the community (for example, street triage). Include:\n\njoint training for police, healthcare and social care staff\n\nagreed protocols for joint working developed and reviewed by a multi-agency group\n\nagreed protocols for effective communication within and between agencies\n\nagreed referral pathways for urgent and emergency care and routine care.\n\nCommissioners and providers of criminal justice services and healthcare services should ensure effective identification, assessment, coordination and delivery of care for all people with a mental health problem in contact with the criminal justice system. This should include people who are transferring from young offender services and those on probation. In particular, ensure that:\n\nall people with a severe or complex mental health problem have a designated care coordinator\n\nduring transitions between services care plans are shared and agreed between all services\n\neffective protocols are in place to support routine data sharing and, when necessary, joint plans of care between health services (including primary and secondary care services) and criminal justice agencies to reduce unnecessary assessments and promote effective interventions.\n\n# Staff training\n\nCommissioners and providers of criminal justice services and healthcare services should ensure that all staff working in the criminal justice system, who provide direct care or supervision, have a comprehensive induction, covering:\n\nthe purpose of the service in which they work, and the role and availability of other related local services, including pathways for referral\n\nthe roles, responsibilities and processes of criminal justice, health and social care staff\n\nlegislation and local policies relevant to their role, for sharing information with others involved in the person's care\n\nprotocols for dealing with mental health problems in the criminal justice system (for example, in-possession medicines, side effects, withdrawal)\n\nthe importance of clear communication, including avoiding acronyms and using consistent terminology.\n\nCommissioners and providers of criminal justice services and healthcare services should educate all staff about:\n\nthe stigma and discrimination associated with mental health problems and associated behaviours, such as self-harm\n\nthe need to avoid judgemental attitudes\n\nthe need to avoid using inappropriate terminology.\n\nProvide multidisciplinary and multi‑agency training (as part of both induction training and continuing professional development) to increase consistency, understanding of ways of working, and promotion of positive working relationships for all staff who work in the criminal justice system on:\n\nthe prevalence of mental health problems in the criminal justice system, and why such problems may bring people into contact with the criminal justice system\n\nthe main features of commonly occurring mental health problems seen in the criminal justice system, and the impact these may have on behaviour and compliance with rules and statutory requirements\n\nrecognising and responding to mental health problems and communication problems that arise from, or are related to, physical health problems.\n\nGive all staff involved in direct care, training (as part of induction training and continuing professional development) and supervision to support them in:\n\ndealing with critical incidents, including emergency life support\n\nmanaging stress associated with working in the criminal justice system and how this may affect their interactions with people and their own mental health and wellbeing\n\nthe recognition, assessment, treatment and management of self-harm and suicide\n\nde-escalation methods to minimise the use of restrictive interventions\n\nrecognition of changes in behaviour, taking into account that these may indicate the onset of, or changes to, mental health problems\n\nknowledge of effective interventions for mental health problems\n\ndeveloping and maintaining safe boundaries and constructive relationships\n\ndelivering interventions within the constraints of the criminal justice system (for example, jail craft training, formulation skills).\n\n# Terms used in this guideline\n\n## Assessment, Care in Custody and Teamwork (ACCT)\n\nACCT is a prisoner-centred, flexible care-planning system which, when used effectively, can reduce risk, primarily of self-harm. The ACCT process is necessarily prescriptive and it is vital that all stages are followed in the timescales prescribed.\n\n## Acquired cognitive impairment\n\nAny cognitive impairment that develops after birth, including traumatic brain injury, stroke, and neurodegenerative disorders such as dementia.\n\n## Appropriate adult\n\nA person who is responsible for protecting (or 'safeguarding') the rights and welfare of a child or 'mentally vulnerable' adult who is either detained by police or is interviewed under caution voluntarily. The role was created alongside the Police and Criminal Evidence Act (PACE) 1984.\n\n## Carer\n\nA person who provides unpaid support to someone who is ill, having trouble coping or who has disabilities.\n\n## Contingency management\n\nA set of techniques that focus on the use of reinforcement to change certain specified behaviours. These may include promoting abstinence from drugs (for example, cocaine), reducing drug misuse (for example, illicit drug use by people receiving methadone maintenance treatment), and improving adherence to interventions that can improve physical health outcomes.\n\n## Correctional Mental Health Screen for men (CMHS‑M) or women (CMHS‑W)\n\nThis is a screening tool that measures acute mental health issues present in people in prison. Questions are answered in a yes–no format, and then rated on a Likert-scale from 1 (low risk or need) to 5 (high risk or need), depending on severity.\n\n## In-possession medicine\n\nMedicine is said to be held in-possession if a person (usually in a prison or other secure setting) is responsible for holding and taking it themselves.\n\n## Jail craft\n\nLearned, knowledgeable work depending on experience and fine judgements in a prison setting – often learned by new staff working in prisons through shadowing and being mentored by experienced staff.\n\n## Liaison and diversion service\n\nThis is a service that aims to identify people who have mental health problems who come into contact with the criminal justice system before they enter prison. They may be able to liaise and refer people they identify with mental health problems to local services or divert someone out of the criminal justice system, for example by arranging a Mental Health Act assessment. A liaison and diversion service may be in the form of a street triage service (see below) or they can be based in police custody suites or the court cells.\n\n## Mental health in-reach team\n\nA secondary mental health team based in prisons to support adults in prison. The team will be part of the NHS trust for the area the prison is located. This team may consist of the same types of staff who work in community mental health teams, including community psychiatric nurses, social workers, psychologists, occupational therapists and psychiatrists.\n\n## Multi-Agency Public Protection Arrangements (MAPPA)\n\nThese arrangements are designed to protect the public, including previous victims of crime, from serious harm by sexual and violent offenders. They require the local criminal justice agencies and other bodies dealing with offenders to work together in partnership in dealing with these offenders.\n\n## Multi-Agency Risk Assessment Conference (MARAC)\n\nThis is a monthly meeting where professionals across criminal justice agencies and other bodies dealing with offenders share information on high risk cases of domestic violence and abuse and put in place a risk management plan.\n\n## Multidisciplinary\n\nA multidisciplinary team Is a group of experts from different disciplines who each provide specific support to a person, working as a team.\n\n## Offender Assessment System (OASys)\n\nThis is a risk and needs assessment tool. It identifies and classifies offending related needs, such as a lack of accommodation, poor educational and employment skills, substance misuse, relationship problems, and problems with thinking and attitudes and the risk of harm offenders pose to themselves and others.\n\n## Programme of care\n\nThis is developed from a comprehensive assessment of a person's needs and sets out how those needs might be met, who is responsible for meeting those needs, and how the programme of care will be evaluated and reviewed.\n\n## Street triage\n\nSchemes involving mental health professionals providing on-the-spot support to police officers who are dealing with people with possible mental health problems.\n\n## SystmOne\n\nA clinical computer system used widely by healthcare professionals in the UK to manage electronic patient records. SystmOne is the standard system currently used in prisons in England and Wales.\n\n This guideline covers the full range of mental health problems including common mental disorders, substance misuse disorders, neurodevelopmental disorders and personality disorders.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "Mental health problems are very common among people in contact with the criminal justice system, with the amount of people affected ranging from 39% in police custody up to 90% in prison. There is also evidence that certain mental disorders, like personality disorders and psychotic disorders, are more prevalent in the prison population than the general population. It has also been reported that certain groups like females, black and minority ethnic groups, people older than 50 years and people with comorbid disorders are over-represented in prisoners with mental health disorders.\n\nThe underlying mechanisms between crime and mental illness are still not yet well understood. There are some suggestions that pre-existing social factors, for example homelessness, may be associated with increased offending. In other areas, such as substance misuse, the urge to use illicit drugs may drive people to commit crimes such as theft. In some cases, the links may relate to either poor adaptive functioning or the consequence of offending and contact with the criminal justice system upon mental health.\n\nCurrently, NHS England is responsible for commissioning healthcare provision including mental healthcare for people in contact with the criminal justice system, with the exceptions of police and court custody. There is also a joint care pilot scheme between the criminal justice system and NHS funded by the Department of Health, with initiatives such as 'street triage' schemes. However, identifying mental health problems in police custody is complicated by the lack of training, education and a standard assessment. There is also a lack of clarity on appropriate signposting and prompt access to a mental healthcare.\n\nThis guideline covers recognition, assessment, treatment and prevention of mental health problems in adults who are in contact with the criminal justice system (police and court custody, prison custody, street triage and liaison and diversion services, as well as probation service providers). Mental health problems include common mental health problems, severe mental illness, paraphilias, neurodevelopmental disorders and acquired cognitive impairment. There are recommendations on care planning and pathways, and organisation and structure of services, as well as training for health, social care and criminal justice professionals and practitioners. Although the focus of this guideline is on healthcare, the Care Act 2014 has relevance to people in the criminal justice system, in the community and in prisons. This may be of particular relevance for people with neurodevelopmental disorders, including learning disability and autistic spectrum disorders.\n\nYou can also see this guideline in the NICE pathway on health of people in the criminal justice system.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on prisons and other secure settings and mental health and behavioural conditions.\n\nSee also the guideline committee's discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Psychological and pharmacological interventions for people with paraphilic disorders\n\nWhat is the clinical effectiveness, cost effectiveness and safety of specific psychological and pharmacological interventions both in and out of prison among people with paraphilic disorders?\n\n## Why this is important\n\nThe limited evidence for pharmacological interventions (for example, medroxyprogesterone acetate) provides no clear evidence of benefit in people with paraphilias. A randomised trial with an adequate sample size is needed to examine the effectiveness of medroxyprogesterone acetate in these populations.\n\nThere is also insufficient evidence on the effectiveness of psychological interventions for people with paraphilias in the criminal justice system. An individual patient data analysis of existing large scale data sets of paedophiles who have been treated in the criminal justice system should be conducted to inform the choice of treatment and the design of any future research. Psychological interventions for paraphilias (such as sex offender treatment programme) should be tested in large randomised controlled trials in criminal justice populations. This research could have a significant impact upon updates of this guideline.\n\nImportant outcomes could include:\n\noffending and re-offending rates\n\nmental health problems\n\ncost-effectiveness\n\nservice utilisation.\n\nWhen designing the trials, consideration should be given to the timing, intensity and duration of interventions in the context of the criminal justice system.\n\n# Structured clinical management interventions in probation service providers\n\nWhat is the effectiveness of structured clinical (case) management in improving mental health outcomes using interventions within probation service providers?\n\n## Why this is important\n\nMany people in contact with the community-based criminal justice services have significant mental health problems, in particular, personality problems and interpersonal difficulties. Evidence from studies of people with such problems in general mental health services suggests that structured organisation and delivery of mental health interventions (structured clinical management) may be of benefit in improving mental health outcomes. A programme of research is needed which would first refine and develop structured clinical management for use in the community rehabilitation companies (CRCs) and the National Probation Service (NPS) and then test this in large scale randomised control trials in both CRCs and the NPS. The comparison should be against standard CRC and NPS care. The trial should consider both clinical outcomes and cost-effectiveness.\n\nImportant outcomes could include:\n\nmental health outcomes\n\noffending and re-offending rates\n\nservice utilisation\n\ncost-effectiveness\n\nbroader measures of social functioning.\n\n# Interventions for coordination and delivery of care to improve access and uptake\n\nWhat models for the coordination and delivery of care for people in contact with the criminal justice system provide for the most effective and efficient coordination of care and improve access and uptake of services?\n\n## Why this is important\n\nThere is low quality evidence for a range of systems for the delivery and coordination of care in the criminal justice system (for example, drug or mental health courts, and case management). However, there is clear evidence of poor engagement, uptake and retention in treatment for people with mental health problems in contact with the criminal justice system. A number of models (for example, case management and collaborative care) have shown benefit for people with common and severe mental health problems in routine healthcare settings. A programme of research and development is needed, which will first develop and test different models of care coordination for the delivery of care in small feasibility studies, and then test models that have shown promise in the feasibility studies in large scale randomised clinical trials in the criminal justice system.\n\nImportant outcomes could include:\n\nimproved mental health outcomes\n\nimproved access and uptake of services\n\nreductions in offending and re-offending\n\ncost effectiveness.\n\n# Tools for case identification for cognitive impairment in criminal justice system populations\n\nWhat are the reliable and valid tools to identify cognitive impairment among people in contact with the criminal justice system (including people who have experienced physical trauma, neurodevelopmental disorders or other acquired cognitive impairment)?\n\n## Why this is important\n\nAcquired cognitive impairment is common in criminal justice system populations and may be associated with poor social, occupational an interpersonal functioning. Also, people with acquired cognitive impairment have high risk of self-harm which is particularly prevalent in the prison population. Acquired cognitive impairment may arise as a result of, for example, traumatic brain injury, a stroke or other neurological conditions. Experts in this area have suggested that early identification of deficits, and implementation of effective management strategies, could be important in limiting the long-term impact of acquired cognitive impairment. However, there is a lack of evidence on reliable and valid case identification tools and methods. It is important that research is developed to assist staff in the criminal justice pathway to help identify people with acquired cognitive impairment and support better understanding and management of acquired cognitive impairment.\n\n# Prevalence of mental health problems\n\nWhat is the prevalence of mental health problems and associated social problems for those in contact with the criminal justice system?\n\n## Why this is important\n\nIt is widely recognised that the people in contact with the criminal justice system have a high prevalence of a whole range of mental health problems and associated problems including unstable housing, long-standing unemployment, a lack of supportive social networks and debt. What is not clear, however, is how the mental and social functioning of this group of people has changed since the last major epidemiological study in the late 1990s. In order to plan for the effective mental health care of people in the criminal justice system, it is important to have a greater understanding of the prevalence of mental health problems and social functioning of this group of people. There are a number of factors which have changed since the last epidemiological study; these include a larger prison population, changing patterns of substance misuse, an aging prison population, changes in probation practice and sentencing policy as well as broader changes in society such as changes in mental health care and social care practice. A series of epidemiological studies of representative criminal justice system populations should be undertaken to address the above problems.\n\n# Identification of factors associated with suicide\n\nWhat factors are associated with suicide attempts and completed suicides?\n\n## Why this is important\n\nThere is high prevalence of suicide attempts among people in contact with the criminal justice system. When developing interventions to prevent self-harm among these populations, it is important to identify and understand the factors related to successful suicide. A retrospective analysis of observational studies of suicidal attempts and completed suicides using suicide as a definitive and measurable outcome should be performed to identify the prognostic factors for successful prevention.\n\nISBN: 978-1-4731-2381-6"}	https://www.nice.org.uk/guidance/ng66	This guideline covers assessing, diagnosing and managing mental health problems in adults (aged 18 and over) who are in contact with the criminal justice system. It aims to improve mental health and wellbeing in this population by establishing principles for assessment and management, and promoting more coordinated care planning and service organisation across the criminal justice system.
28a3bc99543437b63e75b4897599880016488750	nice	Ustekinumab for the treatment of adults with moderate to severe psoriasis	Ustekinumab for the treatment of adults with moderate to severe psoriasis Evidence-based recommendations on ustekinumab (Stelara) for treating psoriasis in adults. # Guidance Ustekinumab is recommended as a treatment option for adults with plaque psoriasis when the following criteria are met. The disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) score of 10 or more and a Dermatology Life Quality Index (DLQI) score of more than 10. The psoriasis has not responded to standard systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or the person is intolerant of or has a contraindication to these treatments. Ustekinumab treatment should be stopped in people whose psoriasis has not responded adequately by 16 weeks after starting treatment. An adequate response is defined as either: a 75% reduction in the PASI score (PASI 75) from when treatment started or a 50% reduction in the PASI score (PASI 50) and a 5-point reduction in the DLQI score from when treatment started. When using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.# The technology Ustekinumab (Stelara, Janssen-Cilag) is a fully human monoclonal antibody that targets interleukin-12 (IL-12) and IL-23. It binds to the p40 subunit, common to both IL-12 and IL-23, which prevents these cytokines from binding to the cell surface of T cells, thereby disrupting the inflammatory cascade implicated in psoriasis. Ustekinumab has a UK marketing authorisation for 'the treatment of moderate to severe plaque psoriasis in adults who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA'. The recommended dose of ustekinumab is 45 mg for people who weigh 100 kg or less, and 90 mg for people who weigh over 100 kg. An initial dose of ustekinumab is administered subcutaneously at week 0, followed by another dose at week 4, and then a further dose every 12 weeks. The summary of product characteristics (SPC) states that ustekinumab is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis. Common adverse events associated with ustekinumab, as reported in the SPC, include upper respiratory tract infection, nasopharyngitis, depression, headache, dizziness, diarrhoea, pruritus, back pain, fatigue and injection site erythema. Contraindications listed in the SPC include clinically important active infection and hypersensitivity to the active substance or to any of the excipients. For full details of side effects and contraindications, see the SPC. Ustekinumab is available in vials containing 45 mg. The cost per vial is £2147 (Monthly Index of Medical Specialities , April 2009). Ustekinumab is not listed in the current version of the 'British national formulary' (BNF; edition 57). The cost of ustekinumab for the two loading doses (at 0 and 4 weeks) is £4294. The cost in the first year is £10,735, with an annual cost thereafter of £9335 (the annual cost assumes an average of 4.3 injections per year). Costs may vary in different settings because of negotiated procurement discounts. The SPC recommends that people whose body weight exceeds 100 kg should receive a dose of 90 mg of ustekinumab. This would be double the cost of the 45 mg dose indicated for the treatment of a person who weighs 100 kg or less. However, the manufacturer has proposed a patient access scheme to the Department of Health. Under the scheme, for people who weigh more than 100 kg and who are prescribed the 90 mg dose (two 45 mg vials), the manufacturer will provide both vials at a total cost of £2147 (the cost of a single vial). The manufacturer has proposed that this patient access scheme will be available to the NHS at least until either a review of the guidance by NICE or the introduction of any new formulations that would render the scheme obsolete. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ustekinumab and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem in the manufacturer's submission compared ustekinumab with adalimumab, efalizumab, etanercept, infliximab and supportive care. Three doses of etanercept were considered: 25 mg twice weekly given intermittently as recommended in NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis, 25 mg twice weekly given continuously, and 50 mg twice weekly given for the first 12 weeks followed by a reduction in dose to 25 mg twice weekly. Clinical outcomes in the manufacturer's submission included improvements in PASI and DLQI scores. PASI is a measure of disease severity based on body surface area affected and the extent, scaliness, thickness and redness of plaques, with scores ranging from 0 to 72. The DLQI is a disease-specific quality-of-life measure with scores ranging from 0 to 30. Moderate to severe psoriasis was defined as a PASI score of 10 or more and a DLQI score of more than 10. The manufacturer's submission included evidence from three randomised controlled trials (RCTs): PHOENIX-1 (n = 766, 5 years' duration), a phase III, multicentre, parallel, randomised, double-blind, placebo-controlled trial based in the USA, Canada and Belgium. PHOENIX-2 (n = 1230, 5 years' duration), a phase III, multicentre, parallel, randomised, double-blind, placebo-controlled trial based in Europe and North America. ACCEPT trial (n = 903, 64 weeks' duration), a phase III, multicentre, parallel RCT based in Europe and North America, which compared ustekinumab with etanercept (50 mg twice weekly for the first 12 weeks). In each of the RCTs, two doses (45 mg and 90 mg) of ustekinumab were investigated and patients were randomised to groups regardless of their body weight. To reflect the licensed dosing of ustekinumab, the manufacturer presented two analyses in their submission. The first analysis used data from all the patients enrolled in the clinical trials and included dosing outside the marketing authorisation (that is, patients weighing 100 kg or less who received ustekinumab 90 mg and patients weighing over 100 kg who received ustekinumab 45 mg). The second was a subgroup analysis that included data only for patients who received ustekinumab according to the marketing authorisation (weight-based dosing; that is, 45 mg for people weighing 100 kg or less and 90 mg for people weighing over 100 kg). The results of the three RCTs using data for all patients demonstrated statistically significant differences in the percentage of patients treated with ustekinumab who achieved a 75% or greater reduction in PASI score (PASI 75; the primary endpoint in the trials) compared with those who received placebo. The percentages of patients with at least a PASI 75 response at week 12 in the ustekinumab 45 mg, ustekinumab 90 mg and placebo groups were 67%, 66% and 3% respectively in the PHOENIX-1 trial (p < 0.001 for both ustekinumab doses compared with placebo) and 67%, 76% and 4% respectively in the PHOENIX-2 trial (p < 0.001). In the ACCEPT trial, the percentages of patients with at least a PASI 75 response at week 12 in the ustekinumab 45 mg, ustekinumab 90 mg and etanercept groups were 68%, 74% and 57% respectively (p = 0.012 for ustekinumab 45 mg and p < 0.001 for ustekinumab 90 mg compared with etanercept). For secondary outcomes recorded in the RCTs, such as the physician's global assessment (PGA) score, the DLQI score and other health-related quality-of-life scores, the ustekinumab groups showed statistically significant improvements compared with the placebo groups. In the PHOENIX-1 trial, the mean change in DLQI score at week 12 was −8.0 for ustekinumab 45 mg, −8.7 for ustekinumab 90 mg and −0.6 for placebo (p < 0.001 versus placebo for both ustekinumab doses). In the PHOENIX-2 trial, the values were −9.3, −10.0 and −0.5 respectively (p < 0.001 versus placebo for both ustekinumab doses). DLQI data were not collected in the ACCEPT trial. Data from the clinical trials suggested that 90 mg is a more effective dose of ustekinumab than 45 mg for patients who weigh more than 100 kg. For example, in the PHOENIX-1 trial, 69% of patients weighing more than 100 kg who received ustekinumab 90 mg achieved a PASI 75 response at 12 weeks, compared with 54% of those who received ustekinumab 45 mg. In the PHOENIX-2 trial, the values were 71% and 49% respectively. The manufacturer included longer-term data from the PHOENIX trials for the weight-based dosing subgroup analysis. These data suggested that the PASI response rates observed during the double-blind, randomised phases of the studies were maintained in the longer term. In the PHOENIX-1 trial, the percentages of patients achieving a PASI 75 response at week 24 were 83% and 80% for ustekinumab 45 mg and 90 mg respectively. In the PHOENIX-2 trial, the respective percentages were each 80%. In the PHOENIX-1 trial, the percentages of patients having one or more adverse events were 57.3%, 51.4% and 47.8% in the ustekinumab 45 mg, ustekinumab 90 mg and placebo groups respectively. The percentages of patients having a serious adverse event were 0.8%, 1.6% and 0.8% respectively. Similar rates of adverse events were reported in the PHOENIX-2 trial. In the ACCEPT trial, the percentages of patients having one or more adverse events were 66.0%, 68.3% and 69.5% in the ustekinumab 45 mg, ustekinumab 90 mg and etanercept groups respectively. The percentages of patients having a serious adverse event were 1.9%, 1.2% and 1.2% respectively. The manufacturer compared ustekinumab with other biological therapies (that is, adalimumab, efalizumab, infliximab and etanercept) using a mixed treatment comparison. This included data from studies that compared different biological therapies directly, as well as indirect comparisons using data from studies that compared biological therapies with placebo using the placebo group as the common factor. The manufacturer included data from the three ustekinumab RCTs, as well as from three RCTs comparing adalimumab with placebo, five comparing efalizumab with placebo, five comparing etanercept with placebo and four comparing infliximab with placebo. The results from the mixed treatment comparison using the ustekinumab data for all patients suggested that the mean probabilities of achieving a PASI 75 response were 69% for ustekinumab 45 mg (95% confidence interval 62% to 75%), 74% for ustekinumab 90 mg (95% CI 68% to 80%), 58% for adalimumab (95% CI 49% to 68%), 80% for infliximab (95% CI 70% to 87%), 39% for etanercept 25 mg (95% CI 30% to 48%), 52% for etanercept 50 mg (95% CI 45% to 59%), 26% for efalizumab (95% CI 21% to 32%) and 4% for supportive care (95% CI 3% to 4%). The manufacturer also included a mixed treatment comparison for the weight-based dosing subgroup analysis. However, the ustekinumab data from this comparison were provided as academic in confidence. The manufacturer based its cost-effectiveness analysis on the economic model used in TA103 and subsequently in NICE's guidance on infliximab for the treatment of adults with psoriasis and adalimumab for the treatment of adults with psoriasis. The model was adapted by the manufacturer of ustekinumab to incorporate additional evidence, including the results of the mixed treatment comparison described in section 3.9. In the model, each person had an initial period of treatment after which response was assessed (this was referred to as the trial period). Continuation of treatment into the next phase (referred to as the treatment period) occurred only if a PASI 75 response was achieved in the trial period. The time at which the response was assessed varied for the different drugs, depending on their dosing regimen. The assessment points were at 12 weeks (etanercept), 10 weeks (infliximab) and 16 weeks (adalimumab and ustekinumab). It was assumed that for people whose psoriasis responded to treatment, 20% stopped treatment each subsequent year. The mean time on treatment using this assumption was calculated to be 3.65 years. The same assumption was used for all biological therapies. The utility data used in the model were based on an estimate of the relationship between PASI response rates and changes in DLQI score from the PHOENIX-1 and PHOENIX-2 trials mapped to EQ-5D scores. First, the mean change in the DLQI score between baseline and week 12 was estimated for groups of patients with different levels of PASI response. Secondly, the manufacturer estimated an algorithm to map DLQI scores to EQ-5D scores from a scatter plot published in the assessment report of TA103. The changes in mean EQ-5D score for PASI responses of less than 50%, between 50% and 74%, between 75% and 89%, and 90% or more were estimated to be 0.04, 0.17, 0.22 and 0.25 respectively. The costs in the economic model included drug costs, administration costs and monitoring costs, and were taken from the model in TA103, NHS Reference Costs and the BNF (edition 56). The Personal Social Services Research Unit (PSSRU) inflation index was used to update costs from 2006 values if current costs were not available. The model assumed that people whose psoriasis had not responded adequately to treatment would have an inpatient admission of 21 days' duration once a year. The manufacturer's base-case analysis assumed a weighted average of weight-based dosing whereby 80% of people received ustekinumab 45 mg and 20% of people received ustekinumab 90 mg. The manufacturer also provided analyses using the data from all patients in the clinical trials and the data from the weight-based dosing approach with separate estimates for ustekinumab 45 mg and 90 mg. All the analyses in the submission assumed that the patient access scheme (see section 2.4) was in place. Under the original patient access scheme the company provided 2x45 mg pre-filled syringes, for patients who needed the higher dose of 90 mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial. The base-case analysis showed that when ustekinumab was compared with supportive care, the QALY gain was 0.156 at an incremental cost of £4615, giving an incremental cost-effectiveness ratio (ICER) of £29,587 per QALY gained. The ICER for ustekinumab compared with etanercept 25 mg given intermittently (assuming 88% of the cost of continuous etanercept) was £27,105 per QALY gained. The ICER for infliximab compared with ustekinumab was £304,566 per QALY gained. Adalimumab and etanercept given continuously rather than intermittently were dominated by ustekinumab (that is, ustekinumab had both greater effectiveness and lower costs). Probabilistic sensitivity analyses suggested that the probabilities of ustekinumab being cost effective at £20,000 and £30,000 per QALY gained were 7.4% and 48.5% respectively. The manufacturer's analyses suggested that ustekinumab was the only biological therapy that was likely to be cost effective at £20,000 and £30,000 per QALY gained. The analyses using data for all patients (that is, no weight-based dosing) presented separate ICERs for ustekinumab 45 mg and 90 mg. These analyses suggested that when ustekinumab 45 mg was compared with supportive care, the QALY gain was 0.1544 at an incremental cost of £4735, giving an ICER of £30,664 per QALY gained. The estimates for ustekinumab 90 mg suggested a QALY gain of 0.1563 and incremental costs of £4613, giving an ICER of £29,520 per QALY gained. The ICERs for ustekinumab in comparison with intermittent etanercept 25 mg were £36,938 per QALY gained for ustekinumab 45 mg and £28,633 per QALY gained for ustekinumab 90 mg. Etanercept 25 mg given continuously was dominated by ustekinumab. Adalimumab was dominated by ustekinumab 90 mg, but for ustekinumab 45 mg the ICER was £16,400 per QALY gained. Sensitivity analyses were carried out to test assumptions in the economic model. When the manufacturer reduced the length of an inpatient stay for people whose psoriasis did not respond adequately to treatment from the base-case estimate of 21 days to 17.5 days, the ICER for ustekinumab in comparison with supportive care increased from £29,587 to £34,387 per QALY gained. When the length of stay was increased to 27.5 days, the ICER decreased to £20,672 per QALY gained. The manufacturer also changed the way in which estimates of utility were obtained: from EQ-5D data mapped from DLQI scores, to SF-6D data transformed from SF-36 values collected in the PHOENIX-1 trial. When SF-6D data were used to estimate utilities, the ICER for ustekinumab compared with supportive care increased from £29,302 to £49,371 per QALY gained. The manufacturer also varied the assumptions about the cost and efficacy of intermittent etanercept. The cost of intermittent compared with continuous etanercept was changed from the base-case estimate of 88% to 74% (the figure used in TA103) and to 98%. Using an estimate of 74%, the ICER for ustekinumab compared with intermittent etanercept 25 mg increased from £27,105 to £68,339 per QALY gained. When an estimate of 98% was used, ustekinumab dominated intermittent etanercept. The relative efficacy of intermittent compared with continuous etanercept was assumed to be 81% in the base case. When this estimate was changed to 71%, the ICER for ustekinumab compared with intermittent etanercept decreased to £22,634 per QALY gained. When the estimate was changed to 91%, the ICER was £32,949 per QALY gained. The ERG concluded that the manufacturer's submission provided an unbiased estimate of the clinical effectiveness of ustekinumab at 12 weeks based on the results of the three randomised comparisons. However, it noted that there was a lack of information about the methodology used for the weight-based dosing subgroup analysis. In addition, it could not determine whether the methods used were appropriate and whether the subgroup analysis supported the weight-based categorisation presented. The ERG commented that there appeared to be differences between the mixed treatment comparison that had been used in the appraisal of etanercept and efalizumab (TA103) and that used in the current appraisal. The ERG also noted that the manufacturer's submission included only minimal discussion of any possible clinical heterogeneity between the trials included in the mixed treatment comparison. It further noted that in the mixed treatment comparison, data from the weight-based dosing analysis of ustekinumab were taken from a subgroup of the trial data, whereas data for all patients were used for the comparator trials. The ERG was concerned that this had affected randomisation. The ERG concluded that the clinical effectiveness of ustekinumab in comparison with the other biological therapies was uncertain. The ERG also noted that the probabilistic sensitivity analysis in the manufacturer's submission appeared to include only variables for utilities, treatment response and the proportion of people weighing more than 100 kg. It did not include other variables to which the ICERs were sensitive, such as the number of hospital days, the effects of different inpatient costs and the relative efficacy of intermittent etanercept. The ERG completed an exploratory analysis that amended the base-case analysis to include the price for ustekinumab 90 mg as double the list price of ustekinumab 45 mg (that is, assuming that there would be no patient access scheme in place). The results showed that the ICER for ustekinumab compared with supportive care increased from £29,587 to £40,952 per QALY gained. A further exploratory analysis assumed that the efficacy of intermittent etanercept 25 mg was the same as that of continuous etanercept 25 mg (as was assumed in the economic model for TA103). Using this assumption, the ICER for ustekinumab compared with intermittent etanercept 25 mg in the base-case analysis increased from £27,105 to £41,449 per QALY gained. The ERG conducted an exploratory probabilistic sensitivity analysis that included a larger number of variables than were included by the manufacturer. The results of the ERG's analysis suggested greater uncertainty around the estimates of cost effectiveness, but the cost-effectiveness acceptability curves did not differ significantly from those of the manufacturer. When the ERG repeated the analysis assuming that the cost of ustekinumab 90 mg was twice that of ustekinumab 45 mg, the results showed that the probability of ustekinumab being considered cost effective at £20,000 and £30,000 per QALY gained was zero. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of plaque psoriasis and the value placed on the benefits of ustekinumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee discussed the likely place of ustekinumab in the management of severe plaque psoriasis. It heard from the clinical specialists that there has been a substantial reduction in hospital admissions for psoriasis as a result of the increasing availability of biological therapies. However, the Committee heard from the clinical specialists that there are currently no treatments that they considered to be effective for people whose psoriasis does not respond adequately to the tumour necrosis factor (TNF) inhibitors (that is, adalimumab, infliximab and etanercept). In addition, with the withdrawal of efalizumab there are no treatment options for people in whom TNF inhibitors are contraindicated, such as people with heart failure or demyelinating disease. The Committee noted that ustekinumab has a different mechanism of action from that of the TNF inhibitors, and heard that the clinical specialists considered that its mechanism of action may be specific in the management of psoriasis. The Committee understood that ustekinumab would be considered to be of value by people with psoriasis and their clinicians. The Committee heard from the clinical specialists and patient experts that ustekinumab may be easier to use than other biological therapies because it is administered subcutaneously just once every 12 weeks after the first 4 weeks. This could enable people to be given the drug during their routine scheduled clinic visits. The Committee was informed by the patient experts that people with psoriasis do not generally have a problem with the frequency of injections, although they prefer less frequent injections. The Committee accepted that the less frequent dosing for ustekinumab, which would allow it to be given during routine scheduled clinic visits, may also help compliance. The Committee heard from the clinical specialists that ustekinumab is a new drug that has been given to far fewer people than the other biological therapies, and therefore its long-term safety profile is less certain. Because of this, the specialists considered that the drug may initially be prescribed more cautiously than existing treatments. The Committee also heard from the clinical specialists and patient experts that people with severe psoriasis are often well informed about drug safety and able to consider benefits and risks before starting treatment. The Committee considered that the RCTs identified in the manufacturer's submission confirmed the clinical effectiveness of ustekinumab compared with placebo in people with moderate to severe psoriasis. The Committee also considered that ustekinumab had been demonstrated to be more clinically effective than etanercept. It noted, however, that the dosage used for etanercept in the comparative trial was different from that currently recommended in TA103. The Committee heard that the inclusion criteria used in the clinical trials were representative of people with psoriasis who are being considered for treatment with biological therapies in clinical practice. The Committee noted that the manufacturer had conducted a mixed treatment comparison to enable a comparison of ustekinumab with all alternative biological therapies currently available for the treatment of psoriasis. The Committee noted that two analyses had been completed: one analysed data from all patients according to their randomisation, whereas the other analysed data from patients according to a weight-based dosing approach. The Committee noted that the results for both analyses suggested a higher probability of a response after treatment with ustekinumab than with etanercept or adalimumab, but a lower probability of a response compared with infliximab. The Committee discussed comments received during consultation on the appraisal consultation document (ACD) suggesting that the efficacy of adalimumab had been underestimated in the mixed treatment comparison because of the possible exclusion of relevant outcome data and the inclusion of a study that had enrolled people with less severe psoriasis. In addition, the Committee discussed the uncertainties about how the analysis had been completed and how it compared with analyses used in previous appraisals. It also considered that randomisation may not have been maintained in the weight-based dosing analysis. The Committee recognised these issues concerning the mixed treatment comparison and took them into account in its decision-making. The Committee considered whether the appropriate comparator for ustekinumab should be etanercept given continuously or intermittently, with the latter regimen being specified in TA103 and in the marketing authorisation for etanercept. The Committee heard from the clinical specialists that biological therapies for psoriasis, including etanercept, are usually used on a continuous basis in clinical practice, although treatment may be interrupted if a person has a sustained remission. The Committee heard that treatment withdrawal was carried out cautiously because a person's condition may deteriorate rapidly and they may subsequently not regain full control of their disease. The Committee heard from the clinical specialists that ustekinumab was likely to be used in a similar way to other biological therapies. The Committee recognised that there is variation in the administration of etanercept in clinical practice, and noted a comment received during consultation on the ACD stating that etanercept is usually given intermittently and only given continuously when required. The Committee was aware that the clinical specialists had indicated that ustekinumab may be used after a person's psoriasis had shown an inadequate response to other biological therapies. It was also aware that guidelines in preparation from the British Association of Dermatology might include advice on the sequential use of such therapies. The Committee took note of comments received on the ACD suggesting the use of ustekinumab after the failure of TNF inhibitors. However, no evidence for the use of ustekinumab after an inadequate response to other biological therapies was placed before the Committee. It noted that 40–50% of people in the PHOENIX trials had received previous treatment with biological therapies, but that a person's psoriasis had not necessarily shown an inadequate response to these therapies before the trial use of ustekinumab. Furthermore, data for this subgroup had not been presented separately. Therefore the Committee felt that it could not make any specific recommendations on the use of ustekinumab after a person's psoriasis had failed to respond to other biological therapies. However, it considered that data on the effectiveness of biological therapies, including ustekinumab, for the sequential treatment of severe plaque psoriasis would be an important part of future assessments. # Cost effectiveness The Committee discussed the results of the economic analysis conducted by the manufacturer. It considered the overall approach to modelling adopted by the manufacturer to be appropriate, but noted comments received during consultation on the ACD relating to the potential limitations of the probabilistic sensitivity analyses. The Committee noted the ERG's concerns that no formal subgroup analysis that justified weight-based dosing had been done. It also discussed comments received during consultation on the ACD that other biological therapies might also demonstrate a weight–dose relationship. However, the Committee noted that weight-based dosing is included in the marketing authorisation for ustekinumab and that evidence had been presented for a dose–response relationship with this drug. The Committee discussed the assumption in the economic model that 20% of people receiving ustekinumab would weigh more than 100 kg. It recognised that this might be an underestimate, because around 30% of the people included in the PHOENIX trials weighed more than 100 kg. However, the Committee considered that comments received during consultation on the ACD had shown that changing this assumption had minimal impact on estimates of cost effectiveness. The Committee noted the assumption in the model that a hospital inpatient period of 21 days would be required for people whose psoriasis had not responded adequately to treatment. The Committee noted that this assumption had been used in the appraisals of other biological therapies for psoriasis. The Committee heard from the clinical specialists and patient experts that 21 days of inpatient treatment in a year was plausible for a person with severe psoriasis that had not responded adequately to treatment. The Committee also heard from the clinical specialists that the cost of £288 per day for an inpatient stay, as assumed in the model, may be too low. Costs as high as £700 per day may be incurred, but these are usually associated with shorter, more intensive inpatient admissions. Additionally, the Committee heard that the cost of supportive care may be higher than calculated in the model because people may receive methotrexate or ciclosporin even if their disease is not adequately controlled by these treatments. The Committee recognised that the costs were similar to those used in previous appraisals, but was concerned about their accuracy. The Committee noted that the economic model assumed that the efficacy of intermittent etanercept was lower than that of continuous etanercept. The Committee was informed that this was based on an RCT showing that, for the outcome measured (PGA score), intermittent etanercept was less effective than continuous etanercept. This difference in effectiveness had then been applied to the PASI response data for continuous etanercept in the mixed treatment comparison in order to determine the efficacy of intermittent etanercept. The Committee considered that an assumption of reduced efficacy of intermittent etanercept may be reasonable, but that the way this had been calculated in the model increased the uncertainty in the results. The Committee discussed comments received during consultation on the ACD about the cost of etanercept 25 mg given intermittently. It recognised that the appraisal of etanercept and efalizumab (TA103) had assumed that the cost of intermittent etanercept 25 mg was 74% that of continuous etanercept. However, in the current appraisal of ustekinumab an estimate of 88% had been used, which reflected that used by another manufacturer in the appraisal of adalimumab. The Committee noted comments received during consultation on the ACD that if the cost of intermittent etanercept 25 mg was 74% of that of continuous etanercept, the ICER for ustekinumab in comparison with intermittent etanercept 25 mg was £68,300 per QALY gained. However, the Committee was mindful of comments from clinical specialists that for people with severe psoriasis, treatment may be given continuously or may have short re-treatment intervals. The Committee recognised that in a scenario where etanercept was given continuously, the manufacturer's analysis suggested that ustekinumab was less costly and more effective. The Committee noted that the economic model included a 20% annual dropout rate for people whose psoriasis responded to treatment and that this rate was assumed to be the same for all biological therapies. The Committee heard from the clinical specialists that people on biological therapies do stop treatment because of a reduction in response or adverse events, and that they considered this estimate to be reasonable. The Committee was aware that EQ-5D data had not been obtained in the clinical trials, and noted that the manufacturer had mapped DLQI scores to EQ-5D scores to obtain estimates of utility. The Committee noted that this approach had been used in TA103. The Committee recognised that the manufacturer had also provided a secondary analysis using SF-36 values from the PHOENIX-1 trial transformed into SF-6D scores. The Committee accepted the manufacturer's use of mapping to determine utility estimates. The Committee noted that the cost-effectiveness analysis included the patient access scheme. It noted that without the patient access scheme the ICERs for ustekinumab would be £41,000 per QALY gained compared with supportive care, £102,000 per QALY gained compared with intermittent etanercept 25 mg, and £300,000 per QALY gained compared with adalimumab. The Committee therefore concluded that ustekinumab could not be considered a cost-effective use of NHS resources without the patient access scheme. The Committee was reassured that the patient access scheme would remain in place until either a review of the guidance by NICE or the introduction of any new formulations that would render the scheme obsolete, and that it would not be withdrawn without the agreement of NICE and the Department of Health. The Committee concluded that it was reasonable to consider the estimates of cost effectiveness that included the patient access scheme. The Committee noted that in the manufacturer's base-case analysis, which included the patient access scheme, ustekinumab had an ICER of £29,600 per QALY gained compared with supportive care, and an ICER of £27,100 per QALY gained compared with etanercept 25 mg given intermittently. The Committee was mindful that this analysis assumed that the cost of intermittent etanercept was 88% of the cost of continuous etanercept. The Committee also noted that the manufacturer's analysis suggested that ustekinumab was less costly and more effective than adalimumab. However, it was aware that revised estimates for the efficacy of adalimumab had been provided during consultation on the ACD, and the resulting ICERs suggested that ustekinumab was not a cost-effective alternative to adalimumab. The Committee considered that the differences in incremental costs and QALYs between all treatments were small, and that this was particularly the case when considering ustekinumab and adalimumab. This meant that these ICERS were very sensitive to small changes in either costs or QALYs and therefore did not represent stable estimates of cost effectiveness. Therefore the Committee concluded that no robust differences in cost effectiveness between adalimumab and ustekinumab had been shown. # Further considerations and summary The Committee considered how the population with severe psoriasis should be defined. It heard from the clinical specialists that a combination of DLQI and PASI scores is used routinely in clinical practice, and agreed that it would be appropriate to define severe disease as a PASI score of 10 or more and a DLQI score of more than 10, in line with TA103. Furthermore, the clinical specialists indicated that the treatment continuation rules defined in section 1.2 of TA103 remain relevant to clinical practice. However, the Committee noted that the response should be measured at 16 weeks for ustekinumab, rather than at 12 weeks as defined for etanercept in TA103, and that this measurement should be carried out before the third (16-week) dose is given. The Committee was mindful of the uncertainties in the resource and cost data and the potential methodological limitations of the mixed treatment comparison. The Committee considered that it would be of value to review all of the biological therapies for psoriasis in a multiple technology appraisal. It also noted that data collection, as described in its recommendations for further research (see section 6), would help decisions to be made in future appraisals. It concluded that the estimates of the cost effectiveness of ustekinumab compared with supportive care were acceptable. It also concluded that, in comparisons of ustekinumab with other biological therapies, the ICERs depended on small differences in costs and benefits that were subject to uncertainty. On balance, the Committee was persuaded that ustekinumab should be recommended as a treatment option for people with severe plaque psoriasis when standard systemic therapies have not produced an adequate response, or if a person is intolerant of or has a contraindication to these therapies. The Committee was aware that there might be some situations when the DLQI may not be a clinically appropriate tool to inform a clinician's conclusion about the severity of psoriasis; for example, if a person has physical, sensory or learning disabilities, or communication difficulties that could affect their responses to the questionnaire. The Committee heard from the clinical specialists that the DLQI is now available in more than 50 languages and that this has improved assessment for those people whose first language is not English. The Committee concluded that healthcare professionals should take any physical, sensory or learning disabilities and communication difficulties into account when using the DLQI and make any adjustments they consider appropriate.# Recommendations for further research The Committee considered that the following research would be of value: Studies comparing ustekinumab and other biological therapies in head-to-head trials, both in people whose psoriasis has shown an inadequate response to the first biological therapy and in people naive to biological therapies. These studies should investigate weight–dose relationships, as far as these can be considered within the marketing authorisations. Studies investigating resource use, including frequency and length of hospitalisation and associated costs. The collection of data on the use of ustekinumab and other biological therapies as part of the British Association of Dermatologists' Biologics Intervention Register (BADBIR).# Review of guidance The guidance on this technology was considered for review in September 2010, at the same time as 'Etanercept and efalizumab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 103), 'Infliximab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 134) and 'Adalimumab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 146). Details are available on the NICE website.Andrew DillonChief ExecutiveSeptember 2009# Changes after publication March 2017: under the original patient access scheme the company provided 2x45‑mg pre-filled syringes, for patients who needed the higher dose of 90‑mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme has been withdrawn because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial. February 2014: implementation section updated to clarify that ustekinumab is recommended as an option for treating moderate to severe psoriasis. Additional minor maintenance update also carried out. ISBN: 978-1-4731-2424-0	{'Guidance': 'Ustekinumab is recommended as a treatment option for adults with plaque psoriasis when the following criteria are met.\n\nThe disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) score of 10 or more and a Dermatology Life Quality Index (DLQI) score of more than 10.\n\nThe psoriasis has not responded to standard systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or the person is intolerant of or has a contraindication to these treatments.\n\nUstekinumab treatment should be stopped in people whose psoriasis has not responded adequately by 16\xa0weeks after starting treatment. An adequate response is defined as either:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5-point reduction in the DLQI score from when treatment started.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.', 'The technology ': "Ustekinumab (Stelara, Janssen-Cilag) is a fully human monoclonal antibody that targets interleukin-12 (IL-12) and IL-23. It binds to the p40 subunit, common to both IL-12 and IL-23, which prevents these cytokines from binding to the cell surface of T cells, thereby disrupting the inflammatory cascade implicated in psoriasis. Ustekinumab has a UK marketing authorisation for 'the treatment of moderate to severe plaque psoriasis in adults who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA'. The recommended dose of ustekinumab is 45\xa0mg for people who weigh 100\xa0kg or less, and 90\xa0mg for people who weigh over 100\xa0kg. An initial dose of ustekinumab is administered subcutaneously at week\xa00, followed by another dose at week 4, and then a further dose every 12 weeks. The summary of product characteristics (SPC) states that ustekinumab is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis.\n\nCommon adverse events associated with ustekinumab, as reported in the SPC, include upper respiratory tract infection, nasopharyngitis, depression, headache, dizziness, diarrhoea, pruritus, back pain, fatigue and injection site erythema. Contraindications listed in the SPC include clinically important active infection and hypersensitivity to the active substance or to any of the excipients. For full details of side effects and contraindications, see the SPC.\n\nUstekinumab is available in vials containing 45\xa0mg. The cost per vial is £2147 (Monthly Index of Medical Specialities [MIMS], April 2009). Ustekinumab is not listed in the current version of the 'British national formulary' (BNF; edition 57). The cost of ustekinumab for the two loading doses (at 0 and 4 weeks) is £4294. The cost in the first year is £10,735, with an annual cost thereafter of £9335 (the annual cost assumes an average of 4.3 injections per year). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe SPC recommends that people whose body weight exceeds 100\xa0kg should receive a dose of 90\xa0mg of ustekinumab. This would be double the cost of the 45\xa0mg dose indicated for the treatment of a person who weighs 100\xa0kg or less. However, the manufacturer has proposed a patient access scheme to the Department of Health. Under the scheme, for people who weigh more than 100\xa0kg and who are prescribed the 90\xa0mg dose (two 45\xa0mg vials), the manufacturer will provide both vials at a total cost of £2147 (the cost of a single vial). The manufacturer has proposed that this patient access scheme will be available to the NHS at least until either a review of the guidance by NICE or the introduction of any new formulations that would render the scheme obsolete. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ustekinumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe decision problem in the manufacturer's submission compared ustekinumab with adalimumab, efalizumab, etanercept, infliximab and supportive care. Three doses of etanercept were considered: 25\xa0mg twice weekly given intermittently as recommended in NICE's technology appraisal guidance on etanercept and efalizumab for the treatment of adults with psoriasis, 25\xa0mg twice weekly given continuously, and 50\xa0mg twice weekly given for the first 12\xa0weeks followed by a reduction in dose to 25\xa0mg twice weekly. Clinical outcomes in the manufacturer's submission included improvements in PASI and DLQI scores. PASI is a measure of disease severity based on body surface area affected and the extent, scaliness, thickness and redness of plaques, with scores ranging from 0 to 72. The DLQI is a disease-specific quality-of-life measure with scores ranging from 0 to 30. Moderate to severe psoriasis was defined as a PASI score of 10 or more and a DLQI score of more than 10.\n\nThe manufacturer's submission included evidence from three randomised controlled trials (RCTs):\n\nPHOENIX-1 (n\xa0=\xa0766, 5 years' duration), a phase III, multicentre, parallel, randomised, double-blind, placebo-controlled trial based in the USA, Canada and Belgium.\n\nPHOENIX-2 (n\xa0=\xa01230, 5 years' duration), a phase III, multicentre, parallel, randomised, double-blind, placebo-controlled trial based in Europe and North America.\n\nACCEPT trial (n\xa0=\xa0903, 64 weeks' duration), a phase III, multicentre, parallel RCT based in Europe and North America, which compared ustekinumab with etanercept (50\xa0mg twice weekly for the first 12 weeks).\n\nIn each of the RCTs, two doses (45\xa0mg and 90\xa0mg) of ustekinumab were investigated and patients were randomised to groups regardless of their body weight. To reflect the licensed dosing of ustekinumab, the manufacturer presented two analyses in their submission. The first analysis used data from all the patients enrolled in the clinical trials and included dosing outside the marketing authorisation (that is, patients weighing 100\xa0kg or less who received ustekinumab 90\xa0mg and patients weighing over 100\xa0kg who received ustekinumab 45\xa0mg). The second was a subgroup analysis that included data only for patients who received ustekinumab according to the marketing authorisation (weight-based dosing; that is, 45\xa0mg for people weighing 100\xa0kg or less and 90\xa0mg for people weighing over 100\xa0kg).\n\nThe results of the three RCTs using data for all patients demonstrated statistically significant differences in the percentage of patients treated with ustekinumab who achieved a 75% or greater reduction in PASI score (PASI\xa075; the primary endpoint in the trials) compared with those who received placebo. The percentages of patients with at least a PASI\xa075 response at week\xa012 in the ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and placebo groups were 67%, 66% and 3% respectively in the PHOENIX-1 trial (p\xa0<\xa00.001 for both ustekinumab doses compared with placebo) and 67%, 76% and 4% respectively in the PHOENIX-2 trial (p\xa0<\xa00.001). In the ACCEPT trial, the percentages of patients with at least a PASI\xa075 response at week 12 in the ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and etanercept groups were 68%, 74% and 57% respectively (p\xa0=\xa00.012 for ustekinumab 45 mg and p\xa0<\xa00.001 for ustekinumab 90\xa0mg compared with etanercept).\n\nFor secondary outcomes recorded in the RCTs, such as the physician's global assessment (PGA) score, the DLQI score and other health-related quality-of-life scores, the ustekinumab groups showed statistically significant improvements compared with the placebo groups. In the PHOENIX-1 trial, the mean change in DLQI score at week 12 was −8.0 for ustekinumab 45\xa0mg, −8.7 for ustekinumab 90\xa0mg and −0.6 for placebo (p\xa0<\xa00.001 versus placebo for both ustekinumab doses). In the PHOENIX-2 trial, the values were −9.3, −10.0 and −0.5 respectively (p\xa0<\xa00.001 versus placebo for both ustekinumab doses). DLQI data were not collected in the ACCEPT trial.\n\nData from the clinical trials suggested that 90\xa0mg is a more effective dose of ustekinumab than 45\xa0mg for patients who weigh more than 100\xa0kg. For example, in the PHOENIX-1 trial, 69% of patients weighing more than 100\xa0kg who received ustekinumab 90\xa0mg achieved a PASI\xa075 response at 12 weeks, compared with 54% of those who received ustekinumab 45\xa0mg. In the PHOENIX-2 trial, the values were 71% and 49% respectively.\n\nThe manufacturer included longer-term data from the PHOENIX trials for the weight-based dosing subgroup analysis. These data suggested that the PASI response rates observed during the double-blind, randomised phases of the studies were maintained in the longer term. In the PHOENIX-1 trial, the percentages of patients achieving a PASI\xa075 response at week 24 were 83% and 80% for ustekinumab 45\xa0mg and 90\xa0mg respectively. In the PHOENIX-2 trial, the respective percentages were each 80%.\n\nIn the PHOENIX-1 trial, the percentages of patients having one or more adverse events were 57.3%, 51.4% and 47.8% in the ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and placebo groups respectively. The percentages of patients having a serious adverse event were 0.8%, 1.6% and 0.8% respectively. Similar rates of adverse events were reported in the PHOENIX-2 trial. In the ACCEPT trial, the percentages of patients having one or more adverse events were 66.0%, 68.3% and 69.5% in the ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and etanercept groups respectively. The percentages of patients having a serious adverse event were 1.9%, 1.2% and 1.2% respectively.\n\nThe manufacturer compared ustekinumab with other biological therapies (that is, adalimumab, efalizumab, infliximab and etanercept) using a mixed treatment comparison. This included data from studies that compared different biological therapies directly, as well as indirect comparisons using data from studies that compared biological therapies with placebo using the placebo group as the common factor. The manufacturer included data from the three ustekinumab RCTs, as well as from three RCTs comparing adalimumab with placebo, five comparing efalizumab with placebo, five comparing etanercept with placebo and four comparing infliximab with placebo. The results from the mixed treatment comparison using the ustekinumab data for all patients suggested that the mean probabilities of achieving a PASI\xa075 response were 69% for ustekinumab 45\xa0mg (95%\xa0confidence interval [CI] 62% to 75%), 74% for ustekinumab 90\xa0mg (95%\xa0CI 68% to 80%), 58% for adalimumab (95%\xa0CI 49% to 68%), 80% for infliximab (95% CI 70% to 87%), 39% for etanercept 25\xa0mg (95%\xa0CI 30% to 48%), 52% for etanercept 50\xa0mg (95% CI 45% to 59%), 26% for efalizumab (95% CI 21% to 32%) and 4% for supportive care (95%\xa0CI 3% to 4%). The manufacturer also included a mixed treatment comparison for the weight-based dosing subgroup analysis. However, the ustekinumab data from this comparison were provided as academic in confidence.\n\nThe manufacturer based its cost-effectiveness analysis on the economic model used in TA103 and subsequently in NICE's guidance on infliximab for the treatment of adults with psoriasis and adalimumab for the treatment of adults with psoriasis. The model was adapted by the manufacturer of ustekinumab to incorporate additional evidence, including the results of the mixed treatment comparison described in section\xa03.9.\n\nIn the model, each person had an initial period of treatment after which response was assessed (this was referred to as the trial period). Continuation of treatment into the next phase (referred to as the treatment period) occurred only if a PASI\xa075 response was achieved in the trial period. The time at which the response was assessed varied for the different drugs, depending on their dosing regimen. The assessment points were at 12\xa0weeks (etanercept), 10\xa0weeks (infliximab) and 16\xa0weeks (adalimumab and ustekinumab). It was assumed that for people whose psoriasis responded to treatment, 20% stopped treatment each subsequent year. The mean time on treatment using this assumption was calculated to be 3.65 years. The same assumption was used for all biological therapies.\n\nThe utility data used in the model were based on an estimate of the relationship between PASI response rates and changes in DLQI score from the PHOENIX-1 and PHOENIX-2 trials mapped to EQ-5D scores. First, the mean change in the DLQI score between baseline and week 12 was estimated for groups of patients with different levels of PASI response. Secondly, the manufacturer estimated an algorithm to map DLQI scores to EQ-5D scores from a scatter plot published in the assessment report of TA103. The changes in mean EQ-5D score for PASI responses of less than 50%, between 50% and 74%, between 75% and 89%, and 90% or more were estimated to be 0.04, 0.17, 0.22 and 0.25 respectively.\n\nThe costs in the economic model included drug costs, administration costs and monitoring costs, and were taken from the model in TA103, NHS Reference Costs and the BNF (edition\xa056). The Personal Social Services Research Unit (PSSRU) inflation index was used to update costs from 2006 values if current costs were not available. The model assumed that people whose psoriasis had not responded adequately to treatment would have an inpatient admission of 21 days' duration once a year.\n\nThe manufacturer's base-case analysis assumed a weighted average of weight-based dosing whereby 80% of people received ustekinumab 45\xa0mg and 20% of people received ustekinumab 90\xa0mg. The manufacturer also provided analyses using the data from all patients in the clinical trials and the data from the weight-based dosing approach with separate estimates for ustekinumab 45\xa0mg and 90\xa0mg. All the analyses in the submission assumed that the patient access scheme (see section 2.4) was in place. Under the original patient access scheme the company provided 2x45\xa0mg pre-filled syringes, for patients who needed the higher dose of 90\xa0mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.\n\nThe base-case analysis showed that when ustekinumab was compared with supportive care, the QALY gain was 0.156 at an incremental cost of £4615, giving an incremental cost-effectiveness ratio (ICER) of £29,587 per QALY gained. The ICER for ustekinumab compared with etanercept 25\xa0mg given intermittently (assuming 88% of the cost of continuous etanercept) was £27,105 per QALY gained. The ICER for infliximab compared with ustekinumab was £304,566 per QALY gained. Adalimumab and etanercept given continuously rather than intermittently were dominated by ustekinumab (that is, ustekinumab had both greater effectiveness and lower costs). Probabilistic sensitivity analyses suggested that the probabilities of ustekinumab being cost effective at £20,000 and £30,000 per QALY gained were 7.4% and 48.5% respectively. The manufacturer's analyses suggested that ustekinumab was the only biological therapy that was likely to be cost effective at £20,000 and £30,000 per QALY gained.\n\nThe analyses using data for all patients (that is, no weight-based dosing) presented separate ICERs for ustekinumab 45\xa0mg and 90\xa0mg. These analyses suggested that when ustekinumab 45\xa0mg was compared with supportive care, the QALY gain was 0.1544 at an incremental cost of £4735, giving an ICER of £30,664 per QALY gained. The estimates for ustekinumab 90\xa0mg suggested a QALY gain of 0.1563 and incremental costs of £4613, giving an ICER of £29,520 per QALY gained. The ICERs for ustekinumab in comparison with intermittent etanercept 25\xa0mg were £36,938 per QALY gained for ustekinumab 45\xa0mg and £28,633 per QALY gained for ustekinumab 90\xa0mg. Etanercept 25\xa0mg given continuously was dominated by ustekinumab. Adalimumab was dominated by ustekinumab 90\xa0mg, but for ustekinumab 45\xa0mg the ICER was £16,400 per QALY gained.\n\nSensitivity analyses were carried out to test assumptions in the economic model. When the manufacturer reduced the length of an inpatient stay for people whose psoriasis did not respond adequately to treatment from the base-case estimate of 21 days to 17.5 days, the ICER for ustekinumab in comparison with supportive care increased from £29,587 to £34,387 per QALY gained. When the length of stay was increased to 27.5 days, the ICER decreased to £20,672 per QALY gained. The manufacturer also changed the way in which estimates of utility were obtained: from EQ-5D data mapped from DLQI scores, to SF-6D data transformed from SF-36 values collected in the PHOENIX-1 trial. When SF-6D data were used to estimate utilities, the ICER for ustekinumab compared with supportive care increased from £29,302 to £49,371 per QALY gained.\n\nThe manufacturer also varied the assumptions about the cost and efficacy of intermittent etanercept. The cost of intermittent compared with continuous etanercept was changed from the base-case estimate of 88% to 74% (the figure used in TA103) and to 98%. Using an estimate of 74%, the ICER for ustekinumab compared with intermittent etanercept 25\xa0mg increased from £27,105 to £68,339 per QALY gained. When an estimate of 98% was used, ustekinumab dominated intermittent etanercept. The relative efficacy of intermittent compared with continuous etanercept was assumed to be 81% in the base case. When this estimate was changed to 71%, the ICER for ustekinumab compared with intermittent etanercept decreased to £22,634 per QALY gained. When the estimate was changed to 91%, the ICER was £32,949 per QALY gained.\n\nThe ERG concluded that the manufacturer's submission provided an unbiased estimate of the clinical effectiveness of ustekinumab at 12 weeks based on the results of the three randomised comparisons. However, it noted that there was a lack of information about the methodology used for the weight-based dosing subgroup analysis. In addition, it could not determine whether the methods used were appropriate and whether the subgroup analysis supported the weight-based categorisation presented.\n\nThe ERG commented that there appeared to be differences between the mixed treatment comparison that had been used in the appraisal of etanercept and efalizumab (TA103) and that used in the current appraisal. The ERG also noted that the manufacturer's submission included only minimal discussion of any possible clinical heterogeneity between the trials included in the mixed treatment comparison. It further noted that in the mixed treatment comparison, data from the weight-based dosing analysis of ustekinumab were taken from a subgroup of the trial data, whereas data for all patients were used for the comparator trials. The ERG was concerned that this had affected randomisation. The ERG concluded that the clinical effectiveness of ustekinumab in comparison with the other biological therapies was uncertain.\n\nThe ERG also noted that the probabilistic sensitivity analysis in the manufacturer's submission appeared to include only variables for utilities, treatment response and the proportion of people weighing more than 100\xa0kg. It did not include other variables to which the ICERs were sensitive, such as the number of hospital days, the effects of different inpatient costs and the relative efficacy of intermittent etanercept.\n\nThe ERG completed an exploratory analysis that amended the base-case analysis to include the price for ustekinumab 90\xa0mg as double the list price of ustekinumab 45\xa0mg (that is, assuming that there would be no patient access scheme in place). The results showed that the ICER for ustekinumab compared with supportive care increased from £29,587 to £40,952 per QALY gained. A further exploratory analysis assumed that the efficacy of intermittent etanercept 25\xa0mg was the same as that of continuous etanercept 25\xa0mg (as was assumed in the economic model for TA103). Using this assumption, the ICER for ustekinumab compared with intermittent etanercept 25\xa0mg in the base-case analysis increased from £27,105 to £41,449 per QALY gained.\n\nThe ERG conducted an exploratory probabilistic sensitivity analysis that included a larger number of variables than were included by the manufacturer. The results of the ERG's analysis suggested greater uncertainty around the estimates of cost effectiveness, but the cost-effectiveness acceptability curves did not differ significantly from those of the manufacturer. When the ERG repeated the analysis assuming that the cost of ustekinumab 90\xa0mg was twice that of ustekinumab 45\xa0mg, the results showed that the probability of ustekinumab being considered cost effective at £20,000 and £30,000 per QALY gained was zero.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of plaque psoriasis and the value placed on the benefits of ustekinumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed the likely place of ustekinumab in the management of severe plaque psoriasis. It heard from the clinical specialists that there has been a substantial reduction in hospital admissions for psoriasis as a result of the increasing availability of biological therapies. However, the Committee heard from the clinical specialists that there are currently no treatments that they considered to be effective for people whose psoriasis does not respond adequately to the tumour necrosis factor (TNF) inhibitors (that is, adalimumab, infliximab and etanercept). In addition, with the withdrawal of efalizumab there are no treatment options for people in whom TNF inhibitors are contraindicated, such as people with heart failure or demyelinating disease. The Committee noted that ustekinumab has a different mechanism of action from that of the TNF inhibitors, and heard that the clinical specialists considered that its mechanism of action may be specific in the management of psoriasis. The Committee understood that ustekinumab would be considered to be of value by people with psoriasis and their clinicians.\n\nThe Committee heard from the clinical specialists and patient experts that ustekinumab may be easier to use than other biological therapies because it is administered subcutaneously just once every 12 weeks after the first 4 weeks. This could enable people to be given the drug during their routine scheduled clinic visits. The Committee was informed by the patient experts that people with psoriasis do not generally have a problem with the frequency of injections, although they prefer less frequent injections. The Committee accepted that the less frequent dosing for ustekinumab, which would allow it to be given during routine scheduled clinic visits, may also help compliance.\n\nThe Committee heard from the clinical specialists that ustekinumab is a new drug that has been given to far fewer people than the other biological therapies, and therefore its long-term safety profile is less certain. Because of this, the specialists considered that the drug may initially be prescribed more cautiously than existing treatments. The Committee also heard from the clinical specialists and patient experts that people with severe psoriasis are often well informed about drug safety and able to consider benefits and risks before starting treatment.\n\nThe Committee considered that the RCTs identified in the manufacturer's submission confirmed the clinical effectiveness of ustekinumab compared with placebo in people with moderate to severe psoriasis. The Committee also considered that ustekinumab had been demonstrated to be more clinically effective than etanercept. It noted, however, that the dosage used for etanercept in the comparative trial was different from that currently recommended in TA103. The Committee heard that the inclusion criteria used in the clinical trials were representative of people with psoriasis who are being considered for treatment with biological therapies in clinical practice.\n\nThe Committee noted that the manufacturer had conducted a mixed treatment comparison to enable a comparison of ustekinumab with all alternative biological therapies currently available for the treatment of psoriasis. The Committee noted that two analyses had been completed: one analysed data from all patients according to their randomisation, whereas the other analysed data from patients according to a weight-based dosing approach. The Committee noted that the results for both analyses suggested a higher probability of a response after treatment with ustekinumab than with etanercept or adalimumab, but a lower probability of a response compared with infliximab.\n\nThe Committee discussed comments received during consultation on the appraisal consultation document (ACD) suggesting that the efficacy of adalimumab had been underestimated in the mixed treatment comparison because of the possible exclusion of relevant outcome data and the inclusion of a study that had enrolled people with less severe psoriasis. In addition, the Committee discussed the uncertainties about how the analysis had been completed and how it compared with analyses used in previous appraisals. It also considered that randomisation may not have been maintained in the weight-based dosing analysis. The Committee recognised these issues concerning the mixed treatment comparison and took them into account in its decision-making.\n\nThe Committee considered whether the appropriate comparator for ustekinumab should be etanercept given continuously or intermittently, with the latter regimen being specified in TA103 and in the marketing authorisation for etanercept. The Committee heard from the clinical specialists that biological therapies for psoriasis, including etanercept, are usually used on a continuous basis in clinical practice, although treatment may be interrupted if a person has a sustained remission. The Committee heard that treatment withdrawal was carried out cautiously because a person's condition may deteriorate rapidly and they may subsequently not regain full control of their disease. The Committee heard from the clinical specialists that ustekinumab was likely to be used in a similar way to other biological therapies. The Committee recognised that there is variation in the administration of etanercept in clinical practice, and noted a comment received during consultation on the ACD stating that etanercept is usually given intermittently and only given continuously when required.\n\nThe Committee was aware that the clinical specialists had indicated that ustekinumab may be used after a person's psoriasis had shown an inadequate response to other biological therapies. It was also aware that guidelines in preparation from the British Association of Dermatology might include advice on the sequential use of such therapies. The Committee took note of comments received on the ACD suggesting the use of ustekinumab after the failure of TNF inhibitors. However, no evidence for the use of ustekinumab after an inadequate response to other biological therapies was placed before the Committee. It noted that 40–50% of people in the PHOENIX trials had received previous treatment with biological therapies, but that a person's psoriasis had not necessarily shown an inadequate response to these therapies before the trial use of ustekinumab. Furthermore, data for this subgroup had not been presented separately. Therefore the Committee felt that it could not make any specific recommendations on the use of ustekinumab after a person's psoriasis had failed to respond to other biological therapies. However, it considered that data on the effectiveness of biological therapies, including ustekinumab, for the sequential treatment of severe plaque psoriasis would be an important part of future assessments.\n\n# Cost effectiveness\n\nThe Committee discussed the results of the economic analysis conducted by the manufacturer. It considered the overall approach to modelling adopted by the manufacturer to be appropriate, but noted comments received during consultation on the ACD relating to the potential limitations of the probabilistic sensitivity analyses. The Committee noted the ERG's concerns that no formal subgroup analysis that justified weight-based dosing had been done. It also discussed comments received during consultation on the ACD that other biological therapies might also demonstrate a weight–dose relationship. However, the Committee noted that weight-based dosing is included in the marketing authorisation for ustekinumab and that evidence had been presented for a dose–response relationship with this drug.\n\nThe Committee discussed the assumption in the economic model that 20% of people receiving ustekinumab would weigh more than 100 kg. It recognised that this might be an underestimate, because around 30% of the people included in the PHOENIX trials weighed more than 100 kg. However, the Committee considered that comments received during consultation on the ACD had shown that changing this assumption had minimal impact on estimates of cost effectiveness.\n\nThe Committee noted the assumption in the model that a hospital inpatient period of 21\xa0days would be required for people whose psoriasis had not responded adequately to treatment. The Committee noted that this assumption had been used in the appraisals of other biological therapies for psoriasis. The Committee heard from the clinical specialists and patient experts that 21 days of inpatient treatment in a year was plausible for a person with severe psoriasis that had not responded adequately to treatment. The Committee also heard from the clinical specialists that the cost of £288 per day for an inpatient stay, as assumed in the model, may be too low. Costs as high as £700 per day may be incurred, but these are usually associated with shorter, more intensive inpatient admissions. Additionally, the Committee heard that the cost of supportive care may be higher than calculated in the model because people may receive methotrexate or ciclosporin even if their disease is not adequately controlled by these treatments. The Committee recognised that the costs were similar to those used in previous appraisals, but was concerned about their accuracy.\n\nThe Committee noted that the economic model assumed that the efficacy of intermittent etanercept was lower than that of continuous etanercept. The Committee was informed that this was based on an RCT showing that, for the outcome measured (PGA score), intermittent etanercept was less effective than continuous etanercept. This difference in effectiveness had then been applied to the PASI response data for continuous etanercept in the mixed treatment comparison in order to determine the efficacy of intermittent etanercept. The Committee considered that an assumption of reduced efficacy of intermittent etanercept may be reasonable, but that the way this had been calculated in the model increased the uncertainty in the results.\n\nThe Committee discussed comments received during consultation on the ACD about the cost of etanercept 25\xa0mg given intermittently. It recognised that the appraisal of etanercept and efalizumab (TA103) had assumed that the cost of intermittent etanercept 25\xa0mg was 74% that of continuous etanercept. However, in the current appraisal of ustekinumab an estimate of 88% had been used, which reflected that used by another manufacturer in the appraisal of adalimumab. The Committee noted comments received during consultation on the ACD that if the cost of intermittent etanercept 25\xa0mg was 74% of that of continuous etanercept, the ICER for ustekinumab in comparison with intermittent etanercept 25\xa0mg was £68,300 per QALY gained. However, the Committee was mindful of comments from clinical specialists that for people with severe psoriasis, treatment may be given continuously or may have short re-treatment intervals. The Committee recognised that in a scenario where etanercept was given continuously, the manufacturer's analysis suggested that ustekinumab was less costly and more effective.\n\nThe Committee noted that the economic model included a 20% annual dropout rate for people whose psoriasis responded to treatment and that this rate was assumed to be the same for all biological therapies. The Committee heard from the clinical specialists that people on biological therapies do stop treatment because of a reduction in response or adverse events, and that they considered this estimate to be reasonable.\n\nThe Committee was aware that EQ-5D data had not been obtained in the clinical trials, and noted that the manufacturer had mapped DLQI scores to EQ-5D scores to obtain estimates of utility. The Committee noted that this approach had been used in TA103. The Committee recognised that the manufacturer had also provided a secondary analysis using SF-36 values from the PHOENIX-1 trial transformed into SF-6D scores. The Committee accepted the manufacturer's use of mapping to determine utility estimates.\n\nThe Committee noted that the cost-effectiveness analysis included the patient access scheme. It noted that without the patient access scheme the ICERs for ustekinumab would be £41,000 per QALY gained compared with supportive care, £102,000 per QALY gained compared with intermittent etanercept 25\xa0mg, and £300,000 per QALY gained compared with adalimumab. The Committee therefore concluded that ustekinumab could not be considered a cost-effective use of NHS resources without the patient access scheme. The Committee was reassured that the patient access scheme would remain in place until either a review of the guidance by NICE or the introduction of any new formulations that would render the scheme obsolete, and that it would not be withdrawn without the agreement of NICE and the Department of Health. The Committee concluded that it was reasonable to consider the estimates of cost effectiveness that included the patient access scheme.\n\nThe Committee noted that in the manufacturer's base-case analysis, which included the patient access scheme, ustekinumab had an ICER of £29,600 per QALY gained compared with supportive care, and an ICER of £27,100 per QALY gained compared with etanercept 25 mg given intermittently. The Committee was mindful that this analysis assumed that the cost of intermittent etanercept was 88% of the cost of continuous etanercept. The Committee also noted that the manufacturer's analysis suggested that ustekinumab was less costly and more effective than adalimumab. However, it was aware that revised estimates for the efficacy of adalimumab had been provided during consultation on the ACD, and the resulting ICERs suggested that ustekinumab was not a cost-effective alternative to adalimumab. The Committee considered that the differences in incremental costs and QALYs between all treatments were small, and that this was particularly the case when considering ustekinumab and adalimumab. This meant that these ICERS were very sensitive to small changes in either costs or QALYs and therefore did not represent stable estimates of cost effectiveness. Therefore the Committee concluded that no robust differences in cost effectiveness between adalimumab and ustekinumab had been shown.\n\n# Further considerations and summary\n\nThe Committee considered how the population with severe psoriasis should be defined. It heard from the clinical specialists that a combination of DLQI and PASI scores is used routinely in clinical practice, and agreed that it would be appropriate to define severe disease as a PASI score of\xa010 or more and a DLQI score of more than\xa010, in line with TA103. Furthermore, the clinical specialists indicated that the treatment continuation rules defined in section 1.2 of TA103 remain relevant to clinical practice. However, the Committee noted that the response should be measured at 16\xa0weeks for ustekinumab, rather than at 12 weeks as defined for etanercept in TA103, and that this measurement should be carried out before the third (16-week) dose is given.\n\nThe Committee was mindful of the uncertainties in the resource and cost data and the potential methodological limitations of the mixed treatment comparison. The Committee considered that it would be of value to review all of the biological therapies for psoriasis in a multiple technology appraisal. It also noted that data collection, as described in its recommendations for further research (see section 6), would help decisions to be made in future appraisals. It concluded that the estimates of the cost effectiveness of ustekinumab compared with supportive care were acceptable. It also concluded that, in comparisons of ustekinumab with other biological therapies, the ICERs depended on small differences in costs and benefits that were subject to uncertainty. On balance, the Committee was persuaded that ustekinumab should be recommended as a treatment option for people with severe plaque psoriasis when standard systemic therapies have not produced an adequate response, or if a person is intolerant of or has a contraindication to these therapies.\n\nThe Committee was aware that there might be some situations when the DLQI may not be a clinically appropriate tool to inform a clinician's conclusion about the severity of psoriasis; for example, if a person has physical, sensory or learning disabilities, or communication difficulties that could affect their responses to the questionnaire. The Committee heard from the clinical specialists that the DLQI is now available in more than 50 languages and that this has improved assessment for those people whose first language is not English. The Committee concluded that healthcare professionals should take any physical, sensory or learning disabilities and communication difficulties into account when using the DLQI and make any adjustments they consider appropriate.", 'Recommendations for further research': "The Committee considered that the following research would be of value:\n\nStudies comparing ustekinumab and other biological therapies in head-to-head trials, both in people whose psoriasis has shown an inadequate response to the first biological therapy and in people naive to biological therapies. These studies should investigate weight–dose relationships, as far as these can be considered within the marketing authorisations.\n\nStudies investigating resource use, including frequency and length of hospitalisation and associated costs.\n\nThe collection of data on the use of ustekinumab and other biological therapies as part of the British Association of Dermatologists' Biologics Intervention Register (BADBIR).", 'Review of guidance': "The guidance on this technology was considered for review in September 2010, at the same time as 'Etanercept and efalizumab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 103), 'Infliximab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 134) and 'Adalimumab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 146). Details are available on the NICE website.Andrew DillonChief ExecutiveSeptember 2009", 'Changes after publication': 'March 2017: under the original patient access scheme the company provided 2x45‑mg pre-filled syringes, for patients who needed the higher dose of 90‑mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme has been withdrawn because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.\n\nFebruary 2014: implementation section updated to clarify that ustekinumab is recommended as an option for treating moderate to severe psoriasis. Additional minor maintenance update also carried out.\n\nISBN: 978-1-4731-2424-0'}	https://www.nice.org.uk/guidance/ta180	Evidence-based recommendations on ustekinumab (Stelara) for treating psoriasis in adults.
552c82187db0efbc90529db32c74bf4857de42a7	nice	Ustekinumab for treating active psoriatic arthritis	Ustekinumab for treating active psoriatic arthritis Evidence-based recommendations on ustekinumab (Stelara) for treating active psoriatic arthritis in adults. # Guidance Ustekinumab is recommended as an option, alone or in combination with methotrexate, for treating active psoriatic arthritis in adults only when: treatment with tumour necrosis factor (TNF) alpha inhibitors is contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis) or the person has had treatment with 1 or more TNF–alpha inhibitors. Ustekinumab treatment should be stopped if the person's psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 24 weeks. An adequate response is defined as an improvement in at least 2 of the 4 criteria (1 of which must be joint tenderness or swelling score), with no worsening in any of the 4 criteria. As recommended in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, people whose disease has a Psoriasis Area and Severity Index (PASI) 75 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see NICE technology appraisal guidance on ustekinumab for the treatment of adults with moderate to severe psoriasis). When using the Psoriatic Arthritis Response Criteria (PsARC) healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. People whose treatment with ustekinumab is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue ustekinumab until they and their NHS clinician consider it appropriate to stop.# The technology Ustekinumab (Stelara, Janssen) is a monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin‑12 (IL‑12) and interleukin‑23 (IL‑23). It is administered by subcutaneous injection. Ustekinumab has a marketing authorisation in the UK for use alone or in combination with methotrexate 'for the treatment of active psoriatic arthritis in adult patients when the response to previous non‑biological disease‑modifying antirheumatic drug (DMARD) therapy has been inadequate'. The summary of product characteristics lists the following common adverse reactions for ustekinumab: dental and upper respiratory tract infections, nasopharyngitis, dizziness, headache, oropharyngeal pain, diarrhoea, nausea, pruritus, back pain, myalgia, arthralgia, fatigue, injection‑site erythema and injection‑site pain. For full details of adverse reactions and contraindications, see the summary of product characteristics. The list price for ustekinumab is £2147 per 45‑mg vial (excluding VAT; British national formulary online ). The recommended dose of ustekinumab is an initial dose of 45 mg, followed by a dose 4 weeks later and further doses every 12 weeks thereafter. A dose of 90 mg may be used in people with a body weight over 100 kg. The summary of product characteristics notes that consideration should be given to stopping treatment in people whose psoriatic arthritis has shown no response after up to 28 weeks of treatment. The average annual acquisition cost for ustekinumab 45 mg is £10,735 in the first year and £9304 per year thereafter. The company has agreed a patient access scheme with the Department of Health, in which the company provides the 90‑mg dose (2 vials) at the same cost as the 45‑mg dose (1 vial), for people who weigh more than 100 kg and need the higher dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.# The company's submission The Appraisal Committee (section 8) considered evidence submitted by Janssen as part of NICE technology appraisal guidance 313, further evidence submitted by Janssen as part of the rapid review and reviews of these submissions by the Evidence Review Group (ERG; section 9). # Clinical effectiveness Evidence on the clinical effectiveness of ustekinumab was taken from 2 clinical studies – PSUMMIT 1 and 2. Both were randomised, double‑blind, placebo‑controlled, phase III studies in adults with active psoriatic arthritis despite current or previous treatment. The studies were almost identical, except for the previous treatment: PSUMMIT 1 (n=615) included people who had previously had disease‑modifying antirheumatic drugs (DMARDs) with or without non‑steroidal anti‑inflammatory drugs (NSAIDs) only, whereas PSUMMIT 2 (n=312) also included people who had previously had tumour necrosis factor (TNF) alpha inhibitors. People in both trials generally had long‑standing moderate to severe active psoriatic arthritis with impaired physical function and high numbers of tender and swollen joints. In both PSUMMIT 1 and 2, approximately 70% of patients had skin disease, and 80–90% of patients had received prior DMARD therapy. Of the 180 people in PSUMMIT 2 who had previously had TNF‑alpha inhibitors (referred to in this document as 'TNF‑alpha inhibitor‑exposed'), more than half had received at least 2 biological drugs. In both studies, patients were randomised to ustekinumab 45 mg or 90 mg (administered at 0 and 4 weeks, then every 12 weeks thereafter) or placebo. People in the placebo group switched to have ustekinumab 45 mg after 16 weeks (if they had less than 5% improvement in both tender and swollen joint counts) or 24 weeks (all others), and people whose disease did not respond to the 45‑mg dose of ustekinumab switched to 90 mg after 16 weeks. People in the studies were followed for up to 100 weeks in PSUMMIT 1 and 52 weeks in PSUMMIT 2. The primary end point in the PSUMMIT 1 and 2 trials was the American College of Rheumatology (ACR) 20 response rate at week 24. This is defined as an improvement of 20% or more in swollen and tender joint counts, and an improvement of 20% or more in 3 of 5 assessments of pain, disease activity and physical function. Secondary end points included measures of joint symptoms (including modified Psoriatic Arthritis Response Criteria and ACR 50/70), skin lesions (Psoriasis Area and Severity Index ), soft tissue symptoms, radiographic response, and disability and quality of life (Health Assessment Questionnaire Disability Index , Dermatology Life Quality Index and 36‑item Short‑Form Health Survey ). In both PSUMMIT 1 and 2, ustekinumab was associated with statistically significantly higher rates of ACR 20 response at week 24 than placebo. ACR 20 response rates in PSUMMIT 1 were 42.4%, 49.5%, 46.0% and 22.8% for ustekinumab 45 mg, ustekinumab 90 mg, ustekinumab 45 mg and 90 mg pooled, and placebo respectively (p<0.0001 for ustekinumab compared with placebo). Ustekinumab showed similar effectiveness compared with placebo regardless of prior exposure to TNF‑alpha inhibitors. ACR 20 response rates in PSUMMIT 2 for ustekinumab 45 mg, ustekinumab 90 mg, ustekinumab 45 mg and 90 mg pooled, and placebo respectively were: no prior TNF‑alpha inhibitors: 53.5%, 55.3%, 54.4% and 28.6% (p≤0.021 for ustekinumab compared with placebo) TNF‑alpha inhibitor‑exposed: 36.7%, 34.5%, 35.6% and 14.5% (p≤0.011 for ustekinumab compared with placebo). Ustekinumab also demonstrated similar efficacy regardless of concomitant methotrexate use. ACR 20 response rates in PSUMMIT 1 for ustekinumab 45 mg, ustekinumab 90 mg, ustekinumab 45 mg and 90 mg pooled, and placebo respectively were: with concomitant methotrexate: 43.4%, 45.5%, 44.5% and 26.0% without concomitant methotrexate: 41.5%, 53.4%, 47.4% and 20.0%.Corresponding results from PSUMMIT 2 were provided as academic in confidence and therefore cannot be reported here. Longer‑term analyses of the primary outcome suggested that response rates with ustekinumab were maintained over 52 weeks. Response rates in the placebo arm increased after week 24 because of people switching from placebo to ustekinumab. The results from secondary outcome analyses at week 24 generally supported the conclusions from the ACR 20 results. The findings were observed across joint, radiographic, skin, soft tissue and health‑related quality‑of‑life end points, although the results varied between outcomes and between trials, and not all outcomes reached statistical significance in all analyses. For example, for all randomised patients in both PSUMMIT 1 and 2, PsARC response rates with ustekinumab (45 mg and 90 mg pooled) and placebo were 58.0% and 35.2% respectively; PASI 75 response rates (people who had at least 75% improvement in PASI score) with ustekinumab (45 mg and 90 mg pooled) and placebo were 57.6% and 8.8% respectively. For all randomised patients in PSUMMIT 1, the median HAQ‑DI changes from baseline with ustekinumab (45 mg and 90 mg pooled) and placebo were −0.25 and 0.00 respectively (p<0.001). For all these examples, results were similar in individual trials and for individual doses. Longer‑term analyses of PASI 75 responses suggested that response rates with ustekinumab were maintained over 52 weeks. Long‑term analyses of other secondary outcomes were provided as academic in confidence and therefore cannot be reported here. In the absence of head‑to‑head randomised controlled trials, the company presented a mixed treatment comparison using a random‑effects model fitted with Bayesian methodology to explore the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors (adalimumab, etanercept, golimumab and infliximab) in people who had not previously had TNF‑alpha inhibitors (referred to in this document as 'TNF‑alpha inhibitor‑naive'). The company did not carry out a mixed treatment comparison for the TNF‑alpha inhibitor‑exposed population because PSUMMIT 2 is the only trial to have included this population. The mixed treatment comparison focused on PsARC, PASI 75 and PASI 90 responses to treatment at weeks 12–16 and 24, which are consistent with the clinical parameters in the economic model. For ustekinumab, patient‑level data were extracted from PSUMMIT 1 and 2 for a weight‑based dosing subgroup in which patients who weighed 100 kg or less had ustekinumab 45 mg, and patients who weighed more than 100 kg had ustekinumab 90 mg. For the TNF‑alpha inhibitors, data were taken directly from 7 randomised, double‑blind, placebo‑controlled studies carried out in people with active psoriatic arthritis. The company reported that the findings showed that ustekinumab and TNF‑alpha inhibitors have better outcomes than placebo in most analyses. The results of the mixed treatment comparison for PsARC and PASI were marked as academic in confidence and cannot be reported here. It noted that, for the analysis of joint symptoms (PsARC), probabilities of response for ustekinumab were lower than for the TNF‑alpha inhibitors, although the 95% credible intervals for ustekinumab 45 mg overlapped with those of adalimumab, golimumab 50 mg and infliximab. The company reported that in the analyses of skin symptoms, there may be higher probabilities of response with infliximab (PASI 75 and PASI 90), golimumab 100 mg (PASI 75) and adalimumab (PASI 90) compared with other biological drugs, although the credible intervals were overlapping. The company presented adverse event data from the PSUMMIT studies, 5‑year extensions of 4 studies of ustekinumab in psoriasis, the Psoriasis Longitudinal Assessment and Registry and the British Society for Rheumatology Biologics Register. The incidence of adverse events in the PSUMMIT studies was similar in the ustekinumab treatment arms compared with the placebo arms. For all randomised patients in PSUMMIT 1 and 2, the incidences were: ustekinumab 45 mg, 48.4%; 90 mg, 49.4%; 45 mg and 90 mg combined, 48.9%; and placebo, 47.9%. There were no disproportionate increases in adverse event rates over time. The most common adverse reactions seen with ustekinumab in the PSUMMIT trials included nasopharyngitis, upper respiratory tract infection, headache, arthralgia (joint pain), nausea and diarrhoea. The overall rates of study discontinuation because of adverse events were low (and higher with placebo than with ustekinumab); the rates were 3.4%, 1.5% and 1.5% for placebo, ustekinumab 45 mg and ustekinumab 90 mg respectively, in the placebo‑controlled period. The psoriasis extension studies and register data reported no clear dose–response effect or cumulative exposure effect for ustekinumab, and suggested that the rates of serious adverse events were comparable between ustekinumab and TNF‑alpha inhibitors. # Cost effectiveness The company presented a de novo economic analysis that assessed the cost effectiveness of ustekinumab for treating adults with active psoriatic arthritis for whom the response to previous DMARD therapy has been inadequate. Ustekinumab was compared with TNF‑alpha inhibitors and conventional management in people who were TNF‑alpha inhibitor‑naive, and with conventional management only in people who were TNF‑alpha inhibitor‑exposed. The patient populations were based on the populations in the company's mixed treatment comparison and PSUMMIT 1 and 2. It was assumed that all patients who weigh less than 100 kg would have ustekinumab 45 mg, and all those who weigh more than 100 kg would have ustekinumab 90 mg. The model comprised a short‑term decision tree followed by a long‑term Markov model with a lifetime (52‑year) time horizon. It was similar to the models used in previous NICE appraisals of treatments for psoriatic arthritis (etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis). In the decision tree phase, people had initial biological therapy for either 12 weeks (TNF‑alpha inhibitors) or 24 weeks (ustekinumab). At this point, people who had a PsARC response (defined as an improvement in at least 2 of the 4 criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria) continued with biological therapy, and those who did not switched to conventional management. All patients then entered the Markov phase of the model. People having a biological therapy continued to have it until they switched to conventional management, either because the biological therapy lacked efficacy or led to adverse events (at a rate of 16.5% per year for all treatments), or they died. No second biological drug was permitted. The model considered costs from an NHS and personal social services perspective, and all costs and health effects were discounted at a rate of 3.5% per year. For the TNF‑alpha inhibitor‑naive population, ustekinumab was compared with 4 TNF‑alpha inhibitors and conventional management, using clinical effectiveness evidence from the mixed treatment comparison. For the TNF‑alpha inhibitor‑exposed population, ustekinumab was compared with conventional management only, because at the time of the submission there were no randomised controlled trials of TNF‑alpha inhibitors in this population. Analyses of this population were based on clinical effectiveness evidence from the TNF‑alpha inhibitor‑exposed sub‑population of PSUMMIT 2. The model captured health‑related quality of life through joint symptoms, disability and skin symptoms (PsARC response, HAQ‑DI score and PASI score). People who had a PsARC or PASI response were assumed to have a fixed improvement in HAQ‑DI or PASI score respectively. This improvement was maintained until a switch to conventional management, at which point the score returned to its baseline value (rebounded). People who did not have an initial response were assumed to have a smaller improvement in HAQ‑DI or PASI score until withdrawal of active treatment. Throughout periods of conventional management, people's disease progressed according to the natural history of psoriatic arthritis, modelled as a linear increase (worsening) in HAQ‑DI over time and a constant PASI score. HAQ‑DI and PASI scores were then mapped to EQ‑5D using an equation used in previous NICE technology appraisal guidance for etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. Costs and disutilities associated with adverse events were not included in the model. Healthcare resource use was estimated based on NHS reference costs, and included resource use associated with biological and conventional treatments (including initial and follow‑up consultations and blood tests) and resource use as a function of health state (including hospitalisations, surgical interventions and concomitant medications). The acquisition costs for TNF‑alpha inhibitors took into account the patient access scheme for golimumab. Administration costs were included for intravenous infliximab only, because all other biological drugs were assumed to be given by subcutaneous injection at no cost to the NHS. A number of iterations of the economic model were presented by the company: the first in its original submission (referred to in this document as the 'original' model), the second corrected after the clarification stage (referred to in this document as the 'post‑clarification' model), and the third corrected during consultation (referred to in this document as the 'post‑consultation' model). A further iteration, incorporating the patient access scheme and 1 amended assumption, was presented by the company in its submission for the rapid review of NICE technology appraisal guidance 313 (referred to in this document as the 'rapid review' model; see section 3.30). The original model was used to develop base‑case, deterministic and probabilistic sensitivity analyses, and a series of scenario analyses; the results of the base‑case and scenario analyses were replaced by the post‑clarification and post‑consultation models and so are not reported here. The post‑clarification model incorporated corrections requested by the ERG during clarification, including amendments to the probability distributions for some variables and to the costs associated with psoriatic arthritis. The company used this model to develop an updated base case and updated scenario analyses. The post‑consultation model submitted during consultation corrected an error, identified by the company and a consultee during consultation, affecting the acquisition cost of golimumab 100 mg. The cost‑effectiveness evidence presented here for the TNF‑alpha inhibitor‑naive population is based on the results of the post‑consultation model, which replaced the previous models. The cost‑effectiveness evidence presented here for the TNF‑alpha inhibitor‑exposed population is based on the post‑clarification model (because the TNF‑alpha inhibitors were not included as comparators in this population, and therefore the golimumab error did not apply). In the TNF‑alpha inhibitor‑naive population (post‑consultation model, probabilistic results), ustekinumab was associated with total costs of £70,249 and a total of 6.23 quality‑adjusted life years (QALYs). Adalimumab was associated with costs of £64,487 and 6.42 QALYs, and therefore dominated ustekinumab (that is, adalimumab was more effective and less expensive). Adalimumab, in turn, was associated with an additional £31,476 in costs and 1.76 QALYs compared with conventional management, giving an incremental cost‑effectiveness ratio (ICER) of £17,868 per QALY gained. The company also presented pairwise comparisons between ustekinumab and conventional management (post‑consultation model, probabilistic results): ustekinumab provided 1.57 additional QALYs compared with conventional management, at an additional cost of £37,239, giving an ICER of £23,723 per QALY gained. The deterministic sensitivity analyses (original model) showed that the results were most sensitive to the change in HAQ‑DI score over time associated with the natural history of psoriatic arthritis, the proportion of people who had a PsARC response and the HAQ‑DI change associated with PsARC response. In the TNF‑alpha inhibitor‑exposed population (post‑clarification model, probabilistic results), ustekinumab provided an additional 1.41 QALYs compared with conventional management, at an additional cost of £41,199, to give an ICER of £29,132 per QALY gained compared with conventional management. The probabilistic sensitivity analysis (original model) indicated there was a 0% and 67% probability of ustekinumab being cost effective compared with conventional management if the maximum acceptable ICERs were £20,000 and £30,000 per QALY gained respectively. The deterministic sensitivity analyses (original model) showed that the results were most sensitive to the HAQ‑DI score change with the natural history of psoriatic arthritis and the HAQ‑DI change associated with a PsARC response. The company presented a series of scenario analyses for both the TNF‑alpha inhibitor‑naive and ‑exposed populations (post‑clarification model). These explored structural assumptions in the model around the treatment continuation rule (timing and criteria), progression of psoriatic arthritis, and utility and clinical effectiveness estimates. In the TNF‑alpha inhibitor‑naive population, all scenario analyses showed that ustekinumab was more expensive and less effective than adalimumab. Ustekinumab was associated with probabilistic ICERs compared with conventional management ranging from £21,628 to £31,469 per QALY gained. In the scenario in which treatment response was assessed at week 24 for all treatments, ustekinumab was associated with additional costs of £38,222 and an additional 1.28 QALYs compared with conventional management, giving a probabilistic ICER of £29,808 per QALY gained for ustekinumab compared with conventional management. In scenario analyses for the TNF‑alpha inhibitor‑exposed population, ustekinumab was associated with probabilistic ICERs compared with conventional management ranging from £27,606 to £40,019 per QALY gained. In the scenario in which treatment response was assessed at week 24 for all treatments, ustekinumab was associated with additional costs of £43,064 and an additional 1.12 QALYs compared with conventional management, giving a probabilistic ICER of £38,516 per QALY gained for ustekinumab compared with conventional management. # Evidence Review Group's critique and exploratory analyses of the company's submission The ERG carried out exploratory analyses to test whether the clinical effectiveness of ustekinumab was influenced by prior TNF‑alpha inhibitor treatment or ustekinumab dose. It stated that there is no convincing evidence of a substantial difference in the effectiveness of ustekinumab between people who have and people who have not previously had TNF‑alpha inhibitors, and that treatment effects were not statistically significantly different between ustekinumab doses. The ERG identified a number of limitations in the evidence available from the PSUMMIT studies. The switch from placebo to ustekinumab at weeks 16 and 24 provides a short‑term comparison for a chronic condition such as psoriatic arthritis. Analyses of TNF‑alpha inhibitor‑exposed patients included only the 180 patients who had previously had varying numbers of TNF‑alpha inhibitors for varying durations. The ERG emphasised that the analyses of PSUMMIT 2 did not distinguish between people who had previously had 1, 2, 3 or more TNF‑alpha inhibitors, and so did not differentiate between people who had tried only some of the available TNF‑alpha inhibitors and people for whom TNF‑alpha inhibitors as a class had failed. The ERG considered that the data on patients whose disease was truly TNF‑alpha inhibitor refractory were scarce. It was also noted that for many of the secondary outcomes (DLQI, SF‑36 and radiographic scores), baseline scores were not reported, making interpretation of the results difficult. The ERG considered that, despite some heterogeneity between trials, the mixed treatment comparison was appropriate to carry out and the results were robust. It did not consider that the weight‑based dosing subgroup matched the marketing authorisation, and noted that this led to exclusion of a large amount of data. However, the ERG noted that an additional analysis including all patients from PSUMMIT 1 and 2 provided fairly similar results to the weight‑based analysis. The ERG noted that overall, the mixed treatment comparison found that ustekinumab had the lowest or one of the lowest response rates for PASI 75, PASI 90 and PsARC. The ERG noted that the company's economic model was similar to those used in previous NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis, although it had a longer time horizon (52 years compared with 40 years). The ERG considered many of the key assumptions used in the model to be broadly acceptable, including change in PASI score with biological treatment, rebound effect on treatment withdrawal, withdrawal rates in the TNF‑alpha inhibitor‑naive population, exclusion of disutilities and costs for adverse events, the equation used to map HAQ‑DI and PASI to EQ‑5D, resource use, drug and health state costs, and the approach to deterministic sensitivity analysis. The ERG cautioned that the results of the model should be interpreted with care, specifically the pairwise ICERs for ustekinumab compared with conventional management in the TNF‑alpha inhibitor‑naive population; it considered that these ICERs represent a scenario in which ustekinumab is the only alternative to conventional management, which is unrealistic. The ERG highlighted weaknesses in the clinical effectiveness parameters used in the model. It noted that the company used a mixture of results from the mixed treatment comparison for the effectiveness of TNF‑alpha inhibitors and PSUMMIT results for the effectiveness of ustekinumab to obtain HAQ‑DI score changes, and considered that there were limitations to this approach. In addition, PsARC response rates for ustekinumab based on the weight‑based dosing subgroup resulted in a loss of data. The ERG considered both of these issues in exploratory analyses (see sections 3.24 and 3.25). Furthermore, the ERG queried the model assumption that people having conventional management did not have any improvement in PASI, whereas in clinical practice skin symptoms often respond well to DMARDs. The ERG noted the simplifying assumption in the model that people switched to conventional management after failure of the intervention being analysed, and did not have subsequent biological therapies. Thus, the costs and benefits associated with subsequent lines of biological treatment were not included in the model. The ERG stated that in clinical practice in the UK, most people whose disease has failed to respond to 1 TNF‑alpha inhibitor would be considered for subsequent‑line TNF‑alpha inhibitor treatment. The ERG emphasised the uncertainties about the natural history progression of psoriatic arthritis scores during conventional management. This is a key driver of the model. The assumptions underlying the gradual increase in HAQ‑DI scores during conventional management were consistent with previous submissions. However, the ERG noted that the estimate for the rate of progression was prepared from limited data in 2009 but not updated. It also queried whether the assumptions about rebound and progression of arthritis symptoms taken from models of TNF‑alpha inhibitors were applicable to ustekinumab, given its different mechanism of action. The ERG highlighted that the TNF‑alpha inhibitor‑exposed population has not been considered in previous appraisals, and noted some uncertainties in the model for this population. By comparing ustekinumab with conventional management, the company made no distinction between people whose disease had not responded to 1, 2, 3 or more TNF‑alpha inhibitors. That is, it did not differentiate between people who had tried only some of the available TNF‑alpha inhibitors and people for whom TNF‑alpha inhibitors as a class had failed. The ERG stated that, in clinical practice in the UK, most people whose disease has failed to respond to 1 TNF‑alpha inhibitor would be considered for subsequent‑line TNF‑alpha inhibitor treatment. The ERG therefore considered the company's model to have severe limitations, noting that ustekinumab should be compared with other TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population. The ERG further noted that much of the evidence informing the model was drawn from people who had not had prior TNF‑alpha inhibitor therapy. In particular, estimates for the natural history progression of HAQ‑DI (a key driver of the model), mortality rates and treatment withdrawal rates were based on TNF‑alpha inhibitor‑naive populations. It queried whether these assumptions were applicable to the TNF‑alpha inhibitor‑exposed population. The ERG carried out exploratory analyses in both the TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations. These explored the sensitivity of the company's model to assumptions about weight‑based dosing, HAQ‑DI rebound and natural history progression, the time horizon, the timing of treatment response assessment, and the inclusion of phototherapy. In the TNF‑alpha inhibitor‑naive population, the ERG's exploratory analyses showed that, in the incremental analysis (comparing ustekinumab, TNF‑alpha inhibitors and conventional management), ustekinumab remained dominated in all modelled scenarios. Probabilistic ICERs for ustekinumab compared with conventional management ranged from £22,455 to £55,029 per QALY gained. In particular, the ERG's analyses showed that assessing the response to treatment at week 24 for both ustekinumab and conventional management increased the ICER by £6987 per QALY gained, compared with the base case. The ERG presented a preferred base case for the TNF‑alpha inhibitor‑naive population, based on what it considered to be the most plausible assumptions. This consisted of the company's post‑clarification model (see section 3.12), with additional corrections added by the ERG (including amendments to the health state costs, probability distributions and baseline PASI and HAQ‑DI scores), applying the weight‑based dosing assumption to ustekinumab 90 mg only, and using HAQ‑DI scores drawn from an update of the mixed treatment comparison developed by the ERG for the NICE technology appraisal guidance on golimumab for the treatment of psoriatic arthritis. In this analysis, ustekinumab was dominated by adalimumab. Compared with conventional management, ustekinumab was associated with additional costs of £37,123 and an additional 1.6 QALYs, giving a probabilistic ICER compared with conventional management of £23,246 per QALY gained. The ERG also presented exploratory analyses in the TNF‑alpha inhibitor‑exposed population. In these exploratory analyses, ustekinumab was associated with probabilistic ICERs compared with conventional management ranging from £28,670 to £69,139 per QALY gained. The ERG carried out an exploratory sequencing analysis for the TNF‑alpha inhibitor‑exposed population, to examine the cost effectiveness of ustekinumab compared with TNF‑alpha inhibitors, when used as second‑line treatments after failure of first‑line TNF‑alpha inhibitors. The ERG presented 3 scenarios for the sequencing analysis: 2 in which first‑line treatments failed because of lack of effectiveness (the first based on evidence from PSUMMIT 2, and the second based on the ERG's estimates) and a third in which first‑line treatments failed because of adverse events. In the first scenario, ustekinumab was associated with ICERs of £32,818 per QALY gained (compared with adalimumab, when etanercept was used as first‑line treatment) to £37,738 per QALY gained (compared with etanercept, when golimumab or adalimumab were used as first‑line treatment), and in the other 2 scenarios it was dominated by other treatments. However, the ERG stressed that this exploratory analysis was based on numerous assumptions and was subject to considerable uncertainty. The ERG did not present a preferred base case for the TNF‑alpha inhibitor‑exposed population because of the uncertainty remaining in the model. # Company's additional analyses provided during consultation and Evidence Review Group's critique In response to consultation, the company submitted additional evidence exploring the cost effectiveness of the 45‑mg dose of ustekinumab alone, based on the post‑consultation model. The company noted that ustekinumab 45 mg could potentially be considered for all patients. In the base‑case analysis for the TNF‑alpha inhibitor‑naive population, ustekinumab 45 mg was the lowest‑cost and least effective biological treatment. In the TNF‑alpha inhibitor‑exposed population (base case, probabilistic analysis), ustekinumab 45 mg was associated with an ICER of £21,789 per QALY gained compared with conventional management. The company also reproduced the ERG's exploratory sequencing analysis and presented scenario analyses to explore the impact of key assumptions. The ERG submitted a critique of these analyses. It noted that, in principle, the scenario in which all patients have ustekinumab 45 mg is reasonable to explore, but highlighted that there is uncertainty about the validity of this scenario in clinical practice. The ERG applied the 45‑mg dosing assumption to its preferred base case for the TNF‑alpha inhibitor‑naive population (see section 3.24), and noted that the results were generally similar to those presented by the company. For the TNF‑alpha inhibitor‑exposed population, the ERG confirmed that the company had correctly reproduced its exploratory sequencing analysis, although it emphasised that this analysis was highly uncertain because it was based on numerous assumptions. # Further evidence Based on a comment received during consultation from a company that manufactures a comparator drug, further evidence was identified by the technical team that provided long‑term analyses of the change from baseline in HAQ‑DI and radiographic scores with ustekinumab compared with placebo (presented in 2 abstracts and a press release: Kavanaugh et al. 2013, McInnes et al. 2013 and Johnson and Johnson 2013). In a pre‑specified pooled analysis of the radiographic scores in PSUMMIT 1 and 2, the mean changes from baseline to week 24 were 0.40, 0.39 and 0.97 (ustekinumab 45 mg, ustekinumab 90 mg and placebo respectively). The mean changes from baseline to week 52 were 0.58, 0.65 and 1.15 (ustekinumab 45 mg, ustekinumab 90 mg and patients randomised to placebo respectively), showing that ustekinumab inhibited radiographic progression compared with placebo and that this inhibition continued to week 52. Data from PSUMMIT 1 alone were consistent with the pooled analysis. However, in PSUMMIT 2 alone there was no statistically significant difference in radiographic progression between ustekinumab and placebo; the company noted that the studies were not individually powered to detect differences in radiographic progression. A long‑term analysis of HAQ‑DI scores in PSUMMIT 1 showed that the mean changes from baseline to 52 weeks were −0.34, −0.43 and −0.37 in patients randomised to ustekinumab 45 mg, ustekinumab 90 mg and placebo respectively, and the mean changes from baseline at 100 weeks were −0.36, −0.45 and −0.36 (ustekinumab 45 mg, ustekinumab 90 mg and patients randomised to placebo respectively). Long‑term analyses of HAQ‑DI scores in PSUMMIT 2 were not available at the time NICE technology appraisal guidance 313 was prepared. # Rapid review of NICE technology appraisal guidance 313: patient access scheme In NICE technology appraisal guidance 313, ustekinumab was not recommended for treating active psoriatic arthritis. After publication, the company agreed a patient access scheme with the Department of Health (see section 2.3) and submitted revised analyses to be considered in a rapid review of the guidance. Under the original patient access scheme the company provided 2x45 mg pre-filled syringes, for patients who needed the higher dose of 90 mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial. The company submitted a revised economic analysis (the 'rapid review' model) based on its post‑consultation model, incorporating the patient access scheme and an altered assumption about the effect of conventional management on skin symptoms (based on the Committee's considerations in NICE technology appraisal guidance 313). It presented analyses for both the TNF‑alpha inhibitor‑naive and ‑exposed populations. For the TNF‑alpha inhibitor‑exposed population, the company also presented a sequencing analysis. This analysis was developed from the ERG's exploratory sequencing analysis (see section 3.25) and used the scenario in which the first TNF‑alpha inhibitor failed because of lack of efficacy and clinical effectiveness data were taken from the PSUMMIT 2 study. The company considered that including the patient access scheme considerably improved the cost effectiveness of ustekinumab. The patient access scheme was incorporated by reducing the unit cost of ustekinumab 90 mg to £2147. The company estimated the additional costs associated with the patient access scheme to be £33 per patient. It considered that these costs were very small and so would not affect the appraisal; therefore, it did not include them in the economic analyses. The company modelled the effect of conventional management on skin symptoms in the same way as it had modelled the effects of biological drugs in the original model – that is, assuming a fixed improvement in PASI score based on PASI response. As part of this change, the company also amended the rebound assumption for people who withdraw from biological therapy, such that the PASI score rebounded to a score based on the effect of conventional management (rather than the baseline score). The PASI scores and response rates for conventional management were taken from the placebo arms of the company's mixed treatment comparison and the PSUMMIT 1 and 2 studies. In the company's base case for the TNF‑alpha inhibitor‑naive population (rapid review model, probabilistic results, incremental analysis), conventional management was the lowest cost option, followed by ustekinumab then adalimumab. Ustekinumab was therefore the least costly biological drug, and was associated with total costs of £59,105, a total of 6.09 QALYs and an ICER compared with conventional management of £23,164 per QALY gained. Adalimumab had a pairwise ICER compared with conventional management of £21,765 per QALY gained. In the company's base case for the TNF‑alpha inhibitor‑exposed population (rapid review model, probabilistic results), ustekinumab was associated with total costs of £62,724 and a total of 4.08 QALYs. It was associated with an ICER of £25,675 per QALY gained, compared with conventional management. In the sequencing analysis, ustekinumab was associated with deterministic ICERs ranging from £21,241 per QALY gained (compared with etanercept, when adalimumab, golimumab or infliximab are used first line) to £25,921 per QALY gained (compared with conventional management, when etanercept is used first line). For both the TNF‑alpha inhibitor‑naive and exposed populations, the company presented a deterministic sensitivity analysis and scenario analyses consistent with those it presented in the original submission. In both populations, the results were most sensitive to the change in HAQ‑DI score over time associated with the natural history of psoriatic arthritis. In scenarios based on the TNF‑alpha inhibitor‑naive population, ustekinumab was associated with deterministic ICERs compared with conventional management of £21,411 to £29,580 per QALY gained. In equivalent scenarios based on the TNF‑alpha inhibitor‑exposed population, ustekinumab was associated with deterministic ICERs compared with conventional management of £23,229 to £33,578 per QALY gained. In scenarios in which the response to all treatments was assessed at week 24, ustekinumab was associated with ICERs of £27,914 per QALY gained (TNF‑alpha inhibitor‑naive population) and £32,608 per QALY gained (TNF‑alpha inhibitor‑exposed population), compared with conventional management. # Evidence Review Group critique of the company's rapid review submission The ERG noted that the company had appropriately incorporated the patient access scheme into the latest version of the economic model from NICE technology appraisal guidance 313 (the post‑consultation model). It agreed with the company that the additional costs associated with the patient access scheme did not significantly alter the cost effectiveness of ustekinumab. The ERG highlighted that, in the company's model for the TNF‑alpha inhibitor‑naive population, ustekinumab was extendedly dominated in all scenarios. An intervention is 'extendedly dominated' when it is more costly and less effective than a combination of 2 comparators; that is, the ICER for the intervention is higher than that of the next more effective comparator when both are compared with another less effective comparator. In the base case, ustekinumab was extendedly dominated by adalimumab and conventional management, because the ICER for ustekinumab compared with conventional management was higher than that of adalimumab compared with conventional management. The ERG commented on the company's inclusion of the effect of conventional management on skin symptoms. It considered that the company's approach was mostly reasonable. However, the ERG highlighted that the PASI score to which people were assumed to rebound when they stop biological treatment was not the same as the average PASI score for people having conventional management. It noted that this difference resulted from differences in PASI response rates between week 12 (as applied to the conventional management arm) and week 24 (as applied to the biological therapy arms). The ERG commented that the effect of this assumption differed between the TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations. The ERG identified a number of errors in the company's economic model, relating to disease‑related costs, medical resource use, the accrual of QALYs in the second year of the model and the application of discounting. It noted that the errors tended to underestimate the costs and QALYs associated with psoriatic arthritis, and hence tended to underestimate the cost effectiveness of more effective treatments. Consequently, the ERG noted that correcting these errors caused the cost effectiveness of ustekinumab to improve relative to conventional management, but worsen relative to TNF‑alpha inhibitors. The ERG presented a scenario analysis to explore the patient access scheme combined with the Committee's preferred assumptions from NICE technology appraisal guidance 313. This analysis was developed from the company's rapid review model with the errors corrected, a 40‑year time horizon and with the response to both ustekinumab and conventional management assessed at week 24. In this scenario (probabilistic analysis), in the TNF‑alpha inhibitor‑naive population ustekinumab remained extendedly dominated (by a combination of conventional management and adalimumab) and had an ICER of £21,857 per QALY gained compared with conventional management. In the TNF‑alpha inhibitor‑exposed population (probabilistic analysis), the ICER for ustekinumab was £25,292 per QALY gained, compared with conventional management. In the sequencing analysis based on this scenario, ustekinumab was associated with an ICER of £25,393 per QALY gained compared with conventional management, when golimumab, adalimumab or etanercept are used first line. The ERG noted that the time horizon had a small effect on the ICER, whereas the effect of the week‑24 assessment time point was larger. Full details of all the evidence are available.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of ustekinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The Committee considered the current treatment pathway for people with psoriatic arthritis. It heard from the clinical experts that treatment of psoriatic arthritis follows current NICE guidance: after initial treatment with non‑steroidal anti‑inflammatory drugs (NSAIDs) and disease‑modifying antirheumatic drugs (DMARDs), most people have treatment with a tumour necrosis factor (TNF) alpha inhibitor. The Committee heard from the clinical experts and a patient expert that TNF‑alpha inhibitors are the only class of treatments with robustly demonstrated efficacy, because conventional management with DMARDs (such as methotrexate) does not appear to provide substantial benefits for joint‑related aspects of psoriatic arthritis. The Committee noted that the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis recommend TNF‑alpha inhibitor therapy for people with psoriatic arthritis if the person has peripheral arthritis with 3 or more tender joints and 3 or more swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least 2 standard DMARDs (individually or in combination). The guidance also recommends that treatment should normally be started with the least expensive drug (taking into account administration costs, required dose and price per dose), and this may need to be varied for individual patients because of differences in the method of administration and treatment schedules. The Committee heard from the clinical experts that the sequential use of TNF‑alpha inhibitors is established practice in the NHS. Therefore, if the condition fails to respond to, or loses response to, an initial TNF‑alpha inhibitor or if the TNF‑alpha inhibitor causes adverse reactions, a second TNF‑alpha inhibitor will often be used. The Committee heard from the clinical experts that they would consider TNF‑alpha inhibitor treatment to have failed if the person had ongoing joint pain and inflammation despite treatment. The Committee heard from the clinical experts and the patient expert that, although the availability of second‑line TNF‑alpha inhibitors varies across the UK, the sequential use of TNF‑alpha inhibitors is extensive. The patient expert emphasised that when a TNF‑alpha inhibitor is withdrawn because of loss of effectiveness or adverse reactions, the detrimental effect on the patient can be substantial if a subsequent TNF‑alpha inhibitor is not available. In light of comments received during consultation, the Committee noted that the NICE commissioning guide on biologic drugs for the treatment of inflammatory disease in rheumatology, dermatology and gastroenterology does not explicitly recommend sequential use of TNF‑alpha inhibitors in psoriatic arthritis, but considered that both the guide and the published technology appraisals do not preclude this use. The Committee acknowledged the variation in practice across the country, but concluded that the sequential use of TNF‑alpha inhibitors is established practice in the NHS. The Committee considered the likely place of ustekinumab in managing psoriatic arthritis. It heard from the clinical experts that if ustekinumab were to be used in people with prior TNF‑alpha inhibitor exposure, it might be used after 1, 2 or more TNF‑alpha inhibitors, depending on person‑specific factors such as the reason for withdrawing the previous TNF‑alpha inhibitor and individual preferences. For example, if the previous TNF‑alpha inhibitor had no effect or caused class‑related adverse reactions, ustekinumab may be used in preference to another TNF‑alpha inhibitor, whereas if the previous TNF‑alpha inhibitor loses efficacy over time, another TNF‑alpha inhibitor might be chosen before ustekinumab. The Committee concluded that the most appropriate comparators for ustekinumab in most people with psoriatic arthritis would be TNF‑alpha inhibitors, both in people who have not had prior TNF‑alpha inhibitors (referred to in this document as 'TNF‑alpha inhibitor‑naive') and in those who have previously had TNF‑alpha inhibitor therapy (referred to in this document as 'TNF‑alpha inhibitor‑exposed'). The Committee heard from the clinical experts that there is a group of people with psoriatic arthritis for whom TNF‑alpha inhibitors are not suitable, because of contraindications such as heart failure or demyelination, or because of failure of TNF‑alpha inhibitors as a class. For these people there is a considerable unmet need. The Committee understood that this affects a number of people and that for people in this situation there are no effective treatment options. The clinical experts considered that ustekinumab has the potential to offer an innovative treatment option to fulfil this need. The Committee acknowledged that this represents a distinct group with an important unmet need that warrants additional consideration. During consultation, the Committee heard from a company that manufactures a TNF‑alpha inhibitor that the contraindications for ustekinumab and TNF‑alpha inhibitors are relatively similar. It therefore considered that the number of people who had not had TNF‑alpha inhibitor therapy (that is, who were TNF‑alpha inhibitor‑naive), for whom TNF‑alpha inhibitors as a class were contraindicated and for whom ustekinumab might be appropriate was unknown but may be relatively small. The Committee concluded that conventional management would be an appropriate comparator in people for whom TNF‑alpha inhibitors were contraindicated and in people whose condition failed to respond to TNF‑alpha inhibitors as a class. The Committee understood that psoriatic arthritis is a lifelong condition that has a serious impact on people's quality of life. It heard from the patient expert that psoriatic arthritis can develop at a young age, and affects all aspects of a person's life including education, work, self‑care, and social and family life. The Committee heard from the patient expert that skin symptoms can have a major psychological impact, and that the joint symptoms have an even greater impact on the psychological and functional aspects of living with this chronic condition. The Committee recognised the potential value of additional treatment options for people with psoriatic arthritis. # Clinical effectiveness The Committee reviewed the overall clinical effectiveness of ustekinumab. It noted that the evidence for the clinical effectiveness of ustekinumab had been taken from 2 randomised placebo‑controlled trials (PSUMMIT 1 and 2), and acknowledged the need for head‑to‑head studies between ustekinumab and TNF‑alpha inhibitors for psoriatic arthritis. The Committee considered that the evidence suggested that ustekinumab is more effective than placebo after 24 weeks of treatment across a number of joint, skin and soft tissue outcomes. It considered that, although the effect is likely to persist for up to 1 year, there is some uncertainty about this because in the trials people switched from placebo to ustekinumab at week 24. The Committee heard from the clinical experts that ustekinumab appeared to be effective across a wide range of skin and joint outcomes and also soft tissue conditions associated with psoriatic arthritis. The Committee also noted that the results from the PSUMMIT studies suggested there was no statistically significant difference in the clinical effectiveness of ustekinumab compared with placebo between TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations for the Psoriatic Arthritis Response Criteria (PsARC) response. The Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations, but acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab. The Committee considered in detail the evidence on the effect of ustekinumab on radiographic outcomes at 24 weeks and 52 weeks. It noted that the effect of ustekinumab compared with placebo appeared to be different to what has been previously observed in clinical trials of golimumab compared with placebo. In particular, ustekinumab appeared to slow the increase (progression) in radiographic score compared with placebo, whereas golimumab (in the NICE technology appraisal guidance on golimumab for the treatment of psoriatic arthritis) had previously been shown to reduce radiographic score from baseline. Furthermore, ustekinumab had not shown a statistically significant difference from placebo in the PSUMMIT 2 study (which included a TNF‑alpha inhibitor‑exposed population). The Committee heard from the company that interpretation of these findings was subject to 4 key difficulties: Changes in radiographic score were very small. The individual studies were not powered for this end point. There was a high level of missing data in the placebo arm because of patient withdrawal (approximately 23%). The link between radiographic score and quality of life in psoriatic arthritis is uncertain. The Committee considered that the evidence on radiographic progression with ustekinumab should be interpreted with caution and it was not able to reach a conclusion on the effectiveness of ustekinumab compared with TNF‑alpha inhibitors for this outcome. However, it concluded that these results provide some evidence to suggest care is needed when applying assumptions based on TNF‑alpha inhibitors to ustekinumab, and noted that this may affect the validity of some assumptions in the company's economic model (see section 4.11). The Committee considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑naive population. The Committee reviewed the findings of the company's mixed treatment comparison (see section 3.7), and noted that the analysis explored the 3 outcomes used as clinical effectiveness inputs in the economic model (Psoriasis Area and Severity Index 75, PASI 90 and PsARC response rates). It discussed this analysis with the clinical experts, and was aware of the limitations of the mixed treatment comparison. The Committee concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for PASI 75, PASI 90 and PsARC response, particularly for the joint outcome. The Committee also considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population. It was aware that there was limited clinical trial evidence in this setting. It understood from comments received during consultation that there is some evidence for the effectiveness of TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population, but was aware that there was not enough evidence to compare ustekinumab and TNF‑alpha inhibitors. The Committee therefore considered the effectiveness of ustekinumab and TNF‑alpha inhibitors compared with conventional management. Although in the PSUMMIT trials there was no difference in clinical effectiveness between TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations in terms of PsARC response, the Committee heard from the clinical experts that evidence presented at a conference suggested that the effectiveness of ustekinumab measured using the American College of Rheumatology (ACR) criteria may decrease with increasing numbers of prior TNF‑alpha inhibitors. The clinical experts noted that the diminishing effectiveness of ustekinumab in TNF‑alpha inhibitor‑exposed populations is broadly consistent with clinical experience with the TNF‑alpha inhibitors, which appear to show diminishing effectiveness as the number of prior therapies increases. The Committee heard from the clinical experts that there is some uncertainty about the size of the diminishing effect. The Committee heard estimates for the response rate with second‑line TNF‑alpha inhibitors ranging from 20% to 70%. Conversely, the Committee noted comments received during consultation from a company that manufactures a comparator drug (including evidence from a randomised controlled trial of certolizumab pegol and open‑label and observation studies of adalimumab) that suggested that the lower estimates in this range may be too low. The Committee also considered whether there may be any variation in clinical effectiveness depending on the reason for withdrawal of the first TNF‑alpha inhibitor (for example, initial lack of efficacy, gradual loss of efficacy over time or adverse reactions), but it acknowledged that there was not enough evidence for this aspect to be considered further. The Committee concluded that there is still uncertainty about the relative effectiveness of ustekinumab and TNF‑alpha inhibitors in people who have previously had TNF‑alpha inhibitors. The Committee queried whether both the 45‑mg and 90‑mg doses of ustekinumab might potentially be used in clinical practice and, if so, how the doses might be used. It noted that the marketing authorisation for ustekinumab in psoriatic arthritis indicates that 45 mg may be used for all patients and 90 mg may be considered in people who weigh more than 100 kg, concluding that this permits, but does not require, a weight‑based dosing strategy. The Committee also noted that it had not been shown detailed evidence on the relative effectiveness of the 2 doses in people of different weights. The Committee considered the evidence in the European public assessment report published by the European Medicines Agency (EMA), which noted that systemic exposure to ustekinumab (that is, the concentration of ustekinumab in the serum) is similar in people who weigh more than 100 kg and have ustekinumab 90 mg, compared with people who weigh less than 100 kg and have ustekinumab 45 mg. Moreover, the EMA noted that the efficacy of ustekinumab 90 mg (in terms of ACR 20 response) was higher than ustekinumab 45 mg, particularly in people who weigh more than 100 kg, in the PSUMMIT 1 study, although not in PSUMMIT 2. The Committee heard from the company that the dose–response effect based on weight for psoriatic arthritis may not be as strong as seen in psoriasis and that the differences between doses were not statistically significant. The Committee also considered evidence from the Evidence Review Group (ERG), which suggested that there was no statistically significant difference in clinical effectiveness between the higher and lower doses, although it was noted that this did not imply the doses are equivalent. The Committee heard from the clinical experts that if ustekinumab were recommended, they would anticipate using both the 45‑mg and 90‑mg doses in clinical practice (rather than only the 45‑mg dose). The Committee acknowledged that there is no clear evidence to support the use of a strict weight‑based dosing strategy, although it concluded that both the 45‑mg and 90‑mg doses would be expected to be used in clinical practice. # Cost effectiveness The Committee considered the structure, assumptions and results in the company's economic model and the critique presented by the ERG. In particular, it discussed key assumptions about the improvement, rebound and progression of joint symptoms, the effect of conventional management on skin symptoms, the use of the utility equation, the timing of the assessment of response and the sequencing of biological treatments in the TNF‑alpha inhibitor‑exposed population. It then reviewed the effect of these assumptions on the cost‑effectiveness estimates for ustekinumab. The Committee also considered the additional analyses incorporating the patient access scheme, presented during the rapid review. The Committee noted that the assumptions about the improvement, rebound and progression of joint symptoms (as captured using the Health Assessment Questionnaire Disability Index ) were key drivers of the economic model. It noted that the approach used in the company's model (in which HAQ‑DI improved by a fixed amount, giving an improved HAQ‑DI score that was maintained at a constant level for the duration of biological treatment, rebounded after treatment withdrawal and then gradually deteriorated during conventional management ) was consistent with the models used in previous NICE technology appraisal guidance on TNF‑alpha inhibitors for psoriatic arthritis (etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis). It heard from the clinical experts that HAQ‑DI is an acceptable and sensitive treatment outcome measure. The clinical experts noted that the HAQ‑DI rebound effect on withdrawal of TNF‑alpha inhibitors is not necessarily immediate, but may be associated with a lag of approximately 6 to 12 months, which may also apply to ustekinumab. Furthermore, the Committee considered it possible that the assumption that people have a fixed improvement in HAQ‑DI that is maintained during treatment may not apply to ustekinumab, because it has a different mechanism of action to TNF‑alpha inhibitors. The observed differences in radiographic progression (see section 4.6) may provide some support for this suggestion. Conversely, the Committee understood that the radiographic progression results must be interpreted with caution, and also noted evidence from the PSUMMIT 1 study on HAQ‑DI scores with ustekinumab after 52–100 weeks that did not suggest a substantial worsening over time (see section 3.28; long‑term analyses of HAQ‑DI scores in PSUMMIT 2 were not available at the time NICE technology appraisal guidance 313 was prepared). The Committee considered it possible that there may be some worsening of HAQ‑DI score during ustekinumab treatment, and that this would be likely to decrease the cost effectiveness of ustekinumab, although the size of this effect is unknown. The Committee acknowledged that there is a lack of robust evidence to reliably inform these assumptions, but would have liked to have seen an assessment of the effect on the model results of worsening HAQ‑DI over time during ustekinumab treatment. The Committee concluded that uncertainty remains as to how well the HAQ‑DI assumptions apply to ustekinumab, but considered that the assumptions in the model were a sufficient basis on which to make a decision. The Committee considered the way in which the effect of conventional management on skin symptoms had been modelled. It noted that the company's original, post‑clarification and post‑consultation models (see section 3.12) assumed that conventional management strategies did not affect skin symptoms, but heard that the ERG's clinical adviser stated that in practice, DMARDs such as methotrexate often improve psoriasis symptoms. During consultation the Committee received additional information, from a company that manufactures a comparator drug, on the effect of conventional management on skin symptoms, taken from a study of adalimumab. In the rapid review, the Committee noted that the company updated its model to incorporate the effect of conventional management on skin symptoms. It heard from the ERG that the modelling approach was consistent with the approach taken for biological treatments in the original model, and understood that the ERG considered this mostly reasonable. The Committee concluded that it was appropriate to include the effect of conventional management on skin symptoms in the economic model. The Committee noted that the company's base‑case analysis was based on utility scores derived using a previously published equation used in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. However, it also noted that health‑related quality‑of‑life evidence had been captured directly in the PSUMMIT studies through the 36‑item Short‑Form Health Survey (SF‑36). The Committee understood that the company used the SF‑36 data to derive an alternative utility equation, and that the impact of this approach on the model results was examined in a sensitivity analysis. However, it further noted that this alternative utility equation was subject to uncertainty, because of a need to map from SF‑36 to EQ‑5D using evidence from people without psoriatic arthritis. The Committee considered that all health‑related quality‑of‑life evidence from the clinical trials – including the SF‑36 data – should ideally be used if possible. However, because of the uncertainty in the newer utility equation, and the fact that the effectiveness of ustekinumab in the PSUMMIT trials was captured through the HAQ‑DI and PASI scores, the Committee concluded that using the previously published equation would be more appropriate and would support a consistent approach between appraisals. The Committee considered the appropriateness of assessing treatment responses at week 12 for TNF‑alpha inhibitors and conventional management, and week 24 for ustekinumab. It heard from the clinical experts that there is some uncertainty about when ustekinumab begins to take effect, although its onset of action may be slower than TNF‑alpha inhibitors. The clinical experts stated that DMARDs such as methotrexate often show little or no effect after 12 weeks, and if they do provide benefits these may arise with longer treatment. It was suggested by the clinical experts that there is no specific reason why ustekinumab and TNF‑alpha inhibitors should be assessed at the same time point, because they are different treatments, although the use of different time points in the economic model is likely to favour ustekinumab. The Committee heard during consultation that the British Society for Rheumatology guidelines define a therapeutic trial of DMARDs as at least 12 weeks, although it noted that this did not preclude assessment of response at 24 weeks. The Committee concluded that, for pairwise comparisons between ustekinumab and conventional management, the treatment response should ideally have been assessed at the same time point. The Committee had a preference for assessing treatment response at 24 weeks for both ustekinumab (in line with its summary of product characteristics and the primary efficacy analysis of the PSUMMIT 1 and 2 studies) and conventional management. However, it understood that the company considered that there was no intrinsic reason why the timing of the assessment for ustekinumab and conventional management in the economic model must be the same, and that assessing the response to conventional management at 24 weeks would be inconsistent with NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. The Committee noted that assessing the response to conventional management at week 24 rather than week 12 increased the incremental cost‑effectiveness ratio (ICER) for ustekinumab. The Committee considered the impact of sensitivity analyses and scenario analyses on the results of the economic model. It noted that the company and the ERG presented a number of analyses (see sections 3.12, 3.24, 3.30 and 3.40). The Committee noted that the model was highly sensitive to assumptions about the HAQ‑DI score. In addition to the key assumptions explored in sections 4.11–14, the Committee noted that there were further assumptions that were subject to uncertainty, but which had little impact on the results of the model. It noted that the company's weight‑based dosing approach did not appear to substantially influence the results of the economic model. The Committee also noted that the longer time horizon in the company's model compared with previous models did not dramatically affect the results, although it highlighted that a 40‑year time horizon was preferable to ensure consistency with previous appraisals. During consultation, a consultee noted that the withdrawal rate for ustekinumab had been taken from studies of TNF‑alpha inhibitors, and that it may be more appropriate to use the withdrawal rate from the PSUMMIT studies. The Committee heard from the company that the withdrawal rate in PSUMMIT 1 was lower than that included in the model. However, the Committee was also aware that this rate was derived from a study of 2 years' duration and the long‑term withdrawal rate for ustekinumab is unknown, but the economic model had a lifetime time horizon. The effect of this assumption on the model was not presented, but the Committee considered that if the withdrawal rate were lower than 16.5%, the ICERs for ustekinumab might be expected to decrease by a small amount. The Committee concluded that the weight‑based dosing assumption, the time horizon and the withdrawal rate were not key drivers of the economic model and they did not have a substantial effect on the ICERs. The Committee considered the appropriateness of appraising ustekinumab 45 mg alone, in light of the additional analyses presented by the company and the ERG (see sections 3.26 and 3.27). Based on input from the clinical experts, the Committee considered that both the 45‑mg and 90‑mg doses were likely to be used in clinical practice (see section 4.9). The Committee also considered whether appraising ustekinumab 45 mg alone could lead to unfair or discriminatory recommendations, if the higher dose were more effective in people weighing more than 100 kg. The Committee concluded that, based on the likely use of ustekinumab in clinical practice and the potential for effectiveness differences between the doses (particularly in people weighing more than 100 kg), it would not be appropriate for it to consider ustekinumab 45 mg alone. The Committee considered the analyses incorporating the patient access scheme provided by the company and the ERG for the rapid review of NICE technology appraisal guidance 313. It noted that the ERG had corrected errors in the company's model, and considered these corrections appropriate. The Committee considered that it would have been preferable to include the additional costs associated with the patient access scheme in the model, although it understood that the effects of these costs on the results would be small. The Committee noted that the company had incorporated the effect of conventional management on skin symptoms in its base case, and that the ERG had incorporated this assumption along with the assessment of treatment response at week 24 for both conventional management and ustekinumab and a 40‑year time horizon in its scenario analysis. The Committee considered that the probabilistic ICERs, when available, were more informative than the deterministic ICERs. It concluded that the ERG's scenario analysis (see section 3.40) reflected the Committee's preferred assumptions and therefore provided the most informative results and the most plausible ICERs, although it noted that the ICERs would decrease if the response to conventional management were assessed at week 12. The Committee considered the cost effectiveness of ustekinumab in the TNF‑alpha inhibitor‑naive population. It considered the incremental analysis to be appropriate for most people with psoriatic arthritis, for whom TNF‑alpha inhibitors are the most appropriate comparator (see section 4.2). The Committee noted that, with the patient access scheme, ustekinumab was the lowest‑cost biological treatment but was extendedly dominated (that is, was more expensive and less effective than a combination of 2 comparators). Moreover, the Committee noted that the cost‑effectiveness analyses were subject to uncertainty because of the potential effect of a possible increase in HAQ‑DI during ustekinumab treatment, which would be expected to reduce the cost effectiveness of ustekinumab. The Committee concluded that ustekinumab is not a cost‑effective option, compared with TNF‑alpha inhibitors, for treating psoriatic arthritis in people who have not previously had TNF‑alpha inhibitors. The Committee also considered the cost effectiveness of ustekinumab in people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are contraindicated. It considered that this population comprises people for whom a TNF‑alpha inhibitor would otherwise be considered (as per the criteria described in etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis, see section 4.1). In this population, the Committee considered that conventional management is the most appropriate comparator. It emphasised that ustekinumab is innovative for this population, because it potentially fulfils an important unmet need. It noted that the number of people in this situation was unknown and may be very small, although it was aware of the need to identify subgroups for which the technology may be cost effective. Moreover, the Committee noted that no evidence had been presented specifically for this population; the available evidence was drawn from the PSUMMIT studies, which were likely to have included a mixture of people for whom TNF‑alpha inhibitors would and would not be appropriate. The Committee noted that when the patient access scheme was applied and its preferred assumptions were incorporated, the most plausible ICER was £21,900 per quality‑adjusted life year (QALY) gained, compared with conventional management. Although it considered that this ICER was still subject to uncertainty because of the possible increase in HAQ‑DI during ustekinumab treatment (see section 4.11), the Committee noted that the ICER would be lower if the response to conventional management were assessed at week 12. It was also conscious that there is considerable unmet need in this population and that ustekinumab is an innovative treatment in this setting. The Committee therefore concluded that ustekinumab is a cost‑effective option for treating psoriatic arthritis in people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are contraindicated. The Committee considered the cost effectiveness of ustekinumab in the TNF‑alpha inhibitor‑exposed population. It noted that for most people, an alternative TNF‑alpha inhibitor is the most appropriate comparator, which was not presented in the company's original submission. The Committee therefore considered the exploratory sequencing analysis initially presented by the ERG, noting that the analysis was reproduced by the company in its rapid review model. This analysis assessed the cost effectiveness of ustekinumab and TNF‑alpha inhibitors when used as second‑line treatments, when first‑line treatment with a TNF‑alpha inhibitor had failed because of lack of efficacy or adverse reactions, and comprised an incremental comparison of ustekinumab, TNF‑alpha inhibitors and conventional management. The ERG and the Committee acknowledged that this analysis is subject to considerable uncertainty. This was because there was no distinction between people whose disease showed no initial response to TNF‑alpha inhibitors and those for whom TNF‑alpha inhibitors failed during long‑term treatment; the clinical experts noted that these groups represent 2 distinct populations. Nevertheless, the Committee considered that this exploratory analysis provided useful information for establishing a full picture of the cost effectiveness of ustekinumab. The Committee considered that the most informative scenario was the one in which the first‑line TNF‑alpha inhibitor failed because of lack of efficacy and clinical effectiveness data for ustekinumab were taken directly from PSUMMIT 2, and noted that this analysis was the most favourable for ustekinumab. With the patient access scheme and the preferred assumptions incorporated, the Committee noted that in the incremental analysis, the most plausible ICER for ustekinumab was £25,400 per QALY gained (compared with conventional management). The Committee was aware that the ICER was subject to uncertainty because of the possible increase in HAQ‑DI during ustekinumab treatment, and noted that the ICER would decrease if the response to conventional management were assessed at week 12. The Committee understood that this analysis was uncertain, but concluded that it was reasonable to recommend ustekinumab as a treatment option for people who have previously had TNF‑alpha inhibitors and for whom treatment with a subsequent TNF‑alpha inhibitor is appropriate. The Committee considered the cost effectiveness of ustekinumab in the TNF‑alpha inhibitor‑exposed population, looking specifically at people for whom TNF‑alpha inhibitors as a class had failed. It understood the important unmet need for people in this situation. The Committee also understood that there is limited evidence for this population, because the PSUMMIT 2 study included a mixture of people for whom subsequent TNF‑alpha inhibitors would and would not be appropriate. It highlighted that conventional management is an appropriate comparator in this population. With the patient access scheme and preferred assumptions incorporated, the Committee considered that the most plausible ICER compared with conventional management in the TNF‑alpha inhibitor‑exposed population was £25,300 per QALY gained. Similarly to the TNF‑alpha inhibitor‑naive population, the Committee understood that this ICER was still subject to uncertainty because of the possible increase in HAQ‑DI during ustekinumab treatment, although it noted that the ICER would decrease if the response to conventional management were assessed at week 12. The Committee was also aware of the considerable unmet need in this population. The Committee concluded that ustekinumab is a cost‑effective option for treating psoriatic arthritis in people who have previously had TNF‑alpha inhibitor therapy and for whom TNF‑alpha inhibitors as a class have failed. The Committee discussed the recommendation to stop treatment based on an inadequate PsARC response in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. The Committee noted that the economic analyses (in all populations) were based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 24 weeks stop treatment with ustekinumab. The Committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as defined in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis) was also appropriate for ustekinumab (assessed at 24 weeks). It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. The Committee considered evidence from the company on the innovative nature of ustekinumab. It heard from the clinical experts that they considered ustekinumab to be an innovative technology, because it is in a different class to the TNF‑alpha inhibitors and targets a different inflammatory pathway. They considered ustekinumab to be a particularly valuable treatment option in people for whom TNF‑alpha inhibitors are not appropriate. The Committee noted that there is an important unmet need in people for whom TNF‑alpha inhibitors are inappropriate or not effective. However, the Committee considered that, although the introduction of TNF‑alpha inhibitors represented a 'step change' in managing psoriatic arthritis, evidence from the mixed treatment comparison suggested that ustekinumab may be less effective than TNF‑alpha inhibitors, and so ustekinumab does not represent a clear‑cut further step change compared with TNF‑alpha inhibitors. The Committee also considered the innovative nature of ustekinumab for people for whom TNF‑alpha inhibitors are inappropriate. It understood that some of the contraindications for TNF‑alpha inhibitors also apply to ustekinumab, so ustekinumab would not be appropriate for all people for whom TNF‑alpha inhibitors are unsuitable. The Committee considered that all of the health‑related benefits associated with ustekinumab had been adequately captured in the economic model, and no changes to the recommendations were needed for that reason. The patient expert highlighted that people with psoriatic arthritis often have concerns about the long‑term safety of treatments for this condition. The Committee was aware of registers that collect evidence on the long‑term treatment outcomes with TNF‑alpha inhibitors for rheumatoid arthritis and psoriasis. The patient expert and the clinical experts emphasised the importance of collecting long‑term data on psoriatic arthritis specifically. The Committee concluded that long‑term evidence on the effectiveness and safety of biological treatments for psoriatic arthritis would be valuable. # Summary of Appraisal Committee's key conclusions TA340 Appraisal title: Ustekinumab for treating active psoriatic arthritis (rapid review of technology appraisal guidance 313) Section Key conclusion Ustekinumab is recommended as an option, alone or in combination with methotrexate, for treating active psoriatic arthritis in adults only when: treatment with tumour necrosis factor (TNF) alpha inhibitors is contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis) or the person has had treatment with 1 or more TNF‑alpha inhibitors. Ustekinumab is recommended only if the company provides the 90 mg dose of ustekinumab for people who weigh more than 100 kg at the same cost as the 45 mg dose, as agreed in the patient access scheme. The Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations. However, based on evidence from the company's mixed treatment comparison, it concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for Psoriasis Area and Severity Index (PASI) 75, PASI 90 and Psoriatic Arthritis Response Criteria (PsARC) response rates, particularly for the joint outcome. The Committee concluded that ustekinumab is not a cost‑effective option in people who have not previously had TNF‑alpha inhibitors. Ustekinumab was the lowest‑cost biological treatment, but was extendedly dominated (that is, was more expensive and less effective than a combination of 2 comparators). The Committee concluded that, with the patient access scheme, ustekinumab is a cost‑effective option for treating psoriatic arthritis: In people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are inappropriate; the most plausible incremental cost effectiveness ratio (ICER) was £21,900 per quality‑adjusted life year (QALY) gained, compared with conventional management. In people who have previously had TNF‑alpha inhibitors and for whom treatment with a subsequent TNF‑alpha inhibitor is appropriate; in the incremental analysis, the most plausible ICER was £25,400 per QALY gained (compared with conventional management). In people who have previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors as a class have failed; the most plausible ICER was £25,300 per QALY gained, compared with conventional management. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard from clinical experts and a patient expert that TNF‑alpha inhibitors are the only class of treatments with robustly demonstrated efficacy, because conventional management with disease‑modifying antirheumatic drugs (DMARDs), such as methotrexate, does not appear to provide substantial benefits for joint‑related aspects of psoriatic arthritis. The Committee heard from the clinical experts that there is a group of people with psoriatic arthritis for whom TNF‑alpha inhibitors are not suitable, because of contraindications such as heart failure or demyelination, or because of failure of TNF‑alpha inhibitors as a class. For these people there is a considerable unmet need. The Committee understood that psoriatic arthritis is a lifelong condition that has a serious impact on people's quality of life. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? Clinical experts considered ustekinumab to be a particularly valuable treatment option in people for whom TNF‑alpha inhibitors are not appropriate. The Committee noted that there is an important unmet need in people for whom TNF‑alpha inhibitors are inappropriate or not effective. The Committee considered that, although the introduction of TNF‑alpha inhibitors represented a 'step change' in managing psoriatic arthritis, evidence from the mixed treatment comparison suggested that ustekinumab may be less effective than TNF‑alpha inhibitors, and so ustekinumab does not represent a clear‑cut further step change compared with TNF‑alpha inhibitors. The Committee considered that ustekinumab is innovative for people for whom TNF‑alpha inhibitors are inappropriate. What is the position of the treatment in the pathway of care for the condition? Ustekinumab has a UK marketing authorisation for use alone or in combination with methotrexate 'for the treatment of active psoriatic arthritis in adult patients when the response to previous non‑biological DMARD therapy has been inadequate'. The Committee heard from the clinical experts that treatment of psoriatic arthritis follows current NICE guidance: after initial treatment with non‑steroidal anti‑inflammatory drugs (NSAIDs) and DMARDs, most people have treatment with a TNF‑alpha inhibitor. The Committee noted that the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis recommend TNF‑alpha inhibitor therapy for people with psoriatic arthritis, and also recommend that treatment should normally be started with the least expensive drug (taking into account administration costs, required dose and price per dose). The Committee heard from the clinical experts that if ustekinumab were to be used in people with prior TNF‑alpha inhibitor exposure, it might be used after 1, 2 or more TNF‑alpha inhibitors, depending on person‑specific factors. The Committee concluded that the most appropriate comparators for ustekinumab in most people with psoriatic arthritis would be TNF‑alpha inhibitors, both in people who have not had prior TNF‑alpha inhibitors and in those who have previously had TNF‑alpha inhibitor therapy. It also concluded that conventional management would be an appropriate comparator in people for whom TNF‑alpha inhibitors were contraindicated and in people whose condition failed to respond to TNF‑alpha inhibitors as a class. Adverse reactions N/A (The Committee made no specific conclusions about adverse reactions.) Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that the evidence for the clinical effectiveness of ustekinumab had been taken from 2 randomised placebo‑controlled trials (PSUMMIT 1 and 2). The Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations, but acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab. The Committee considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑naive population. The Committee reviewed the findings of the company's mixed treatment comparison and discussed them with the clinical experts, and was aware of the limitations of the mixed treatment comparison. It concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for PASI 75, PASI 90 and PsARC response, particularly for the joint outcome. Relevance to general clinical practice in the NHS N/A (The Committee made no specific conclusions about relevance to general clinical practice in the NHS.) Uncertainties generated by the evidence The Committee considered that, although the effect of ustekinumab is likely to persist for up to 1 year, there is some uncertainty about this because in the trials people switched from placebo to ustekinumab at week 24. It considered that the evidence on radiographic progression with ustekinumab should be interpreted with caution. It also acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab. The Committee was aware of the limitations of the mixed treatment comparison. The Committee concluded that there is still uncertainty about the relative effectiveness of ustekinumab and TNF‑alpha inhibitors in people who have previously had TNF‑alpha inhibitors. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑naive population. It concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for PASI 75, PASI 90 and PsARC response, particularly for the joint outcome. The Committee also considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population. It was aware that there was limited clinical trial evidence in this setting. It understood that there is some evidence for the effectiveness of TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population, but that there was not enough evidence to compare ustekinumab and TNF‑alpha inhibitors. Evidence presented at a conference suggested that the effectiveness of ustekinumab measured using the American College of Rheumatology (ACR) criteria may decrease with increasing numbers of prior TNF‑alpha inhibitors. The Committee concluded that there is still uncertainty about the relative effectiveness of ustekinumab and TNF‑alpha inhibitors in people who have previously had TNF‑alpha inhibitors. The Committee also considered whether there may be any variation in clinical effectiveness depending on the reason for withdrawal of the first TNF‑alpha inhibitor but it acknowledged that there was not enough evidence for this aspect to be considered further. The Committee acknowledged that there is no clear evidence to support the use of a strict weight‑based dosing strategy. Estimate of the size of the clinical effectiveness including strength of supporting evidence In both PSUMMIT 1 and 2, ustekinumab was associated with statistically significantly higher rates of ACR 20 response at week 24 than placebo. ACR 20 response rates in PSUMMIT 1 were 46.0% and 22.8% for ustekinumab 45 mg and 90 mg pooled, and placebo respectively (p<0.0001). The Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations, but acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab. Evidence for cost effectiveness Availability and nature of evidence The company's economic model comprised a short‑term decision tree followed by a long‑term Markov model with a lifetime (52‑year) time horizon. It was similar to the models used in previous NICE appraisals of treatments for psoriatic arthritis (etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis). The Committee considered the structure, assumptions and results in the company's economic model and the critique presented by the Evidence Review Group (ERG). Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee discussed key assumptions about the improvement, rebound and progression of joint symptoms, the effect of conventional management on skin symptoms, the use of the utility equation, the timing of the assessment of response and the sequencing of biological treatments in the TNF‑alpha inhibitor‑exposed population. The Committee concluded that uncertainty remains as to how well the Health Assessment Questionnaire Disability Index (HAQ‑DI) assumptions apply to ustekinumab, but considered that the assumptions in the model were a sufficient basis on which to make a decision. The Committee noted that the company's rapid review model incorporated the effect of conventional management on skin symptoms. It concluded that it was appropriate to include the effect of conventional management on skin symptoms in the economic model. The Committee considered that all health‑related quality‑of‑life evidence from the clinical trials – including the 36‑item Short‑Form Health Survey (SF‑36) data – should ideally be used if possible. However, because of the uncertainty in the newer utility equation, it concluded that using the previously published equation would be more appropriate. The Committee concluded that, for pairwise comparisons between ustekinumab and conventional management, the treatment response should ideally have been assessed at the same time point. The Committee had a preference for assessing treatment response at 24 weeks for both ustekinumab (in line with its summary of product characteristics and the primary efficacy analysis of the PSUMMIT 1 and 2 studies) and conventional management. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? The model captured health‑related quality of life through joint symptoms, disability and skin symptoms (PsARC response, HAQ‑DI score and PASI score). HAQ‑DI and PASI scores were then mapped to EQ‑5D using an equation used in previous technology appraisal guidance for etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. The Committee noted that the company's base‑case analysis was based on utility scores derived using a previously published equation used in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. It also noted that health‑related quality‑of‑life evidence had been captured directly in the PSUMMIT studies through SF‑36. The Committee considered that all health‑related quality‑of‑life evidence from the clinical trials – including the SF‑36 data – should ideally be used if possible. However, because of the uncertainty in the newer utility equation, and the fact that the effectiveness of ustekinumab in the PSUMMIT trials was captured through the HAQ‑DI and PASI scores, the Committee concluded that using the previously published equation would be more appropriate. Are there specific groups of people for whom the technology is particularly cost effective? The Committee concluded that ustekinumab is not a cost‑effective option, compared with TNF‑alpha inhibitors, for treating psoriatic arthritis in people who have not previously had TNF‑alpha inhibitors. The Committee also considered the cost effectiveness of ustekinumab in people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are contraindicated. It considered that this population comprises people for whom a TNF‑alpha inhibitor would otherwise be considered. It concluded that ustekinumab is a cost‑effective treatment option for this group. The Committee concluded that ustekinumab is a cost‑effective option for treating psoriatic arthritis in people who have had previous treatment with TNF‑alpha inhibitors. What are the key drivers of cost effectiveness? Deterministic sensitivity analyses showed that the results were most sensitive to the change in HAQ‑DI score over time associated with the natural history of psoriatic arthritis, the proportion of people who had a PsARC response, and the HAQ‑DI change associated with PsARC response. In particular, the Committee discussed key assumptions about the improvement, rebound and progression of joint symptoms, the effect of conventional management on skin symptoms, the use of the utility equation, the timing of the assessment of response and the sequencing of biological treatments in the TNF‑alpha inhibitor‑exposed population. Most likely cost‑effectiveness estimate (given as an ICER) With the patient access scheme: In the TNF‑alpha inhibitor‑naive population, ustekinumab was extendedly dominated (that is, was more expensive and less effective than a combination of 2 comparators). In people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are inappropriate because of contraindications, the Committee concluded that the most plausible ICER was £21,900 per QALY gained. In the TNF‑alpha inhibitor‑exposed population, the Committee noted that in the incremental analysis, the most plausible ICER was £25,400 per QALY gained (compared with conventional management). In the TNF‑alpha inhibitor‑exposed population, looking specifically at people for whom TNF‑alpha inhibitors as a class had failed, the Committee considered that the most plausible ICER for ustekinumab compared with conventional management was £25,300 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health, in which the company provides the 90‑mg dose (2 vials) at the same cost as the 45‑mg dose (1 vial), for people who weigh more than 100 kg and need the higher dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End‑of‑life considerations N/A Equalities considerations and social value judgements The Committee also considered whether appraising ustekinumab 45 mg alone could lead to unfair or discriminatory recommendations, if the higher dose were more effective in people weighing more than 100 kg. It concluded that, based on the likely use of ustekinumab in clinical practice and the potential for effectiveness differences between the doses (particularly in people weighing more than 100 kg), it would not be appropriate for it to consider ustekinumab 45 mg alone. The Committee noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC. , 4.22# Recommendations for further research The Committee considered that there is an important need for head‑to‑head comparisons between biological treatments for psoriatic arthritis, particularly in people for whom treatment with tumour necrosis factor (TNF) alpha inhibitors has been unsuccessful.# Review of guidance The guidance on this technology will be considered for review 3 years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMay 2015# Changes after publication March 2017: under the original patient access scheme the company provided 2x45‑mg pre-filled syringes, for patients who needed the higher dose of 90‑mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme has been withdrawn because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial. ISBN: 978‑1‑4731‑1156‑1	{'Guidance': "Ustekinumab is recommended as an option, alone or in combination with methotrexate, for treating active psoriatic arthritis in adults only when:\n\ntreatment with tumour necrosis factor (TNF) alpha inhibitors is contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis) or\n\nthe person has had treatment with 1 or more TNF–alpha inhibitors.\n\nUstekinumab treatment should be stopped if the person's psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 24\xa0weeks. An adequate response is defined as an improvement in at least 2\xa0of the 4\xa0criteria (1 of which must be joint tenderness or swelling score), with no worsening in any of the 4\xa0criteria. As recommended in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, people whose disease has a Psoriasis Area and Severity Index (PASI)\xa075 response but whose PsARC response does not justify continuing treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see NICE technology appraisal guidance on ustekinumab for the treatment of adults with moderate to severe psoriasis).\n\nWhen using the Psoriatic Arthritis Response Criteria (PsARC) healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.\n\nPeople whose treatment with ustekinumab is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue ustekinumab until they and their NHS clinician consider it appropriate to stop.", 'The technology ': "Ustekinumab (Stelara, Janssen) is a monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin‑12 (IL‑12) and interleukin‑23 (IL‑23). It is administered by subcutaneous injection. Ustekinumab has a marketing authorisation in the UK for use alone or in combination with methotrexate 'for the treatment of active psoriatic arthritis in adult patients when the response to previous non‑biological disease‑modifying antirheumatic drug (DMARD) therapy has been inadequate'.\n\nThe summary of product characteristics lists the following common adverse reactions for ustekinumab: dental and upper respiratory tract infections, nasopharyngitis, dizziness, headache, oropharyngeal pain, diarrhoea, nausea, pruritus, back pain, myalgia, arthralgia, fatigue, injection‑site erythema and injection‑site pain. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe list price for ustekinumab is £2147 per 45‑mg vial (excluding VAT; British national formulary online [accessed February 2015]). The recommended dose of ustekinumab is an initial dose of 45\xa0mg, followed by a dose 4\xa0weeks later and further doses every 12\xa0weeks thereafter. A dose of 90\xa0mg may be used in people with a body weight over 100\xa0kg. The summary of product characteristics notes that consideration should be given to stopping treatment in people whose psoriatic arthritis has shown no response after up to 28\xa0weeks of treatment. The average annual acquisition cost for ustekinumab 45\xa0mg is £10,735 in the first year and £9304 per year thereafter. The company has agreed a patient access scheme with the Department of Health, in which the company provides the 90‑mg dose (2\xa0vials) at the same cost as the 45‑mg dose (1\xa0vial), for people who weigh more than 100\xa0kg and need the higher dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.", "The company's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by Janssen as part of NICE technology appraisal guidance 313, further evidence submitted by Janssen as part of the rapid review and reviews of these submissions by the Evidence Review Group (ERG; section\xa09).\n\n# Clinical effectiveness\n\nEvidence on the clinical effectiveness of ustekinumab was taken from 2\xa0clinical studies – PSUMMIT\xa01 and\xa02. Both were randomised, double‑blind, placebo‑controlled, phase\xa0III studies in adults with active psoriatic arthritis despite current or previous treatment. The studies were almost identical, except for the previous treatment: PSUMMIT\xa01 (n=615) included people who had previously had disease‑modifying antirheumatic drugs (DMARDs) with or without non‑steroidal anti‑inflammatory drugs (NSAIDs) only, whereas PSUMMIT\xa02 (n=312) also included people who had previously had tumour necrosis factor (TNF) alpha inhibitors. People in both trials generally had long‑standing moderate to severe active psoriatic arthritis with impaired physical function and high numbers of tender and swollen joints. In both PSUMMIT\xa01 and\xa02, approximately 70% of patients had skin disease, and 80–90% of patients had received prior DMARD therapy. Of the 180\xa0people in PSUMMIT\xa02 who had previously had TNF‑alpha inhibitors (referred to in this document as 'TNF‑alpha inhibitor‑exposed'), more than half had received at least 2\xa0biological drugs. In both studies, patients were randomised to ustekinumab 45\xa0mg or 90\xa0mg (administered at 0\xa0and 4\xa0weeks, then every 12\xa0weeks thereafter) or placebo. People in the placebo group switched to have ustekinumab 45\xa0mg after 16\xa0weeks (if they had less than 5% improvement in both tender and swollen joint counts) or 24\xa0weeks (all others), and people whose disease did not respond to the 45‑mg dose of ustekinumab switched to 90\xa0mg after 16\xa0weeks. People in the studies were followed for up to 100\xa0weeks in PSUMMIT\xa01 and 52\xa0weeks in PSUMMIT\xa02.\n\nThe primary end point in the PSUMMIT\xa01 and 2 trials was the American College of Rheumatology (ACR)\xa020 response rate at week\xa024. This is defined as an improvement of 20% or more in swollen and tender joint counts, and an improvement of 20% or more in 3\xa0of 5\xa0assessments of pain, disease activity and physical function. Secondary end points included measures of joint symptoms (including modified Psoriatic Arthritis Response Criteria [PsARC] and ACR\xa050/70), skin lesions (Psoriasis Area and Severity Index [PASI]), soft tissue symptoms, radiographic response, and disability and quality of life (Health Assessment Questionnaire Disability Index [HAQ‑DI], Dermatology Life Quality Index [DLQI] and 36‑item Short‑Form Health Survey [SF‑36]).\n\nIn both PSUMMIT\xa01 and\xa02, ustekinumab was associated with statistically significantly higher rates of ACR\xa020 response at week\xa024 than placebo. ACR\xa020 response rates in PSUMMIT\xa01 were 42.4%, 49.5%, 46.0% and 22.8% for ustekinumab 45\xa0mg, ustekinumab 90\xa0mg, ustekinumab 45\xa0mg and 90\xa0mg pooled, and placebo respectively (p<0.0001 for ustekinumab compared with placebo). Ustekinumab showed similar effectiveness compared with placebo regardless of prior exposure to TNF‑alpha inhibitors. ACR\xa020 response rates in PSUMMIT\xa02 for ustekinumab 45\xa0mg, ustekinumab 90\xa0mg, ustekinumab 45\xa0mg and 90\xa0mg pooled, and placebo respectively were:\n\nno prior TNF‑alpha inhibitors: 53.5%, 55.3%, 54.4% and 28.6% (p≤0.021 for ustekinumab compared with placebo)\n\nTNF‑alpha inhibitor‑exposed: 36.7%, 34.5%, 35.6% and 14.5% (p≤0.011 for ustekinumab compared with placebo).\n\nUstekinumab also demonstrated similar efficacy regardless of concomitant methotrexate use. ACR\xa020 response rates in PSUMMIT\xa01 for ustekinumab 45\xa0mg, ustekinumab 90\xa0mg, ustekinumab 45\xa0mg and 90\xa0mg pooled, and placebo respectively were:\n\nwith concomitant methotrexate: 43.4%, 45.5%, 44.5% and 26.0%\n\nwithout concomitant methotrexate: 41.5%, 53.4%, 47.4% and 20.0%.Corresponding results from PSUMMIT\xa02 were provided as academic in confidence and therefore cannot be reported here.\n\nLonger‑term analyses of the primary outcome suggested that response rates with ustekinumab were maintained over 52\xa0weeks. Response rates in the placebo arm increased after week\xa024 because of people switching from placebo to ustekinumab.\n\nThe results from secondary outcome analyses at week\xa024 generally supported the conclusions from the ACR\xa020 results. The findings were observed across joint, radiographic, skin, soft tissue and health‑related quality‑of‑life end points, although the results varied between outcomes and between trials, and not all outcomes reached statistical significance in all analyses. For example, for all randomised patients in both PSUMMIT\xa01 and\xa02, PsARC response rates with ustekinumab (45\xa0mg and 90\xa0mg pooled) and placebo were 58.0% and 35.2% respectively; PASI\xa075 response rates (people who had at least 75% improvement in PASI score) with ustekinumab (45\xa0mg and 90\xa0mg pooled) and placebo were 57.6% and 8.8% respectively. For all randomised patients in PSUMMIT\xa01, the median HAQ‑DI changes from baseline with ustekinumab (45\xa0mg and 90\xa0mg pooled) and placebo were −0.25 and 0.00 respectively (p<0.001). For all these examples, results were similar in individual trials and for individual doses. Longer‑term analyses of PASI\xa075 responses suggested that response rates with ustekinumab were maintained over 52\xa0weeks. Long‑term analyses of other secondary outcomes were provided as academic in confidence and therefore cannot be reported here.\n\nIn the absence of head‑to‑head randomised controlled trials, the company presented a mixed treatment comparison using a random‑effects model fitted with Bayesian methodology to explore the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors (adalimumab, etanercept, golimumab and infliximab) in people who had not previously had TNF‑alpha inhibitors (referred to in this document as 'TNF‑alpha inhibitor‑naive'). The company did not carry out a mixed treatment comparison for the TNF‑alpha inhibitor‑exposed population because PSUMMIT\xa02 is the only trial to have included this population. The mixed treatment comparison focused on PsARC, PASI\xa075 and PASI\xa090 responses to treatment at weeks\xa012–16 and\xa024, which are consistent with the clinical parameters in the economic model. For ustekinumab, patient‑level data were extracted from PSUMMIT\xa01 and\xa02 for a weight‑based dosing subgroup in which patients who weighed 100\xa0kg or less had ustekinumab 45\xa0mg, and patients who weighed more than 100\xa0kg had ustekinumab 90\xa0mg. For the TNF‑alpha inhibitors, data were taken directly from 7\xa0randomised, double‑blind, placebo‑controlled studies carried out in people with active psoriatic arthritis. The company reported that the findings showed that ustekinumab and TNF‑alpha inhibitors have better outcomes than placebo in most analyses. The results of the mixed treatment comparison for PsARC and PASI were marked as academic in confidence and cannot be reported here. It noted that, for the analysis of joint symptoms (PsARC), probabilities of response for ustekinumab were lower than for the TNF‑alpha inhibitors, although the 95% credible intervals for ustekinumab 45\xa0mg overlapped with those of adalimumab, golimumab 50\xa0mg and infliximab. The company reported that in the analyses of skin symptoms, there may be higher probabilities of response with infliximab (PASI\xa075 and PASI\xa090), golimumab 100\xa0mg (PASI\xa075) and adalimumab (PASI\xa090) compared with other biological drugs, although the credible intervals were overlapping.\n\nThe company presented adverse event data from the PSUMMIT studies, 5‑year extensions of 4\xa0studies of ustekinumab in psoriasis, the Psoriasis Longitudinal Assessment and Registry and the British Society for Rheumatology Biologics Register. The incidence of adverse events in the PSUMMIT studies was similar in the ustekinumab treatment arms compared with the placebo arms. For all randomised patients in PSUMMIT\xa01 and\xa02, the incidences were: ustekinumab 45\xa0mg, 48.4%; 90\xa0mg, 49.4%; 45\xa0mg and 90\xa0mg combined, 48.9%; and placebo, 47.9%. There were no disproportionate increases in adverse event rates over time. The most common adverse reactions seen with ustekinumab in the PSUMMIT trials included nasopharyngitis, upper respiratory tract infection, headache, arthralgia (joint pain), nausea and diarrhoea. The overall rates of study discontinuation because of adverse events were low (and higher with placebo than with ustekinumab); the rates were 3.4%, 1.5% and 1.5% for placebo, ustekinumab 45\xa0mg and ustekinumab 90\xa0mg respectively, in the placebo‑controlled period. The psoriasis extension studies and register data reported no clear dose–response effect or cumulative exposure effect for ustekinumab, and suggested that the rates of serious adverse events were comparable between ustekinumab and TNF‑alpha inhibitors.\n\n# Cost effectiveness\n\nThe company presented a de novo economic analysis that assessed the cost effectiveness of ustekinumab for treating adults with active psoriatic arthritis for whom the response to previous DMARD therapy has been inadequate. Ustekinumab was compared with TNF‑alpha inhibitors and conventional management in people who were TNF‑alpha inhibitor‑naive, and with conventional management only in people who were TNF‑alpha inhibitor‑exposed. The patient populations were based on the populations in the company's mixed treatment comparison and PSUMMIT\xa01 and\xa02. It was assumed that all patients who weigh less than 100\xa0kg would have ustekinumab 45\xa0mg, and all those who weigh more than 100\xa0kg would have ustekinumab 90\xa0mg. The model comprised a short‑term decision tree followed by a long‑term Markov model with a lifetime (52‑year) time horizon. It was similar to the models used in previous NICE appraisals of treatments for psoriatic arthritis (etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis). In the decision tree phase, people had initial biological therapy for either 12\xa0weeks (TNF‑alpha inhibitors) or 24\xa0weeks (ustekinumab). At this point, people who had a PsARC response (defined as an improvement in at least 2\xa0of the 4\xa0criteria, 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4\xa0criteria) continued with biological therapy, and those who did not switched to conventional management. All patients then entered the Markov phase of the model. People having a biological therapy continued to have it until they switched to conventional management, either because the biological therapy lacked efficacy or led to adverse events (at a rate of 16.5% per year for all treatments), or they died. No second biological drug was permitted. The model considered costs from an NHS and personal social services perspective, and all costs and health effects were discounted at a rate of 3.5% per year.\n\nFor the TNF‑alpha inhibitor‑naive population, ustekinumab was compared with 4\xa0TNF‑alpha inhibitors and conventional management, using clinical effectiveness evidence from the mixed treatment comparison. For the TNF‑alpha inhibitor‑exposed population, ustekinumab was compared with conventional management only, because at the time of the submission there were no randomised controlled trials of TNF‑alpha inhibitors in this population. Analyses of this population were based on clinical effectiveness evidence from the TNF‑alpha inhibitor‑exposed sub‑population of PSUMMIT\xa02.\n\nThe model captured health‑related quality of life through joint symptoms, disability and skin symptoms (PsARC response, HAQ‑DI score and PASI score). People who had a PsARC or PASI response were assumed to have a fixed improvement in HAQ‑DI or PASI score respectively. This improvement was maintained until a switch to conventional management, at which point the score returned to its baseline value (rebounded). People who did not have an initial response were assumed to have a smaller improvement in HAQ‑DI or PASI score until withdrawal of active treatment. Throughout periods of conventional management, people's disease progressed according to the natural history of psoriatic arthritis, modelled as a linear increase (worsening) in HAQ‑DI over time and a constant PASI score. HAQ‑DI and PASI scores were then mapped to EQ‑5D using an equation used in previous NICE technology appraisal guidance for etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. Costs and disutilities associated with adverse events were not included in the model. Healthcare resource use was estimated based on NHS reference costs, and included resource use associated with biological and conventional treatments (including initial and follow‑up consultations and blood tests) and resource use as a function of health state (including hospitalisations, surgical interventions and concomitant medications). The acquisition costs for TNF‑alpha inhibitors took into account the patient access scheme for golimumab. Administration costs were included for intravenous infliximab only, because all other biological drugs were assumed to be given by subcutaneous injection at no cost to the NHS.\n\nA number of iterations of the economic model were presented by the company: the first in its original submission (referred to in this document as the 'original' model), the second corrected after the clarification stage (referred to in this document as the 'post‑clarification' model), and the third corrected during consultation (referred to in this document as the 'post‑consultation' model). A\xa0further iteration, incorporating the patient access scheme and 1\xa0amended assumption, was presented by the company in its submission for the rapid review of NICE technology appraisal guidance 313 (referred to in this document as the 'rapid review' model; see section\xa03.30). The original model was used to develop base‑case, deterministic and probabilistic sensitivity analyses, and a series of scenario analyses; the results of the base‑case and scenario analyses were replaced by the post‑clarification and post‑consultation models and so are not reported here. The post‑clarification model incorporated corrections requested by the ERG during clarification, including amendments to the probability distributions for some variables and to the costs associated with psoriatic arthritis. The company used this model to develop an updated base case and updated scenario analyses. The post‑consultation model submitted during consultation corrected an error, identified by the company and a consultee during consultation, affecting the acquisition cost of golimumab 100\xa0mg. The cost‑effectiveness evidence presented here for the TNF‑alpha inhibitor‑naive population is based on the results of the post‑consultation model, which replaced the previous models. The cost‑effectiveness evidence presented here for the TNF‑alpha inhibitor‑exposed population is based on the post‑clarification model (because the TNF‑alpha inhibitors were not included as comparators in this population, and therefore the golimumab error did not apply).\n\nIn the TNF‑alpha inhibitor‑naive population (post‑consultation model, probabilistic results), ustekinumab was associated with total costs of £70,249 and a total of 6.23\xa0quality‑adjusted life years (QALYs). Adalimumab was associated with costs of £64,487 and 6.42\xa0QALYs, and therefore dominated ustekinumab (that is, adalimumab was more effective and less expensive). Adalimumab, in turn, was associated with an additional £31,476 in costs and 1.76\xa0QALYs compared with conventional management, giving an incremental cost‑effectiveness ratio (ICER) of £17,868 per QALY gained. The company also presented pairwise comparisons between ustekinumab and conventional management (post‑consultation model, probabilistic results): ustekinumab provided 1.57 additional QALYs compared with conventional management, at an additional cost of £37,239, giving an ICER of £23,723 per QALY gained. The deterministic sensitivity analyses (original model) showed that the results were most sensitive to the change in HAQ‑DI score over time associated with the natural history of psoriatic arthritis, the proportion of people who had a PsARC response and the HAQ‑DI change associated with PsARC response.\n\nIn the TNF‑alpha inhibitor‑exposed population (post‑clarification model, probabilistic results), ustekinumab provided an additional 1.41\xa0QALYs compared with conventional management, at an additional cost of £41,199, to give an ICER of £29,132 per QALY gained compared with conventional management. The probabilistic sensitivity analysis (original model) indicated there was a 0% and 67% probability of ustekinumab being cost effective compared with conventional management if the maximum acceptable ICERs were £20,000 and £30,000 per QALY gained respectively. The deterministic sensitivity analyses (original model) showed that the results were most sensitive to the HAQ‑DI score change with the natural history of psoriatic arthritis and the HAQ‑DI change associated with a PsARC response.\n\nThe company presented a series of scenario analyses for both the TNF‑alpha inhibitor‑naive and ‑exposed populations (post‑clarification model). These explored structural assumptions in the model around the treatment continuation rule (timing and criteria), progression of psoriatic arthritis, and utility and clinical effectiveness estimates. In the TNF‑alpha inhibitor‑naive population, all scenario analyses showed that ustekinumab was more expensive and less effective than adalimumab. Ustekinumab was associated with probabilistic ICERs compared with conventional management ranging from £21,628 to £31,469 per QALY gained. In the scenario in which treatment response was assessed at week\xa024 for all treatments, ustekinumab was associated with additional costs of £38,222 and an additional 1.28\xa0QALYs compared with conventional management, giving a probabilistic ICER of £29,808 per QALY gained for ustekinumab compared with conventional management. In scenario analyses for the TNF‑alpha inhibitor‑exposed population, ustekinumab was associated with probabilistic ICERs compared with conventional management ranging from £27,606 to £40,019 per QALY gained. In the scenario in which treatment response was assessed at week\xa024 for all treatments, ustekinumab was associated with additional costs of £43,064 and an additional 1.12\xa0QALYs compared with conventional management, giving a probabilistic ICER of £38,516 per QALY gained for ustekinumab compared with conventional management.\n\n# Evidence Review Group's critique and exploratory analyses of the company's submission\n\nThe ERG carried out exploratory analyses to test whether the clinical effectiveness of ustekinumab was influenced by prior TNF‑alpha inhibitor treatment or ustekinumab dose. It stated that there is no convincing evidence of a substantial difference in the effectiveness of ustekinumab between people who have and people who have not previously had TNF‑alpha inhibitors, and that treatment effects were not statistically significantly different between ustekinumab doses.\n\nThe ERG identified a number of limitations in the evidence available from the PSUMMIT studies. The switch from placebo to ustekinumab at weeks\xa016 and\xa024 provides a short‑term comparison for a chronic condition such as psoriatic arthritis. Analyses of TNF‑alpha inhibitor‑exposed patients included only the 180\xa0patients who had previously had varying numbers of TNF‑alpha inhibitors for varying durations. The ERG emphasised that the analyses of PSUMMIT\xa02 did not distinguish between people who had previously had 1, 2, 3 or more TNF‑alpha inhibitors, and so did not differentiate between people who had tried only some of the available TNF‑alpha inhibitors and people for whom TNF‑alpha inhibitors as a class had failed. The ERG considered that the data on patients whose disease was truly TNF‑alpha inhibitor refractory were scarce. It was also noted that for many of the secondary outcomes (DLQI, SF‑36 and radiographic scores), baseline scores were not reported, making interpretation of the results difficult.\n\nThe ERG considered that, despite some heterogeneity between trials, the mixed treatment comparison was appropriate to carry out and the results were robust. It did not consider that the weight‑based dosing subgroup matched the marketing authorisation, and noted that this led to exclusion of a large amount of data. However, the ERG noted that an additional analysis including all patients from PSUMMIT\xa01 and\xa02 provided fairly similar results to the weight‑based analysis. The ERG noted that overall, the mixed treatment comparison found that ustekinumab had the lowest or one of the lowest response rates for PASI\xa075, PASI\xa090 and PsARC.\n\nThe ERG noted that the company's economic model was similar to those used in previous NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis, although it had a longer time horizon (52\xa0years compared with 40\xa0years). The ERG considered many of the key assumptions used in the model to be broadly acceptable, including change in PASI score with biological treatment, rebound effect on treatment withdrawal, withdrawal rates in the TNF‑alpha inhibitor‑naive population, exclusion of disutilities and costs for adverse events, the equation used to map HAQ‑DI and PASI to EQ‑5D, resource use, drug and health state costs, and the approach to deterministic sensitivity analysis. The ERG cautioned that the results of the model should be interpreted with care, specifically the pairwise ICERs for ustekinumab compared with conventional management in the TNF‑alpha inhibitor‑naive population; it considered that these ICERs represent a scenario in which ustekinumab is the only alternative to conventional management, which is unrealistic.\n\nThe ERG highlighted weaknesses in the clinical effectiveness parameters used in the model. It noted that the company used a mixture of results from the mixed treatment comparison for the effectiveness of TNF‑alpha inhibitors and PSUMMIT results for the effectiveness of ustekinumab to obtain HAQ‑DI score changes, and considered that there were limitations to this approach. In addition, PsARC response rates for ustekinumab based on the weight‑based dosing subgroup resulted in a loss of data. The ERG considered both of these issues in exploratory analyses (see sections 3.24 and 3.25). Furthermore, the ERG queried the model assumption that people having conventional management did not have any improvement in PASI, whereas in clinical practice skin symptoms often respond well to DMARDs.\n\nThe ERG noted the simplifying assumption in the model that people switched to conventional management after failure of the intervention being analysed, and did not have subsequent biological therapies. Thus, the costs and benefits associated with subsequent lines of biological treatment were not included in the model. The ERG stated that in clinical practice in the UK, most people whose disease has failed to respond to 1\xa0TNF‑alpha inhibitor would be considered for subsequent‑line TNF‑alpha inhibitor treatment.\n\nThe ERG emphasised the uncertainties about the natural history progression of psoriatic arthritis scores during conventional management. This is a key driver of the model. The assumptions underlying the gradual increase in HAQ‑DI scores during conventional management were consistent with previous submissions. However, the ERG noted that the estimate for the rate of progression was prepared from limited data in 2009 but not updated. It also queried whether the assumptions about rebound and progression of arthritis symptoms taken from models of TNF‑alpha inhibitors were applicable to ustekinumab, given its different mechanism of action.\n\nThe ERG highlighted that the TNF‑alpha inhibitor‑exposed population has not been considered in previous appraisals, and noted some uncertainties in the model for this population. By comparing ustekinumab with conventional management, the company made no distinction between people whose disease had not responded to 1, 2, 3 or more TNF‑alpha inhibitors. That is, it did not differentiate between people who had tried only some of the available TNF‑alpha inhibitors and people for whom TNF‑alpha inhibitors as a class had failed. The ERG stated that, in clinical practice in the UK, most people whose disease has failed to respond to 1\xa0TNF‑alpha inhibitor would be considered for subsequent‑line TNF‑alpha inhibitor treatment. The ERG therefore considered the company's model to have severe limitations, noting that ustekinumab should be compared with other TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population. The ERG further noted that much of the evidence informing the model was drawn from people who had not had prior TNF‑alpha inhibitor therapy. In particular, estimates for the natural history progression of HAQ‑DI (a key driver of the model), mortality rates and treatment withdrawal rates were based on TNF‑alpha inhibitor‑naive populations. It queried whether these assumptions were applicable to the TNF‑alpha inhibitor‑exposed population.\n\nThe ERG carried out exploratory analyses in both the TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations. These explored the sensitivity of the company's model to assumptions about weight‑based dosing, HAQ‑DI rebound and natural history progression, the time horizon, the timing of treatment response assessment, and the inclusion of phototherapy. In the TNF‑alpha inhibitor‑naive population, the ERG's exploratory analyses showed that, in the incremental analysis (comparing ustekinumab, TNF‑alpha inhibitors and conventional management), ustekinumab remained dominated in all modelled scenarios. Probabilistic ICERs for ustekinumab compared with conventional management ranged from £22,455 to £55,029 per QALY gained. In particular, the ERG's analyses showed that assessing the response to treatment at week\xa024 for both ustekinumab and conventional management increased the ICER by £6987 per QALY gained, compared with the base case. The ERG presented a preferred base case for the TNF‑alpha inhibitor‑naive population, based on what it considered to be the most plausible assumptions. This consisted of the company's post‑clarification model (see section\xa03.12), with additional corrections added by the ERG (including amendments to the health state costs, probability distributions and baseline PASI and HAQ‑DI scores), applying the weight‑based dosing assumption to ustekinumab 90\xa0mg only, and using HAQ‑DI scores drawn from an update of the mixed treatment comparison developed by the ERG for the NICE technology appraisal guidance on golimumab for the treatment of psoriatic arthritis. In this analysis, ustekinumab was dominated by adalimumab. Compared with conventional management, ustekinumab was associated with additional costs of £37,123 and an additional 1.6\xa0QALYs, giving a probabilistic ICER compared with conventional management of £23,246 per QALY gained.\n\nThe ERG also presented exploratory analyses in the TNF‑alpha inhibitor‑exposed population. In these exploratory analyses, ustekinumab was associated with probabilistic ICERs compared with conventional management ranging from £28,670 to £69,139 per QALY gained. The ERG carried out an exploratory sequencing analysis for the TNF‑alpha inhibitor‑exposed population, to examine the cost effectiveness of ustekinumab compared with TNF‑alpha inhibitors, when used as second‑line treatments after failure of first‑line TNF‑alpha inhibitors. The ERG presented 3\xa0scenarios for the sequencing analysis: 2 in which first‑line treatments failed because of lack of effectiveness (the first based on evidence from PSUMMIT\xa02, and the second based on the ERG's estimates) and a third in which first‑line treatments failed because of adverse events. In the first scenario, ustekinumab was associated with ICERs of £32,818 per QALY gained (compared with adalimumab, when etanercept was used as first‑line treatment) to £37,738 per QALY gained (compared with etanercept, when golimumab or adalimumab were used as first‑line treatment), and in the other 2\xa0scenarios it was dominated by other treatments. However, the ERG stressed that this exploratory analysis was based on numerous assumptions and was subject to considerable uncertainty. The ERG did not present a preferred base case for the TNF‑alpha inhibitor‑exposed population because of the uncertainty remaining in the model.\n\n# Company's additional analyses provided during consultation and Evidence Review Group's critique\n\nIn response to consultation, the company submitted additional evidence exploring the cost effectiveness of the 45‑mg dose of ustekinumab alone, based on the post‑consultation model. The company noted that ustekinumab 45\xa0mg could potentially be considered for all patients. In the base‑case analysis for the TNF‑alpha inhibitor‑naive population, ustekinumab 45\xa0mg was the lowest‑cost and least effective biological treatment. In the TNF‑alpha inhibitor‑exposed population (base case, probabilistic analysis), ustekinumab 45\xa0mg was associated with an ICER of £21,789 per QALY gained compared with conventional management. The company also reproduced the ERG's exploratory sequencing analysis and presented scenario analyses to explore the impact of key assumptions.\n\nThe ERG submitted a critique of these analyses. It noted that, in principle, the scenario in which all patients have ustekinumab 45\xa0mg is reasonable to explore, but highlighted that there is uncertainty about the validity of this scenario in clinical practice. The ERG applied the 45‑mg dosing assumption to its preferred base case for the TNF‑alpha inhibitor‑naive population (see section 3.24), and noted that the results were generally similar to those presented by the company. For the TNF‑alpha inhibitor‑exposed population, the ERG confirmed that the company had correctly reproduced its exploratory sequencing analysis, although it emphasised that this analysis was highly uncertain because it was based on numerous assumptions.\n\n# Further evidence\n\nBased on a comment received during consultation from a company that manufactures a comparator drug, further evidence was identified by the technical team that provided long‑term analyses of the change from baseline in HAQ‑DI and radiographic scores with ustekinumab compared with placebo (presented in 2\xa0abstracts and a press release: Kavanaugh et al. 2013, McInnes et al. 2013 and Johnson and Johnson 2013). In a pre‑specified pooled analysis of the radiographic scores in PSUMMIT\xa01 and\xa02, the mean changes from baseline to week\xa024 were 0.40, 0.39 and 0.97 (ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and placebo respectively). The mean changes from baseline to week\xa052 were 0.58, 0.65 and 1.15 (ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and patients randomised to placebo respectively), showing that ustekinumab inhibited radiographic progression compared with placebo and that this inhibition continued to week\xa052. Data from PSUMMIT\xa01 alone were consistent with the pooled analysis. However, in PSUMMIT\xa02 alone there was no statistically significant difference in radiographic progression between ustekinumab and placebo; the company noted that the studies were not individually powered to detect differences in radiographic progression. A long‑term analysis of HAQ‑DI scores in PSUMMIT\xa01 showed that the mean changes from baseline to 52\xa0weeks were −0.34, −0.43 and −0.37 in patients randomised to ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and placebo respectively, and the mean changes from baseline at 100\xa0weeks were −0.36, −0.45 and −0.36 (ustekinumab 45\xa0mg, ustekinumab 90\xa0mg and patients randomised to placebo respectively). Long‑term analyses of HAQ‑DI scores in PSUMMIT\xa02 were not available at the time NICE technology appraisal guidance 313 was prepared.\n\n# Rapid review of NICE technology appraisal guidance 313: patient access scheme\n\nIn NICE technology appraisal guidance 313, ustekinumab was not recommended for treating active psoriatic arthritis. After publication, the company agreed a patient access scheme with the Department of Health (see section\xa02.3) and submitted revised analyses to be considered in a rapid review of the guidance. Under the original patient access scheme the company provided 2x45\xa0mg pre-filled syringes, for patients who needed the higher dose of 90\xa0mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme was withdrawn in January 2017 because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.\n\nThe company submitted a revised economic analysis (the 'rapid review' model) based on its post‑consultation model, incorporating the patient access scheme and an altered assumption about the effect of conventional management on skin symptoms (based on the Committee's considerations in NICE technology appraisal guidance 313). It presented analyses for both the TNF‑alpha inhibitor‑naive and ‑exposed populations. For the TNF‑alpha inhibitor‑exposed population, the company also presented a sequencing analysis. This analysis was developed from the ERG's exploratory sequencing analysis (see section\xa03.25) and used the scenario in which the first TNF‑alpha inhibitor failed because of lack of efficacy and clinical effectiveness data were taken from the PSUMMIT\xa02 study. The company considered that including the patient access scheme considerably improved the cost effectiveness of ustekinumab.\n\nThe patient access scheme was incorporated by reducing the unit cost of ustekinumab 90\xa0mg to £2147. The company estimated the additional costs associated with the patient access scheme to be £33 per patient. It considered that these costs were very small and so would not affect the appraisal; therefore, it did not include them in the economic analyses.\n\nThe company modelled the effect of conventional management on skin symptoms in the same way as it had modelled the effects of biological drugs in the original model – that is, assuming a fixed improvement in PASI score based on PASI response. As part of this change, the company also amended the rebound assumption for people who withdraw from biological therapy, such that the PASI score rebounded to a score based on the effect of conventional management (rather than the baseline score). The PASI scores and response rates for conventional management were taken from the placebo arms of the company's mixed treatment comparison and the PSUMMIT\xa01 and\xa02 studies.\n\nIn the company's base case for the TNF‑alpha inhibitor‑naive population (rapid review model, probabilistic results, incremental analysis), conventional management was the lowest cost option, followed by ustekinumab then adalimumab. Ustekinumab was therefore the least costly biological drug, and was associated with total costs of £59,105, a total of 6.09\xa0QALYs and an ICER compared with conventional management of £23,164 per QALY gained. Adalimumab had a pairwise ICER compared with conventional management of £21,765 per QALY gained.\n\nIn the company's base case for the TNF‑alpha inhibitor‑exposed population (rapid review model, probabilistic results), ustekinumab was associated with total costs of £62,724 and a total of 4.08\xa0QALYs. It was associated with an ICER of £25,675 per QALY gained, compared with conventional management. In the sequencing analysis, ustekinumab was associated with deterministic ICERs ranging from £21,241 per QALY gained (compared with etanercept, when adalimumab, golimumab or infliximab are used first line) to £25,921 per QALY gained (compared with conventional management, when etanercept is used first line).\n\nFor both the TNF‑alpha inhibitor‑naive and exposed populations, the company presented a deterministic sensitivity analysis and scenario analyses consistent with those it presented in the original submission. In both populations, the results were most sensitive to the change in HAQ‑DI score over time associated with the natural history of psoriatic arthritis. In scenarios based on the TNF‑alpha inhibitor‑naive population, ustekinumab was associated with deterministic ICERs compared with conventional management of £21,411 to £29,580 per QALY gained. In equivalent scenarios based on the TNF‑alpha inhibitor‑exposed population, ustekinumab was associated with deterministic ICERs compared with conventional management of £23,229 to £33,578 per QALY gained. In scenarios in which the response to all treatments was assessed at week\xa024, ustekinumab was associated with ICERs of £27,914 per QALY gained (TNF‑alpha inhibitor‑naive population) and £32,608 per QALY gained (TNF‑alpha inhibitor‑exposed population), compared with conventional management.\n\n# Evidence Review Group critique of the company's rapid review submission\n\nThe ERG noted that the company had appropriately incorporated the patient access scheme into the latest version of the economic model from NICE technology appraisal guidance 313 (the post‑consultation model). It agreed with the company that the additional costs associated with the patient access scheme did not significantly alter the cost effectiveness of ustekinumab.\n\nThe ERG highlighted that, in the company's model for the TNF‑alpha inhibitor‑naive population, ustekinumab was extendedly dominated in all scenarios. An intervention is 'extendedly dominated' when it is more costly and less effective than a combination of 2\xa0comparators; that is, the ICER for the intervention is higher than that of the next more effective comparator when both are compared with another less effective comparator. In the base case, ustekinumab was extendedly dominated by adalimumab and conventional management, because the ICER for ustekinumab compared with conventional management was higher than that of adalimumab compared with conventional management.\n\nThe ERG commented on the company's inclusion of the effect of conventional management on skin symptoms. It considered that the company's approach was mostly reasonable. However, the ERG highlighted that the PASI score to which people were assumed to rebound when they stop biological treatment was not the same as the average PASI score for people having conventional management. It noted that this difference resulted from differences in PASI response rates between week\xa012 (as applied to the conventional management arm) and week\xa024 (as applied to the biological therapy arms). The ERG commented that the effect of this assumption differed between the TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations.\n\nThe ERG identified a number of errors in the company's economic model, relating to disease‑related costs, medical resource use, the accrual of QALYs in the second year of the model and the application of discounting. It noted that the errors tended to underestimate the costs and QALYs associated with psoriatic arthritis, and hence tended to underestimate the cost effectiveness of more effective treatments. Consequently, the ERG noted that correcting these errors caused the cost effectiveness of ustekinumab to improve relative to conventional management, but worsen relative to TNF‑alpha inhibitors.\n\nThe ERG presented a scenario analysis to explore the patient access scheme combined with the Committee's preferred assumptions from NICE technology appraisal guidance 313. This analysis was developed from the company's rapid review model with the errors corrected, a 40‑year time horizon and with the response to both ustekinumab and conventional management assessed at week\xa024. In this scenario (probabilistic analysis), in the TNF‑alpha inhibitor‑naive population ustekinumab remained extendedly dominated (by a combination of conventional management and adalimumab) and had an ICER of £21,857 per QALY gained compared with conventional management. In the TNF‑alpha inhibitor‑exposed population (probabilistic analysis), the ICER for ustekinumab was £25,292 per QALY gained, compared with conventional management. In the sequencing analysis based on this scenario, ustekinumab was associated with an ICER of £25,393 per QALY gained compared with conventional management, when golimumab, adalimumab or etanercept are used first line. The ERG noted that the time horizon had a small effect on the ICER, whereas the effect of the week‑24 assessment time point was larger.\n\nFull details of all the evidence are available.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of ustekinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe Committee considered the current treatment pathway for people with psoriatic arthritis. It heard from the clinical experts that treatment of psoriatic arthritis follows current NICE guidance: after initial treatment with non‑steroidal anti‑inflammatory drugs (NSAIDs) and disease‑modifying antirheumatic drugs (DMARDs), most people have treatment with a tumour necrosis factor (TNF) alpha inhibitor. The Committee heard from the clinical experts and a patient expert that TNF‑alpha inhibitors are the only class of treatments with robustly demonstrated efficacy, because conventional management with DMARDs (such as methotrexate) does not appear to provide substantial benefits for joint‑related aspects of psoriatic arthritis. The Committee noted that the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis recommend TNF‑alpha inhibitor therapy for people with psoriatic arthritis if the person has peripheral arthritis with 3 or more tender joints and 3 or more swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least 2\xa0standard DMARDs (individually or in combination). The guidance also recommends that treatment should normally be started with the least expensive drug (taking into account administration costs, required dose and price per dose), and this may need to be varied for individual patients because of differences in the method of administration and treatment schedules. The Committee heard from the clinical experts that the sequential use of TNF‑alpha inhibitors is established practice in the NHS. Therefore, if the condition fails to respond to, or loses response to, an initial TNF‑alpha inhibitor or if the TNF‑alpha inhibitor causes adverse reactions, a second TNF‑alpha inhibitor will often be used. The Committee heard from the clinical experts that they would consider TNF‑alpha inhibitor treatment to have failed if the person had ongoing joint pain and inflammation despite treatment. The Committee heard from the clinical experts and the patient expert that, although the availability of second‑line TNF‑alpha inhibitors varies across the UK, the sequential use of TNF‑alpha inhibitors is extensive. The patient expert emphasised that when a TNF‑alpha inhibitor is withdrawn because of loss of effectiveness or adverse reactions, the detrimental effect on the patient can be substantial if a subsequent TNF‑alpha inhibitor is not available. In light of comments received during consultation, the Committee noted that the NICE commissioning guide on biologic drugs for the treatment of inflammatory disease in rheumatology, dermatology and gastroenterology does not explicitly recommend sequential use of TNF‑alpha inhibitors in psoriatic arthritis, but considered that both the guide and the published technology appraisals do not preclude this use. The Committee acknowledged the variation in practice across the country, but concluded that the sequential use of TNF‑alpha inhibitors is established practice in the NHS.\n\nThe Committee considered the likely place of ustekinumab in managing psoriatic arthritis. It heard from the clinical experts that if ustekinumab were to be used in people with prior TNF‑alpha inhibitor exposure, it might be used after 1, 2 or more TNF‑alpha inhibitors, depending on person‑specific factors such as the reason for withdrawing the previous TNF‑alpha inhibitor and individual preferences. For example, if the previous TNF‑alpha inhibitor had no effect or caused class‑related adverse reactions, ustekinumab may be used in preference to another TNF‑alpha inhibitor, whereas if the previous TNF‑alpha inhibitor loses efficacy over time, another TNF‑alpha inhibitor might be chosen before ustekinumab. The Committee concluded that the most appropriate comparators for ustekinumab in most people with psoriatic arthritis would be TNF‑alpha inhibitors, both in people who have not had prior TNF‑alpha inhibitors (referred to in this document as 'TNF‑alpha inhibitor‑naive') and in those who have previously had TNF‑alpha inhibitor therapy (referred to in this document as 'TNF‑alpha inhibitor‑exposed').\n\nThe Committee heard from the clinical experts that there is a group of people with psoriatic arthritis for whom TNF‑alpha inhibitors are not suitable, because of contraindications such as heart failure or demyelination, or because of failure of TNF‑alpha inhibitors as a class. For these people there is a considerable unmet need. The Committee understood that this affects a number of people and that for people in this situation there are no effective treatment options. The clinical experts considered that ustekinumab has the potential to offer an innovative treatment option to fulfil this need. The Committee acknowledged that this represents a distinct group with an important unmet need that warrants additional consideration. During consultation, the Committee heard from a company that manufactures a TNF‑alpha inhibitor that the contraindications for ustekinumab and TNF‑alpha inhibitors are relatively similar. It therefore considered that the number of people who had not had TNF‑alpha inhibitor therapy (that is, who were TNF‑alpha inhibitor‑naive), for whom TNF‑alpha inhibitors as a class were contraindicated and for whom ustekinumab might be appropriate was unknown but may be relatively small. The Committee concluded that conventional management would be an appropriate comparator in people for whom TNF‑alpha inhibitors were contraindicated and in people whose condition failed to respond to TNF‑alpha inhibitors as a class.\n\nThe Committee understood that psoriatic arthritis is a lifelong condition that has a serious impact on people's quality of life. It heard from the patient expert that psoriatic arthritis can develop at a young age, and affects all aspects of a person's life including education, work, self‑care, and social and family life. The Committee heard from the patient expert that skin symptoms can have a major psychological impact, and that the joint symptoms have an even greater impact on the psychological and functional aspects of living with this chronic condition. The Committee recognised the potential value of additional treatment options for people with psoriatic arthritis.\n\n# Clinical effectiveness\n\nThe Committee reviewed the overall clinical effectiveness of ustekinumab. It noted that the evidence for the clinical effectiveness of ustekinumab had been taken from 2\xa0randomised placebo‑controlled trials (PSUMMIT\xa01 and\xa02), and acknowledged the need for head‑to‑head studies between ustekinumab and TNF‑alpha inhibitors for psoriatic arthritis. The Committee considered that the evidence suggested that ustekinumab is more effective than placebo after 24\xa0weeks of treatment across a number of joint, skin and soft tissue outcomes. It considered that, although the effect is likely to persist for up to 1\xa0year, there is some uncertainty about this because in the trials people switched from placebo to ustekinumab at week\xa024. The Committee heard from the clinical experts that ustekinumab appeared to be effective across a wide range of skin and joint outcomes and also soft tissue conditions associated with psoriatic arthritis. The Committee also noted that the results from the PSUMMIT studies suggested there was no statistically significant difference in the clinical effectiveness of ustekinumab compared with placebo between TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations for the Psoriatic Arthritis Response Criteria (PsARC) response. The Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations, but acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab.\n\nThe Committee considered in detail the evidence on the effect of ustekinumab on radiographic outcomes at 24\xa0weeks and 52\xa0weeks. It noted that the effect of ustekinumab compared with placebo appeared to be different to what has been previously observed in clinical trials of golimumab compared with placebo. In particular, ustekinumab appeared to slow the increase (progression) in radiographic score compared with placebo, whereas golimumab (in the NICE technology appraisal guidance on golimumab for the treatment of psoriatic arthritis) had previously been shown to reduce radiographic score from baseline. Furthermore, ustekinumab had not shown a statistically significant difference from placebo in the PSUMMIT\xa02 study (which included a TNF‑alpha inhibitor‑exposed population). The Committee heard from the company that interpretation of these findings was subject to 4\xa0key difficulties:\n\nChanges in radiographic score were very small.\n\nThe individual studies were not powered for this end point.\n\nThere was a high level of missing data in the placebo arm because of patient withdrawal (approximately 23%).\n\nThe link between radiographic score and quality of life in psoriatic arthritis is uncertain. The Committee considered that the evidence on radiographic progression with ustekinumab should be interpreted with caution and it was not able to reach a conclusion on the effectiveness of ustekinumab compared with TNF‑alpha inhibitors for this outcome. However, it concluded that these results provide some evidence to suggest care is needed when applying assumptions based on TNF‑alpha inhibitors to ustekinumab, and noted that this may affect the validity of some assumptions in the company's economic model (see section\xa04.11).\n\nThe Committee considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑naive population. The Committee reviewed the findings of the company's mixed treatment comparison (see section\xa03.7), and noted that the analysis explored the 3\xa0outcomes used as clinical effectiveness inputs in the economic model (Psoriasis Area and Severity Index [PASI]\xa075, PASI\xa090 and PsARC response rates). It discussed this analysis with the clinical experts, and was aware of the limitations of the mixed treatment comparison. The Committee concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for PASI\xa075, PASI\xa090 and PsARC response, particularly for the joint outcome.\n\nThe Committee also considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population. It was aware that there was limited clinical trial evidence in this setting. It understood from comments received during consultation that there is some evidence for the effectiveness of TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population, but was aware that there was not enough evidence to compare ustekinumab and TNF‑alpha inhibitors. The Committee therefore considered the effectiveness of ustekinumab and TNF‑alpha inhibitors compared with conventional management. Although in the PSUMMIT trials there was no difference in clinical effectiveness between TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations in terms of PsARC response, the Committee heard from the clinical experts that evidence presented at a conference suggested that the effectiveness of ustekinumab measured using the American College of Rheumatology (ACR) criteria may decrease with increasing numbers of prior TNF‑alpha inhibitors. The clinical experts noted that the diminishing effectiveness of ustekinumab in TNF‑alpha inhibitor‑exposed populations is broadly consistent with clinical experience with the TNF‑alpha inhibitors, which appear to show diminishing effectiveness as the number of prior therapies increases. The Committee heard from the clinical experts that there is some uncertainty about the size of the diminishing effect. The Committee heard estimates for the response rate with second‑line TNF‑alpha inhibitors ranging from 20% to 70%. Conversely, the Committee noted comments received during consultation from a company that manufactures a comparator drug (including evidence from a randomised controlled trial of certolizumab pegol and open‑label and observation studies of adalimumab) that suggested that the lower estimates in this range may be too low. The Committee also considered whether there may be any variation in clinical effectiveness depending on the reason for withdrawal of the first TNF‑alpha inhibitor (for example, initial lack of efficacy, gradual loss of efficacy over time or adverse reactions), but it acknowledged that there was not enough evidence for this aspect to be considered further. The Committee concluded that there is still uncertainty about the relative effectiveness of ustekinumab and TNF‑alpha inhibitors in people who have previously had TNF‑alpha inhibitors.\n\nThe Committee queried whether both the 45‑mg and 90‑mg doses of ustekinumab might potentially be used in clinical practice and, if so, how the doses might be used. It noted that the marketing authorisation for ustekinumab in psoriatic arthritis indicates that 45\xa0mg may be used for all patients and 90\xa0mg may be considered in people who weigh more than 100\xa0kg, concluding that this permits, but does not require, a weight‑based dosing strategy. The Committee also noted that it had not been shown detailed evidence on the relative effectiveness of the 2\xa0doses in people of different weights. The Committee considered the evidence in the European public assessment report published by the European Medicines Agency (EMA), which noted that systemic exposure to ustekinumab (that is, the concentration of ustekinumab in the serum) is similar in people who weigh more than 100\xa0kg and have ustekinumab 90\xa0mg, compared with people who weigh less than 100\xa0kg and have ustekinumab 45\xa0mg. Moreover, the EMA noted that the efficacy of ustekinumab 90\xa0mg (in terms of ACR\xa020 response) was higher than ustekinumab 45\xa0mg, particularly in people who weigh more than 100\xa0kg, in the PSUMMIT\xa01 study, although not in PSUMMIT\xa02. The Committee heard from the company that the dose–response effect based on weight for psoriatic arthritis may not be as strong as seen in psoriasis and that the differences between doses were not statistically significant. The Committee also considered evidence from the Evidence Review Group (ERG), which suggested that there was no statistically significant difference in clinical effectiveness between the higher and lower doses, although it was noted that this did not imply the doses are equivalent. The Committee heard from the clinical experts that if ustekinumab were recommended, they would anticipate using both the 45‑mg and 90‑mg doses in clinical practice (rather than only the 45‑mg dose). The Committee acknowledged that there is no clear evidence to support the use of a strict weight‑based dosing strategy, although it concluded that both the 45‑mg and 90‑mg doses would be expected to be used in clinical practice.\n\n# Cost effectiveness\n\nThe Committee considered the structure, assumptions and results in the company's economic model and the critique presented by the ERG. In particular, it discussed key assumptions about the improvement, rebound and progression of joint symptoms, the effect of conventional management on skin symptoms, the use of the utility equation, the timing of the assessment of response and the sequencing of biological treatments in the TNF‑alpha inhibitor‑exposed population. It then reviewed the effect of these assumptions on the cost‑effectiveness estimates for ustekinumab. The Committee also considered the additional analyses incorporating the patient access scheme, presented during the rapid review.\n\nThe Committee noted that the assumptions about the improvement, rebound and progression of joint symptoms (as captured using the Health Assessment Questionnaire Disability Index [HAQ‑DI]) were key drivers of the economic model. It noted that the approach used in the company's model (in which HAQ‑DI improved by a fixed amount, giving an improved HAQ‑DI score that was maintained at a constant level for the duration of biological treatment, rebounded after treatment withdrawal and then gradually deteriorated during conventional management [see section\xa03.11]) was consistent with the models used in previous NICE technology appraisal guidance on TNF‑alpha inhibitors for psoriatic arthritis (etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis). It heard from the clinical experts that HAQ‑DI is an acceptable and sensitive treatment outcome measure. The clinical experts noted that the HAQ‑DI rebound effect on withdrawal of TNF‑alpha inhibitors is not necessarily immediate, but may be associated with a lag of approximately 6\xa0to 12\xa0months, which may also apply to ustekinumab. Furthermore, the Committee considered it possible that the assumption that people have a fixed improvement in HAQ‑DI that is maintained during treatment may not apply to ustekinumab, because it has a different mechanism of action to TNF‑alpha inhibitors. The observed differences in radiographic progression (see section 4.6) may provide some support for this suggestion. Conversely, the Committee understood that the radiographic progression results must be interpreted with caution, and also noted evidence from the PSUMMIT\xa01 study on HAQ‑DI scores with ustekinumab after 52–100\xa0weeks that did not suggest a substantial worsening over time (see section\xa03.28; long‑term analyses of HAQ‑DI scores in PSUMMIT\xa02 were not available at the time NICE technology appraisal guidance 313 was prepared). The Committee considered it possible that there may be some worsening of HAQ‑DI score during ustekinumab treatment, and that this would be likely to decrease the cost effectiveness of ustekinumab, although the size of this effect is unknown. The Committee acknowledged that there is a lack of robust evidence to reliably inform these assumptions, but would have liked to have seen an assessment of the effect on the model results of worsening HAQ‑DI over time during ustekinumab treatment. The Committee concluded that uncertainty remains as to how well the HAQ‑DI assumptions apply to ustekinumab, but considered that the assumptions in the model were a sufficient basis on which to make a decision.\n\nThe Committee considered the way in which the effect of conventional management on skin symptoms had been modelled. It noted that the company's original, post‑clarification and post‑consultation models (see section\xa03.12) assumed that conventional management strategies did not affect skin symptoms, but heard that the ERG's clinical adviser stated that in practice, DMARDs such as methotrexate often improve psoriasis symptoms. During consultation the Committee received additional information, from a company that manufactures a comparator drug, on the effect of conventional management on skin symptoms, taken from a study of adalimumab. In the rapid review, the Committee noted that the company updated its model to incorporate the effect of conventional management on skin symptoms. It heard from the ERG that the modelling approach was consistent with the approach taken for biological treatments in the original model, and understood that the ERG considered this mostly reasonable. The Committee concluded that it was appropriate to include the effect of conventional management on skin symptoms in the economic model.\n\nThe Committee noted that the company's base‑case analysis was based on utility scores derived using a previously published equation used in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. However, it also noted that health‑related quality‑of‑life evidence had been captured directly in the PSUMMIT studies through the 36‑item Short‑Form Health Survey (SF‑36). The Committee understood that the company used the SF‑36 data to derive an alternative utility equation, and that the impact of this approach on the model results was examined in a sensitivity analysis. However, it further noted that this alternative utility equation was subject to uncertainty, because of a need to map from SF‑36 to EQ‑5D using evidence from people without psoriatic arthritis. The Committee considered that all health‑related quality‑of‑life evidence from the clinical trials – including the SF‑36 data – should ideally be used if possible. However, because of the uncertainty in the newer utility equation, and the fact that the effectiveness of ustekinumab in the PSUMMIT trials was captured through the HAQ‑DI and PASI scores, the Committee concluded that using the previously published equation would be more appropriate and would support a consistent approach between appraisals.\n\nThe Committee considered the appropriateness of assessing treatment responses at week\xa012 for TNF‑alpha inhibitors and conventional management, and week\xa024 for ustekinumab. It heard from the clinical experts that there is some uncertainty about when ustekinumab begins to take effect, although its onset of action may be slower than TNF‑alpha inhibitors. The clinical experts stated that DMARDs such as methotrexate often show little or no effect after 12\xa0weeks, and if they do provide benefits these may arise with longer treatment. It was suggested by the clinical experts that there is no specific reason why ustekinumab and TNF‑alpha inhibitors should be assessed at the same time point, because they are different treatments, although the use of different time points in the economic model is likely to favour ustekinumab. The Committee heard during consultation that the British Society for Rheumatology guidelines define a therapeutic trial of DMARDs as at least 12\xa0weeks, although it noted that this did not preclude assessment of response at 24\xa0weeks. The Committee concluded that, for pairwise comparisons between ustekinumab and conventional management, the treatment response should ideally have been assessed at the same time point. The Committee had a preference for assessing treatment response at 24\xa0weeks for both ustekinumab (in line with its summary of product characteristics and the primary efficacy analysis of the PSUMMIT\xa01 and\xa02 studies) and conventional management. However, it understood that the company considered that there was no intrinsic reason why the timing of the assessment for ustekinumab and conventional management in the economic model must be the same, and that assessing the response to conventional management at 24\xa0weeks would be inconsistent with NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. The Committee noted that assessing the response to conventional management at week\xa024 rather than week\xa012 increased the incremental cost‑effectiveness ratio (ICER) for ustekinumab.\n\nThe Committee considered the impact of sensitivity analyses and scenario analyses on the results of the economic model. It noted that the company and the ERG presented a number of analyses (see sections\xa03.12, 3.24, 3.30 and 3.40). The Committee noted that the model was highly sensitive to assumptions about the HAQ‑DI score. In addition to the key assumptions explored in sections\xa04.11–14, the Committee noted that there were further assumptions that were subject to uncertainty, but which had little impact on the results of the model. It noted that the company's weight‑based dosing approach did not appear to substantially influence the results of the economic model. The Committee also noted that the longer time horizon in the company's model compared with previous models did not dramatically affect the results, although it highlighted that a 40‑year time horizon was preferable to ensure consistency with previous appraisals. During consultation, a consultee noted that the withdrawal rate for ustekinumab had been taken from studies of TNF‑alpha inhibitors, and that it may be more appropriate to use the withdrawal rate from the PSUMMIT studies. The Committee heard from the company that the withdrawal rate in PSUMMIT\xa01 was lower than that included in the model. However, the Committee was also aware that this rate was derived from a study of 2\xa0years' duration and the long‑term withdrawal rate for ustekinumab is unknown, but the economic model had a lifetime time horizon. The effect of this assumption on the model was not presented, but the Committee considered that if the withdrawal rate were lower than 16.5%, the ICERs for ustekinumab might be expected to decrease by a small amount. The Committee concluded that the weight‑based dosing assumption, the time horizon and the withdrawal rate were not key drivers of the economic model and they did not have a substantial effect on the ICERs.\n\nThe Committee considered the appropriateness of appraising ustekinumab 45\xa0mg alone, in light of the additional analyses presented by the company and the ERG (see sections\xa03.26 and\xa03.27). Based on input from the clinical experts, the Committee considered that both the 45‑mg and 90‑mg doses were likely to be used in clinical practice (see section\xa04.9). The Committee also considered whether appraising ustekinumab 45\xa0mg alone could lead to unfair or discriminatory recommendations, if the higher dose were more effective in people weighing more than 100\xa0kg. The Committee concluded that, based on the likely use of ustekinumab in clinical practice and the potential for effectiveness differences between the doses (particularly in people weighing more than 100\xa0kg), it would not be appropriate for it to consider ustekinumab 45\xa0mg alone.\n\nThe Committee considered the analyses incorporating the patient access scheme provided by the company and the ERG for the rapid review of NICE technology appraisal guidance 313. It noted that the ERG had corrected errors in the company's model, and considered these corrections appropriate. The Committee considered that it would have been preferable to include the additional costs associated with the patient access scheme in the model, although it understood that the effects of these costs on the results would be small. The Committee noted that the company had incorporated the effect of conventional management on skin symptoms in its base case, and that the ERG had incorporated this assumption along with the assessment of treatment response at week\xa024 for both conventional management and ustekinumab and a 40‑year time horizon in its scenario analysis. The Committee considered that the probabilistic ICERs, when available, were more informative than the deterministic ICERs. It concluded that the ERG's scenario analysis (see section 3.40) reflected the Committee's preferred assumptions and therefore provided the most informative results and the most plausible ICERs, although it noted that the ICERs would decrease if the response to conventional management were assessed at week\xa012.\n\nThe Committee considered the cost effectiveness of ustekinumab in the TNF‑alpha inhibitor‑naive population. It considered the incremental analysis to be appropriate for most people with psoriatic arthritis, for whom TNF‑alpha inhibitors are the most appropriate comparator (see section\xa04.2). The Committee noted that, with the patient access scheme, ustekinumab was the lowest‑cost biological treatment but was extendedly dominated (that is, was more expensive and less effective than a combination of 2\xa0comparators). Moreover, the Committee noted that the cost‑effectiveness analyses were subject to uncertainty because of the potential effect of a possible increase in HAQ‑DI during ustekinumab treatment, which would be expected to reduce the cost effectiveness of ustekinumab. The Committee concluded that ustekinumab is not a cost‑effective option, compared with TNF‑alpha inhibitors, for treating psoriatic arthritis in people who have not previously had TNF‑alpha inhibitors.\n\nThe Committee also considered the cost effectiveness of ustekinumab in people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are contraindicated. It considered that this population comprises people for whom a TNF‑alpha inhibitor would otherwise be considered (as per the criteria described in etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis, see section\xa04.1). In this population, the Committee considered that conventional management is the most appropriate comparator. It emphasised that ustekinumab is innovative for this population, because it potentially fulfils an important unmet need. It noted that the number of people in this situation was unknown and may be very small, although it was aware of the need to identify subgroups for which the technology may be cost effective. Moreover, the Committee noted that no evidence had been presented specifically for this population; the available evidence was drawn from the PSUMMIT studies, which were likely to have included a mixture of people for whom TNF‑alpha inhibitors would and would not be appropriate. The Committee noted that when the patient access scheme was applied and its preferred assumptions were incorporated, the most plausible ICER was £21,900 per quality‑adjusted life year (QALY) gained, compared with conventional management. Although it considered that this ICER was still subject to uncertainty because of the possible increase in HAQ‑DI during ustekinumab treatment (see section\xa04.11), the Committee noted that the ICER would be lower if the response to conventional management were assessed at week\xa012. It was also conscious that there is considerable unmet need in this population and that ustekinumab is an innovative treatment in this setting. The Committee therefore concluded that ustekinumab is a cost‑effective option for treating psoriatic arthritis in people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are contraindicated.\n\nThe Committee considered the cost effectiveness of ustekinumab in the TNF‑alpha inhibitor‑exposed population. It noted that for most people, an alternative TNF‑alpha inhibitor is the most appropriate comparator, which was not presented in the company's original submission. The Committee therefore considered the exploratory sequencing analysis initially presented by the ERG, noting that the analysis was reproduced by the company in its rapid review model. This analysis assessed the cost effectiveness of ustekinumab and TNF‑alpha inhibitors when used as second‑line treatments, when first‑line treatment with a TNF‑alpha inhibitor had failed because of lack of efficacy or adverse reactions, and comprised an incremental comparison of ustekinumab, TNF‑alpha inhibitors and conventional management. The ERG and the Committee acknowledged that this analysis is subject to considerable uncertainty. This was because there was no distinction between people whose disease showed no initial response to TNF‑alpha inhibitors and those for whom TNF‑alpha inhibitors failed during long‑term treatment; the clinical experts noted that these groups represent 2\xa0distinct populations. Nevertheless, the Committee considered that this exploratory analysis provided useful information for establishing a full picture of the cost effectiveness of ustekinumab. The Committee considered that the most informative scenario was the one in which the first‑line TNF‑alpha inhibitor failed because of lack of efficacy and clinical effectiveness data for ustekinumab were taken directly from PSUMMIT\xa02, and noted that this analysis was the most favourable for ustekinumab. With the patient access scheme and the preferred assumptions incorporated, the Committee noted that in the incremental analysis, the most plausible ICER for ustekinumab was £25,400 per QALY gained (compared with conventional management). The Committee was aware that the ICER was subject to uncertainty because of the possible increase in HAQ‑DI during ustekinumab treatment, and noted that the ICER would decrease if the response to conventional management were assessed at week\xa012. The Committee understood that this analysis was uncertain, but concluded that it was reasonable to recommend ustekinumab as a treatment option for people who have previously had TNF‑alpha inhibitors and for whom treatment with a subsequent TNF‑alpha inhibitor is appropriate.\n\nThe Committee considered the cost effectiveness of ustekinumab in the TNF‑alpha inhibitor‑exposed population, looking specifically at people for whom TNF‑alpha inhibitors as a class had failed. It understood the important unmet need for people in this situation. The Committee also understood that there is limited evidence for this population, because the PSUMMIT\xa02 study included a mixture of people for whom subsequent TNF‑alpha inhibitors would and would not be appropriate. It highlighted that conventional management is an appropriate comparator in this population. With the patient access scheme and preferred assumptions incorporated, the Committee considered that the most plausible ICER compared with conventional management in the TNF‑alpha inhibitor‑exposed population was £25,300 per QALY gained. Similarly to the TNF‑alpha inhibitor‑naive population, the Committee understood that this ICER was still subject to uncertainty because of the possible increase in HAQ‑DI during ustekinumab treatment, although it noted that the ICER would decrease if the response to conventional management were assessed at week\xa012. The Committee was also aware of the considerable unmet need in this population. The Committee concluded that ustekinumab is a cost‑effective option for treating psoriatic arthritis in people who have previously had TNF‑alpha inhibitor therapy and for whom TNF‑alpha inhibitors as a class have failed.\n\nThe Committee discussed the recommendation to stop treatment based on an inadequate PsARC response in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. The Committee noted that the economic analyses (in all populations) were based on the assumption that people whose psoriatic arthritis has not shown an adequate PsARC response at 24\xa0weeks stop treatment with ustekinumab. The Committee considered that the recommendation to stop treatment based on an inadequate PsARC response (as defined in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis) was also appropriate for ustekinumab (assessed at 24\xa0weeks). It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC.\n\nThe Committee considered evidence from the company on the innovative nature of ustekinumab. It heard from the clinical experts that they considered ustekinumab to be an innovative technology, because it is in a different class to the TNF‑alpha inhibitors and targets a different inflammatory pathway. They considered ustekinumab to be a particularly valuable treatment option in people for whom TNF‑alpha inhibitors are not appropriate. The Committee noted that there is an important unmet need in people for whom TNF‑alpha inhibitors are inappropriate or not effective. However, the Committee considered that, although the introduction of TNF‑alpha inhibitors represented a 'step change' in managing psoriatic arthritis, evidence from the mixed treatment comparison suggested that ustekinumab may be less effective than TNF‑alpha inhibitors, and so ustekinumab does not represent a clear‑cut further step change compared with TNF‑alpha inhibitors. The Committee also considered the innovative nature of ustekinumab for people for whom TNF‑alpha inhibitors are inappropriate. It understood that some of the contraindications for TNF‑alpha inhibitors also apply to ustekinumab, so ustekinumab would not be appropriate for all people for whom TNF‑alpha inhibitors are unsuitable. The Committee considered that all of the health‑related benefits associated with ustekinumab had been adequately captured in the economic model, and no changes to the recommendations were needed for that reason.\n\nThe patient expert highlighted that people with psoriatic arthritis often have concerns about the long‑term safety of treatments for this condition. The Committee was aware of registers that collect evidence on the long‑term treatment outcomes with TNF‑alpha inhibitors for rheumatoid arthritis and psoriasis. The patient expert and the clinical experts emphasised the importance of collecting long‑term data on psoriatic arthritis specifically. The Committee concluded that long‑term evidence on the effectiveness and safety of biological treatments for psoriatic arthritis would be valuable.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA340\n\nAppraisal title: Ustekinumab for treating active psoriatic arthritis (rapid review of technology appraisal guidance 313)\n\nSection\n\nKey conclusion\n\nUstekinumab is recommended as an option, alone or in combination with methotrexate, for treating active psoriatic arthritis in adults only when:\n\ntreatment with tumour necrosis factor (TNF) alpha inhibitors is contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis) or\n\nthe person has had treatment with 1 or more TNF‑alpha inhibitors.\n\nUstekinumab is recommended only if the company provides the 90\xa0mg dose of ustekinumab for people who weigh more than 100\xa0kg at the same cost as the 45\xa0mg dose, as agreed in the patient access scheme.\n\nThe Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations. However, based on evidence from the company's mixed treatment comparison, it concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for Psoriasis Area and Severity Index (PASI)\xa075, PASI\xa090 and Psoriatic Arthritis Response Criteria (PsARC) response rates, particularly for the joint outcome.\n\nThe Committee concluded that ustekinumab is not a cost‑effective option in people who have not previously had TNF‑alpha inhibitors. Ustekinumab was the lowest‑cost biological treatment, but was extendedly dominated (that is, was more expensive and less effective than a combination of 2 comparators).\n\nThe Committee concluded that, with the patient access scheme, ustekinumab is a cost‑effective option for treating psoriatic arthritis:\n\nIn people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are inappropriate; the most plausible incremental cost effectiveness ratio (ICER) was £21,900 per quality‑adjusted life year (QALY) gained, compared with conventional management.\n\nIn people who have previously had TNF‑alpha inhibitors and for whom treatment with a subsequent TNF‑alpha inhibitor is appropriate; in the incremental analysis, the most plausible ICER was £25,400 per QALY gained (compared with conventional management).\n\nIn people who have previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors as a class have failed; the most plausible ICER was £25,300 per QALY gained, compared with conventional management.\n\n, 4.5, 4.7, 4.18, 4.20, 4.21\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from clinical experts and a patient expert that TNF‑alpha inhibitors are the only class of treatments with robustly demonstrated efficacy, because conventional management with disease‑modifying antirheumatic drugs (DMARDs), such as methotrexate, does not appear to provide substantial benefits for joint‑related aspects of psoriatic arthritis.\n\nThe Committee heard from the clinical experts that there is a group of people with psoriatic arthritis for whom TNF‑alpha inhibitors are not suitable, because of contraindications such as heart failure or demyelination, or because of failure of TNF‑alpha inhibitors as a class. For these people there is a considerable unmet need.\n\nThe Committee understood that psoriatic arthritis is a lifelong condition that has a serious impact on people's quality of life.\n\n, 4.3, 4.4\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nClinical experts considered ustekinumab to be a particularly valuable treatment option in people for whom TNF‑alpha inhibitors are not appropriate. The Committee noted that there is an important unmet need in people for whom TNF‑alpha inhibitors are inappropriate or not effective.\n\nThe Committee considered that, although the introduction of TNF‑alpha inhibitors represented a 'step change' in managing psoriatic arthritis, evidence from the mixed treatment comparison suggested that ustekinumab may be less effective than TNF‑alpha inhibitors, and so ustekinumab does not represent a clear‑cut further step change compared with TNF‑alpha inhibitors. The Committee considered that ustekinumab is innovative for people for whom TNF‑alpha inhibitors are inappropriate.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nUstekinumab has a UK marketing authorisation for use alone or in combination with methotrexate 'for the treatment of active psoriatic arthritis in adult patients when the response to previous non‑biological DMARD therapy has been inadequate'.\n\nThe Committee heard from the clinical experts that treatment of psoriatic arthritis follows current NICE guidance: after initial treatment with non‑steroidal anti‑inflammatory drugs (NSAIDs) and DMARDs, most people have treatment with a TNF‑alpha inhibitor. The Committee noted that the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis recommend TNF‑alpha inhibitor therapy for people with psoriatic arthritis, and also recommend that treatment should normally be started with the least expensive drug (taking into account administration costs, required dose and price per dose).\n\nThe Committee heard from the clinical experts that if ustekinumab were to be used in people with prior TNF‑alpha inhibitor exposure, it might be used after 1, 2 or more TNF‑alpha inhibitors, depending on person‑specific factors.\n\nThe Committee concluded that the most appropriate comparators for ustekinumab in most people with psoriatic arthritis would be TNF‑alpha inhibitors, both in people who have not had prior TNF‑alpha inhibitors and in those who have previously had TNF‑alpha inhibitor therapy. It also concluded that conventional management would be an appropriate comparator in people for whom TNF‑alpha inhibitors were contraindicated and in people whose condition failed to respond to TNF‑alpha inhibitors as a class.\n\n, 4.1, 4.2, 4.3\n\nAdverse reactions\n\nN/A (The Committee made no specific conclusions about adverse reactions.)\n\n‑\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that the evidence for the clinical effectiveness of ustekinumab had been taken from 2 randomised placebo‑controlled trials (PSUMMIT\xa01 and\xa02).\n\nThe Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations, but acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab.\n\nThe Committee considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑naive population. The Committee reviewed the findings of the company's mixed treatment comparison and discussed them with the clinical experts, and was aware of the limitations of the mixed treatment comparison. It concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for PASI\xa075, PASI\xa090 and PsARC response, particularly for the joint outcome.\n\n, 4.7\n\nRelevance to general clinical practice in the NHS\n\nN/A (The Committee made no specific conclusions about relevance to general clinical practice in the NHS.)\n\n‑\n\nUncertainties generated by the evidence\n\nThe Committee considered that, although the effect of ustekinumab is likely to persist for up to 1\xa0year, there is some uncertainty about this because in the trials people switched from placebo to ustekinumab at week\xa024.\n\nIt considered that the evidence on radiographic progression with ustekinumab should be interpreted with caution.\n\nIt also acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab.\n\nThe Committee was aware of the limitations of the mixed treatment comparison.\n\nThe Committee concluded that there is still uncertainty about the relative effectiveness of ustekinumab and TNF‑alpha inhibitors in people who have previously had TNF‑alpha inhibitors.\n\n, 4.6, 4.7, 4.8\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑naive population. It concluded that ustekinumab appeared to be less effective than TNF‑alpha inhibitors for PASI\xa075, PASI\xa090 and PsARC response, particularly for the joint outcome.\n\nThe Committee also considered the clinical effectiveness of ustekinumab compared with TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population. It was aware that there was limited clinical trial evidence in this setting. It understood that there is some evidence for the effectiveness of TNF‑alpha inhibitors in the TNF‑alpha inhibitor‑exposed population, but that there was not enough evidence to compare ustekinumab and TNF‑alpha inhibitors. Evidence presented at a conference suggested that the effectiveness of ustekinumab measured using the American College of Rheumatology (ACR) criteria may decrease with increasing numbers of prior TNF‑alpha inhibitors.\n\nThe Committee concluded that there is still uncertainty about the relative effectiveness of ustekinumab and TNF‑alpha inhibitors in people who have previously had TNF‑alpha inhibitors.\n\nThe Committee also considered whether there may be any variation in clinical effectiveness depending on the reason for withdrawal of the first TNF‑alpha inhibitor but it acknowledged that there was not enough evidence for this aspect to be considered further.\n\nThe Committee acknowledged that there is no clear evidence to support the use of a strict weight‑based dosing strategy.\n\n, 4.8, 4.9\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nIn both PSUMMIT\xa01 and\xa02, ustekinumab was associated with statistically significantly higher rates of ACR\xa020 response at week\xa024 than placebo. ACR\xa020 response rates in PSUMMIT\xa01 were 46.0% and 22.8% for ustekinumab 45\xa0mg and 90\xa0mg pooled, and placebo respectively (p<0.0001).\n\nThe Committee concluded that ustekinumab is clinically effective compared with conventional management, in both TNF‑alpha inhibitor‑naive and TNF‑alpha inhibitor‑exposed populations, but acknowledged that there remains some uncertainty about the long‑term effects of ustekinumab.\n\n, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company's economic model comprised a short‑term decision tree followed by a long‑term Markov model with a lifetime (52‑year) time horizon. It was similar to the models used in previous NICE appraisals of treatments for psoriatic arthritis (etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis).\n\nThe Committee considered the structure, assumptions and results in the company's economic model and the critique presented by the Evidence Review Group (ERG).\n\n, 4.10\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee discussed key assumptions about the improvement, rebound and progression of joint symptoms, the effect of conventional management on skin symptoms, the use of the utility equation, the timing of the assessment of response and the sequencing of biological treatments in the TNF‑alpha inhibitor‑exposed population.\n\nThe Committee concluded that uncertainty remains as to how well the Health Assessment Questionnaire Disability Index (HAQ‑DI) assumptions apply to ustekinumab, but considered that the assumptions in the model were a sufficient basis on which to make a decision.\n\nThe Committee noted that the company's rapid review model incorporated the effect of conventional management on skin symptoms. It concluded that it was appropriate to include the effect of conventional management on skin symptoms in the economic model.\n\nThe Committee considered that all health‑related quality‑of‑life evidence from the clinical trials – including the 36‑item Short‑Form Health Survey (SF‑36) data – should ideally be used if possible. However, because of the uncertainty in the newer utility equation, it concluded that using the previously published equation would be more appropriate.\n\nThe Committee concluded that, for pairwise comparisons between ustekinumab and conventional management, the treatment response should ideally have been assessed at the same time point. The Committee had a preference for assessing treatment response at 24\xa0weeks for both ustekinumab (in line with its summary of product characteristics and the primary efficacy analysis of the PSUMMIT\xa01 and\xa02 studies) and conventional management.\n\n, 4.11, 4.12, 4.13, 4.14\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe model captured health‑related quality of life through joint symptoms, disability and skin symptoms (PsARC response, HAQ‑DI score and PASI score). HAQ‑DI and PASI scores were then mapped to EQ‑5D using an equation used in previous technology appraisal guidance for etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis.\n\nThe Committee noted that the company's base‑case analysis was based on utility scores derived using a previously published equation used in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis.\n\nIt also noted that health‑related quality‑of‑life evidence had been captured directly in the PSUMMIT studies through SF‑36. The Committee considered that all health‑related quality‑of‑life evidence from the clinical trials – including the SF‑36 data – should ideally be used if possible. However, because of the uncertainty in the newer utility equation, and the fact that the effectiveness of ustekinumab in the PSUMMIT trials was captured through the HAQ‑DI and PASI scores, the Committee concluded that using the previously published equation would be more appropriate.\n\n, 4.13\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that ustekinumab is not a cost‑effective option, compared with TNF‑alpha inhibitors, for treating psoriatic arthritis in people who have not previously had TNF‑alpha inhibitors.\n\nThe Committee also considered the cost effectiveness of ustekinumab in people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are contraindicated. It considered that this population comprises people for whom a TNF‑alpha inhibitor would otherwise be considered. It concluded that ustekinumab is a cost‑effective treatment option for this group.\n\nThe Committee concluded that ustekinumab is a cost‑effective option for treating psoriatic arthritis in people who have had previous treatment with TNF‑alpha inhibitors.\n\n, 4.19, 4.20, 4.21\n\nWhat are the key drivers of cost effectiveness?\n\nDeterministic sensitivity analyses showed that the results were most sensitive to the change in HAQ‑DI score over time associated with the natural history of psoriatic arthritis, the proportion of people who had a PsARC response, and the HAQ‑DI change associated with PsARC response.\n\nIn particular, the Committee discussed key assumptions about the improvement, rebound and progression of joint symptoms, the effect of conventional management on skin symptoms, the use of the utility equation, the timing of the assessment of response and the sequencing of biological treatments in the TNF‑alpha inhibitor‑exposed population.\n\n, 3.14, 4.10\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nWith the patient access scheme:\n\nIn the TNF‑alpha inhibitor‑naive population, ustekinumab was extendedly dominated (that is, was more expensive and less effective than a combination of 2 comparators).\n\nIn people who have not previously had TNF‑alpha inhibitors and for whom TNF‑alpha inhibitors are inappropriate because of contraindications, the Committee concluded that the most plausible ICER was £21,900 per QALY gained.\n\nIn the TNF‑alpha inhibitor‑exposed population, the Committee noted that in the incremental analysis, the most plausible ICER was £25,400 per QALY gained (compared with conventional management).\n\nIn the TNF‑alpha inhibitor‑exposed population, looking specifically at people for whom TNF‑alpha inhibitors as a class had failed, the Committee considered that the most plausible ICER for ustekinumab compared with conventional management was £25,300 per QALY gained.\n\n, 4.19, 4.20, 4.21\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health, in which the company provides the 90‑mg dose (2\xa0vials) at the same cost as the 45‑mg dose (1\xa0vial), for people who weigh more than 100\xa0kg and need the higher dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd‑of‑life considerations\n\nN/A\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee also considered whether appraising ustekinumab 45\xa0mg alone could lead to unfair or discriminatory recommendations, if the higher dose were more effective in people weighing more than 100\xa0kg. It concluded that, based on the likely use of ustekinumab in clinical practice and the potential for effectiveness differences between the doses (particularly in people weighing more than 100\xa0kg), it would not be appropriate for it to consider ustekinumab 45\xa0mg alone.\n\nThe Committee noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to components of the PsARC, and concluded that this should be taken into account when using the PsARC.\n\n, 4.22", 'Recommendations for further research ': 'The Committee considered that there is an important need for head‑to‑head comparisons between biological treatments for psoriatic arthritis, particularly in people for whom treatment with tumour necrosis factor (TNF) alpha inhibitors has been unsuccessful.', 'Review of guidance': 'The guidance on this technology will be considered for review 3\xa0years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMay 2015', 'Changes after publication': 'March 2017: under the original patient access scheme the company provided 2x45‑mg pre-filled syringes, for patients who needed the higher dose of 90‑mg, at the same total cost to the NHS as for a single 45‑mg pre-filled syringe. The patient access scheme has been withdrawn because the company now provides a 90‑mg vial at the same cost as the 45‑mg vial.\n\nISBN: 978‑1‑4731‑1156‑1'}	https://www.nice.org.uk/guidance/ta340	Evidence-based recommendations on ustekinumab (Stelara) for treating active psoriatic arthritis in adults.
066c458c32e5862308809e20b7e2c5c8c460df04	nice	Drug misuse prevention: targeted interventions	Drug misuse prevention: targeted interventions This guideline covers targeted interventions to prevent misuse of drugs, including illegal drugs, ‘legal highs’ and prescription-only medicines. It aims to prevent or delay harmful use of drugs in children, young people and adults who are most likely to start using drugs or who are already experimenting or using drugs occasionally. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Delivering drug misuse prevention activities as part of existing services Deliver drug misuse prevention activities for people in groups at risk through a range of existing statutory, voluntary or private services, including: health services, such as primary care services, community-based health services, mental health services, sexual and reproductive health services, drug and alcohol services, and school nursing and health visiting services specialist services for people in groups at risk community-based criminal justice services, including adult, youth and family justice services accident and emergency services. Ensure activities targeting groups at risk are consistent with any population-level (universal) activities aimed at preventing drug misuse. # Assessment At routine appointments and opportunistic contacts with statutory and other services, such as those listed in recommendation 1.1.1, assess whether someone is vulnerable to drug misuse. Examples of routine appointments and opportunistic contacts include: health assessments for children and young people who are looked after or care leavers, including initial assessments, any reviews and contacts appointments with GPs, nurses, school nurses or health visitors attendances at emergency departments as a result of alcohol or drug use contacts with the community-based criminal justice system. Use a consistent, locally agreed approach to assessment that is respectful, non-judgemental and proportionate to the person's presenting vulnerabilities. For an example for young people, see the practice standards for young people with substance misuse problems. Discuss the person's circumstances, taking account of their age and developmental stage. The initial discussion could include: their physical and mental health and their personal, social, educational or employment circumstances (which may trigger a more in-depth assessment) any drug use (including the type used and how often).If the person is already misusing drugs, see NICE's guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older, needle and syringe programs, and diagnosis and management of alcohol-use disorders. Think about the immediate safety of the person being assessed and any people under their care, and whether any action is needed. Discuss with the person what their priorities are and take into account how these might affect next steps or referral to other services. # Children and young people assessed as vulnerable to drug misuse Consider skills training for children and young people who are assessed as vulnerable to drug misuse. If skills training is delivered to children and young people, ensure that their carers or families also receive skills training. For older children and young people, think about whether providing information (see recommendations in section 1.4) may be a more appropriate approach. Ensure any skills training is: commissioned as part of existing services (see recommendation 1.1.1) delivered as part of activities designed to increase resilience and reduce risk delivered by people competent to provide skills training. If skills training is offered to children and young people and their carers or families, ensure it helps children and young people develop a range of personal and social skills, such as: listening conflict resolution refusal identifying and managing stress making decisions coping with criticism dealing with feelings of exclusion making healthy behaviour choices.Ensure that personal and social skills training for children and young people who are looked after and care leavers puts particular emphasis on how to deal with feelings of exclusion. If skills training is offered to children and young people and their carers and families, ensure that it helps carers and families develop a range of skills, such as: communication developing and maintaining healthy relationships conflict resolution problem solving. Ensure that skills training for foster carers includes using behaviour reinforcement strategies alongside the other skills listed. Take into account the age, developmental stage, presenting vulnerabilities, cultural context, religion, ethnicity and any other specific needs or preferences of the child or young person when deciding: whether to offer training sessions to children and young people and their carers or families together, or whether to offer separate sessions the content of the skills training whether to provide individual or group-based sessions the number of sessions needed (a minimum of 2 sessions should be offered) where to hold the sessions how long each session should last.For more information, see the Department of Health's quality criteria for young people friendly services. Discuss and agree a plan for follow-up at the skills training sessions, to assess whether additional skills training or referral to specialist services is needed. # Adults assessed as vulnerable to drug misuse Offer adults who are assessed as vulnerable to drug misuse (see section 1.2) the following: clear information on drugs and their effects advice and feedback on any existing drug use information on local services and where to find further advice and support (see recommendation 1.5.3).This information should be provided at the same time as the assessment. Offer information and advice both verbally and in writing. Provide advice in a non-judgemental way and tailor it to the person's preferences, needs and level of understanding about their health. Ensure that information and advice is delivered in line with NICE's guidelines on general and individual approaches to behaviour change and patient experience in adult NHS services. Discuss and agree a plan for follow-up at the assessment, to determine whether additional information or referral to specialist services is needed. # People at risk of using drugs Consider providing information about drug use in settings that groups who use drugs or are at risk of using drugs may attend. These settings could include: nightclubs or festivals wider health services, such as sexual and reproductive health services or primary care supported accommodation or hostels for people without permanent accommodation gyms (to target people who are taking, or considering taking, image- and performance-enhancing drugs). Consider providing information in different formats, including web-based information (such as digital and social media) and printed information (such as leaflets). Consider providing information on: drugs and their effects (for example, on NHS Choices) local services and where to find further advice and support -nline self-assessment and feedback to help people assess their own drug use. Ensure that information provided is in line with NICE's guidelines on general and individual approaches to behaviour change and patient experience in adult NHS services. # Terms used in this guideline This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary. ## Care leavers People aged 25 or under who have been looked after by a local authority for at least 13 weeks since age 14, and who were looked after by the local authority at school leaving age or after that date. ## Children and young people who are looked after Children and young people looked after by the state for whom the Children Act 1989 applies. The term includes children and young people who are subject to a care order or temporarily classed as looked after on a planned basis for short breaks or respite care. The term also includes those in residential care, foster care or boarding school, or with birth parents, other family or carers. It includes children and young people in placements out of the child or young person's home area. Children and young people who are in young offender or other secure institutions are not included in this definition, because this group is outside the scope of the guideline. ## Drugs Drugs described in the Misuse of Drugs Act 1971 and the Psychoactive Substances Act 2016, as well as new psychoactive substances (often described as 'legal highs'), solvents, volatile substances, image- and performance-enhancing drugs, prescription-only medicines and over-the-counter medicines. ## Drug misuse Dependence on, or regular excessive consumption of, psychoactive substances, leading to physical, mental or social problems. This term does not include occasional or experimental drug use in adults. ## Groups at risk Groups at risk of drug misuse, including: people who have mental health problems people who are being sexually exploited or sexually assaulted people involved in commercial sex work people who are lesbian, gay, bisexual or transgender people not in employment, education or training (including children and young people who are excluded from school or who truant regularly) children and young people whose carers or families use drugs children and young people who are looked after or care leavers children and young people who are in contact with young offender teams but not in secure environments (prisons and young offender institutions) people who are considered homeless people who attend nightclubs and festivals people who are known to use drugs occasionally or recreationally. ## Prevention Preventing or delaying drug use, preventing people who are already using some drugs from using other drugs, and preventing people who already experiment or use drugs occasionally from using drugs regularly and excessively. ## Treatment The clinical management of drug misuse or dependence. This could comprise, for example, pharmacotherapy, psychosocial therapy or a combination of these. ## Vulnerable to drug misuse People in groups at risk who may be particularly vulnerable to drug misuse. This may include people: in multiple groups at risk whose personal circumstances put them at increased risk who may already be using drugs on an occasional basis who may already be regularly excessively consuming another substance, such as alcohol. ## Young people People aged 10 to 18. This term also includes people aged up to 25 who have special educational needs or a disability (consistent with the Children and Families Act 2014).# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through a range of different communication channels. These could include digital and social media, alongside regular channels such as email, newsletters, meetings, internal staff briefings and communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes, include milestones and a business case which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context The Misuse of Drugs Act 1971 and the Psychoactive Substances Act 2016 list all illegal (or controlled) drugs in the UK. According to the Home Office report Drug misuse: findings from the 2015 to 2016 Crime Survey for England and Wales: Around 8% of people aged 16 to 59 had taken an illegal drug or used a substance unlawfully in the past year, and around 4% had taken one in the past month. Among young adults aged 16 to 24, this was 18% in the past year and 9% in the past month. More than one third of adults aged 16 to 59 (35%) have taken an illegal drug or used a substance unlawfully at some point in their lives. Cannabis was the most common, with 7% using it in the past year, followed by powder cocaine (2%) and ecstasy (2%). In the same age group, 3% were defined as frequent drug users (having taken an illegal drug or used a substance unlawfully more than once a month, on average, in the past year). Among young adults aged 16 to 24, this figure was 5%. Use of any class A drug was around 10 times higher among people who had visited a nightclub at least 4 times in the past month (18%) compared with those who had not visited a nightclub in the past month (2%). A similar pattern was found for those visiting pubs and bars more frequently. The government's What About YOUth survey (Health and Wellbeing of 15-year-olds in England – Main findings from the What About YOUth? Survey 2014) found that: % of 15 year-olds had used cannabis in the past month % had used cannabis in the past year, and 2% had used it more than a year ago % said that they had been offered drugs other than cannabis, and 2% had tried other drugs. The Health and Social Care Information Centre's survey on Smoking, Drinking and Drug Use Among Young People in England – 2014 found that: around 3% of 11 to 15 year-olds reported inhaling glue, gas or other solvents -f the 11 to 13 year-olds who reported some drug use in the past year, 53% reported using volatile substances. The Home Office's National drug strategy for England 2010 sets out plans for helping people to live a drug-free life. The third annual review of this strategy was published in 2015 (Drug strategy annual review: 2014 to 2015). As part of the Health and Social Care Act 2012, local authorities became responsible for commissioning drug misuse treatment services. The Home Office's drug strategy annual review highlights the key role local authorities play in helping to reduce both the supply of, and demand for, illegal drugs. This includes preventing problematic drug use and helping people to recover from drug addiction by developing their personal and social capital, through providing education, housing, public health and social care services. The Public Health England and Association of Directors of Public Health Review of drug and alcohol commissioning (2014) identified that in many areas there is a continued desire to improve outcomes, delivery and performance, but service funding may be uncertain. The primary focus for many areas is treatment rather than prevention. Drug services are increasingly integrated with services to reduce alcohol dependency and services to support younger people, as well as services associated with the community criminal justice system and local health delivery. You can also see this guideline in the NICE pathway on drug misuse prevention. To find out what NICE has said on topics related to this guideline, see our web page on drug misuse. See also the evidence reviews and information about how the guideline was developed, including details of the committee.# The committee's discussion Evidence statement numbers are given in square brackets. For an explanation of the evidence statement numbering, see the evidence reviews section. # Approach of this guideline The committee discussed that this guideline only covers prevention of drug misuse for groups at risk. The evidence base for population-level (universal) approaches and for wider determinants of drug use in the general population or at risk groups was not considered. The committee discussed that wider determinants of health, such as housing, education and employment opportunities, social support, and personal resilience, are likely to have a fundamental effect on both the risk of drug misuse and the effectiveness of interventions to prevent drug misuse. The committee discussed the groups at risk presented in the scope for this guideline. Based on the evidence considered, it agreed that the recommendations should be targeted at these groups. The committee also noted there may be additional groups who have not been considered, such as young people with behavioural or social problems, and that some people would be included in more than 1 group at risk. For example, a person could be considered homeless and lesbian, gay, bisexual or transgender. The committee understood that the nature of drug use and the risk to health varies within the specified groups at risk. The groups covered by the guideline include people who are not currently using drugs but are at increased risk of doing so, through to people who are known to use drugs occasionally or recreationally. Recommendations for treating people who are dependent on drugs are outside the scope of this guideline. The committee acknowledged that there is wide variation in vulnerability to drug misuse within each of the groups at risk. The committee noted that the variation in vulnerability within the groups at risk means that different people in each group at risk have different needs, despite being in the same group. The committee agreed that not all people in a group at risk will use drugs. It commented that drug use is more likely in some people within each group at risk than in others, such as those in multiple groups at risk, whose personal circumstances put them at increased risk, who may already be using drugs on an occasional basis, or who may already be misusing another substance, such as alcohol. The committee developed the recommendations in the current guideline on the assumption that they would be considered alongside other relevant NICE guidance, such as social and emotional wellbeing in primary and secondary education, diagnosis and management of alcohol-use disorders, looked-after children and young people, community engagement, and coexisting severe mental illness and substance misuse. The committee also noted the importance of considering the recommendations in this guideline alongside others on preventing and managing drug use (for more information, see NICE's guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older). # Overview of the effectiveness and acceptability evidence The committee noted that there is limited evidence for effectiveness and acceptability of drug misuse prevention interventions across the groups at risk. No direct effectiveness evidence was identified for 3 of the groups at risk in the scope: people involved in commercial sex work or who are being sexually exploited; people not in employment, education or training ; and people who attend nightclubs and festivals . Either no, or limited, evidence was identified on the effectiveness and acceptability of interventions delivered as part of planned outreach activities or peer education initiatives . No evidence for the acceptability of interventions was identified for 4 of the groups at risk in the scope: people with mental health problems ; people involved in commercial sex work ; people not in employment, education or training ; and children and young people whose parents use drugs . The committee acknowledged that most studies compared an intervention with current practice, assessment only or another intervention rather than with no intervention. The committee agreed that data showing no significant difference between the intervention and comparator tended to show a similar improvement in outcome in both the intervention and comparator groups, rather than the intervention not having an effect at all . Therefore, it agreed that the interventions in the included studies were likely to be at least as effective as the comparator. The committee noted that none of the studies reported any adverse effects such as death or overdose. Therefore, it agreed that the interventions in the included studies were unlikely to be harmful. The committee agreed that the acceptability studies found that drug misuse prevention interventions are generally well received. # Overview of the cost-effectiveness evidence The committee noted that the literature review for cost-effectiveness evidence did not find any studies that were directly relevant to drug misuse prevention in the UK. Health economic modelling was undertaken to provide cost-effectiveness evidence for this guideline. Health economic modelling was undertaken on 7 interventions that were identified in evidence review 1. These interventions were family-based interventions, web-based interventions and motivational interviewing interventions. The committee acknowledged that the health economic modelling did not identify any drug misuse prevention interventions that were cost effective in the base case . However, the results of the modelling did suggest that some interventions, such as those that are web-based or family-based, could be cost effective if they could be provided at a lower cost and their effects sustained over a longer duration than was considered in the base case economic analysis . For example, an intervention costing £100 per person that reduced drug use by 5 percentage points maintained over 2 years would be cost effective. If the intervention cost more than £100, the reduction in drug use or duration of effect would need to be higher for the intervention to be cost effective. The committee acknowledged that there are several reasons why the interventions included in the health economic modelling do not appear to be cost effective. Most of the interventions did not change drug use by more than 5 percentage points. In addition, none of the studies showed a reduction in drug use that was maintained for more than 1 year. This means it is difficult for the interventions to make a large reduction in societal costs. In addition, most of the studies looked at cannabis and ecstasy use, and it is not clear how the social costs of using cannabis and ecstasy compare to those of other drugs. The committee agreed that it remains unclear whether there is a causal link between use of 1 substance and other substances (the 'gateway hypothesis') and what effect a causal relationship might have on costs to the NHS (or society more broadly). So committee members agreed that the relationship should not be assumed within the economic model. # Section 1.1 Delivering drug misuse prevention activities as part of existing services The discussion below explains how we made the recommendations in section 1.1. ## Recommendations 1.1.1 and 1.1.2 The committee heard expert testimony that the focus of commissioning new drug misuse prevention interventions is changing . Many areas are increasingly integrating drug misuse prevention activities with drug treatment or wider health and social care activities, such as activities to increase general resilience and decrease risky behaviours within sexual health services or educational support services to address truancy . The committee acknowledged that the misuse of substances such as illegal drugs and alcohol rarely happens in isolation. Many people at increased risk of drug misuse may already be in contact with statutory, voluntary or private services such as mental health, community-based criminal justice, alcohol and drug services, and services for children and young people who are looked after and care leavers. The committee heard expert testimony that local authorities are well placed to address the wider needs of some groups at risk, such as their housing needs . However, local authorities also need to collaborate with wider services, such as healthcare services, schools, or police and crime commissioners, to provide effective drug misuse prevention activities . The committee noted that none of the interventions included in the health economic modelling were cost effective as stand-alone programmes (see overview of the cost-effectiveness evidence) . However, they could be cost effective if added to existing programmes of care at an additional cost of less than £100 per person . Taking into account the changing focus of commissioning, wider determinants of drug use and the health economic modelling, the committee recommended that drug misuse prevention interventions should be delivered through a range of existing services for people in groups at risk, rather than setting up dedicated services. # Section 1.2 Assessment The discussion below explains how we made recommendations in section 1.2. ## Recommendation 1.2.1 The committee discussed assessing whether people are vulnerable to drug misuse. The committee agreed that it was essential to have an assessment before intervention to ensure that the intervention offered is appropriate and no harm is done. It noted that an assessment of drug use was a consistent part of effective interventions included in evidence review 1. No studies were identified that included an assessment only arm compared with assessment plus intervention and no intervention. However, the committee discussed that if comparator groups were offered assessment, improved drug or other outcomes were consistently reported. The committee also noted that there was weak evidence from review 2 that assessments of substance use and other risky behaviours may prompt reductions in drug use . The committee noted that none of the 7 interventions modelled by the health economic team were cost effective in the base case as a stand-alone intervention (see overview of the cost-effectiveness evidence) . The committee noted from the health economic modelling that to be cost effective an intervention would need to cost less than £100 per person and would need to reduce the number of people misusing drugs by at least 5 percentage points over 2 years . The committee agreed that a reduction of at least 5 percentage points in the number of people at risk of misusing drugs was most likely to occur in people who are assessed as vulnerable to drug misuse. As such, interventions are likely to be cost effective only in people who are vulnerable to drug misuse. The committee discussed that interventions that target people assessed as most vulnerable to drug misuse are more likely to be cost effective. The committee agreed that drug misuse prevention activities cannot be targeted to people most vulnerable to drug misuse if those people have not been assessed. It noted that undertaking assessment before an intervention is consistent with the related NICE guideline on psychosocial interventions for drug misuse in people aged 16 years and older. The assessment could be part of either a routine appointment (such as health needs assessments for children and young people who are looked after) or an opportunistic appointment (such as when someone attends an emergency department as a result of alcohol use, or when young people come into contact with the community-based criminal justice system). Many different practitioners may be working with people at risk of drug misuse. These practitioners have an important role in identifying people who may benefit from drug misuse prevention activities, even if the practitioners do not provide drug misuse prevention activities themselves. The committee therefore recommended that routine and opportunistic appointments provided by statutory and other services should be used to assess vulnerability to drug misuse. The committee agreed that all practitioners who have contact with people in groups at risk, including practitioners working in health services, social care services and the criminal justice system, should be aware of drug misuse prevention and should use every contact to identify those at risk. ## Recommendation 1.2.2 The committee was not able to recommend a particular assessment tool for a number of reasons. The committee noted that most tools that are available focus on people who already use drugs rather than those at risk of misusing drugs. Comments from stakeholders during consultation on the draft guideline highlighted several assessment tools that stakeholders believed could be useful. However, the committee noted that these tools may not fit easily into routine and opportunistic appointments provided by statutory and other services. Some of the tools focused on alcohol use rather than drug use. The committee was aware that there is no single tool that is suitable for use in all groups at risk and for assessing all vulnerabilities. It was concerned that recommending a tool for a particular group at risk may result in the tool being used with other groups at risk, which may not be appropriate. The committee noted evidence that whatever approach is chosen, it should be non-judgemental, which is likely to be more acceptable to participants . So the committee was unable to recommend a specific assessment tool, but recommended that a consistent, locally agreed, respectful and non-judgemental approach is used. The committee recommended that the approach for assessment should be proportionate to the person's presenting vulnerabilities. The committee noted that the assessor may become more aware of potential vulnerabilities through their discussion with the person and may therefore need to do a more intensive assessment to explore these vulnerabilities. The committee noted that there are existing practice standards for young people with substance misuse problems from the Royal College of General Practitioners, Alcohol Concern, DrugScope and Royal College of Psychiatrists. The overall quality of the practice standards document was rated as 5 out of 7 using the AGREE II tool, where 1 indicates 'lowest possible quality' and 7 indicates 'highest possible quality'. The practice standards document scored well on several domains in the tool, including being clear on the aim of the guideline and its target population, involving stakeholders throughout development, presenting recommendations clearly, and providing information on implementation. It did not score as well on describing how the evidence was selected, the strengths and limitations of the evidence, or the methods for formulating the recommendations. However, this information can be found in the guidance (including NICE guidance) that the recommendations in the practice standards document are based on. The committee noted that there is no corresponding practice standards document for adults. However, it believed that many of the practice standards were relevant for adults as well as young people. The committee agreed that the practice standards are a useful example of an approach for assessing a person's vulnerability to drug misuse. ## Recommendation 1.2.3 The committee discussed the importance of an assessment considering how the wider health and personal context, such as a person's age and developmental stage, as well as their personal, social, health, mental health and educational or employment circumstances, may affect their vulnerability to drug misuse. It also discussed the importance of assessment addressing the possible harm associated with any existing drug use by that person. The committee recommended that assessors should be aware that the person's circumstances may be complex. The committee acknowledged that people working with groups at risk need to have an understanding of the potential vulnerabilities to drug misuse. They should also be aware that people may present with more than 1 vulnerability, and that people who do present with more than 1 vulnerability may be at increased risk of drug misuse. The committee agreed that an assessment might identify people who are already misusing drugs. As previously noted, it can be difficult to make a distinction between occasional or recreational use and regular or excessive use. The committee highlighted that the definition of 'excessive use' is subjective and may vary depending on the individual (for example, their age and developmental stage) and their circumstances. For example, drug use that is not considered excessive in an adult may be considered excessive in a younger person. Treatment of people who use drugs or alcohol regularly or excessively is outside the scope of this guideline. NICE has guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older, diagnosis and management of alcohol-use disorders in people aged 10 years and older, and needle and syringe programmes for adults and young people, including those under 16. ## Recommendation 1.2.4 The committee discussed the role of safeguarding. It acknowledged that safeguarding includes protecting vulnerable people of any age from physical and emotional maltreatment, sexual abuse, neglect and exploitation. It agreed that safeguarding is everyone's responsibility. It added that all practitioners who are in contact with vulnerable people have a duty to protect them from maltreatment and share information with other services. The committee agreed that practitioners undertaking assessment of whether someone is vulnerable to drug misuse should be aware that the assessment may raise safeguarding concerns. It acknowledged that safeguarding concerns may become more apparent to the practitioner once the assessment has ended and they are reflecting on the discussion. Although the committee emphasised the importance of safeguarding, it acknowledged that recommending referral to specialist services, such as child protection services, as a result of safeguarding concerns is outside the scope of the current guideline. The committee also acknowledged that not all concerns need immediate intervention from social care services, and that other factors (such as problems at school) may have a larger effect on the person's vulnerability to drug misuse. The committee therefore recommended that the assessor should think about whether there are concerns for the safety of the person being assessed and any people under their care. ## Recommendation 1.2.5 The committee recommended that people undertaking assessments should discuss the person's priorities and consider what effect their priorities have on prevention activities or referral to specialist services. The committee highlighted that there are existing practice standards for young people with substance misuse problems from the Royal College of General Practitioners, Alcohol Concern, DrugScope and the Royal College of Psychiatrists. # Section 1.3 Children and young people assessed as vulnerable to drug misuse The discussion below explains how we made recommendations in section 1.3. ## Recommendation 1.3.1 The committee noted that the health economic team modelled 7 drug misuse prevention interventions. None of these were cost effective in the base case as a stand-alone intervention (see overview of the cost-effectiveness evidence) . The committee noted from the health economic modelling that to be cost effective, an intervention would need to cost less than £100 per person and would need to reduce the number of people misusing drugs by at least 5 percentage points over 2 years . The committee agreed that a reduction of at least 5 percentage points in the number of people at risk of misusing drugs was most likely to occur in people who are assessed as vulnerable to drug misuse. As such, interventions are likely to be cost effective only in people who are vulnerable to drug misuse. The committee recommended that interventions are prioritised for those with increased vulnerability. Evidence for the effectiveness of offering personal and social skills training to children and young people at risk of drugs misuse and to their parents and carers came from 4 studies reported in 4 papers . Two trials reported a significant reduction in drug use, including a trial undertaken with children and young people who are looked after and their foster carers. There was also evidence from 3 studies of a significant improvement in personal and social skills after skills training for children and young people and their parents or carers, which supports the studies that found a significant reduction in drug use. One of the trials of personal and social skills training for children and young people and their parents and carers reported an increase in cannabis use in children and young people who underwent skills training. However, the committee believed this finding could be a result of participants changing their drug use from other drugs to cannabis during the study, because the study also reported a decrease in the use of drugs other than cannabis. An additional study did not report a significant reduction in drug use after the intervention; however, in this study drug use was measured immediately after the intervention only and no longer-term data were collected. The committee noted that there was evidence from evidence review 2 that group-based skills training and opportunistic skills training, advice and information provision are acceptable to participants . However, it also acknowledged that it may not be appropriate to include carers or families in all cases, such as if children have been sexually abused. Personal and social skills training for only children and young people who are vulnerable to drug misuse was not recommended because the evidence was limited and inconsistent . Two studies of the effectiveness of skills training for children and young people showed an inconsistent effect on drug use, with the use of some drugs being significantly reduced but the use of other drugs not changing significantly. A third study reported no difference in drug use after skills training for children and young people. One study reported a significant improvement in drug refusal skills, problem-solving skills, and coping skills after the intervention. Another study concluded that skills training for children had no significant effect on feelings of self-worth, but it did not report data, p values or an effect size. One study reported that the intervention may have affected intention to use drugs, but the data were not reported. Another study reported a statistically significant improvement in knowledge of drugs and their risks after the intervention with peer educators but not with adult educators. Personal and social skills training for only carers and families of children and young people at risk of drug misuse was not recommended. This was because it was not clear that skills training for parents and carers alone had a significant effect on drug use in the children and young people they cared for. Evidence for the effectiveness of skills training for parents or carers came from 4 trials reported in 7 papers . One trial and 2 follow-up studies reported no statistically significant difference in drug use. Three trials and a secondary analysis of one of the trials reported significantly reduced drug use after the intervention. However, 2 of the trials that reported significantly reduced drug use included other interventions for the families in addition to skills training, such as case management, weekly family therapy, individual therapy, and motivational interviewing. It is not clear whether the skills training or the other interventions had a significant effect on drug use. Family-based interventions as a whole were not recommended because they were unlikely to be cost effective for the populations included in the current guideline. The committee acknowledged the evidence on family-based interventions showed a mixed effect on drug use, with 5 studies in 6 papers showing a significant reduction in drug use, 4 studies in 6 papers showing no significant effect on drug use, and 1 study showing a significant increase in drug use . However, the committee noted that the evidence base included studies of Multidimensional Treatment Foster Care and motivational interviewing, which are more intensive than skills training alone. The committee was aware that family-based interventions were recommended in NICE's guideline on substance misuse interventions for vulnerable under 25s. It noted that this recommendation included motivational interviewing and family therapy, which were very unlikely to be cost effective for the populations included in the current guideline. The health economic modelling looked at 3 family-based interventions that included skills training . None of the interventions were found to be cost effective in the base case scenario. However, the committee noted that these interventions involved other activities as well as skills training, such as motivational interviewing, which would have made them more costly. The committee noted that the results of the modelling showed that 2 of the interventions could be cost effective if the cost of delivering them was lower and the effects of the interventions could be sustained over 2 years or more . It also noted that interventions could be made cost effective if they were added to existing programmes of care at an additional cost of less than £100 per person . Manualised and licensed programmes, of which 4 out of5 were family-based, were not recommended because they were costly and may not be effective for the populations included in the current guideline. The committee noted that evidence review 1 included studies of manualised and licensed programmes, namely Focus on Families , Family Competence Program , Multidimensional Treatment Foster Care , Familias Unidas and Free Talk . The studies either showed no significant effect on drug use , an inconsistent effect on drug use or did not report drug use outcomes . The committee noted that such programmes are costly and that adapting programmes to make them cost less than £100 per person could have an impact on effectiveness. The committee also noted that none of the studies of manualised and licensed programmes were from the UK, and it is not clear whether the programmes would have the same effectiveness in a different country from where the study was performed. The committee concluded that it could not recommend adapting existing manualised or licensed drug misuse prevention programmes for use in the UK. Motivational interventions were not recommended because of the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence. The evidence review identified 3 main types of motivational intervention: 'motivational interviewing'; 'brief interventions'; and 'motivational enhancement therapy' (see evidence tables for details of the interventions). The committee noted that most studies did not clearly describe the intervention and used terminology that may not match the committee's understanding. It acknowledged that the programme development group for NICE's guideline on individual approaches to behaviour change noted similar issues. The programme development group concluded that it was not possible to recommend motivational interviewing because the studies did not specify which principles and components were used. The committee therefore considered the evidence for motivational interventions as a whole. The committee noted that there were 15 unique trials of motivational interventions, of which 9 were in children and young people . Two of the 9 trials reported significant reductions in drug use. However, 1 of these trials showed a significant difference in the use of some drugs at some time points but not others, and the other trial showed reduced drug use in some contexts but not others. The committee agreed that, overall, motivational interventions were unlikely to be significantly more effective than skills training. The committee discussed the health economic modelling for motivational interventions. It showed that motivational interviewing was not cost effective in the base case, ranging from £131,000 per QALY gained to £485,000 per QALY gained . The modelling showed that motivational interviewing would only be cost effective if it could be delivered for less than £190 and could reduce drug use for at least 2 years . The committee agreed that motivational interventions were unlikely to be cost effective compared with skills training. Taking into account the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence, the committee concluded that it was unable to recommend motivational interventions for groups at risk of drug misuse. The committee recommended that research is undertaken in this area (see research recommendation 3). The committee agreed that skills training for children and young people as well as for their carers or families was likely to be a more cost effective way to reduce the risk of drug misuse than family-based interventions or manualised or licensed programs, and motivational interventions for children and young people. This is because it is more likely that skills training could be delivered as part of existing services for less than £100 per person. The committee noted that skills training is likely to improve a range of outcomes, including those that are not related to drug misuse. It did not believe there was enough evidence to recommend skills training just for children and young people, or just for their carers and families. The committee reiterated that any skills training should be delivered as part of existing services, as in recommendation 1.1.1. The committee discussed the different groups of people that this guideline is relevant to. It acknowledged that services aimed at groups at risk use different ages to distinguish between child and adult services. For example, specialist services for drug treatment aimed at adults may include people aged 16 and over, whereas services for children and young people that are looked after may include those aged up to 25. The committee was aware that 'young people' can include people with a range of ages and developmental stages. It acknowledged that for some young people it may be more appropriate to offer skills training, and for other young people it may be more appropriate to offer information on drugs and their effects. The committee recommended that following an assessment of whether a young person in a group at risk is vulnerable to drug misuse, the most appropriate prevention options for that young person should be considered. ## Recommendation 1.3.2 The committee agreed that integrating skills training for children and young people and their carers and families into existing services could lower the additional cost of the interventions and therefore be a cost-effective way to deliver drug misuse prevention interventions. The committee heard expert testimony that integrating skills training into existing services is becoming a more common approach . Based on the cost-effectiveness evidence, the committee recommended that skills training for children or young people and their carers or families should be commissioned as part of existing services (see discussion section on recommendation 1.2.1). The committee noted that skills training is likely to be delivered by people who do not work in drug and alcohol services. It agreed that any skills training should be delivered by people who are already competent to provide it, instead of investing resources in training people to deliver it. It noted that the NICE guidance on antisocial behaviour and conduct disorders in children and young people includes recommendations on the training and competencies of staff working with children and young people. ## Recommendations 1.3.3 and 1.3.4 The committee discussed the content of skills training sessions, noting that different approaches were used in different studies and that most studies included training on more than 1 type of skill. The skills training interventions for children and young people that successfully reduced the risk of drug use and improved personal and social skills included skills such as listening, conflict resolution and refusal. Other components of effective skills training interventions were identifying and managing stress, making decisions, coping with criticism, dealing with feelings of exclusion, and making healthy behaviour choices . The committee noted that the skills training interventions for parents and carers of children at risk of drug use that successfully reduced the risk of drug use and improved personal and social skills included skills such as communication, developing and maintaining healthy relationships, conflict resolution, and problem solving . The committee recommended that skills training should aim to develop a range of skills, with the skills used in the studies as examples. The committee agreed that skills training for children and young people who are looked after and care leavers, and their carers, needed particular consideration, because there was clearer evidence of the success of skills training for this group compared with other groups. Successful skills training interventions for children and young people who are looked after and care leavers included social skills and how to deal with feelings of exclusion . For foster carers, the important component was how to use behaviour reinforcement systems . The committee recommended that skills training for children and young people who are looked after, care leavers and foster carers emphasised these skills. ## Recommendations 1.3.5 and 1.3.6 The committee discussed the wide variation in age and developmental stage in the groups at risk. The committee noted that skills training sessions can be used for people of different ages; however, sessions aimed at a young child might not be appropriate for a young adult. The committee recommended that age and developmental stage should be taken into account when deciding on the details of the skills training sessions. The committee considered other aspects that might influence the effectiveness of skills training offered to children and young people. It agreed that presenting vulnerabilities, cultural context, religion and ethnicity may be important. It recommended that these factors be taken into account, along with any other specific needs or preferences of the child or young person vulnerable to drug misuse, when deciding the details of what training sessions to provide. It also noted the evidence that interventions should be made engaging, relevant and creative . The committee considered whether interventions should be provided one-to-one or in a group-based setting. It acknowledged there was mixed evidence for the effectiveness of group-based behaviour therapy (including skills training) for children and young people , but that it is generally well received . The committee agreed that group-based skills training is likely to cost less per person than one-to-one skills training. None of the studies looked at the effectiveness of one-to-one skills training, but the committee acknowledged that group environments may not be appropriate for everyone in groups at risk. The committee recommended taking into account the child or young person's needs and preferences when deciding whether sessions should be provided one-to-one or in groups. The committee considered the number and duration of skills training sessions that should be delivered. It acknowledged that the overall effectiveness of family-based interventions did not appear to vary by the intensity or duration of the intervention . However, it was not clear whether this was also true for the subset of family-based interventions that included skills training sessions for children or young people and their parents or carers. Studies used different numbers (3 to 14 sessions) and durations of training sessions (from not reported to 1.5 to 2 hours), and the committee noted no consistent pattern of effectiveness. The committee felt unable to recommend a specific number or duration of sessions. However, it acknowledged that skills training is likely to be offered as part of a larger programme, in which skills related to drug misuse prevention may be a small part of each training session. Therefore, the committee recommended that skills training should consist of 2 sessions as a minimum. The committee recommended taking the needs of the child or young person into account when determining the number and duration of skills training sessions. It also recommended discussing and agreeing a plan for follow-up at the skills training sessions to determine whether additional skills training or referral to specialist services is needed. The committee also considered where skills training interventions should be delivered. It noted evidence that participants reported having access to a trusted setting in which they are surrounded by likeminded peers could stop them misusing drugs . The committee recommended that the settings in which skills training will be delivered should also be considered. The committee was unable to recommend details of the skills training, such as where to hold the sessions, as this information was not available from the evidence. However, the committee was aware that the Department of Health has published quality criteria for young people friendly services. It recommended that these criteria are used for information when considering skills training for children and young people. # Section 1.4 Adults assessed as vulnerable to drug misuse The discussion below explains how we made recommendations in section 1.4. ## Recommendation 1.4.1 The committee noted that the health economic team modelled 7 drug misuse prevention interventions. None of these were cost effective in the base case as a stand-alone intervention (see overview of the cost-effectiveness evidence) . The committee noted from the health economic modelling that to be cost effective, an intervention would need to cost less than £100 per person and would need to reduce the number of people misusing drugs by at least 5 percentage points over 2 years . The committee agreed that a reduction of at least 5 percentage points in the number of people at risk of misusing drugs was most likely to occur in people who are assessed as vulnerable to drug misuse. As such, interventions are likely to be cost effective only in people who are vulnerable to drug misuse, and the committee recommended that interventions are prioritised for those with increased vulnerability. The committee was unable to recommend skills training for adults at risk of drug misuse because the evidence was limited . The committee noted that only 1 study of skills training for adults at risk of drug misuse reported significantly reduced drug use compared with before the intervention. The committee acknowledged there was mixed evidence for the effectiveness of group-based skills training as a whole; however, it noted that this evidence included studies in children and young people at risk of drug misuse, as well as adults . Motivational interventions were not recommended because of the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence. The evidence review identified 3 main types of motivational intervention: 'motivational interviewing', 'brief interventions' and 'motivational enhancement therapy' (see evidence tables for details of the interventions). The committee noted that most studies did not clearly describe the intervention and used terminology that may not match the committee's understanding. It acknowledged that the programme development group for NICE's guideline on individual approaches to behaviour change noted similar issues. The programme development group concluded that it was impossible to recommend motivational interviewing because the studies did not specify which principles and components were used. The committee therefore considered the evidence for motivational interventions as a whole. The committee noted that there were 15 unique trials of motivational interventions, of which 6 were in adults . Of these 6 trials, 3 trials reported significant reductions in drug use. One trial showed a significant reduction in drug use compared with no assessment or intervention, but no significant reduction in drug use compared with education or information. The committee discussed the health economic modelling for motivational interventions. It showed that motivational interviewing was not cost effective in the base case, ranging from £131,000 per QALY gained to £485,000 per QALY gained . The modelling showed that motivational interviewing would only be cost effective if it could be delivered for less than £190 and could reduce drug use for at least 2 years . The committee agreed that motivational interventions were unlikely to be cost effective compared with other interventions or current practice. Taking into account the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence, the committee concluded that it was unable to recommend motivational interventions for groups at risk of drug misuse. The committee recommended that research is undertaken in this area (see research recommendation 3). The committee was unable to recommend skills training or motivational interventions for adults who are assessed as vulnerable to drug misuse; however, it wanted to recommend some action should be taken. The committee agreed it should provide recommendations on what current practice involves. The committee considered what current practice involved in studies that found current practice to be as effective as motivational interventions . Current practice was found to include brief information and education on drugs and their effects (such as health and social effects), and feedback. The committee recommended that adults who are assessed as vulnerable to drug misuse should receive these components of current practice. It also recommended research in this area (see research recommendation 2). The committee considered whether additional components should be added to the care of adults who are vulnerable to drug misuse. It agreed that information on sources of advice or support would be helpful for adults at increased risk. The committee agreed that information and advice should be offered at the time of their assessment. ## Recommendation 1.4.2 The committee considered whether the information and advice offered to adults assessed as vulnerable to drug misuse should be provided in a verbal or written format. The committee acknowledged the evidence from 1 study that participants did not find written information as useful as verbal information and they thought it was outdated . However, it noted that this may not be true for all written information and that written information can be useful for people who want to revisit information in their own time. The committee noted the evidence that participants stressed the value of being able to ask questions, and this is only likely to happen when information is provided verbally . The committee therefore recommended that information and advice is provided in a written and verbal format. The committee considered factors that may affect the provision of information to adults who are vulnerable to drug misuse. It discussed the different levels of understanding about health across groups of people. It noted that the level of understanding about health is likely to vary widely among adults who are vulnerable to drug misuse. The committee also noted that NICE's guideline on patient experience in adult NHS services recommends taking people's general literacy levels into account to meet their needs. The committee agreed that the person's level of understanding about health needs to be considered when providing information to adults who are vulnerable to drug misuse. The committee noted evidence that a non-judgemental approach to providing advice was more acceptable to participants . It therefore recommended using a respectful and non-judgemental approach. The committee noted that NICE has existing guidance on general and individual approaches to behaviour change. It recommended that information and advice is provided in line with these guidelines. ## Recommendation 1.4.3 The committee considered the number of information sessions needed for adults who are vulnerable to drug misuse. It agreed that the approach used to provide information will need to vary to account for the wide range of adults who are vulnerable to drug misuse. The committee recommended that a plan for follow-up is discussed and agreed at the time of the person's assessment (see recommendation 1.2.1). # Section 1.5 People at risk of using drugs The discussion below explains how we made recommendations in section 1.5. ## Recommendation 1.5.1 The committee discussed the groups at risk that may not present to health or social care services. Committee members heard expert testimony that people who use image- and performance-enhancing drugs are less likely to present because they may not identify as drug users . They noted that people in some of the groups at risk may not be in contact with health or social care services (for example, people who go to nightclubs and festivals, people who are homeless, people who go to gyms, and children and young people at school) or may be in contact only with wider health services, such as sexual and reproductive health services. People may also avoid seeking advice because much drug use involves illegal drugs . ## Recommendations 1.5.2 and 1.5.3 The committee considered what drug misuse prevention services could be offered to people in groups at risk who do not present to health or social care services. Digital technologies can allow interventions to be offered to people who are either unable or choose not to access services, and can offer anonymity. The committee noted the evidence showed that web-based interventions did not significantly reduce drug use compared with assessment only or a waiting list control . However, 1 study did show promising effects of web-based information and advice in a subgroup analysis of people with a family history of drug problems . Web-based interventions were generally well received . The health economic modelling did not find web-based interventions to be cost effective in the base case (£329,000 per QALY). If an intervention was delivered at a cost of less than £1 per person, it would be less costly and more effective than a 'do nothing' alternative . The committee considered that web-based interventions could feasibly be produced at a low cost and was aware of existing online sources of information, including NHS Choices. It noted that the NHS Choices website provides reliable information and also provides links to other helpful sources of information. The committee therefore recommended that targeted new media (including web-based information as well as digital and social media), that give reliable information, and online self-assessment and feedback to help people assess their own drug use, could be provided to people at increased risk. These approaches may be particularly useful in those less likely to be in contact with health and social care services. The committee also recommended that further research should be undertaken on the effectiveness of digital technologies (see research recommendation 5). The committee noted that some people in groups at risk may not be able to access online services. It recommended that written information should be made available for people not in contact with health or social care services. The committee also recommended that information given to people not in contact with health or social care services should include information on local services and sources of advice and support. ## Recommendation 1.5.4 The committee noted that NICE has existing guidance on general and individual approaches to behaviour change. It recommended that information is provided to people at risk of using drugs in line with these guidelines. # Evidence not used to make a recommendation The committee did not make recommendations for all of the evidence statements. For some interventions, the effectiveness evidence was not strong enough or was too inconsistent to make a recommendation for or against using an intervention . Some evidence statements stated that no relevant evidence was identified . The committee was unable to consider evidence on the acceptability or cost effectiveness for interventions that either were not effective at reducing drug use or for which no effectiveness evidence was identified . For details of the evidence statements used to make recommendations, see the evidence reviews section. The committee discussed the different outcomes reported in the studies identified in the evidence reviews. It noted that drug use behaviour does not always reflect attitudes and intentions towards drug use. It was agreed that drug use outcomes were the most important outcomes from the evidence. Therefore, if use was reported, other outcomes were not prioritised when the committee drafted recommendations. Some evidence statements reported on outcomes other than drug use for interventions for which drug use outcomes were reported, so were not used to make recommendations . It was unclear from the evidence whether the effectiveness of an intervention varies by who delivers it . The committee discussed the importance of the skills and competencies of people delivering assessments and interventions. It agreed that people should have training and continuing professional development to ensure that interventions can be delivered effectively. The committee noted that little evidence was found for whether the effectiveness of interventions varied by the content and framing of the intervention . In addition, no evidence was found for whether the effectiveness of interventions varied by mode of delivery , where the intervention was delivered , or the intended recipient of the intervention . The committee was aware that the evidence review did not find any evidence on drug misuse prevention strategies for image- and performance-enhancing drugs or new psychoactive substances. Committee members heard expert testimony that it is difficult to identify and intervene when people are using these drugs, because they tend not to label themselves as drug users. In addition, image- and performance-enhancing drugs are available online and so can be accessed by a wide range of people. The committee recommended research is undertaken in this area (see research recommendation 6). The committee considered digital technologies other than web-based interventions that could be used for drug misuse prevention interventions. It acknowledged the evidence that responsive text messaging can reduce the odds of cannabis use in some contexts, but not others , and is generally acceptable to young people . It noted that one study also involved face-to-face brief motivational enhancement therapy, which is unlikely to be cost effective. The committee agreed there was a lack of evidence for the effectiveness of interventions using only digital technologies. The committee recommended that further research is needed into digital technologies (see research recommendation 5). # Limitations of the evidence ## Limitations of the effectiveness and acceptability evidence The committee noted that most of the included studies used small sample sizes, short follow-up times, self-reported drug use and intermediate outcomes (such as knowledge about drugs, rather than change in drug-using behaviour). It was not possible to determine whether some studies were poorly conducted or poorly reported. Some studies may not have been adequately powered to identify significant differences between groups. In addition, some participants in some studies did not attend any of the intervention sessions, and many studies did not include a true control group. As a result, the efficacy of the intervention could have been underestimated in these studies. The committee noted that single small studies were presented for more than 1 group at risk, resulting in multiple evidence statements from the same studies. This makes the evidence base look larger and stronger than it actually is. Overarching evidence statements have been used to summarise the body of evidence across population groups . The committee acknowledged that limited evidence was available on the effectiveness of interventions in the UK. Most interventions considered were undertaken in the US. Although the evidence is likely to be applicable in the UK, the committee discussed that key differences in social norms, education, care, and criminal justice and healthcare systems may influence the effectiveness of interventions transferred to UK settings. In addition, the committee noted that the comparators included in the studies may vary from those seen in the UK. It also agreed that current practice (referred to in the studies as 'standard care') was not well defined or consistently reported in the studies. Current practice can vary depending on which group at risk is included in a study, and the country and setting in which the study was conducted. The committee discussed that some of the interventions in the studies were likely to have been delivered in a research setting; for example, a university research facility. It was felt that the results may have been different if the interventions had been delivered in real-world settings, such as homeless shelters, nightclubs or music events, youth clubs and organisations, or environments where drugs may be used in a sexual context (such as 'chemsex' parties). The committee agreed that the group 'people who are known to use drugs occasionally or recreationally' represents a diverse population. Although several studies were identified for this group, it is likely that the evidence does not cover the whole target population. The committee noted that no good quality evidence is available for some groups at risk, despite the research recommendations made in NICE's previous guideline on substance misuse interventions for vulnerable under 25s. Committee members agreed that more evidence from well designed and adequately powered studies is needed. The committee recommended that research is undertaken on the effectiveness and acceptability of drug misuse prevention interventions in groups at risk (see research recommendations 3 and 4). The committee noted that studies of pregnant women were excluded from the evidence reviews for this guideline. There is existing NICE guidance on pregnancy and complex social factors, which includes substance misuse in pregnant women. General antenatal and postnatal care is covered in existing NICE guidance. In addition, it was agreed that studies on drug use in pregnant women are most likely to be studies of treatment for dependent drug users rather than prevention studies. ## Limitations of the cost-effectiveness evidence The studies used in the health economic modelling were identified in the evidence review. Therefore the limitations of the studies in the evidence review also apply to the cost-effectiveness evidence. The committee noted that the effect on someone of having a criminal record was not taken into account in the health economic modelling. It acknowledged that drug use can lead to a criminal record, and that people with a criminal record have difficulties securing employment. Therefore, avoiding a criminal record is a potential positive outcome of drug misuse prevention activities. It agreed that including the effect on an individual of having a criminal record in the health economic modelling would have increased the cost effectiveness of the interventions. The committee also recognised that the long-term harms and associated costs of drug use are mostly unknown. The size of the groups at risk is unknown, and it is not known what percentage of people in these groups will go on to misuse drugs. These factors will affect the accuracy of the health economic modelling. The committee therefore recommended research is done on the long-term consequences of drug use (see research recommendation 1). ## Terminology The committee discussed that many terms used in the literature to describe drug use are subjective and often used inconsistently or interchangeably (for example, terms such as 'use', 'misuse', 'occasional' or 'recreational', 'dependency' and 'abuse'). It discussed that the definition of 'recreational' use in particular was subjective. For example, fortnightly use of cannabis by an adult might be considered recreational, but fortnightly use by a child or young person may be considered problematic. The committee discussed the term 'primary care'. It acknowledged that the use of the term by the public focuses on general practitioners. However, the committee agreed that the use of the term in this guideline includes all primary care services, including healthcare professionals such as pharmacists, dentists and optometrists. Although treatment for drug misuse fell outside the remit of this guideline, there is an overlap between treatment, harm reduction (aiming to prevent or reduce negative effects of drugs) and prevention in this field. Despite careful consideration by 3 reviewers, some studies of harm reduction interventions may have been misinterpreted as treatment studies and so would not have been considered in this guideline. The committee noted that NICE has a range of products that cover drug misuse, and in particular that treatment has been considered by related NICE guidelines (psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older). # Existing NICE guidance The committee was aware of several relevant pieces of NICE guidance. The committee considered the NICE guideline on individual approaches to behaviour change in the context of the current guideline. This guideline recommends delivering very brief, brief, extended brief and high intensity behaviour change interventions and programmes to people who are at risk of damaging their health through their behaviour. When considering the evidence for the guideline on individual approaches to behaviour change, the committee for that guideline noted that, across all interventions, those targeting the general population were more likely to be cost effective than those aimed at vulnerable populations (targeted approaches). However, it is important to note that evidence directly relating to drug misuse was not included. The committee for that guideline also noted similar difficulties to the committee for this guideline in determining the interventions used in the studies. The committee did not think it was appropriate to directly apply the recommendations from the guideline on individual approaches to behaviour change to the groups at risk in this guideline, because the evidence base for that guideline did not include studies of drug misuse interventions. However, it was agreed that those recommendations should be kept in mind when following the recommendations in the current guideline. The committee considered the NICE guideline on prevention of alcohol-use disorders to be particularly relevant to this guideline because many people who misuse drugs also misuse alcohol (Psychosocial interventions to reduce alcohol consumption in concurrent problem alcohol and illicit drug users Klimas et al. 2014). This can result in people having multiple issues when they present to healthcare services. However, the committee noted that alcohol misuse is not illegal, allowing for interventions and data collection to be done more easily. The committee agreed that the recommendations for alcohol misuse prevention cannot be directly translated into recommendations for drug misuse prevention because of the lack of data for drug misuse prevention. The committee agreed that, because of the large overlap in the target populations of the current guideline and the guideline on prevention of alcohol-use disorders, the recommendations in the guideline on prevention of alcohol-use disorders should be kept in mind when providing drug misuse prevention activities. The committee considered the NICE guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older. It noted that treatment of drug misuse was outside of the scope of this guideline, but acknowledged that it can be difficult to distinguish between prevention and treatment strategies. The committee agreed that people who are drug dependent may be identified during the prevention activities recommended in this guideline. NICE's guidelines on psychosocial interventions and opioid detoxification in drug misuse can be used to determine what treatment should be provided. The committee highlighted that the existing NICE guidelines on the treatment of drug misuse do not include recommendations for children and young people under the age of 16. The committee also noted that NICE's guidelines on child maltreatment, needle and syringe programmes, attention deficit hyperactivity disorder, looked-after children and young people, domestic violence and abuse, coexisting severe mental illness and substance misuse, and physical health of people in prison are relevant to drug misuse prevention. NICE also has a quality standard on looked-after children and young people. The current guideline on drugs misuse prevention should be considered in the context of this other guidance. # Recommendations from NICE's guideline on substance misuse interventions for vulnerable under 25s This guideline will update and replace the NICE guideline on substance misuse interventions for vulnerable under 25s (PH4, published 2007). The committee discussed the recommendations and considerations in the guideline being updated and considered the view of the experts in the review decision. It acknowledged that the populations included in the scope for the above guideline differ to some extent to those included in the current guideline. The current guideline also includes adults aged over 25. The current guideline does not include black, Asian and minority ethnic groups as a specific group at risk because they are no longer considered a group at risk. The current guideline also did not include people who were considered 'at risk' or 'vulnerable' without further explanation. The current guideline only includes children and young adults in contact with young offender teams but not in secure environments. This is in contrast to PH4, which included young offenders per se as a group at risk. As a result, some of the evidence considered for guideline development is likely to differ. Despite this, the committee agreed that it had considered sufficient evidence on effectiveness and cost effectiveness on the groups at risk for this guideline, along with their wider knowledge of this topic area and current provision, to make a judgement on the recommendations from PH4. The committee agreed that recommendation 1 and recommendation 2 from 'substance misuse interventions for vulnerable under 25s' should be withdrawn because they are now covered in the implementation section of the current guideline. It also agreed that recommendation 3 should be replaced with the current recommendations. The committee discussed that although the family-based interventions that it had considered were effective, they were not shown to be cost effective. Similarly, the intensive family-based intervention as described in PH4 recommendation 3 is highly unlikely to be cost effective, particularly given that the committee agreed that motivational interventions were unlikely to be significantly more effective than other interventions, such as skills training. The committee discussed that recommendation 1.3 in the current guideline would be likely to be cost effective if delivered through existing services. It discussed that the elements included in recommendation 1.3 in this guideline did cover aspects of PH4 recommendation 3, and, while not a family-based programme, encouraged involvement of carers and families. The committee did not consider the original evidence base for PH4. However, it was made aware that recommendation 3 in PH4 was based on evidence from 4 studies that all targeted 'high risk' groups (the groups were not more specifically described), and only 2 reported drug-related outcomes. Recommendation 4 in PH4 covers persistently aggressive and disruptive children. This target group are included in the current guideline but no evidence was identified. The committee agreed that the recommendation was now covered by the recommendations on child-focused programmes in the NICE guideline on antisocial behaviour and conduct disorders in children and young people. The committee agreed that recommendation 5 is out of the scope of the current guideline because it refers to people who are dependent on drugs. The committee agreed that for young people aged over 16, the recommendation could be replaced by NICE guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older. The committee noted that there is currently no guideline on treatment of children and young people aged under 16. # Evidence reviews Details of the evidence discussed are in evidence reviews, reports and papers from experts in the area. The evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from. All of the evidence statements are presented in the paper Evidence statements from all reviews. The paper also includes overarching statements that summarise the evidence across the groups at risk. Evidence statement (ES) letter 'a' indicates that the linked statement is lettered 'a' in 'Evidence statements from all reviews'. Evidence statement (ES) number 1.1 indicates that the linked statement is numbered 1 in evidence review 1. ES2.1 indicates that the linked statement is numbered 1 in evidence review 2. ES3.1 indicates that the linked statement is numbered 1 in the health economic evidence review. ES4.1 indicates that the linked statement is numbered 1 in the health economic modelling report. EP1 indicates that expert paper 1 'Current provision and future issues (opportunities and difficulties) for commissioning' is linked to a recommendation. EP2 indicates that expert paper 2 'The use of image and performance enhancing drugs in the United Kingdom' is linked. EP3 indicates that expert paper 3 'Night time environment and local partners role in managing harm' is linked. If a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1.1.1: ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7, ES4.9; EP1 Recommendation 1.1.2: EP1 Recommendation 1.2.1: ES2.22; IDE Recommendation 1.2.2: ES2.17, ES2.20, ES2.32; IDE Recommendation 1.2.3: IDE Recommendation 1.2.4: IDE Recommendation 1.2.5: IDE Recommendation 1.3.1: ESa, ESb, ESc, ES1.50, ES2.33, ES2.39, ES2.46, ES4.1, ES4.3, ES4.7, ES4.9; EP1; IDE Recommendation 1.3.2: EP1; IDE Recommendation 1.3.3: ES1.7, ES1.8, ES1.11, ES1.13, ES1.14, ES1.15, ES1.17, ES1.21, ES1.23, ES1.57, ES1.58, ES1.60 Recommendation 1.3.4: ES1.11, ES1.13, ES1.15, ES1.17, ES1.21, ES1.23, ES1.57, ES1.58, ES1.60 Recommendation 1.3.5: ES1.54, ES1.68, ES2.12, ES2.13, ES2.18, ES2.19; IDE Recommendation 1.3.6: IDE Recommendation 1.4.1: ESd, ES1.2, ES1.22, ES1.36, ES1.37, ES1.42; IDE Recommendation 1.4.2: ES2.17, ES2.20, ES2.27, ES2.31, ES2.32; IDE Recommendation 1.4.3: IDE Recommendation 1.5.1: ES2.29, ES2.30, ES1.32, ES1.33, ES1.34, ES1.48, ES2.41, ES4.2; EP2; IDE Recommendation 1.5.2: IDE Recommendation 1.5.3: IDE Recommendation 1.5.4: IDE# Recommendations for research The advisory committee has made the following recommendations for research. # . Long-term consequences of drug use What are the long-term consequences of drug use? ## Why this is important We identified little evidence on the long-term health and social consequences of using drugs. This made it difficult to determine the full consequences and effect of drug use on people in groups at risk. In particular, there was limited evidence on the long-term effects of using drugs other than cannabis. More evidence on the long-term consequences of drug use would enable more accurate modelling of the costs of drug use. This would in turn allow more accurate modelling of the cost effectiveness of drug misuse prevention interventions. # . Identifying current practice and provision What drug misuse prevention activities are currently used in the UK for groups at risk of drug misuse? ## Why this is important It is unclear what current practice is, and what provision is currently in place, for drug misuse prevention in groups at risk in the UK. Studies in the current review showed that active interventions were no more effective than current practice (as received by a control group). In addition, there is a lack of UK-based studies, and it is not clear whether the current practice that was used as a control group in studies conducted elsewhere is applicable to the UK population. It is not clear how many of the people that are referred to drug misuse prevention services attend (or are brought to) the services. Identifying existing practice and provision will allow new drug misuse prevention activities to be compared with current practice, identify gaps in current provision, and determine what proportion of people referred to drug misuse prevention services do not attend (or are not brought) to services. # . Effectiveness and cost effectiveness of drug misuse prevention interventions for groups vulnerable to drug misuse What is the effectiveness and cost effectiveness of drug misuse prevention interventions for groups vulnerable to drug misuse in the UK? ## Why this is important We identified limited evidence of effectiveness or cost effectiveness of interventions for groups vulnerable to drug misuse in the UK. In particular, no evidence was identified on the effectiveness and cost effectiveness of drug misuse prevention interventions for people involved in commercial sex work or who are being sexually exploited, people not in employment, education or training, and people who attend nightclubs and festivals. Most of the evidence identified comes from studies in the US. Furthermore, it was unclear which components of interventions were essential for effectiveness and cost effectiveness. The differential effect of interventions on groups at risk needs to be established, particularly for people with multiple vulnerabilities. The accuracy of tools for assessing vulnerability to drug misuse also needs to be determined. Interventions of interest include one-to-one skills training, information and advice as part of planned outreach activities, and wider behaviour change strategies. It is also important to know whether the effectiveness of interventions is affected by the content and framing of the message, the mode of delivery, where the intervention is delivered and the intended recipient of the intervention. Primary outcomes of interest include a direct measure of drug use. Longer term outcomes (longer than 1 year) from longitudinal studies are needed. Research on location-based interventions, for example at nightclubs or festivals, would provide prevention data for hard-to-reach groups and those who do not access existing services. Research could also consider prevention in people with multiple vulnerabilities and the use of new psychoactive substances. # . Acceptability of drug misuse prevention interventions How acceptable are drug misuse prevention interventions among groups vulnerable to drug misuse in the UK? How acceptable are drug misuse prevention interventions among practitioners in the UK? How can acceptability be improved for groups that are vulnerable to drug misuse and practitioners? ## Why this is important We identified little evidence on the acceptability of drug misuse prevention interventions for groups vulnerable to drug misuse. The evidence that was available was limited by the small number of studies and participants, and in the overall quality of the studies. Acceptable interventions are important to increase the uptake of interventions and reduce the number of people who do not attend (or are not brought to) services following a referral. Studies are needed on interventions that are acceptable to people with different levels of self-efficacy and understanding about health. It is also important to know which interventions are more acceptable to particular groups at risk. Interventions that are more acceptable to practitioners are more likely to be implemented with groups at risk. Research on the framing of messages, such as abstinence-based approaches, is needed because some ways of framing interventions may be more acceptable than others to people in groups at risk. Research is also needed on who delivers the interventions, as this may also affect the acceptability of an intervention. # . Effectiveness of digital technologies How effective and cost effective are digital technologies, such as web-based interventions, online self-assessment or targeted new media, for drug misuse prevention among groups at risk in the UK? ## Why this is important We identified limited evidence on digital interventions and targeted new media, with existing studies focusing on web-based and text messaging interventions. Interventions and assessments that use digital technology are potentially more cost effective than those delivered face to face and could be used for prevention activities in groups at risk who are harder to reach or who do not present to services. The use of digital technology could also allow people to use sources of support anonymously and help maintain engagement. Research is needed on effectiveness, cost effectiveness and acceptability of interventions and self-assessment using digital technology. Studies could compare interventions delivered using digital technology with face-to-face interventions. Studies could also look at using interventions that use digital technologies as part of a stepped care model. # . Use of image- and performance-enhancing drugs What are the most effective and cost effective interventions to prevent and reduce the use of image- and performance-enhancing drugs? ## Why this is important No evidence was identified for interventions to reduce the use of image- and performance-enhancing drugs. Several different types of drugs can be classed as image- and performance-enhancing, including drugs that are used by people trying to lose weight (such as laxatives), those used to gain weight or increase physical performance (such as anabolic steroids), and those used to increase cognitive ability (such as methylphenidate). People using these drugs may not identify as drug users, making it difficult to provide preventative interventions. In addition, image-and performance-enhancing drugs are available online and can be accessed by a wide range of people.# Glossary Behaviour reinforcement strategies Approaches that link behaviour with outcomes, to encourage positive behaviour and discourage negative behaviour. This includes rewarding positive behaviour (such as going to school or work) and rewarding the absence of negative behaviour (such as using aggressive language). Brief interventions Either a short session of structured brief advice or a longer, more motivationally-based session (that is, an extended brief intervention). Both aim to help someone reduce their drug use and can be carried out by non-drug specialists. Dependent A person who is dependent on drugs has a strong desire or sense of compulsion to take a substance, a difficulty in controlling their drug use, a physiological withdrawal state, tolerance of the use of the drug, neglect of alternative pleasures and interests, and persistently uses the drug, despite harm to themselves and others (adapted from the World Health Organization, Lexicon of alcohol and drug terms, 2006). Digital technology Technology that requires the use of a device containing a computer or microcomputer. This includes smartphones, laptops and desktop computers, tablets and other electronic devices. Devices do not have to have internet access to be classed as digital technology, although many do. The term 'digital technology' includes the use of websites and social media, apps on smartphones or tablets, and text-based computer programs. Some types of digital technology may be more commonly used by some age groups than others. Foster carers People who care for children and young people who are looked after. This includes people who provide long-term care, emergency overnight care and short-term care. Motivational interviewing A brief psychotherapeutic intervention. For people who misuse drugs, the aim is to help people reflect on their substance use in the context of their own values and goals and motivate them to change (adapted from The efficacy of single-session motivational interviewing in reducing drug consumption and perceptions of drug-related risk and harm among young people: results from a multi-site cluster randomized trial McCambridge and Strang 2004). Psychoeducation Education sessions for people affected by mental illness and their families and carers. Psychoeducation uses shared learning to empower people to cope better. Skills training The teaching of specific verbal and non-verbal behaviours (including personal and social skills) and the practising of these behaviours by the person receiving the training. For other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster. ISBN: 978-1-4731-2339-7	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Delivering drug misuse prevention activities as part of existing services\n\nDeliver drug misuse\xa0prevention activities for people in groups at risk through a range of existing statutory, voluntary or private services, including:\n\nhealth services, such as primary care services, community-based health services, mental health services, sexual and reproductive health services, drug and alcohol services, and school nursing and health visiting services\n\nspecialist services for people in groups at risk\n\ncommunity-based criminal justice services, including adult, youth and family justice services\n\naccident and emergency services.\n\nEnsure activities targeting groups at risk are consistent with any population-level (universal) activities aimed at preventing drug misuse.\n\n# Assessment\n\nAt routine appointments and opportunistic contacts with statutory and other services, such as those listed in recommendation\xa01.1.1, assess whether someone is vulnerable to drug misuse. Examples of routine appointments and opportunistic contacts include:\n\nhealth assessments for children and young people who are looked after or care leavers, including initial assessments, any reviews and contacts\n\nappointments with GPs, nurses, school nurses or health visitors\n\nattendances at emergency departments as a result of alcohol or drug use\n\ncontacts with the community-based criminal justice system.\n\nUse a consistent, locally agreed approach to assessment that is respectful, non-judgemental and proportionate to the person's presenting vulnerabilities. For an example for young people, see the practice standards for young people with substance misuse problems.\n\nDiscuss the person's circumstances, taking account of their age and developmental stage. The initial discussion could include:\n\ntheir physical and mental health and their personal, social, educational or employment circumstances (which may trigger a more in-depth assessment)\n\nany drug use (including the type used and how often).If the person is already misusing drugs, see NICE's guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older, needle and syringe programs, and diagnosis and management of alcohol-use disorders.\n\nThink about the immediate safety of the person being assessed and any people under their care, and whether any action is needed.\n\nDiscuss with the person what their priorities are and take into account how these might affect next steps or referral to other services.\n\n# Children and young people assessed as vulnerable to drug misuse\n\nConsider skills training for children and young people who are assessed as vulnerable to drug misuse. If skills training is delivered to children and young people, ensure that their carers or families also receive skills training. For older children and young people, think about whether providing information (see recommendations in section\xa01.4) may be a more appropriate approach.\n\nEnsure any skills training is:\n\ncommissioned as part of existing services (see recommendation\xa01.1.1)\n\ndelivered as part of activities designed to increase resilience and reduce risk\n\ndelivered by people competent to provide skills training.\n\nIf skills training is offered to children and young people and their carers or families, ensure it helps children and young people develop a range of personal and social skills, such as:\n\nlistening\n\nconflict resolution\n\nrefusal\n\nidentifying and managing stress\n\nmaking decisions\n\ncoping with criticism\n\ndealing with feelings of exclusion\n\nmaking healthy behaviour choices.Ensure that personal and social skills training for children and young people who are looked after and care leavers puts particular emphasis on how to deal with feelings of exclusion.\n\nIf skills training is offered to children and young people and their carers and families, ensure that it helps carers and families develop a range of skills, such as:\n\ncommunication\n\ndeveloping and maintaining healthy relationships\n\nconflict resolution\n\nproblem solving. Ensure that skills training for foster carers includes using behaviour reinforcement strategies alongside the other skills listed.\n\nTake into account the age, developmental stage, presenting vulnerabilities, cultural context, religion, ethnicity and any other specific needs or preferences of the child or young person when deciding:\n\nwhether to offer training sessions to children and young people and their carers or families together, or whether to offer separate sessions\n\nthe content of the skills training\n\nwhether to provide individual or group-based sessions\n\nthe number of sessions needed (a minimum of 2\xa0sessions should be offered)\n\nwhere to hold the sessions\n\nhow long each session should last.For more information, see the Department of Health's quality criteria for young people friendly services.\n\nDiscuss and agree a plan for follow-up at the skills training sessions, to assess whether additional skills training or referral to specialist services is needed.\n\n# Adults assessed as vulnerable to drug misuse\n\nOffer adults who are assessed as vulnerable to drug misuse (see section\xa01.2) the following:\n\nclear information on drugs and their effects\n\nadvice and feedback on any existing drug use\n\ninformation on local services and where to find further advice and support (see recommendation\xa01.5.3).This information should be provided at the same time as the assessment.\n\nOffer information and advice both verbally and in writing. Provide advice in a non-judgemental way and tailor it to the person's preferences, needs and level of understanding about their health. Ensure that information and advice is delivered in line with NICE's guidelines on general and individual approaches to behaviour change and patient experience in adult NHS services.\n\nDiscuss and agree a plan for follow-up at the assessment, to determine whether additional information or referral to specialist services is needed.\n\n# People at risk of using drugs\n\nConsider providing information about drug use in settings that groups who use drugs or are at risk of using drugs may attend. These settings could include:\n\nnightclubs or festivals\n\nwider health services, such as sexual and reproductive health services or primary care\n\nsupported accommodation or hostels for people without permanent accommodation\n\ngyms (to target people who are taking, or considering taking, image- and performance-enhancing drugs).\n\nConsider providing information in different formats, including web-based information (such as digital and social media) and printed information (such as leaflets).\n\nConsider providing information on:\n\ndrugs and their effects (for example, on NHS Choices)\n\nlocal services and where to find further advice and support\n\nonline self-assessment and feedback to help people assess their own drug use.\n\nEnsure that information provided is in line with NICE's guidelines on general and individual approaches to behaviour change and patient experience in adult NHS services.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.\n\n## Care leavers\n\nPeople aged 25\xa0or under who have been looked after by a local authority for at least 13\xa0weeks since age\xa014, and who were looked after by the local authority at school leaving age or after that date.\n\n## Children and young people who are looked after\n\nChildren and young people looked after by the state for whom the Children Act 1989 applies. The term includes children and young people who are subject to a care order or temporarily classed as looked after on a planned basis for short breaks or respite care. The term also includes those in residential care, foster care or boarding school, or with birth parents, other family or carers. It includes children and young people in placements out of the child or young person's home area. Children and young people who are in young offender or other secure institutions are not included in this definition, because this group is outside the scope of the guideline.\n\n## Drugs\n\nDrugs described in the Misuse of Drugs Act 1971 and the Psychoactive Substances Act 2016, as well as new psychoactive substances (often described as 'legal highs'), solvents, volatile substances, image- and performance-enhancing drugs, prescription-only medicines and over-the-counter medicines.\n\n## Drug misuse\n\nDependence on, or regular excessive consumption of, psychoactive substances, leading to physical, mental or social problems. This term does not include occasional or experimental drug use in adults.\n\n## Groups at risk\n\nGroups at risk of drug misuse, including:\n\npeople who have mental health problems\n\npeople who are being sexually exploited or sexually assaulted\n\npeople involved in commercial sex work\n\npeople who are lesbian, gay, bisexual or transgender\n\npeople not in employment, education or training (including children and young people who are excluded from school or who truant regularly)\n\nchildren and young people whose carers or families use drugs\n\nchildren and young people who are looked after or care leavers\n\nchildren and young people who are in contact with young offender teams but not in secure environments (prisons and young offender institutions)\n\npeople who are considered homeless\n\npeople who attend nightclubs and festivals\n\npeople who are known to use drugs occasionally or recreationally.\n\n## Prevention\n\nPreventing or delaying drug use, preventing people who are already using some drugs from using other drugs, and preventing people who already experiment or use drugs occasionally from using drugs regularly and excessively.\n\n## Treatment\n\nThe clinical management of drug misuse or dependence. This could comprise, for example, pharmacotherapy, psychosocial therapy or a combination of these.\n\n## Vulnerable to drug misuse\n\nPeople in groups at risk who may be particularly vulnerable to drug misuse. This may include people:\n\nin multiple groups at risk\n\nwhose personal circumstances put them at increased risk\n\nwho may already be using drugs on an occasional basis\n\nwho may already be regularly excessively consuming another substance, such as alcohol.\n\n## Young people\n\nPeople aged 10\xa0to\xa018. This term also includes people aged up\xa0to\xa025 who have special educational needs or a disability (consistent with the Children and Families Act 2014).", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through a range of different communication channels. These could include digital and social media, alongside regular channels such as email, newsletters, meetings, internal staff briefings and communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes, include milestones and a business case which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "The Misuse of Drugs Act 1971 and the Psychoactive Substances Act 2016 list all illegal (or controlled) drugs in the UK. According to the Home Office report Drug misuse: findings from the 2015 to 2016 Crime Survey for England and Wales:\n\nAround 8% of people aged 16\xa0to\xa059 had taken an illegal drug or used a substance unlawfully in the past year, and around 4% had taken one in the past month. Among young adults aged 16\xa0to\xa024, this was 18% in the past year and 9% in the past month.\n\nMore than one third of adults aged 16\xa0to\xa059 (35%) have taken an illegal drug or used a substance unlawfully at some point in their lives. Cannabis was the most common, with 7% using it in the past year, followed by powder cocaine (2%) and ecstasy (2%).\n\nIn the same age group, 3% were defined as frequent drug users (having taken an illegal drug or used a substance unlawfully more than once a month, on average, in the past year).\n\nAmong young adults aged 16\xa0to\xa024, this figure was 5%.\n\nUse of any class\xa0A drug was around 10\xa0times higher among people who had visited a nightclub at least 4\xa0times in the past month (18%) compared with those who had not visited a nightclub in the past month (2%). A similar pattern was found for those visiting pubs and bars more frequently.\n\nThe government's What About YOUth survey (Health and Wellbeing of 15-year-olds in England – Main findings from the What About YOUth? Survey 2014) found that:\n\n% of 15\xa0year-olds had used cannabis in the past month\n\n% had used cannabis in the past year, and 2% had used it more than a year ago\n\n% said that they had been offered drugs other than cannabis, and 2% had tried other drugs.\n\nThe Health and Social Care Information Centre's survey on Smoking, Drinking and Drug Use Among Young People in England – 2014 found that:\n\naround 3% of 11\xa0to 15\xa0year-olds reported inhaling glue, gas or other solvents\n\nof the 11\xa0to 13\xa0year-olds who reported some drug use in the past year, 53% reported using volatile substances.\n\nThe Home Office's National drug strategy for England 2010 sets out plans for helping people to live a drug-free life. The third annual review of this strategy was published in 2015 (Drug strategy annual review: 2014 to 2015).\n\nAs part of the Health and Social Care Act 2012, local authorities became responsible for commissioning drug misuse\xa0treatment services. The Home Office's drug strategy annual review highlights the key role local authorities play in helping to reduce both the supply of, and demand for, illegal drugs. This includes preventing problematic drug use and helping people to recover from drug addiction by developing their personal and social capital, through providing education, housing, public health and social care services.\n\nThe Public Health England and Association of Directors of Public Health Review of drug and alcohol commissioning (2014) identified that in many areas there is a continued desire to improve outcomes, delivery and performance, but service funding may be uncertain. The primary focus for many areas is treatment rather than prevention. Drug services are increasingly integrated with services to reduce alcohol dependency and services to support younger people, as well as services associated with the community criminal justice system and local health delivery.\n\nYou can also see this guideline in the NICE pathway on drug misuse prevention.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on drug misuse.\n\nSee also the evidence reviews and information about how the guideline was developed, including details of the committee.", "The committee's discussion": "Evidence statement numbers are given in square brackets. For an explanation of the evidence statement numbering, see the evidence reviews section.\n\n# Approach of this guideline\n\nThe committee discussed that this guideline only covers prevention of drug misuse for groups at risk. The evidence base for population-level (universal) approaches and for wider determinants of drug use in the general population or at risk groups was not considered. The committee discussed that wider determinants of health, such as housing, education and employment opportunities, social support, and personal resilience, are likely to have a fundamental effect on both the risk of drug misuse and the effectiveness of interventions to prevent drug misuse.\n\nThe committee discussed the groups at risk presented in the scope for this guideline. Based on the evidence considered, it agreed that the recommendations should be targeted at these groups. The committee also noted there may be additional groups who have not been considered, such as young people with behavioural or social problems, and that some people would be included in more than\xa01 group at risk. For example, a person could be considered homeless and lesbian, gay, bisexual or transgender.\n\nThe committee understood that the nature of drug use and the risk to health varies within the specified groups at risk. The groups covered by the guideline include people who are not currently using drugs but are at increased risk of doing so, through to people who are known to use drugs occasionally or recreationally. Recommendations for treating people who are dependent on drugs are outside the scope of this guideline.\n\nThe committee acknowledged that there is wide variation in vulnerability to drug misuse within each of the groups at risk. The committee noted that the variation in vulnerability within the groups at risk means that different people in each group at risk have different needs, despite being in the same group. The committee agreed that not all people in a group at risk will use drugs. It commented that drug use is more likely in some people within each group at risk than in others, such as those in multiple groups at risk, whose personal circumstances put them at increased risk, who may already be using drugs on an occasional basis, or who may already be misusing another substance, such as alcohol.\n\nThe committee developed the recommendations in the current guideline on the assumption that they would be considered alongside other relevant NICE guidance, such as social and emotional wellbeing in primary and secondary education, diagnosis and management of alcohol-use disorders, looked-after children and young people, community engagement, and coexisting severe mental illness and substance misuse. The committee also noted the importance of considering the recommendations in this guideline alongside others on preventing and managing drug use (for more information, see NICE's guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older).\n\n# Overview of the effectiveness and acceptability evidence\n\nThe committee noted that there is limited evidence for effectiveness and acceptability of drug misuse\xa0prevention interventions across the groups at risk.\n\nNo direct effectiveness evidence was identified for 3\xa0of the groups at risk in the scope: people involved in commercial sex work [ES1.5] or who are being sexually exploited; people not in employment, education or training [ES1.9]; and people who attend nightclubs and festivals [ES1.25].\n\nEither no, or limited, evidence was identified on the effectiveness and acceptability of interventions delivered as part of planned outreach activities [ES1.45, ES1.47, ES2.35, ES2.36] or peer education initiatives [ES1.46, ES2.37, ES2.38].\n\nNo evidence for the acceptability of interventions was identified for 4 of the groups at risk in the scope: people with mental health problems [ES2.1, ES2.2]; people involved in commercial sex work [ES2.3, ES2.4]; people not in employment, education or training [ES2.7, ES2.8]; and children and young people whose parents use drugs [ES2.9, ES2.10].\n\nThe committee acknowledged that most studies compared an intervention with current practice, assessment only or another intervention rather than with no intervention. The committee agreed that data showing no significant difference between the intervention and comparator tended to show a similar improvement in outcome in both the intervention and comparator groups, rather than the intervention not having an effect at all [ES1.1]. Therefore, it agreed that the interventions in the included studies were likely to be at least as effective as the comparator.\n\nThe committee noted that none of the studies reported any adverse effects such as death or overdose. Therefore, it agreed that the interventions in the included studies were unlikely to be harmful.\n\nThe committee agreed that the acceptability studies found that drug misuse prevention interventions are generally well received.\n\n# Overview of the cost-effectiveness evidence\n\nThe committee noted that the literature review for cost-effectiveness evidence did not find any studies that were directly relevant to drug misuse\xa0prevention in the UK. Health economic modelling was undertaken to provide cost-effectiveness evidence for this guideline.\n\nHealth economic modelling was undertaken on 7\xa0interventions that were identified in evidence review\xa01. These interventions were family-based interventions, web-based interventions and motivational interviewing interventions. The committee acknowledged that the health economic modelling did not identify any drug misuse prevention interventions that were cost effective in the base case [ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7].\n\nHowever, the results of the modelling did suggest that some interventions, such as those that are web-based or family-based, could be cost effective if they could be provided at a lower cost and their effects sustained over a longer duration than was considered in the base case economic analysis [ES4.2, ES4.3, ES4.6]. For example, an intervention costing £100 per person that reduced drug use by 5\xa0percentage points maintained over 2\xa0years would be cost effective. If the intervention cost more than £100, the reduction in drug use or duration of effect would need to be higher for the intervention to be cost effective.\n\nThe committee acknowledged that there are several reasons why the interventions included in the health economic modelling do not appear to be cost effective. Most of the interventions did not change drug use by more than 5\xa0percentage points. In addition, none of the studies showed a reduction in drug use that was maintained for more than 1\xa0year. This means it is difficult for the interventions to make a large reduction in societal costs. In addition, most of the studies looked at cannabis and ecstasy use, and it is not clear how the social costs of using cannabis and ecstasy compare to those of other drugs.\n\nThe committee agreed that it remains unclear whether there is a causal link between use of 1\xa0substance and other substances (the 'gateway hypothesis') and what effect a causal relationship might have on costs to the NHS (or society more broadly). So committee members agreed that the relationship should not be assumed within the economic model.\n\n# Section 1.1 Delivering drug misuse prevention activities as part of existing services\n\nThe discussion below explains how we made the recommendations in section 1.1.\n\n## Recommendations 1.1.1 and 1.1.2\n\nThe committee heard expert testimony that the focus of commissioning new drug misuse\xa0prevention interventions is changing [EP1]. Many areas are increasingly integrating drug misuse prevention activities with drug\xa0treatment or wider health and social care activities, such as activities to increase general resilience and decrease risky behaviours within sexual health services or educational support services to address truancy [EP1].\n\nThe committee acknowledged that the misuse of substances such as illegal drugs and alcohol rarely happens in isolation. Many people at increased risk of drug misuse may already be in contact with statutory, voluntary or private services such as mental health, community-based criminal justice, alcohol and drug services, and services for children and young people who are looked after and care leavers. The committee heard expert testimony that local authorities are well placed to address the wider needs of some groups at risk, such as their housing needs [EP1]. However, local authorities also need to collaborate with wider services, such as healthcare services, schools, or police and crime commissioners, to provide effective drug misuse prevention activities [EP1].\n\nThe committee noted that none of the interventions included in the health economic modelling were cost effective as stand-alone programmes (see overview of the cost-effectiveness evidence) [ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7]. However, they could be cost effective if added to existing programmes of care at an additional cost of less than £100 per person [ES4.9].\n\nTaking into account the changing focus of commissioning, wider determinants of drug use and the health economic modelling, the committee recommended that drug misuse prevention interventions should be delivered through a range of existing services for people in groups at risk, rather than setting up dedicated services.\n\n# Section 1.2 Assessment\n\nThe discussion below explains how we made recommendations in section\xa01.2.\n\n## Recommendation 1.2.1\n\nThe committee discussed assessing whether people are vulnerable to drug misuse. The committee agreed that it was essential to have an assessment before intervention to ensure that the intervention offered is appropriate and no harm is done. It noted that an assessment of drug use was a consistent part of effective interventions included in evidence review\xa01. No studies were identified that included an assessment only arm compared with assessment plus intervention and no intervention. However, the committee discussed that if comparator groups were offered assessment, improved drug or other outcomes were consistently reported. The committee also noted that there was weak evidence from review\xa02 that assessments of substance use and other risky behaviours may prompt reductions in drug use [ES2.22].\n\nThe committee noted that none of the 7\xa0interventions modelled by the health economic team were cost effective in the base case as a stand-alone intervention (see overview of the cost-effectiveness evidence) [ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7]. The committee noted from the health economic modelling that to be cost effective an intervention would need to cost less than £100 per person and would need to reduce the number of people misusing drugs by at least 5\xa0percentage points over 2\xa0years [ES4.8]. The committee agreed that a reduction of at least 5\xa0percentage points in the number of people at risk of misusing drugs was most likely to occur in people who are assessed as vulnerable to drug misuse. As such, interventions are likely to be cost effective only in people who are vulnerable to drug misuse.\n\nThe committee discussed that interventions that target people assessed as most vulnerable to drug misuse are more likely to be cost effective. The committee agreed that drug misuse\xa0prevention activities cannot be targeted to people most vulnerable to drug misuse if those people have not been assessed. It noted that undertaking assessment before an intervention is consistent with the related NICE guideline on psychosocial interventions for drug misuse in people aged 16\xa0years and older.\n\nThe assessment could be part of either a routine appointment (such as health needs assessments for children and young people who are looked after) or an opportunistic appointment (such as when someone attends an emergency department as a result of alcohol use, or when young people come into contact with the community-based criminal justice system). Many different practitioners may be working with people at risk of drug misuse. These practitioners have an important role in identifying people who may benefit from drug misuse prevention activities, even if the practitioners do not provide drug misuse prevention activities themselves. The committee therefore recommended that routine and opportunistic appointments provided by statutory and other services should be used to assess vulnerability to drug misuse.\n\nThe committee agreed that all practitioners who have contact with people in groups at risk, including practitioners working in health services, social care services and the criminal justice system, should be aware of drug misuse prevention and should use every contact to identify those at risk.\n\n## Recommendation 1.2.2\n\nThe committee was not able to recommend a particular assessment tool for a number of reasons. The committee noted that most tools that are available focus on people who already use drugs rather than those at risk of misusing drugs. Comments from stakeholders during consultation on the draft guideline highlighted several assessment tools that stakeholders believed could be useful. However, the committee noted that these tools may not fit easily into routine and opportunistic appointments provided by statutory and other services. Some of the tools focused on alcohol use rather than drug use. The committee was aware that there is no single tool that is suitable for use in all groups at risk and for assessing all vulnerabilities. It was concerned that recommending a tool for a particular group at risk may result in the tool being used with other groups at risk, which may not be appropriate. The committee noted evidence that whatever approach is chosen, it should be non-judgemental, which is likely to be more acceptable to participants [ES2.17, ES2.20, ES2.32]. So the committee was unable to recommend a specific assessment tool, but recommended that a consistent, locally agreed, respectful and non-judgemental approach is used.\n\nThe committee recommended that the approach for assessment should be proportionate to the person's presenting vulnerabilities. The committee noted that the assessor may become more aware of potential vulnerabilities through their discussion with the person and may therefore need to do a more intensive assessment to explore these vulnerabilities.\n\nThe committee noted that there are existing practice standards for young people with substance misuse problems from the Royal College of General Practitioners, Alcohol Concern, DrugScope and Royal College of Psychiatrists. The overall quality of the practice standards document was rated as 5\xa0out of\xa07 using the AGREE\xa0II tool, where\xa01 indicates 'lowest possible quality' and 7\xa0indicates 'highest possible quality'. The practice standards document scored well on several domains in the tool, including being clear on the aim of the guideline and its target population, involving stakeholders throughout development, presenting recommendations clearly, and providing information on implementation. It did not score as well on describing how the evidence was selected, the strengths and limitations of the evidence, or the methods for formulating the recommendations. However, this information can be found in the guidance (including NICE guidance) that the recommendations in the practice standards document are based on. The committee noted that there is no corresponding practice standards document for adults. However, it believed that many of the practice standards were relevant for adults as well as young people. The committee agreed that the practice standards are a useful example of an approach for assessing a person's vulnerability to drug misuse.\n\n## Recommendation 1.2.3\n\nThe committee discussed the importance of an assessment considering how the wider health and personal context, such as a person's age and developmental stage, as well as their personal, social, health, mental health and educational or employment circumstances, may affect their vulnerability to drug misuse. It also discussed the importance of assessment addressing the possible harm associated with any existing drug use by that person.\n\nThe committee recommended that assessors should be aware that the person's circumstances may be complex. The committee acknowledged that people working with groups at risk need to have an understanding of the potential vulnerabilities to drug misuse. They should also be aware that people may present with more than\xa01 vulnerability, and that people who do present with more than\xa01 vulnerability may be at increased risk of drug misuse.\n\nThe committee agreed that an assessment might identify people who are already misusing drugs. As previously noted, it can be difficult to make a distinction between occasional or recreational use and regular or excessive use. The committee highlighted that the definition of 'excessive use' is subjective and may vary depending on the individual (for example, their age and developmental stage) and their circumstances. For example, drug use that is not considered excessive in an adult may be considered excessive in a younger person.\n\nTreatment of people who use drugs or alcohol regularly or excessively is outside the scope of this guideline. NICE has guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16\xa0years and older, diagnosis and management of alcohol-use disorders in people aged 10\xa0years and older, and needle and syringe programmes for adults and young people, including those under\xa016.\n\n## Recommendation 1.2.4\n\nThe committee discussed the role of safeguarding. It acknowledged that safeguarding includes protecting vulnerable people of any age from physical and emotional maltreatment, sexual abuse, neglect and exploitation. It agreed that safeguarding is everyone's responsibility. It added that all practitioners who are in contact with vulnerable people have a duty to protect them from maltreatment and share information with other services.\n\nThe committee agreed that practitioners undertaking assessment of whether someone is vulnerable to drug misuse should be aware that the assessment may raise safeguarding concerns. It acknowledged that safeguarding concerns may become more apparent to the practitioner once the assessment has ended and they are reflecting on the discussion. Although the committee emphasised the importance of safeguarding, it acknowledged that recommending referral to specialist services, such as child protection services, as a result of safeguarding concerns is outside the scope of the current guideline.\n\nThe committee also acknowledged that not all concerns need immediate intervention from social care services, and that other factors (such as problems at school) may have a larger effect on the person's vulnerability to drug misuse. The committee therefore recommended that the assessor should think about whether there are concerns for the safety of the person being assessed and any people under their care.\n\n## Recommendation 1.2.5\n\nThe committee recommended that people undertaking assessments should discuss the person's priorities and consider what effect their priorities have on prevention activities or referral to specialist services. The committee highlighted that there are existing practice standards for young people with substance misuse problems from the Royal College of General Practitioners, Alcohol Concern, DrugScope and the Royal College of Psychiatrists.\n\n# Section 1.3 Children and young people assessed as vulnerable to drug misuse\n\nThe discussion below explains how we made recommendations in section\xa01.3.\n\n## Recommendation 1.3.1\n\nThe committee noted that the health economic team modelled 7\xa0drug misuse\xa0prevention interventions. None of these were cost effective in the base case as a stand-alone intervention (see overview of the cost-effectiveness evidence) [ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7].\n\nThe committee noted from the health economic modelling that to be cost effective, an intervention would need to cost less than £100 per person and would need to reduce the number of people misusing drugs by at least 5\xa0percentage points over 2\xa0years [ES4.8]. The committee agreed that a reduction of at least 5\xa0percentage points in the number of people at risk of misusing drugs was most likely to occur in people who are assessed as vulnerable to drug misuse. As such, interventions are likely to be cost effective only in people who are vulnerable to drug misuse. The committee recommended that interventions are prioritised for those with increased vulnerability.\n\nEvidence for the effectiveness of offering personal and social skills training to children and young people at risk of drugs misuse and to their parents and carers came from 4\xa0studies reported in 4\xa0papers [Esc]. Two trials reported a significant reduction in drug use, including a trial undertaken with children and young people who are looked after and their foster carers. There was also evidence from 3 studies of a significant improvement in personal and social skills after skills training for children and young people and their parents or carers, which supports the studies that found a significant reduction in drug use.\n\nOne of the trials of personal and social skills training for children and young people and their parents and carers reported an increase in cannabis use in children and young people who underwent skills training. However, the committee believed this finding could be a result of participants changing their drug use from other drugs to cannabis during the study, because the study also reported a decrease in the use of drugs other than cannabis. An additional study did not report a significant reduction in drug use after the intervention; however, in this study drug use was measured immediately after the intervention only and no longer-term data were collected.\n\nThe committee noted that there was evidence from evidence review\xa02 that group-based skills training [ES2.33, ES2.46] and opportunistic skills training, advice and information provision are acceptable to participants [ES2.39]. However, it also acknowledged that it may not be appropriate to include carers or families in all cases, such as if children have been sexually abused.\n\nPersonal and social skills training for only children and young people who are vulnerable to drug misuse was not recommended because the evidence was limited and inconsistent [Esa]. Two studies of the effectiveness of skills training for children and young people showed an inconsistent effect on drug use, with the use of some drugs being significantly reduced but the use of other drugs not changing significantly. A third study reported no difference in drug use after skills training for children and young people. One study reported a significant improvement in drug refusal skills, problem-solving skills, and coping skills after the intervention. Another study concluded that skills training for children had no significant effect on feelings of self-worth, but it did not report data, p\xa0values or an effect size. One study reported that the intervention may have affected intention to use drugs, but the data were not reported. Another study reported a statistically significant improvement in knowledge of drugs and their risks after the intervention with peer educators but not with adult educators.\n\nPersonal and social skills training for only carers and families of children and young people at risk of drug misuse was not recommended. This was because it was not clear that skills training for parents and carers alone had a significant effect on drug use in the children and young people they cared for. Evidence for the effectiveness of skills training for parents or carers came from 4\xa0trials reported in 7\xa0papers [Esb]. One trial and 2\xa0follow-up studies reported no statistically significant difference in drug use. Three trials and a secondary analysis of one of the trials reported significantly reduced drug use after the intervention. However, 2\xa0of the trials that reported significantly reduced drug use included other interventions for the families in addition to skills training, such as case management, weekly family therapy, individual therapy, and motivational interviewing. It is not clear whether the skills training or the other interventions had a significant effect on drug use.\n\nFamily-based interventions as a whole were not recommended because they were unlikely to be cost effective for the populations included in the current guideline. The committee acknowledged the evidence on family-based interventions showed a mixed effect on drug use, with 5 studies in 6 papers showing a significant reduction in drug use, 4\xa0studies in 6\xa0papers showing no significant effect on drug use, and 1\xa0study showing a significant increase in drug use [ES1.50]. However, the committee noted that the evidence base included studies of Multidimensional Treatment Foster Care and motivational interviewing, which are more intensive than skills training alone. The committee was aware that family-based interventions were recommended in NICE's guideline on substance misuse interventions for vulnerable under\xa025s. It noted that this recommendation included motivational interviewing and family therapy, which were very unlikely to be cost effective for the populations included in the current guideline.\n\nThe health economic modelling looked at 3\xa0family-based interventions that included skills training [ES4.1, ES4.3, ES4.7]. None of the interventions were found to be cost effective in the base case scenario. However, the committee noted that these interventions involved other activities as well as skills training, such as motivational interviewing, which would have made them more costly. The committee noted that the results of the modelling showed that 2\xa0of the interventions could be cost effective if the cost of delivering them was lower and the effects of the interventions could be sustained over 2\xa0years or more [ES4.3, ES4.7]. It also noted that interventions could be made cost effective if they were added to existing programmes of care at an additional cost of less than £100 per person [ES4.9].\n\nManualised and licensed programmes, of which 4\xa0out of5 were family-based, were not recommended because they were costly and may not be effective for the populations included in the current guideline. The committee noted that evidence review\xa01 included studies of manualised and licensed programmes, namely Focus on Families [ES1.10], Family Competence Program [ES1.11], Multidimensional Treatment Foster Care [ES1.14, ES1.18], Familias Unidas [ES1.17] and Free Talk [ES1.19]. The studies either showed no significant effect on drug use [ES1.10, 1.19], an inconsistent effect on drug use [ES1.14, ES1.18] or did not report drug use outcomes [ES1.11]. The committee noted that such programmes are costly and that adapting programmes to make them cost less than £100 per person could have an impact on effectiveness. The committee also noted that none of the studies of manualised and licensed programmes were from the UK, and it is not clear whether the programmes would have the same effectiveness in a different country from where the study was performed. The committee concluded that it could not recommend adapting existing manualised or licensed drug misuse prevention programmes for use in the UK.\n\nMotivational interventions were not recommended because of the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence. The evidence review identified 3\xa0main types of motivational intervention: 'motivational interviewing'; 'brief interventions'; and 'motivational enhancement therapy' (see evidence tables for details of the interventions). The committee noted that most studies did not clearly describe the intervention and used terminology that may not match the committee's understanding. It acknowledged that the programme development group for NICE's guideline on individual approaches to behaviour change noted similar issues. The programme development group concluded that it was not possible to recommend motivational interviewing because the studies did not specify which principles and components were used. The committee therefore considered the evidence for motivational interventions as a whole.\n\nThe committee noted that there were 15 unique trials of motivational interventions, of which 9 were in children and young people [Ese, Esf, Esg]. Two\xa0of the 9\xa0trials reported significant reductions in drug use. However, 1\xa0of these trials showed a significant difference in the use of some drugs at some time points but not others, and the other trial showed reduced drug use in some contexts but not others. The committee agreed that, overall, motivational interventions were unlikely to be significantly more effective than skills training.\n\nThe committee discussed the health economic modelling for motivational interventions. It showed that motivational interviewing was not cost effective in the base case, ranging from £131,000 per QALY gained to £485,000 per QALY gained [ES4.4, ES4.5, ES4.6]. The modelling showed that motivational interviewing would only be cost effective if it could be delivered for less than £190 and could reduce drug use for at least 2\xa0years [ES4.4, ES4.5, ES4.6]. The committee agreed that motivational interventions were unlikely to be cost effective compared with skills training.\n\nTaking into account the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence, the committee concluded that it was unable to recommend motivational interventions for groups at risk of drug misuse. The committee recommended that research is undertaken in this area (see research recommendation\xa03).\n\nThe committee agreed that skills training for children and young people as well as for their carers or families was likely to be a more cost effective way to reduce the risk of drug misuse than family-based interventions or manualised or licensed programs, and motivational interventions for children and young people. This is because it is more likely that skills training could be delivered as part of existing services for less than £100 per person. The committee noted that skills training is likely to improve a range of outcomes, including those that are not related to drug misuse. It did not believe there was enough evidence to recommend skills training just for children and young people, or just for their carers and families. The committee reiterated that any skills training should be delivered as part of existing services, as in recommendation\xa01.1.1.\n\nThe committee discussed the different groups of people that this guideline is relevant to. It acknowledged that services aimed at groups at risk use different ages to distinguish between child and adult services. For example, specialist services for drug treatment aimed at adults may include people aged\xa016 and over, whereas services for children and young people that are looked after may include those aged up to\xa025. The committee was aware that 'young people' can include people with a range of ages and developmental stages. It acknowledged that for some young people it may be more appropriate to offer skills training, and for other young people it may be more appropriate to offer information on drugs and their effects. The committee recommended that following an assessment of whether a young person in a group at risk is vulnerable to drug misuse, the most appropriate prevention options for that young person should be considered.\n\n## Recommendation 1.3.2\n\nThe committee agreed that integrating skills training for children and young people and their carers and families into existing services could lower the additional cost of the interventions and therefore be a cost-effective way to deliver drug misuse prevention interventions. The committee heard expert testimony that integrating skills training into existing services is becoming a more common approach [EP1].\n\nBased on the cost-effectiveness evidence, the committee recommended that skills training for children or young people and their carers or families should be commissioned as part of existing services (see discussion section on recommendation\xa01.2.1).\n\nThe committee noted that skills training is likely to be delivered by people who do not work in drug and alcohol services. It agreed that any skills training should be delivered by people who are already competent to provide it, instead of investing resources in training people to deliver it. It noted that the NICE guidance on antisocial behaviour and conduct disorders in children and young people includes recommendations on the training and competencies of staff working with children and young people.\n\n## Recommendations 1.3.3 and 1.3.4\n\nThe committee discussed the content of skills training sessions, noting that different approaches were used in different studies and that most studies included training on more than 1\xa0type of skill. The skills training interventions for children and young people that successfully reduced the risk of drug use and improved personal and social skills included skills such as listening, conflict resolution and refusal. Other components of effective skills training interventions were identifying and managing stress, making decisions, coping with criticism, dealing with feelings of exclusion, and making healthy behaviour choices [ES1.7, ES1.8, ES1.11, ES1.13, ES1.15, ES1.21, ES1.23].\n\nThe committee noted that the skills training interventions for parents and carers of children at risk of drug use that successfully reduced the risk of drug use and improved personal and social skills included skills such as communication, developing and maintaining healthy relationships, conflict resolution, and problem solving [ES1.11, ES1.13, ES1.15, ES1.17, ES1.21, ES1.23, ES1.57, ES1.58, ES1.60]. The committee recommended that skills training should aim to develop a range of skills, with the skills used in the studies as examples.\n\nThe committee agreed that skills training for children and young people who are looked after and care leavers, and their carers, needed particular consideration, because there was clearer evidence of the success of skills training for this group compared with other groups. Successful skills training interventions for children and young people who are looked after and care leavers included social skills and how to deal with feelings of exclusion [ES1.13]. For foster carers, the important component was how to use behaviour reinforcement systems [ES1.13, ES1.14]. The committee recommended that skills training for children and young people who are looked after, care leavers and foster carers emphasised these skills.\n\n## Recommendations 1.3.5 and 1.3.6\n\nThe committee discussed the wide variation in age and developmental stage in the groups at risk. The committee noted that skills training sessions can be used for people of different ages; however, sessions aimed at a young child might not be appropriate for a young adult. The committee recommended that age and developmental stage should be taken into account when deciding on the details of the skills training sessions.\n\nThe committee considered other aspects that might influence the effectiveness of skills training offered to children and young people. It agreed that presenting vulnerabilities, cultural context, religion and ethnicity may be important. It recommended that these factors be taken into account, along with any other specific needs or preferences of the child or young person vulnerable to drug misuse, when deciding the details of what training sessions to provide. It also noted the evidence that interventions should be made engaging, relevant and creative [ES2.12, ES2.18].\n\nThe committee considered whether interventions should be provided one-to-one or in a group-based setting. It acknowledged there was mixed evidence for the effectiveness of group-based behaviour therapy (including skills training) for children and young people [ES1.54], but that it is generally well received [ES2.13]. The committee agreed that group-based skills training is likely to cost less per person than one-to-one skills training. None of the studies looked at the effectiveness of one-to-one skills training, but the committee acknowledged that group environments may not be appropriate for everyone in groups at risk. The committee recommended taking into account the child or young person's needs and preferences when deciding whether sessions should be provided one-to-one or in groups.\n\nThe committee considered the number and duration of skills training sessions that should be delivered. It acknowledged that the overall effectiveness of family-based interventions did not appear to vary by the intensity or duration of the intervention [ES1.68]. However, it was not clear whether this was also true for the subset of family-based interventions that included skills training sessions for children or young people and their parents or carers. Studies used different numbers (3\xa0to\xa014 sessions) and durations of training sessions (from not reported to 1.5\xa0to\xa02 hours), and the committee noted no consistent pattern of effectiveness.\n\nThe committee felt unable to recommend a specific number or duration of sessions. However, it acknowledged that skills training is likely to be offered as part of a larger programme, in which skills related to drug misuse prevention may be a small part of each training session. Therefore, the committee recommended that skills training should consist of 2\xa0sessions as a minimum. The committee recommended taking the needs of the child or young person into account when determining the number and duration of skills training sessions. It also recommended discussing and agreeing a plan for follow-up at the skills training sessions to determine whether additional skills training or referral to specialist services is needed.\n\nThe committee also considered where skills training interventions should be delivered. It noted evidence that participants reported having access to a trusted setting in which they are surrounded by likeminded peers could stop them misusing drugs [ES2.19]. The committee recommended that the settings in which skills training will be delivered should also be considered.\n\nThe committee was unable to recommend details of the skills training, such as where to hold the sessions, as this information was not available from the evidence. However, the committee was aware that the Department of Health has published quality criteria for young people friendly services. It recommended that these criteria are used for information when considering skills training for children and young people.\n\n# Section 1.4 Adults assessed as vulnerable to drug misuse\n\nThe discussion below explains how we made recommendations in section\xa01.4.\n\n## Recommendation 1.4.1\n\nThe committee noted that the health economic team modelled 7\xa0drug misuse\xa0prevention interventions. None of these were cost effective in the base case as a stand-alone intervention (see overview of the cost-effectiveness evidence) [ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7].\n\nThe committee noted from the health economic modelling that to be cost effective, an intervention would need to cost less than £100 per person and would need to reduce the number of people misusing drugs by at least 5\xa0percentage points over 2\xa0years [ES4.8]. The committee agreed that a reduction of at least 5\xa0percentage points in the number of people at risk of misusing drugs was most likely to occur in people who are assessed as vulnerable to drug misuse. As such, interventions are likely to be cost effective only in people who are vulnerable to drug misuse, and the committee recommended that interventions are prioritised for those with increased vulnerability.\n\nThe committee was unable to recommend skills training for adults at risk of drug misuse because the evidence was limited [Esd]. The committee noted that only 1\xa0study of skills training for adults at risk of drug misuse reported significantly reduced drug use compared with before the intervention. The committee acknowledged there was mixed evidence for the effectiveness of group-based skills training as a whole; however, it noted that this evidence included studies in children and young people at risk of drug misuse, as well as adults [ES1.42].\n\nMotivational interventions were not recommended because of the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence. The evidence review identified 3 main types of motivational intervention: 'motivational interviewing', 'brief interventions' and 'motivational enhancement therapy' (see evidence tables for details of the interventions). The committee noted that most studies did not clearly describe the intervention and used terminology that may not match the committee's understanding. It acknowledged that the programme development group for NICE's guideline on individual approaches to behaviour change noted similar issues. The programme development group concluded that it was impossible to recommend motivational interviewing because the studies did not specify which principles and components were used. The committee therefore considered the evidence for motivational interventions as a whole.\n\nThe committee noted that there were 15\xa0unique trials of motivational interventions, of which 6\xa0were in adults [Ese, Esf, Esg]. Of these 6\xa0trials, 3\xa0trials reported significant reductions in drug use. One trial showed a significant reduction in drug use compared with no assessment or intervention, but no significant reduction in drug use compared with education or information.\n\nThe committee discussed the health economic modelling for motivational interventions. It showed that motivational interviewing was not cost effective in the base case, ranging from £131,000 per QALY gained to £485,000 per QALY gained [ES4.4, ES4.5, ES4.6]. The modelling showed that motivational interviewing would only be cost effective if it could be delivered for less than £190 and could reduce drug use for at least 2\xa0years [ES4.4, ES4.5, ES4.6]. The committee agreed that motivational interventions were unlikely to be cost effective compared with other interventions or current practice.\n\nTaking into account the uncertainty in the terminology and the effectiveness and cost-effectiveness evidence, the committee concluded that it was unable to recommend motivational interventions for groups at risk of drug misuse. The committee recommended that research is undertaken in this area (see research recommendation 3).\n\nThe committee was unable to recommend skills training or motivational interventions for adults who are assessed as vulnerable to drug misuse; however, it wanted to recommend some action should be taken. The committee agreed it should provide recommendations on what current practice involves. The committee considered what current practice involved in studies that found current practice to be as effective as motivational interventions [ES1.2, ES1.22, ES1.36, ES1.37]. Current practice was found to include brief information and education on drugs and their effects (such as health and social effects), and feedback. The committee recommended that adults who are assessed as vulnerable to drug misuse should receive these components of current practice. It also recommended research in this area (see research recommendation\xa02).\n\nThe committee considered whether additional components should be added to the care of adults who are vulnerable to drug misuse. It agreed that information on sources of advice or support would be helpful for adults at increased risk. The committee agreed that information and advice should be offered at the time of their assessment.\n\n## Recommendation 1.4.2\n\nThe committee considered whether the information and advice offered to adults assessed as vulnerable to drug misuse should be provided in a verbal or written format. The committee acknowledged the evidence from 1\xa0study that participants did not find written information as useful as verbal information [ES2.27] and they thought it was outdated [ES2.31]. However, it noted that this may not be true for all written information and that written information can be useful for people who want to revisit information in their own time. The committee noted the evidence that participants stressed the value of being able to ask questions, and this is only likely to happen when information is provided verbally [ES2.31]. The committee therefore recommended that information and advice is provided in a written and verbal format.\n\nThe committee considered factors that may affect the provision of information to adults who are vulnerable to drug misuse. It discussed the different levels of understanding about health across groups of people. It noted that the level of understanding about health is likely to vary widely among adults who are vulnerable to drug misuse. The committee also noted that NICE's guideline on patient experience in adult NHS services recommends taking people's general literacy levels into account to meet their needs. The committee agreed that the person's level of understanding about health needs to be considered when providing information to adults who are vulnerable to drug misuse.\n\nThe committee noted evidence that a non-judgemental approach to providing advice was more acceptable to participants [ES2.17, ES2.20, ES2.32]. It therefore recommended using a respectful and non-judgemental approach.\n\nThe committee noted that NICE has existing guidance on general and individual approaches to behaviour change. It recommended that information and advice is provided in line with these guidelines.\n\n## Recommendation 1.4.3\n\nThe committee considered the number of information sessions needed for adults who are vulnerable to drug misuse. It agreed that the approach used to provide information will need to vary to account for the wide range of adults who are vulnerable to drug misuse. The committee recommended that a plan for follow-up is discussed and agreed at the time of the person's assessment (see recommendation\xa01.2.1).\n\n# Section 1.5 People at risk of using drugs\n\nThe discussion below explains how we made recommendations in section\xa01.5.\n\n## Recommendation 1.5.1\n\nThe committee discussed the groups at risk that may not present to health or social care services. Committee members heard expert testimony that people who use image- and performance-enhancing drugs are less likely to present because they may not identify as drug users [EP2]. They noted that people in some of the groups at risk may not be in contact with health or social care services (for example, people who go to nightclubs and festivals, people who are homeless, people who go to gyms, and children and young people at school) [EP2] or may be in contact only with wider health services, such as sexual and reproductive health services. People may also avoid seeking advice because much drug use involves illegal drugs [EP2].\n\n## Recommendations 1.5.2 and 1.5.3\n\nThe committee considered what drug misuse\xa0prevention services could be offered to people in groups at risk who do not present to health or social care services. Digital technologies can allow interventions to be offered to people who are either unable or choose not to access services, and can offer anonymity. The committee noted the evidence showed that web-based interventions did not significantly reduce drug use [ES1.48] compared with assessment only [ES1.32, ES1.33] or a waiting list control [ES1.34]. However, 1\xa0study did show promising effects of web-based information and advice in a subgroup analysis of people with a family history of drug problems [ES4.2]. Web-based interventions were generally well received [ES2.29, ES2.30, ES2.41].\n\nThe health economic modelling did not find web-based interventions to be cost effective in the base case (£329,000 per QALY). If an intervention was delivered at a cost of less than £1\xa0per person, it would be less costly and more effective than a 'do nothing' alternative [ES4.2].\n\nThe committee considered that web-based interventions could feasibly be produced at a low cost and was aware of existing online sources of information, including NHS Choices. It noted that the NHS Choices website provides reliable information and also provides links to other helpful sources of information. The committee therefore recommended that targeted new media (including web-based information as well as digital and social media), that give reliable information, and online self-assessment and feedback to help people assess their own drug use, could be provided to people at increased risk. These approaches may be particularly useful in those less likely to be in contact with health and social care services. The committee also recommended that further research should be undertaken on the effectiveness of digital technologies (see research recommendation\xa05).\n\nThe committee noted that some people in groups at risk may not be able to access online services. It recommended that written information should be made available for people not in contact with health or social care services.\n\nThe committee also recommended that information given to people not in contact with health or social care services should include information on local services and sources of advice and support.\n\n## Recommendation 1.5.4\n\nThe committee noted that NICE has existing guidance on general and individual approaches to behaviour change. It recommended that information is provided to people at risk of using drugs in line with these guidelines.\n\n# Evidence not used to make a recommendation\n\nThe committee did not make recommendations for all of the evidence statements. For some interventions, the effectiveness evidence was not strong enough or was too inconsistent to make a recommendation for or against using an intervention [ES 1.1, ES1.7, ES1.10, ES1.12, ES1.14, ES1.17, ES1.18, ES1.20, ES1.67]. Some evidence statements stated that no relevant evidence was identified [ES1.5, ES1.9, ES1.25, ES1.45, ES1.46, ES1.63, ES1.66, ES1.69, ES2.1, ES2.2, ES2.3, ES2.4, ES2.7, ES2.8, ES2.9, ES2.10, ES2.14, ES2.24, ES2.35, ES2.36, ES2.37, ES2.38, ES2.44, ES2.48, ES2.49].\n\nThe committee was unable to consider evidence on the acceptability or cost effectiveness for interventions that either were not effective at reducing drug use or for which no effectiveness evidence was identified [ES2.5, ES2.15, ES2.16, ES2.21, ES2.22, ES2.23, ES2.25, ES2.26, ES2.27, ES2.28, ES2.31, ES2.34, ES2.40, ES2.45, ES3.1, ES3.2, ES3.3]. For details of the evidence statements used to make recommendations, see the evidence reviews section.\n\nThe committee discussed the different outcomes reported in the studies identified in the evidence reviews. It noted that drug use behaviour does not always reflect attitudes and intentions towards drug use. It was agreed that drug use outcomes were the most important outcomes from the evidence. Therefore, if use was reported, other outcomes were not prioritised when the committee drafted recommendations. Some evidence statements reported on outcomes other than drug use for interventions for which drug use outcomes were reported, so were not used to make recommendations [ES1.3, ES1.4, ES1.24, ES1.38, ES1.39, ES1.40, ES1.41, ES1.43, ES1.44, ES1.51, ES1.52, ES1.53, ES1.55, ES1.56, ES1.59, ES1.60, ES1.61].\n\nIt was unclear from the evidence whether the effectiveness of an intervention varies by who delivers it [ES1.64, ES1.65]. The committee discussed the importance of the skills and competencies of people delivering assessments and interventions. It agreed that people should have training and continuing professional development to ensure that interventions can be delivered effectively.\n\nThe committee noted that little evidence was found for whether the effectiveness of interventions varied by the content and framing of the intervention [ES1.62]. In addition, no evidence was found for whether the effectiveness of interventions varied by mode of delivery [ES1.63], where the intervention was delivered [ES1.66], or the intended recipient of the intervention [ES1.69].\n\nThe committee was aware that the evidence review did not find any evidence on drug misuse\xa0prevention strategies for image- and performance-enhancing drugs or new psychoactive substances. Committee members heard expert testimony that it is difficult to identify and intervene when people are using these drugs, because they tend not to label themselves as drug users. In addition, image- and performance-enhancing drugs are available online and so can be accessed by a wide range of people. The committee recommended research is undertaken in this area (see research recommendation\xa06).\n\nThe committee considered digital technologies other than web-based interventions that could be used for drug misuse prevention interventions. It acknowledged the evidence that responsive text messaging can reduce the odds of cannabis use in some contexts, but not others [ES1.49], and is generally acceptable to young people [ES2.42, ES2.43]. It noted that one study also involved face-to-face brief motivational enhancement therapy, which is unlikely to be cost effective. The committee agreed there was a lack of evidence for the effectiveness of interventions using only digital technologies.\n\nThe committee recommended that further research is needed into digital technologies (see research recommendation\xa05).\n\n# Limitations of the evidence\n\n## Limitations of the effectiveness and acceptability evidence\n\nThe committee noted that most of the included studies used small sample sizes, short follow-up times, self-reported drug use and intermediate outcomes (such as knowledge about drugs, rather than change in drug-using behaviour). It was not possible to determine whether some studies were poorly conducted or poorly reported. Some studies may not have been adequately powered to identify significant differences between groups. In addition, some participants in some studies did not attend any of the intervention sessions, and many studies did not include a true control group. As a result, the efficacy of the intervention could have been underestimated in these studies.\n\nThe committee noted that single small studies were presented for more than 1\xa0group at risk, resulting in multiple evidence statements from the same studies. This makes the evidence base look larger and stronger than it actually is. Overarching evidence statements have been used to summarise the body of evidence across population groups [ESa, ESb, ESc, ESd, ESe, ESf].\n\nThe committee acknowledged that limited evidence was available on the effectiveness of interventions in the UK. Most interventions considered were undertaken in the US. Although the evidence is likely to be applicable in the UK, the committee discussed that key differences in social norms, education, care, and criminal justice and healthcare systems may influence the effectiveness of interventions transferred to UK settings. In addition, the committee noted that the comparators included in the studies may vary from those seen in the UK. It also agreed that current practice (referred to in the studies as 'standard care') was not well defined or consistently reported in the studies. Current practice can vary depending on which group at risk is included in a study, and the country and setting in which the study was conducted.\n\nThe committee discussed that some of the interventions in the studies were likely to have been delivered in a research setting; for example, a university research facility. It was felt that the results may have been different if the interventions had been delivered in real-world settings, such as homeless shelters, nightclubs or music events, youth clubs and organisations, or environments where drugs may be used in a sexual context (such as 'chemsex' parties).\n\nThe committee agreed that the group 'people who are known to use drugs occasionally or recreationally' represents a diverse population. Although several studies were identified for this group, it is likely that the evidence does not cover the whole target population.\n\nThe committee noted that no good quality evidence is available for some groups at risk, despite the research recommendations made in NICE's previous guideline on substance misuse interventions for vulnerable under\xa025s. Committee members agreed that more evidence from well designed and adequately powered studies is needed. The committee recommended that research is undertaken on the effectiveness and acceptability of drug misuse\xa0prevention interventions in groups at risk (see research recommendations 3\xa0and\xa04).\n\nThe committee noted that studies of pregnant women were excluded from the evidence reviews for this guideline. There is existing NICE guidance on pregnancy and complex social factors, which includes substance misuse in pregnant women. General antenatal and postnatal care is covered in existing NICE guidance. In addition, it was agreed that studies on drug use in pregnant women are most likely to be studies of treatment for dependent drug users rather than prevention studies.\n\n## Limitations of the cost-effectiveness evidence\n\nThe studies used in the health economic modelling were identified in the evidence review. Therefore the limitations of the studies in the evidence review also apply to the cost-effectiveness evidence.\n\nThe committee noted that the effect on someone of having a criminal record was not taken into account in the health economic modelling. It acknowledged that drug use can lead to a criminal record, and that people with a criminal record have difficulties securing employment. Therefore, avoiding a criminal record is a potential positive outcome of drug misuse prevention activities. It agreed that including the effect on an individual of having a criminal record in the health economic modelling would have increased the cost effectiveness of the interventions.\n\nThe committee also recognised that the long-term harms and associated costs of drug use are mostly unknown. The size of the groups at risk is unknown, and it is not known what percentage of people in these groups will go on to misuse drugs. These factors will affect the accuracy of the health economic modelling. The committee therefore recommended research is done on the long-term consequences of drug use (see research recommendation\xa01).\n\n## Terminology\n\nThe committee discussed that many terms used in the literature to describe drug use are subjective and often used inconsistently or interchangeably (for example, terms such as 'use', 'misuse', 'occasional' or 'recreational', 'dependency' and 'abuse'). It discussed that the definition of 'recreational' use in particular was subjective. For example, fortnightly use of cannabis by an adult might be considered recreational, but fortnightly use by a child or young person may be considered problematic.\n\nThe committee discussed the term 'primary care'. It acknowledged that the use of the term by the public focuses on general practitioners. However, the committee agreed that the use of the term in this guideline includes all primary care services, including healthcare professionals such as pharmacists, dentists and optometrists.\n\nAlthough treatment for drug misuse fell outside the remit of this guideline, there is an overlap between treatment, harm reduction (aiming to prevent or reduce negative effects of drugs) and prevention in this field. Despite careful consideration by 3\xa0reviewers, some studies of harm reduction interventions may have been misinterpreted as treatment studies and so would not have been considered in this guideline. The committee noted that NICE has a range of products that cover drug misuse, and in particular that treatment has been considered by related NICE guidelines (psychosocial interventions and opioid detoxification for drug misuse in people aged 16\xa0years and older).\n\n# Existing NICE guidance\n\nThe committee was aware of several relevant pieces of NICE guidance.\n\nThe committee considered the NICE guideline on individual approaches to behaviour change in the context of the current guideline. This guideline recommends delivering very brief, brief, extended brief and high intensity behaviour change interventions and programmes to people who are at risk of damaging their health through their behaviour.\n\nWhen considering the evidence for the guideline on individual approaches to behaviour change, the committee for that guideline noted that, across all interventions, those targeting the general population were more likely to be cost effective than those aimed at vulnerable populations (targeted approaches). However, it is important to note that evidence directly relating to drug misuse was not included. The committee for that guideline also noted similar difficulties to the committee for this guideline in determining the interventions used in the studies.\n\nThe committee did not think it was appropriate to directly apply the recommendations from the guideline on individual approaches to behaviour change to the groups at risk in this guideline, because the evidence base for that guideline did not include studies of drug misuse interventions. However, it was agreed that those recommendations should be kept in mind when following the recommendations in the current guideline.\n\nThe committee considered the NICE guideline on prevention of alcohol-use disorders to be particularly relevant to this guideline because many people who misuse drugs also misuse alcohol (Psychosocial interventions to reduce alcohol consumption in concurrent problem alcohol and illicit drug users Klimas et al. 2014). This can result in people having multiple issues when they present to healthcare services. However, the committee noted that alcohol misuse is not illegal, allowing for interventions and data collection to be done more easily. The committee agreed that the recommendations for alcohol misuse prevention cannot be directly translated into recommendations for drug misuse prevention because of the lack of data for drug misuse prevention. The committee agreed that, because of the large overlap in the target populations of the current guideline and the guideline on prevention of alcohol-use disorders, the recommendations in the guideline on prevention of alcohol-use disorders should be kept in mind when providing drug misuse prevention activities.\n\nThe committee considered the NICE guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16 years and older. It noted that treatment of drug misuse was outside of the scope of this guideline, but acknowledged that it can be difficult to distinguish between prevention and treatment strategies. The committee agreed that people who are drug dependent may be identified during the prevention activities recommended in this guideline. NICE's guidelines on psychosocial interventions and opioid detoxification in drug misuse can be used to determine what treatment should be provided. The committee highlighted that the existing NICE guidelines on the treatment of drug misuse do not include recommendations for children and young people under the age of 16.\n\nThe committee also noted that NICE's guidelines on child maltreatment, needle and syringe programmes, attention deficit hyperactivity disorder, looked-after children and young people, domestic violence and abuse, coexisting severe mental illness and substance misuse, and physical health of people in prison are relevant to drug misuse prevention. NICE also has a quality standard on looked-after children and young people. The current guideline on drugs misuse prevention should be considered in the context of this other guidance.\n\n# Recommendations from NICE's guideline on substance misuse interventions for vulnerable under 25s\n\nThis guideline will update and replace the NICE guideline on substance misuse interventions for vulnerable under\xa025s (PH4, published 2007).\n\nThe committee discussed the recommendations and considerations in the guideline being updated and considered the view of the experts in the review decision. It acknowledged that the populations included in the scope for the above guideline differ to some extent to those included in the current guideline. The current guideline also includes adults aged over\xa025. The current guideline does not include black, Asian and minority ethnic groups as a specific group at risk because they are no longer considered a group at risk. The current guideline also did not include people who were considered 'at risk' or 'vulnerable' without further explanation.\n\nThe current guideline only includes children and young adults in contact with young offender teams but not in secure environments. This is in contrast to PH4, which included young offenders per se as a group at risk. As a result, some of the evidence considered for guideline development is likely to differ. Despite this, the committee agreed that it had considered sufficient evidence on effectiveness and cost effectiveness on the groups at risk for this guideline, along with their wider knowledge of this topic area and current provision, to make a judgement on the recommendations from PH4.\n\nThe committee agreed that recommendation\xa01 and recommendation\xa02 from 'substance misuse interventions for vulnerable under\xa025s' should be withdrawn because they are now covered in the implementation section of the current guideline.\n\nIt also agreed that recommendation\xa03 should be replaced with the current recommendations. The committee discussed that although the family-based interventions that it had considered were effective, they were not shown to be cost effective. Similarly, the intensive family-based intervention as described in PH4 recommendation\xa03 is highly unlikely to be cost effective, particularly given that the committee agreed that motivational interventions were unlikely to be significantly more effective than other interventions, such as skills training.\n\nThe committee discussed that recommendation\xa01.3 in the current guideline would be likely to be cost effective if delivered through existing services. It discussed that the elements included in recommendation\xa01.3 in this guideline did cover aspects of PH4 recommendation\xa03, and, while not a family-based programme, encouraged involvement of carers and families. The committee did not consider the original evidence base for PH4. However, it was made aware that recommendation\xa03 in PH4 was based on evidence from 4\xa0studies that all targeted 'high risk' groups (the groups were not more specifically described), and only 2\xa0reported drug-related outcomes.\n\nRecommendation\xa04 in PH4 covers persistently aggressive and disruptive children. This target group are included in the current guideline but no evidence was identified. The committee agreed that the recommendation was now covered by the recommendations on child-focused programmes in the NICE guideline on antisocial behaviour and conduct disorders in children and young people.\n\nThe committee agreed that recommendation\xa05 is out of the scope of the current guideline because it refers to people who are dependent on drugs. The committee agreed that for young people aged over\xa016, the recommendation could be replaced by NICE guidelines on psychosocial interventions and opioid detoxification for drug misuse in people aged 16\xa0years and older. The committee noted that there is currently no guideline on treatment of children and young people aged under\xa016.\n\n# Evidence reviews\n\nDetails of the evidence discussed are in evidence reviews, reports and papers from experts in the area.\n\nThe evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from. All of the evidence statements are presented in the paper Evidence statements from all reviews. The paper also includes overarching statements that summarise the evidence across the groups at risk.\n\nEvidence statement (ES) letter 'a' indicates that the linked statement is lettered 'a' in 'Evidence statements from all reviews'. Evidence statement (ES) number\xa01.1 indicates that the linked statement is numbered\xa01 in evidence review\xa01. ES2.1 indicates that the linked statement is numbered\xa01 in evidence review\xa02. ES3.1 indicates that the linked statement is numbered\xa01 in the health economic evidence review. ES4.1 indicates that the linked statement is numbered\xa01 in the health economic modelling report. EP1 indicates that expert paper\xa01 'Current provision and future issues (opportunities and difficulties) for commissioning' is linked to a recommendation. EP2 indicates that expert paper\xa02 'The use of image and performance enhancing drugs in the United Kingdom' is linked. EP3 indicates that expert paper\xa03 'Night time environment and local partners role in managing harm' is linked.\n\nIf a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation\xa01.1.1: ES4.1, ES4.2, ES4.3, ES4.4, ES4.5, ES4.6, ES4.7, ES4.9; EP1\n\nRecommendation\xa01.1.2: EP1\n\nRecommendation\xa01.2.1: ES2.22; IDE\n\nRecommendation\xa01.2.2: ES2.17, ES2.20, ES2.32; IDE\n\nRecommendation\xa01.2.3: IDE\n\nRecommendation\xa01.2.4: IDE\n\nRecommendation\xa01.2.5: IDE\n\nRecommendation\xa01.3.1: ESa, ESb, ESc, ES1.50, ES2.33, ES2.39, ES2.46, ES4.1, ES4.3, ES4.7, ES4.9; EP1; IDE\n\nRecommendation\xa01.3.2: EP1; IDE\n\nRecommendation\xa01.3.3: ES1.7, ES1.8, ES1.11, ES1.13, ES1.14, ES1.15, ES1.17, ES1.21, ES1.23, ES1.57, ES1.58, ES1.60\n\nRecommendation\xa01.3.4: ES1.11, ES1.13, ES1.15, ES1.17, ES1.21, ES1.23, ES1.57, ES1.58, ES1.60\n\nRecommendation\xa01.3.5: ES1.54, ES1.68, ES2.12, ES2.13, ES2.18, ES2.19; IDE\n\nRecommendation\xa01.3.6: IDE\n\nRecommendation\xa01.4.1: ESd, ES1.2, ES1.22, ES1.36, ES1.37, ES1.42; IDE\n\nRecommendation\xa01.4.2: ES2.17, ES2.20, ES2.27, ES2.31, ES2.32; IDE\n\nRecommendation\xa01.4.3: IDE\n\nRecommendation\xa01.5.1: ES2.29, ES2.30, ES1.32, ES1.33, ES1.34, ES1.48, ES2.41, ES4.2; EP2; IDE\n\nRecommendation\xa01.5.2: IDE\n\nRecommendation\xa01.5.3: IDE\n\nRecommendation\xa01.5.4: IDE", 'Recommendations for research': 'The advisory committee has made the following recommendations for research.\n\n# . Long-term consequences of drug use\n\nWhat are the long-term consequences of drug use?\n\n## Why this is important\n\nWe identified little evidence on the long-term health and social consequences of using drugs. This made it difficult to determine the full consequences and effect of drug use on people in groups at risk. In particular, there was limited evidence on the long-term effects of using drugs other than cannabis. More evidence on the long-term consequences of drug use would enable more accurate modelling of the costs of drug use. This would in turn allow more accurate modelling of the cost effectiveness of drug misuse\xa0prevention interventions.\n\n# . Identifying current practice and provision\n\nWhat drug misuse prevention activities are currently used in the UK for groups at risk of drug misuse?\n\n## Why this is important\n\nIt is unclear what current practice is, and what provision is currently in place, for drug misuse prevention in groups at risk in the UK. Studies in the current review showed that active interventions were no more effective than current practice (as received by a control group). In addition, there is a lack of UK-based studies, and it is not clear whether the current practice that was used as a control group in studies conducted elsewhere is applicable to the UK population.\n\nIt is not clear how many of the people that are referred to drug misuse prevention services attend (or are brought to) the services. Identifying existing practice and provision will allow new drug misuse prevention activities to be compared with current practice, identify gaps in current provision, and determine what proportion of people referred to drug misuse prevention services do not attend (or are not brought) to services.\n\n# . Effectiveness and cost effectiveness of drug misuse prevention interventions for groups vulnerable to drug misuse\n\nWhat is the effectiveness and cost effectiveness of drug misuse prevention interventions for groups vulnerable to drug misuse in the UK?\n\n## Why this is important\n\nWe identified limited evidence of effectiveness or cost effectiveness of interventions for groups vulnerable to drug misuse in the UK. In particular, no evidence was identified on the effectiveness and cost effectiveness of drug misuse prevention interventions for people involved in commercial sex work or who are being sexually exploited, people not in employment, education or training, and people who attend nightclubs and festivals.\n\nMost of the evidence identified comes from studies in the US. Furthermore, it was unclear which components of interventions were essential for effectiveness and cost effectiveness.\n\nThe differential effect of interventions on groups at risk needs to be established, particularly for people with multiple vulnerabilities. The accuracy of tools for assessing vulnerability to drug misuse also needs to be determined. Interventions of interest include one-to-one skills training, information and advice as part of planned outreach activities, and wider behaviour change strategies. It is also important to know whether the effectiveness of interventions is affected by the content and framing of the message, the mode of delivery, where the intervention is delivered and the intended recipient of the intervention.\n\nPrimary outcomes of interest include a direct measure of drug use. Longer term outcomes (longer than 1\xa0year) from longitudinal studies are needed. Research on location-based interventions, for example at nightclubs or festivals, would provide prevention data for hard-to-reach groups and those who do not access existing services. Research could also consider prevention in people with multiple vulnerabilities and the use of new psychoactive substances.\n\n# . Acceptability of drug misuse prevention interventions\n\nHow acceptable are drug misuse prevention interventions among groups vulnerable to drug misuse in the UK? How acceptable are drug misuse prevention interventions among practitioners in the UK? How can acceptability be improved for groups that are vulnerable to drug misuse and practitioners?\n\n## Why this is important\n\nWe identified little evidence on the acceptability of drug misuse prevention interventions for groups vulnerable to drug misuse. The evidence that was available was limited by the small number of studies and participants, and in the overall quality of the studies.\n\nAcceptable interventions are important to increase the uptake of interventions and reduce the number of people who do not attend (or are not brought to) services following a referral. Studies are needed on interventions that are acceptable to people with different levels of self-efficacy and understanding about health. It is also important to know which interventions are more acceptable to particular groups at risk. Interventions that are more acceptable to practitioners are more likely to be implemented with groups at risk. Research on the framing of messages, such as abstinence-based approaches, is needed because some ways of framing interventions may be more acceptable than others to people in groups at risk. Research is also needed on who delivers the interventions, as this may also affect the acceptability of an intervention.\n\n# . Effectiveness of digital technologies\n\nHow effective and cost effective are digital technologies, such as web-based interventions, online self-assessment or targeted new media, for drug misuse prevention among groups at risk in the UK?\n\n## Why this is important\n\nWe identified limited evidence on digital interventions and targeted new media, with existing studies focusing on web-based and text messaging interventions. Interventions and assessments that use digital technology are potentially more cost effective than those delivered face to face and could be used for prevention activities in groups at risk who are harder to reach or who do not present to services. The use of digital technology could also allow people to use sources of support anonymously and help maintain engagement.\n\nResearch is needed on effectiveness, cost effectiveness and acceptability of interventions and self-assessment using digital technology. Studies could compare interventions delivered using digital technology with face-to-face interventions. Studies could also look at using interventions that use digital technologies as part of a stepped care model.\n\n# . Use of image- and performance-enhancing drugs\n\nWhat are the most effective and cost effective interventions to prevent and reduce the use of image- and performance-enhancing drugs?\n\n## Why this is important\n\nNo evidence was identified for interventions to reduce the use of image- and performance-enhancing drugs. Several different types of drugs can be classed as image- and performance-enhancing, including drugs that are used by people trying to lose weight (such as laxatives), those used to gain weight or increase physical performance (such as anabolic steroids), and those used to increase cognitive ability (such as methylphenidate). People using these drugs may not identify as drug users, making it difficult to provide preventative interventions. In addition, image-and performance-enhancing drugs are available online and can be accessed by a wide range of people.', 'Glossary': "Behaviour reinforcement strategies\n\nApproaches that link behaviour with outcomes, to encourage positive behaviour and discourage negative behaviour. This includes rewarding positive behaviour (such as going to school or work) and rewarding the absence of negative behaviour (such as using aggressive language).\n\nBrief interventions\n\nEither a short session of structured brief advice or a longer, more motivationally-based session (that is, an extended brief intervention). Both aim to help someone reduce their drug use and can be carried out by non-drug specialists.\n\nDependent [on drugs]\n\nA person who is dependent on drugs has a strong desire or sense of compulsion to take a substance, a difficulty in controlling their drug use, a physiological withdrawal state, tolerance of the use of the drug, neglect of alternative pleasures and interests, and persistently uses the drug, despite harm to themselves and others (adapted from the World Health Organization, Lexicon of alcohol and drug terms, 2006).\n\nDigital technology\n\nTechnology that requires the use of a device containing a computer or microcomputer. This includes smartphones, laptops and desktop computers, tablets and other electronic devices. Devices do not have to have internet access to be classed as digital technology, although many do. The term 'digital technology' includes the use of websites and social media, apps on smartphones or tablets, and text-based computer programs. Some types of digital technology may be more commonly used by some age groups than others.\n\nFoster carers\n\nPeople who care for children and young people who are looked after. This includes people who provide long-term care, emergency overnight care and short-term care.\n\nMotivational interviewing\n\nA brief psychotherapeutic intervention. For people who misuse drugs, the aim is to help people reflect on their substance use in the context of their own values and goals and motivate them to change (adapted from The efficacy of single-session motivational interviewing in reducing drug consumption and perceptions of drug-related risk and harm among young people: results from a multi-site cluster randomized trial McCambridge and Strang 2004).\n\nPsychoeducation\n\nEducation sessions for people affected by mental illness and their families and carers. Psychoeducation uses shared learning to empower people to cope better.\n\nSkills training\n\nThe teaching of specific verbal and non-verbal behaviours (including personal and social skills) and the practising of these behaviours by the person receiving the training.\n\nFor other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.\n\nISBN: 978-1-4731-2339-7"}	https://www.nice.org.uk/guidance/ng64	This guideline covers targeted interventions to prevent misuse of drugs, including illegal drugs, ‘legal highs’ and prescription-only medicines. It aims to prevent or delay harmful use of drugs in children, young people and adults who are most likely to start using drugs or who are already experimenting or using drugs occasionally.
8a4b46fa7f634bb789561a00be0d3561cd8d0cca	nice	Everolimus for advanced renal cell carcinoma after previous treatment	Everolimus for advanced renal cell carcinoma after previous treatment Evidence-based recommendations on everolimus (Afinitor) for advanced renal cell carcinoma after previous treatment. # Recommendations Everolimus is recommended within its marketing authorisation as an option for treating advanced renal cell carcinoma that has progressed during or after treatment with vascular endothelial growth factor targeted therapy, only if the company provides it with the discount agreed in the patient access scheme.# The technology Description of the technology Everolimus (Afinitor, Novartis Pharmaceuticals) is an active inhibitor of the mammalian target of rapamycin (mTOR) protein, a central regulator of tumour cell division and blood vessel growth in cancer cells. Marketing authorisation Everolimus has a UK marketing authorisation for 'the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF- targeted therapy'. Adverse reactions Everolimus is contraindicated in people who have hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients. The summary of product characteristics lists the following as special warnings and precautions for everolimus use: non-infectious pneumonitis, localised and systemic infections (including pneumonia, other bacterial infections and invasive fungal infections), hypersensitivity reactions and oral ulcerations. For full details of side effects and contraindications, see the summary of product characteristics. Recommended dose and schedule Everolimus is administered orally. The recommended dosage is 10 mg once daily, and treatment should continue as long as there is clinical benefit or until there are unacceptable adverse events. Management of severe or intolerable adverse events may need dose reduction to a suggested dosage of 5 mg daily or temporary withholding of everolimus. Price The price for a pack of 10‑mg tablets (30 tablets per pack) is £2,673 (excluding VAT; 'British national formulary' online, December 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of everolimus, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Novartis Pharmaceuticals and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the NICE technology appraisal guidance on everolimus for the second-line treatment of advanced renal cell carcinoma. The company submission focused on cost-effectiveness analyses using a revised patient access scheme, which provides a simple discount to the list price of everolimus. The level of the discount is commercial in confidence. See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on everolimus for the second-line treatment of advanced renal cell carcinoma.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of everolimus, having considered evidence on the nature of advanced renal cell carcinoma (RCC) and the value placed on the benefits of everolimus by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness (NICE technology appraisal guidance 219) The committee heard from clinical and patient experts that there are limited treatment options for people with advanced RCC. The committee heard from the clinical and patient experts that advanced RCC is a relatively rare cancer, and noted the views of experts on the severity of the disease. The committee also heard that people having second-line chemotherapy valued the increased life expectancy offered and were prepared to cope with the adverse effects of these treatments. The committee noted the increased frequency of adverse events (including serious adverse events) associated with everolimus treatment in the RECORD‑1 trial. In particular, the committee noted that the most common grade 3 or 4 adverse events suspected to be related to everolimus treatment were anaemia, hyperglycaemia, stomatitis, fatigue, hypercholesterolaemia and dyspnoea. However, the committee was advised by the clinical and patient experts that everolimus would be tolerated by most people with advanced RCC, and that people having everolimus would do so after having had sunitinib as a first-line treatment, and so would be prepared for the adverse effects associated with everolimus. The committee discussed the risk of pneumonitis and immunosuppression associated with everolimus. The clinical expert confirmed that, although pneumonitis and immunosuppression had been associated with everolimus in clinical practice, these adverse events would stop on stopping treatment and were therefore considered manageable. The committee discussed the evidence of clinical effectiveness (from the RECORD‑1 trial) of everolimus in people with advanced RCC whose disease had progressed during, or within 6 months of stopping, vascular endothelial growth factor targeted treatment. The committee noted that most of the trial population had a good performance status. The clinical expert highlighted that, in clinical practice, only people with a good performance status would be considered for second-line therapy because people with a poorer performance status would be too ill to have any active treatment. Therefore, the committee accepted that the trial population was likely to be similar to people considered for second-line therapy in UK clinical practice. The committee also agreed that the RECORD‑1 trial was of good methodological quality and therefore the results could be considered robust. The committee discussed the results of the RECORD‑1 placebo-controlled trial. The committee agreed that the results showed that everolimus plus best supportive care had increased progression-free survival by approximately 3 months compared with placebo plus best supportive care. The committee acknowledged that the relative estimates of overall survival according to the intention-to-treat analyses were biased because 81% of people had crossed over to have everolimus in the trial. The committee heard from the clinical expert that an increase in progression-free survival would be expected to result in an increase in overall survival because gains in overall survival had been seen in clinical practice with the introduction of sequential chemotherapy for advanced RCC. The committee noted the meta-analysis submitted by the manufacturer and accepted that a 1.4‑month increase in overall survival per 1‑month increase in progression-free survival for patients with advanced RCC who had had prior therapy was plausible. The committee agreed that it was appropriate to adjust the intention-to-treat results (which gave a median overall survival estimate of 14.8 months for everolimus plus best supportive care and 14.4 months for best supportive care alone) to control for the crossover using statistical modelling techniques. However, the committee agreed that any estimate of overall survival obtained using statistical modelling would be subject to uncertainty. The committee acknowledged that the manufacturer had updated both the Inverse Probability of Censoring Weight (IPCW) and the Rank Preserving Structural Failure Time (RPSFT) analyses in response to comments received during consultation. The committee noted that the resulting estimates of overall survival were 16.2 and 16.1 months with everolimus plus best supportive care and 9.6 and 7.9 months with best supportive care using the IPCW and RPSFT methods respectively. The differences in overall survival were 6.5 months and 8.2 months respectively. The evidence review group (ERG) conducted exploratory analyses of the manufacturer's estimates derived using the RPSFT method and noted that the estimates of overall survival were 14.1 months with everolimus plus best supportive care and 8.9 months with best supportive care (difference in overall survival of 5.2 months). The committee noted that the overall survival estimates for both everolimus and best supportive care were higher with the ERG's exploratory analyses than the manufacturer's analyses. The committee concluded that, although there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care, the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial. However, the committee accepted that overall survival gain would be more than 3 months. # Cost effectiveness (NICE technology appraisal guidance 219) The committee noted that the key factor in determining the cost effectiveness was the estimate of overall survival and discussed the IPCW and the RPSFT methods used to estimate this from the RECORD‑1 trial data. It heard from the ERG that it considered the RPSFT method to be more methodologically robust because the IPCW method assumes there are no unmeasured confounders. In addition, the committee understood that the manufacturer's revised IPCW analysis contained a number of unexplained differences between the original and revised models, and so the ERG could not conduct a full critique of the revised IPCW analysis. The committee also noted that the RPSFT method had been used previously in NICE's technology appraisal guidance on sunitinib for the treatment of gastrointestinal stromal tumours. The committee therefore concluded that, in this instance, it was more appropriate to evaluate the cost effectiveness of everolimus based on the estimates generated using the RPSFT method. The committee discussed the validity of the estimates of overall survival from the manufacturer's and ERG's RPSFT analyses. The committee noted the ERG's criticism that the manufacturer's extrapolation of long-term survival in the best supportive care arm was still not based on all of the available data (it was based on the mean of cycles 5 and 6 derived from the RPSFT analysis) and that these data may not be representative of the whole trial population. The committee accepted that the use of a Weibull distribution was a more appropriate method for fitting and extrapolating the curve because all available data were used. The committee therefore agreed that this method produced the most plausible estimate of overall survival. The committee accepted for this appraisal that the costs and utilities associated with living in the 'progressed disease' health state were similar in patients having everolimus and patients having best supportive care. It also agreed that the incremental difference in overall survival was a key factor in determining the cost effectiveness. The committee acknowledged comments received that overall survival with best supportive care in the ERG's exploratory analyses using the Weibull distribution (8.9 months) was higher that was seen in clinical practice, and that the estimate in the manufacturer's analysis (7.9 months) was more likely to reflect clinical practice. The committee noted that the difference in overall survival between patients having everolimus and those having best supportive care was 8.2 months in the manufacturer's revised RPSFT analysis and 5.2 months in the ERG's revised RPSFT analysis. It noted the earlier conclusion that an increase in overall survival of 1.4 months per 1 month of increased progression-free survival was plausible. Therefore, the committee agreed that the incremental overall survival derived using the manufacturer's revised RPSFT analysis (8.2 months) was greater than expected, based on the increase in progression-free survival of 3 months seen in the RECORD‑1 trial. The committee accepted that the ERG's estimate of overall survival for patients having best supportive care using the RPSFT analysis was higher than seen in clinical practice, but the incremental difference in overall survival for everolimus versus best supportive care (5.2 months) was more plausible than that derived by the manufacturer and was based on all of the available data. The committee then discussed the manufacturer's updated estimate of cost effectiveness derived using the RPSFT analysis. The revised deterministic base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) for everolimus plus best supportive care compared with best supportive care alone of £49,300 per quality-adjusted life year (QALY) gained. The committee understood that the updated estimate also included a revised patient access scheme that had been agreed with the Department of Health. The committee then discussed the results of the manufacturer's probabilistic sensitivity analysis using the adjusted 95% confidence interval around the hazard ratio for overall survival, which gave a mean ICER of £49,500 per QALY gained. The committee noted that this analysis incorporated confidence intervals for the hazard ratio for overall survival adjusted by the manufacturer, rather than the limits as derived directly from the RPSFT analysis. The committee noted that the lower limit of the 95% confidence interval for the hazard ratio for overall survival (0.27) had been derived from clinical opinion data collected by the manufacturer. The committee noted that these data were from a small sample of clinicians and details about the distribution of values within the dataset had not been provided. The committee therefore agreed that these data were likely to be biased. The committee therefore agreed that it would not consider further the results of this analysis. The committee discussed the ERG's critique of the manufacturer's probabilistic and one-way sensitivity analyses and accepted that the ERG's criticisms of these analyses were valid. The committee noted that the ERG's re-run of the probabilistic sensitivity analysis, which incorporated the 95% confidence interval obtained from the RPSFT analysis, resulted in a mean ICER for everolimus plus best supportive care compared with best supportive care alone of £51,700 per QALY gained. This gave a 24.0% and 52.7% probability of everolimus plus best supportive care being cost effective compared with best supportive care alone if the maximum acceptable amount to pay for an additional QALY gained was £30,000 or £50,000 respectively. The committee concluded that, because of the errors identified in the manufacturer's analysis, the ERG's probabilistic analysis was the most plausible. The committee then discussed other aspects of the manufacturer's model and the critique by the ERG. The committee considered that the time horizon and discounting in the analyses were appropriate. However, the committee had concerns about the validity of some of the assumptions used in the economic model. Firstly, it noted that all patients entered the economic model in the 'stable disease without adverse events' health state. The committee heard from the clinical expert that, in practice, patients eligible for treatment would present with progressed disease and it was likely that some people starting a second-line therapy for advanced RCC experienced adverse events. Secondly, the committee was concerned about the model assumption that the costs of managing associated adverse events would apply for only 1 treatment cycle. However, the committee heard from the clinical expert that adverse events would be managed by 'drug holidays' or dose reduction and therefore treatment of adverse events would not be expected to incur significant ongoing costs. The committee also heard from the clinical expert that the primary ongoing adverse event with everolimus was fatigue, but that this was common to all cancer treatments and there were currently no treatments for its management. Therefore, the committee agreed that the cost estimates used for adverse events in the model were acceptable. The committee noted that the utility estimates in the model were neither directly obtained nor mapped from the RECORD‑1 trial. The committee noted that the estimates of utility for each of the disease states were similar. The committee accepted that a larger decrement in utility may be plausible when a person moves from a 'stable disease' health state to a 'progressed disease' health state. The committee noted comments from the ERG and the results of the one-way sensitivity analyses, which showed changes in utility estimates had little effect on the ICERs. The committee agreed that, although the utility estimates were subject to some uncertainty, the utility assumptions in the economic model were acceptable. The committee was aware of the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust. The committee then discussed whether everolimus as a second-line treatment for advanced RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that in England and Wales the total number of people who would be eligible for treatment with everolimus was less than 4,000. The committee heard from the clinical expert that the life expectancy for people with advanced RCC having best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 5 months. The committee also noted that the evidence from the RPSFT analysis suggested that everolimus increased survival by more than 3 months compared with best supportive care. In summary, the committee was satisfied that everolimus met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust. The committee then discussed whether, in view of the estimates of cost effectiveness, everolimus was an appropriate use of NHS resources for a life-extending, end-of-life treatment. The committee considered 2 key issues: first the central estimate of the ICERs, and second the robustness and certainty of the ICER. It noted that the deterministic ICER of £49,300 per QALY gained was high and close to the range considered acceptable for end-of-life treatments. The committee also noted the wide confidence intervals and uncertainty introduced by the novel methodology used to obtain this ICER. Therefore the committee considered the importance of considering the mean probabilistic ICER of £51,700 per QALY gained from the ERG's exploratory probabilistic sensitivity analysis (incorporating the revised patient access scheme). It noted that this ICER was higher than those considered acceptable for end-of-life treatments to date. The committee noted that the ERG's probabilistic sensitivity analysis had indicated that, if the maximum acceptable amount to pay for an additional QALY gained was £30,000, the probability that everolimus was cost effective compared with best supportive care alone was only 24.0%. It also noted that, if the maximum acceptable amount to pay for an additional QALY gained was £50,000, the probability that everolimus was cost effective compared with best supportive care alone was only 52.7%. The committee concluded that, because the ICERs were subject to considerable uncertainty and were high, the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group was too high for the cost effectiveness of the drug to fall within the range currently considered a cost-effective use of NHS resources. Taking into account both the value of the ICERs and the uncertainty around the ICERs, the committee concluded that it could not recommend everolimus for the second-line treatment of advanced RCC as a cost-effective use of NHS resources. # Equality issues (NICE technology appraisal guidance 219) The committee considered whether there were any subgroups of patients for whom everolimus would be considered a cost-effective use of NHS resources, and whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations in any way. The committee noted that no subgroups of patients had been identified and agreed that that there are no specific equality issues relevant to this appraisal. # Cancer Drugs Fund reconsideration This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on everolimus for the second-line treatment of advanced RCC. Everolimus has been available through the Cancer Drugs Fund. In its revised submission updating its cost-effectiveness analysis, the company: introduced a revised patient access scheme that provides a simple discount to the list price of everolimus (the level of the discount is commercial in confidence) updated unit cost data to 2016 values and presented evidence comparing everolimus with axitinib, based on the updated NICE scope for the Cancer Drugs Fund reconsideration. ## Clinical management The committee recognised that the treatment pathway for advanced RCC has changed since the publication of NICE's original technology appraisal guidance on everolimus. New treatments recommended by NICE are now available: axitinib is recommended as an option after treatment failure with a first-line tyrosine kinase inhibitor or a cytokine. This was reflected in the updated NICE scope for the Cancer Drugs Fund reconsideration. Axitinib and best supportive care were considered to be comparators for everolimus. In addition, nivolumab was recommended for previously treated advanced RCC in adults in November 2016 and can be now used at this place in the pathway. The committee heard from clinical experts that there is still unmet clinical need for some patients with advanced RCC. The committee agreed that everolimus remains a valuable treatment option for people with advanced RCC. No new clinical evidence comparing everolimus with best supportive care was submitted (sections 4.2–4.7 describe the clinical effectiveness in NICE technology appraisal guidance 219). The company presented evidence comparing everolimus and axitinib using matched indirect comparison of RECORD‑1 subgroup of patients who had previously had sunitinib and data from the AXIS trial (comparing axitinib and sorafenib). The median progression-free survival was 5.1 months for everolimus and 4.8 months for axitinib. The company did not do the matched indirect comparison for overall survival as no statistically significant results were reported in the RECORD‑1 and AXIS trials for overall survival. The ERG also identified a published matched indirect comparison with a median progression-free survival of 4.7 months for everolimus and 4.8 months for axitinib. The company suggested that progression-free survival and overall survival for everolimus and axitinib can be considered the same. The ERG agreed that this assumption is plausible. The committee noted the conclusion in the original appraisal that everolimus increased progression-free and overall survival compared with best supportive care (section 4.7). The committee concluded that it was reasonable to assume similar progression-free survival and overall survival for everolimus and axitinib. ## Cost effectiveness The company presented updated cost-effectiveness analyses, which included all committee's preferred assumptions and a revised patient access scheme that provides a simple discount to the list price of everolimus as in everolimus with exemestane for treating advanced breast cancer after endocrine therapy (the level of the discount is commercial in confidence). The updated NICE scope for the Cancer Drugs Fund reconsideration included axitinib and best supportive care as the comparators for everolimus. However, the model compared everolimus with best supportive care only. The resulting ICERs cannot be reported here because they are commercial in confidence. The committee concluded that the most plausible ICER for everolimus compared with best supportive care would be less than £30,000 per QALY gained. The company also provided cost-minimisation analyses comparing everolimus with axitinib. These analyses assumed progression-free survival and overall for everolimus and axitinib to be equivalent and compared the cost of axitinib and everolimus treatments. Similarly, the ERG proposed that, given that progression-free survival and overall survival for everolimus and axitinib can considered to be the same, a cost-minimisation analysis would be an appropriate approach. The committee agreed that cost-minimisation analyses comparing everolimus and axitinib were suitable for its decision-making. In the cost-minimisation analyses, the cost of everolimus treatment was lower than the cost of axitinib treatment. The committee concluded that everolimus compared with axitinib is a cost-effective use of NHS resources for advanced RCC. ## End-of-life considerations The committee noted the conclusion in the original appraisal that the end-of-life criteria for everolimus compared with best supported care had been met (section 4.16); and considered whether this was still the case. The committee was aware that the most plausible ICER for this comparison would be less than £30,000 per QALY gained (section 4.22) and therefore that advice about life-extending treatments for people with a short life expectancy was not needed for the economic analyses. It also noted that the evidence suggesting that everolimus increased survival by more than 3 months compared with best supportive care (section 4.16) had not changed. The committee earlier concluded that similar survival can be assumed for everolimus and axitinib (section 4.21). Overall, the committee considered the end-of-life criteria to be fulfilled but only when everolimus was compared with best supportive care. ## Conclusion Taking into account the cost-effectiveness analyses, including the revised patient access scheme, the committee recommended everolimus as a cost-effective use of NHS resources within its marketing authorisation as an option for treating advanced renal cell carcinoma that has progressed during or after treatment with vascular endothelial growth factor targeted therapy, only if the company provides it with the discount agreed in the patient access scheme. # Summary of Appraisal Committee's key conclusions TA432 Appraisal title: Everolimus for advanced renal cell carcinoma after previous treatment Section Key conclusion (Cancer Drugs Fund reconsideration of TA219) Everolimus is recommended within its marketing authorisation as an option for treating advanced renal cell carcinoma (RCC). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme. The committee understood that, in the company's Cancer Drugs Fund reconsideration submission, it provided an updated cost-effectiveness analysis. The committee concluded everolimus was a cost-effective use of NHS resources. Current practice (TA219) Clinical need of patients including the availability of alternative treatments The committee heard from the clinical and patient experts that advanced RCC is a relatively rare cancer and noted the views of clinical and patient experts on the severity of the disease.The committee also heard that people having second-line chemotherapy valued the increased life expectancy offered and were prepared to cope with the adverse effects of these treatments. The technology (TA219) Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee acknowledged that there are no second-line treatments recommended by NICE for people whose disease has stopped responding to sunitinib and that everolimus could offer an option for the second-line treatment of advanced RCC in people whose disease has progressed on first-line treatment with sunitinib. What is the position of the treatment in the pathway of care for the condition? The committee acknowledged that everolimus could offer an option for the second-line treatment of advanced RCC in people whose disease has progressed on first-line treatment with sunitinib. Adverse events The committee noted the increased frequency of adverse events (including serious adverse events) associated with everolimus treatment in the RECORD‑1 trial. The committee concluded that, although there were adverse events that had been associated with everolimus in clinical practice, these adverse events would stop on stopping treatment and were therefore considered manageable. Evidence for clinical effectiveness (TA219) Availability, nature and quality of evidence The committee agreed that the RECORD‑1 trial was of good methodological quality and therefore the results could be considered robust. The committee agreed that everolimus plus best supportive care had increased progression-free survival by approximately 3 months compared with placebo plus best supportive care. The committee acknowledged that the relative estimates of overall survival according to the intention-to-treat analyses were biased because 81% of people had crossed over to have everolimus in the trial. Therefore, the committee agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques. The committee noted that the resulting estimates of overall survival were 16.2 and 16.1 months with everolimus plus best supportive care and 9.6 and 7.9 months with best supportive care using the Inverse Probability of Censoring Weight (IPCW) and the Rank Preserving Structural Failure Time (RPSFT) methods respectively. The evidence review group (ERG) conducted exploratory analyses of the manufacturer's estimates derived using the RPSFT method and noted that the estimates of overall survival were 14.1 months with everolimus plus best supportive care and 8.9 months with best supportive care. The committee therefore concluded that, although there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care, the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial, but accepted that it would be more than 3 months. Relevance to general clinical practice in the NHS The committee accepted that the trial population was likely to be similar to people considered for second-line therapy in UK clinical practice. Uncertainties generated by the evidence The committee agreed that any estimate of overall survival obtained using statistical modelling would be subject to some uncertainty because a number of assumptions would have to be made. However, the committee concluded that there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care. It noted that the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial, but accepted that it would be more than 3 months. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee did not identify any specific groups of people for whom the technology was considered particularly effective. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care. It noted that the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial, but accepted that it would be more than 3 months. Evidence for cost effectiveness (TA219) Availability and nature of evidence The manufacturer developed a Markov model to assess the cost effectiveness of everolimus plus best supportive care compared with best supportive care alone. The committee noted that the key factor in determining the cost effectiveness was the estimate of overall survival and heard from the ERG that it considered the RPSFT method to be more methodologically robust because the IPCW method assumes there are no unmeasured confounders. In addition, the committee understood that the manufacturer's revised IPCW analysis contained a number of unexplained differences between the original and revised models, and so the ERG could not conduct a full critique of the revised IPCW analysis. The committee therefore concluded that, in this instance, it was more appropriate to evaluate the cost effectiveness of everolimus based on the estimates generated using the RPSFT method. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee acknowledged comments received that overall survival with best supportive care in the ERG's exploratory analyses using the Weibull distribution (8.9 months) was higher than was seen in clinical practice, and that the estimate in the manufacturer's analysis (7.9 months) was more likely to reflect clinical practice. The committee noted that the difference in overall survival between patients having everolimus and those having best supportive care was 8.2 months in the manufacturer's revised RPSFT analysis and 5.2 months in the ERG's revised RPSFT analysis. The committee accepted that the ERG's estimate of overall survival for patients having best supportive care using the RPSFT analysis was higher than seen in clinical practice, but the incremental difference in overall survival for everolimus compared with best supportive care (5.2 months) was more plausible than that derived by the manufacturer, and it was based on all of the available data. The ERG reviewed the manufacturer's updated RPSFT analysis, which incorporated the revised patient access scheme. The ERG was satisfied that the model appropriately incorporated the conditions of the revised scheme. The ERG was also satisfied that the other changes made to the manufacturer's model had been satisfactorily incorporated (adopting the assumptions used in the ERG's RPSFT analysis). The ERG expressed concern that the hazard ratio for overall survival between treatment arms had wide confidence intervals and therefore this was the major source of uncertainty in the model. The committee concluded that, because of the errors identified in the manufacturer's analysis, the ERG's probabilistic analysis was the most plausible. Incorporation of health-related quality of life benefits and utility values The committee noted that the utility estimates in the model were neither directly obtained nor mapped from the RECORD‑1 trial. The committee noted that the estimates of utility for each of the disease states were similar. The committee accepted that a larger decrement in utility may be plausible when a person moves from a 'stable disease' health state to a 'progressed disease' health state. The committee agreed that, although the utility estimates were subject to some uncertainty, the utility assumptions in the economic model were acceptable. Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? No potential health-related benefits have been identified that were not included in the economic model. Are there specific groups of people for whom the technology is particularly cost effective? The committee noted that no subgroups of patients had been identified. What are the key factors in determining cost effectiveness? The committee noted that the key factor in determining the cost effectiveness was the estimate of overall survival. Most likely cost-effectiveness estimate (given as an ICER) The committee considered the deterministic incremental cost-effectiveness ratio (ICER) of £49.300 per quality-adjusted life year (QALY) gained (derived by the manufacturer) and the mean probabilistic ICER of £51,700 per QALY gained (derived by the ERG). Additional factors taken into account (TA219) Patient access scheme The manufacturer agreed a patient access scheme with the Department of Health in which the first treatment pack of everolimus is free to the NHS and following treatment packs cost £2,822 (that is, a 5% discount on the acquisition cost of everolimus). A revised patient access scheme was subsequently agreed, the details of which are confidential. End-of-life considerations The committee concluded that everolimus for advanced RCC met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust. Equalities considerations, social value judgements No equality issues relating to population groups protected by equality legislation were highlighted when the scope for this appraisal was developed, or during the appraisal. Cancer Drugs Fund reconsideration of TA219 Current practice Everolimus remains a valuable treatment option for people with advanced RCC. Evidence for cost effectiveness The committee concluded that the most plausible ICER for everolimus compared with best supportive care would be less than £30,000 per QALY gained including the revised patient access scheme. The committee concluded that everolimus compared with axitinib is a cost-effective use of NHS resources. Additional factors taken into account The committee acknowledged that the Cancer Drugs Fund reconsideration submission included the patient access scheme as in everolimus with exemestane for treating advanced breast cancer after endocrine therapy.	{'Recommendations': 'Everolimus is recommended within its marketing authorisation as an option for treating advanced renal cell carcinoma that has progressed during or after treatment with vascular endothelial growth factor targeted therapy, only if the company provides it with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nEverolimus (Afinitor, Novartis Pharmaceuticals) is an active inhibitor of the mammalian target of rapamycin (mTOR) protein, a central regulator of tumour cell division and blood vessel growth in cancer cells.\n\nMarketing authorisation\n\nEverolimus has a UK marketing authorisation for 'the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF- [vascular endothelial growth factor] targeted therapy'.\n\nAdverse reactions\n\nEverolimus is contraindicated in people who have hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients. The summary of product characteristics lists the following as special warnings and precautions for everolimus use: non-infectious pneumonitis, localised and systemic infections (including pneumonia, other bacterial infections and invasive fungal infections), hypersensitivity reactions and oral ulcerations. For full details of side effects and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nEverolimus is administered orally. The recommended dosage is 10\xa0mg once daily, and treatment should continue as long as there is clinical benefit or until there are unacceptable adverse events. Management of severe or intolerable adverse events may need dose reduction to a suggested dosage of 5\xa0mg daily or temporary withholding of everolimus.\n\nPrice\n\nThe price for a pack of 10‑mg tablets (30\xa0tablets per pack) is £2,673 (excluding VAT; 'British national formulary' [BNF] online, December 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of everolimus, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Novartis Pharmaceuticals and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the NICE technology appraisal guidance on everolimus for the second-line treatment of advanced renal cell carcinoma. The company submission focused on cost-effectiveness analyses using a revised patient access scheme, which provides a simple discount to the list price of everolimus. The level of the discount is commercial in confidence.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on everolimus for the second-line treatment of advanced renal cell carcinoma.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of everolimus, having considered evidence on the nature of advanced renal cell carcinoma (RCC) and the value placed on the benefits of everolimus by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0219)\n\nThe committee heard from clinical and patient experts that there are limited treatment options for people with advanced RCC.\n\nThe committee heard from the clinical and patient experts that advanced RCC is a relatively rare cancer, and noted the views of experts on the severity of the disease. The committee also heard that people having second-line chemotherapy valued the increased life expectancy offered and were prepared to cope with the adverse effects of these treatments. The committee noted the increased frequency of adverse events (including serious adverse events) associated with everolimus treatment in the RECORD‑1 trial. In particular, the committee noted that the most common grade\xa03 or\xa04 adverse events suspected to be related to everolimus treatment were anaemia, hyperglycaemia, stomatitis, fatigue, hypercholesterolaemia and dyspnoea. However, the committee was advised by the clinical and patient experts that everolimus would be tolerated by most people with advanced RCC, and that people having everolimus would do so after having had sunitinib as a first-line treatment, and so would be prepared for the adverse effects associated with everolimus. The committee discussed the risk of pneumonitis and immunosuppression associated with everolimus. The clinical expert confirmed that, although pneumonitis and immunosuppression had been associated with everolimus in clinical practice, these adverse events would stop on stopping treatment and were therefore considered manageable.\n\nThe committee discussed the evidence of clinical effectiveness (from the RECORD‑1 trial) of everolimus in people with advanced RCC whose disease had progressed during, or within 6\xa0months of stopping, vascular endothelial growth factor targeted treatment. The committee noted that most of the trial population had a good performance status. The clinical expert highlighted that, in clinical practice, only people with a good performance status would be considered for second-line therapy because people with a poorer performance status would be too ill to have any active treatment. Therefore, the committee accepted that the trial population was likely to be similar to people considered for second-line therapy in UK clinical practice. The committee also agreed that the RECORD‑1 trial was of good methodological quality and therefore the results could be considered robust.\n\nThe committee discussed the results of the RECORD‑1 placebo-controlled trial. The committee agreed that the results showed that everolimus plus best supportive care had increased progression-free survival by approximately 3\xa0months compared with placebo plus best supportive care. The committee acknowledged that the relative estimates of overall survival according to the intention-to-treat analyses were biased because 81% of people had crossed over to have everolimus in the trial. The committee heard from the clinical expert that an increase in progression-free survival would be expected to result in an increase in overall survival because gains in overall survival had been seen in clinical practice with the introduction of sequential chemotherapy for advanced RCC. The committee noted the meta-analysis submitted by the manufacturer and accepted that a 1.4‑month increase in overall survival per 1‑month increase in progression-free survival for patients with advanced RCC who had had prior therapy was plausible.\n\nThe committee agreed that it was appropriate to adjust the intention-to-treat results (which gave a median overall survival estimate of 14.8\xa0months for everolimus plus best supportive care and 14.4\xa0months for best supportive care alone) to control for the crossover using statistical modelling techniques. However, the committee agreed that any estimate of overall survival obtained using statistical modelling would be subject to uncertainty.\n\nThe committee acknowledged that the manufacturer had updated both the Inverse Probability of Censoring Weight (IPCW) and the Rank Preserving Structural Failure Time (RPSFT) analyses in response to comments received during consultation. The committee noted that the resulting estimates of overall survival were 16.2\xa0and 16.1\xa0months with everolimus plus best supportive care and 9.6\xa0and 7.9\xa0months with best supportive care using the IPCW and RPSFT methods respectively. The differences in overall survival were 6.5\xa0months and 8.2\xa0months respectively. The evidence review group (ERG) conducted exploratory analyses of the manufacturer's estimates derived using the RPSFT method and noted that the estimates of overall survival were 14.1\xa0months with everolimus plus best supportive care and 8.9\xa0months with best supportive care (difference in overall survival of 5.2\xa0months). The committee noted that the overall survival estimates for both everolimus and best supportive care were higher with the ERG's exploratory analyses than the manufacturer's analyses. The committee concluded that, although there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care, the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial. However, the committee accepted that overall survival gain would be more than 3\xa0months.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0219)\n\nThe committee noted that the key factor in determining the cost effectiveness was the estimate of overall survival and discussed the IPCW and the RPSFT methods used to estimate this from the RECORD‑1 trial data. It heard from the ERG that it considered the RPSFT method to be more methodologically robust because the IPCW method assumes there are no unmeasured confounders. In addition, the committee understood that the manufacturer's revised IPCW analysis contained a number of unexplained differences between the original and revised models, and so the ERG could not conduct a full critique of the revised IPCW analysis. The committee also noted that the RPSFT method had been used previously in NICE's technology appraisal guidance on sunitinib for the treatment of gastrointestinal stromal tumours. The committee therefore concluded that, in this instance, it was more appropriate to evaluate the cost effectiveness of everolimus based on the estimates generated using the RPSFT method.\n\nThe committee discussed the validity of the estimates of overall survival from the manufacturer's and ERG's RPSFT analyses. The committee noted the ERG's criticism that the manufacturer's extrapolation of long-term survival in the best supportive care arm was still not based on all of the available data (it was based on the mean of cycles\xa05 and\xa06 derived from the RPSFT analysis) and that these data may not be representative of the whole trial population. The committee accepted that the use of a Weibull distribution was a more appropriate method for fitting and extrapolating the curve because all available data were used. The committee therefore agreed that this method produced the most plausible estimate of overall survival.\n\nThe committee accepted for this appraisal that the costs and utilities associated with living in the 'progressed disease' health state were similar in patients having everolimus and patients having best supportive care. It also agreed that the incremental difference in overall survival was a key factor in determining the cost effectiveness. The committee acknowledged comments received that overall survival with best supportive care in the ERG's exploratory analyses using the Weibull distribution (8.9\xa0months) was higher that was seen in clinical practice, and that the estimate in the manufacturer's analysis (7.9\xa0months) was more likely to reflect clinical practice. The committee noted that the difference in overall survival between patients having everolimus and those having best supportive care was 8.2\xa0months in the manufacturer's revised RPSFT analysis and 5.2\xa0months in the ERG's revised RPSFT analysis. It noted the earlier conclusion that an increase in overall survival of 1.4\xa0months per 1\xa0month of increased progression-free survival was plausible. Therefore, the committee agreed that the incremental overall survival derived using the manufacturer's revised RPSFT analysis (8.2\xa0months) was greater than expected, based on the increase in progression-free survival of 3\xa0months seen in the RECORD‑1 trial. The committee accepted that the ERG's estimate of overall survival for patients having best supportive care using the RPSFT analysis was higher than seen in clinical practice, but the incremental difference in overall survival for everolimus versus best supportive care (5.2\xa0months) was more plausible than that derived by the manufacturer and was based on all of the available data.\n\nThe committee then discussed the manufacturer's updated estimate of cost effectiveness derived using the RPSFT analysis. The revised deterministic base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) for everolimus plus best supportive care compared with best supportive care alone of £49,300 per quality-adjusted life year (QALY) gained. The committee understood that the updated estimate also included a revised patient access scheme that had been agreed with the Department of Health. The committee then discussed the results of the manufacturer's probabilistic sensitivity analysis using the adjusted 95% confidence interval around the hazard ratio for overall survival, which gave a mean ICER of £49,500 per QALY gained. The committee noted that this analysis incorporated confidence intervals for the hazard ratio for overall survival adjusted by the manufacturer, rather than the limits as derived directly from the RPSFT analysis. The committee noted that the lower limit of the 95% confidence interval for the hazard ratio for overall survival (0.27) had been derived from clinical opinion data collected by the manufacturer. The committee noted that these data were from a small sample of clinicians and details about the distribution of values within the dataset had not been provided. The committee therefore agreed that these data were likely to be biased. The committee therefore agreed that it would not consider further the results of this analysis.\n\nThe committee discussed the ERG's critique of the manufacturer's probabilistic and one-way sensitivity analyses and accepted that the ERG's criticisms of these analyses were valid. The committee noted that the ERG's re-run of the probabilistic sensitivity analysis, which incorporated the 95% confidence interval obtained from the RPSFT analysis, resulted in a mean ICER for everolimus plus best supportive care compared with best supportive care alone of £51,700 per QALY gained. This gave a 24.0% and 52.7% probability of everolimus plus best supportive care being cost effective compared with best supportive care alone if the maximum acceptable amount to pay for an additional QALY gained was £30,000 or £50,000 respectively. The committee concluded that, because of the errors identified in the manufacturer's analysis, the ERG's probabilistic analysis was the most plausible.\n\nThe committee then discussed other aspects of the manufacturer's model and the critique by the ERG. The committee considered that the time horizon and discounting in the analyses were appropriate. However, the committee had concerns about the validity of some of the assumptions used in the economic model. Firstly, it noted that all patients entered the economic model in the 'stable disease without adverse events' health state. The committee heard from the clinical expert that, in practice, patients eligible for treatment would present with progressed disease and it was likely that some people starting a second-line therapy for advanced RCC experienced adverse events. Secondly, the committee was concerned about the model assumption that the costs of managing associated adverse events would apply for only 1\xa0treatment cycle. However, the committee heard from the clinical expert that adverse events would be managed by 'drug holidays' or dose reduction and therefore treatment of adverse events would not be expected to incur significant ongoing costs. The committee also heard from the clinical expert that the primary ongoing adverse event with everolimus was fatigue, but that this was common to all cancer treatments and there were currently no treatments for its management. Therefore, the committee agreed that the cost estimates used for adverse events in the model were acceptable.\n\nThe committee noted that the utility estimates in the model were neither directly obtained nor mapped from the RECORD‑1 trial. The committee noted that the estimates of utility for each of the disease states were similar. The committee accepted that a larger decrement in utility may be plausible when a person moves from a 'stable disease' health state to a 'progressed disease' health state. The committee noted comments from the ERG and the results of the one-way sensitivity analyses, which showed changes in utility estimates had little effect on the ICERs. The committee agreed that, although the utility estimates were subject to some uncertainty, the utility assumptions in the economic model were acceptable.\n\nThe committee was aware of the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe committee then discussed whether everolimus as a second-line treatment for advanced RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that in England and Wales the total number of people who would be eligible for treatment with everolimus was less than 4,000. The committee heard from the clinical expert that the life expectancy for people with advanced RCC having best supportive care alone was unlikely to be greater than 24\xa0months and was potentially as low as 5\xa0months. The committee also noted that the evidence from the RPSFT analysis suggested that everolimus increased survival by more than 3\xa0months compared with best supportive care. In summary, the committee was satisfied that everolimus met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.\n\nThe committee then discussed whether, in view of the estimates of cost effectiveness, everolimus was an appropriate use of NHS resources for a life-extending, end-of-life treatment. The committee considered 2\xa0key issues: first the central estimate of the ICERs, and second the robustness and certainty of the ICER. It noted that the deterministic ICER of £49,300 per QALY gained was high and close to the range considered acceptable for end-of-life treatments. The committee also noted the wide confidence intervals and uncertainty introduced by the novel methodology used to obtain this ICER. Therefore the committee considered the importance of considering the mean probabilistic ICER of £51,700 per QALY gained from the ERG's exploratory probabilistic sensitivity analysis (incorporating the revised patient access scheme). It noted that this ICER was higher than those considered acceptable for end-of-life treatments to date. The committee noted that the ERG's probabilistic sensitivity analysis had indicated that, if the maximum acceptable amount to pay for an additional QALY gained was £30,000, the probability that everolimus was cost effective compared with best supportive care alone was only 24.0%. It also noted that, if the maximum acceptable amount to pay for an additional QALY gained was £50,000, the probability that everolimus was cost effective compared with best supportive care alone was only 52.7%. The committee concluded that, because the ICERs were subject to considerable uncertainty and were high, the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group was too high for the cost effectiveness of the drug to fall within the range currently considered a cost-effective use of NHS resources. Taking into account both the value of the ICERs and the uncertainty around the ICERs, the committee concluded that it could not recommend everolimus for the second-line treatment of advanced RCC as a cost-effective use of NHS resources.\n\n# Equality issues (NICE technology appraisal guidance\xa0219)\n\nThe committee considered whether there were any subgroups of patients for whom everolimus would be considered a cost-effective use of NHS resources, and whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations in any way. The committee noted that no subgroups of patients had been identified and agreed that that there are no specific equality issues relevant to this appraisal.\n\n# Cancer Drugs Fund reconsideration\n\nThis appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on everolimus for the second-line treatment of advanced RCC. Everolimus has been available through the Cancer Drugs Fund. In its revised submission updating its cost-effectiveness analysis, the company:\n\nintroduced a revised patient access scheme that provides a simple discount to the list price of everolimus (the level of the discount is commercial in confidence)\n\nupdated unit cost data to 2016 values and\n\npresented evidence comparing everolimus with axitinib, based on the updated NICE scope for the Cancer Drugs Fund reconsideration.\n\n## Clinical management\n\nThe committee recognised that the treatment pathway for advanced RCC has changed since the publication of NICE's original technology appraisal guidance on everolimus. New treatments recommended by NICE are now available: axitinib is recommended as an option after treatment failure with a first-line tyrosine kinase inhibitor or a cytokine. This was reflected in the updated NICE scope for the Cancer Drugs Fund reconsideration. Axitinib and best supportive care were considered to be comparators for everolimus. In addition, nivolumab was recommended for previously treated advanced RCC in adults in November 2016 and can be now used at this place in the pathway. The committee heard from clinical experts that there is still unmet clinical need for some patients with advanced RCC. The committee agreed that everolimus remains a valuable treatment option for people with advanced RCC.\n\nNo new clinical evidence comparing everolimus with best supportive care was submitted (sections\xa04.2–4.7 describe the clinical effectiveness in NICE technology appraisal guidance\xa0219). The company presented evidence comparing everolimus and axitinib using matched indirect comparison of RECORD‑1 subgroup of patients who had previously had sunitinib and data from the AXIS trial (comparing axitinib and sorafenib). The median progression-free survival was 5.1\xa0months for everolimus and 4.8\xa0months for axitinib. The company did not do the matched indirect comparison for overall survival as no statistically significant results were reported in the RECORD‑1 and AXIS trials for overall survival. The ERG also identified a published matched indirect comparison with a median progression-free survival of 4.7\xa0months for everolimus and 4.8\xa0months for axitinib. The company suggested that progression-free survival and overall survival for everolimus and axitinib can be considered the same. The ERG agreed that this assumption is plausible. The committee noted the conclusion in the original appraisal that everolimus increased progression-free and overall survival compared with best supportive care (section\xa04.7). The committee concluded that it was reasonable to assume similar progression-free survival and overall survival for everolimus and axitinib.\n\n## Cost effectiveness\n\nThe company presented updated cost-effectiveness analyses, which included all committee's preferred assumptions and a revised patient access scheme that provides a simple discount to the list price of everolimus as in everolimus with exemestane for treating advanced breast cancer after endocrine therapy (the level of the discount is commercial in confidence). The updated NICE scope for the Cancer Drugs Fund reconsideration included axitinib and best supportive care as the comparators for everolimus. However, the model compared everolimus with best supportive care only. The resulting ICERs cannot be reported here because they are commercial in confidence. The committee concluded that the most plausible ICER for everolimus compared with best supportive care would be less than £30,000 per QALY gained.\n\nThe company also provided cost-minimisation analyses comparing everolimus with axitinib. These analyses assumed progression-free survival and overall for everolimus and axitinib to be equivalent and compared the cost of axitinib and everolimus treatments. Similarly, the ERG proposed that, given that progression-free survival and overall survival for everolimus and axitinib can considered to be the same, a cost-minimisation analysis would be an appropriate approach. The committee agreed that cost-minimisation analyses comparing everolimus and axitinib were suitable for its decision-making. In the cost-minimisation analyses, the cost of everolimus treatment was lower than the cost of axitinib treatment. The committee concluded that everolimus compared with axitinib is a cost-effective use of NHS resources for advanced RCC.\n\n## End-of-life considerations\n\nThe committee noted the conclusion in the original appraisal that the end-of-life criteria for everolimus compared with best supported care had been met (section\xa04.16); and considered whether this was still the case. The committee was aware that the most plausible ICER for this comparison would be less than £30,000 per QALY gained (section\xa04.22) and therefore that advice about life-extending treatments for people with a short life expectancy was not needed for the economic analyses. It also noted that the evidence suggesting that everolimus increased survival by more than 3\xa0months compared with best supportive care (section\xa04.16) had not changed. The committee earlier concluded that similar survival can be assumed for everolimus and axitinib (section\xa04.21). Overall, the committee considered the end-of-life criteria to be fulfilled but only when everolimus was compared with best supportive care.\n\n## Conclusion\n\nTaking into account the cost-effectiveness analyses, including the revised patient access scheme, the committee recommended everolimus as a cost-effective use of NHS resources within its marketing authorisation as an option for treating advanced renal cell carcinoma that has progressed during or after treatment with vascular endothelial growth factor targeted therapy, only if the company provides it with the discount agreed in the patient access scheme.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA432\n\nAppraisal title: Everolimus for advanced renal cell carcinoma after previous treatment\n\nSection\n\nKey conclusion (Cancer Drugs Fund reconsideration of TA219)\n\nEverolimus is recommended within its marketing authorisation as an option for treating advanced renal cell carcinoma (RCC).\n\nThe drug is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\n\n\nThe committee understood that, in the company's Cancer Drugs Fund reconsideration submission, it provided an updated cost-effectiveness analysis. The committee concluded everolimus was a cost-effective use of NHS resources.\n\n\n\n\n\nCurrent practice (TA219)\n\nClinical need of patients including the availability of alternative treatments\n\nThe committee heard from the clinical and patient experts that advanced RCC is a relatively rare cancer and noted the views of clinical and patient experts on the severity of the disease.The committee also heard that people having second-line chemotherapy valued the increased life expectancy offered and were prepared to cope with the adverse effects of these treatments.\n\n\n\nThe technology (TA219)\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee acknowledged that there are no second-line treatments recommended by NICE for people whose disease has stopped responding to sunitinib and that everolimus could offer an option for the second-line treatment of advanced RCC in people whose disease has progressed on first-line treatment with sunitinib.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee acknowledged that everolimus could offer an option for the second-line treatment of advanced RCC in people whose disease has progressed on first-line treatment with sunitinib.\n\n\n\nAdverse events\n\nThe committee noted the increased frequency of adverse events (including serious adverse events) associated with everolimus treatment in the RECORD‑1 trial. The committee concluded that, although there were adverse events that had been associated with everolimus in clinical practice, these adverse events would stop on stopping treatment and were therefore considered manageable.\n\n\n\nEvidence for clinical effectiveness (TA219)\n\nAvailability, nature and quality of evidence\n\nThe committee agreed that the RECORD‑1 trial was of good methodological quality and therefore the results could be considered robust.\n\nThe committee agreed that everolimus plus best supportive care had increased progression-free survival by approximately 3\xa0months compared with placebo plus best supportive care.\n\nThe committee acknowledged that the relative estimates of overall survival according to the intention-to-treat analyses were biased because 81% of people had crossed over to have everolimus in the trial. Therefore, the committee agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques.\n\nThe committee noted that the resulting estimates of overall survival were 16.2\xa0and 16.1\xa0months with everolimus plus best supportive care and 9.6\xa0and 7.9\xa0months with best supportive care using the Inverse Probability of Censoring Weight (IPCW) and the Rank Preserving Structural Failure Time (RPSFT) methods respectively. The evidence review group (ERG) conducted exploratory analyses of the manufacturer's estimates derived using the RPSFT method and noted that the estimates of overall survival were 14.1\xa0months with everolimus plus best supportive care and 8.9\xa0months with best supportive care.\n\nThe committee therefore concluded that, although there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care, the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial, but accepted that it would be more than 3\xa0months.\n\n–4.7\n\nRelevance to general clinical practice in the NHS\n\nThe committee accepted that the trial population was likely to be similar to people considered for second-line therapy in UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee agreed that any estimate of overall survival obtained using statistical modelling would be subject to some uncertainty because a number of assumptions would have to be made.\n\nHowever, the committee concluded that there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care. It noted that the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial, but accepted that it would be more than 3\xa0months.\n\n, 4.7\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee did not identify any specific groups of people for whom the technology was considered particularly effective.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that there was sufficient evidence that everolimus increased progression-free and overall survival compared with best supportive care. It noted that the exact magnitude of the overall survival gain was uncertain because it was based on modelled data as opposed to data directly seen in the trial, but accepted that it would be more than 3\xa0months.\n\n\n\nEvidence for cost effectiveness (TA219)\n\nAvailability and nature of evidence\n\nThe manufacturer developed a Markov model to assess the cost effectiveness of everolimus plus best supportive care compared with best supportive care alone.\n\n\n\nThe committee noted that the key factor in determining the cost effectiveness was the estimate of overall survival and heard from the ERG that it considered the RPSFT method to be more methodologically robust because the IPCW method assumes there are no unmeasured confounders. In addition, the committee understood that the manufacturer's revised IPCW analysis contained a number of unexplained differences between the original and revised models, and so the ERG could not conduct a full critique of the revised IPCW analysis. The committee therefore concluded that, in this instance, it was more appropriate to evaluate the cost effectiveness of everolimus based on the estimates generated using the RPSFT method.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee acknowledged comments received that overall survival with best supportive care in the ERG's exploratory analyses using the Weibull distribution (8.9\xa0months) was higher than was seen in clinical practice, and that the estimate in the manufacturer's analysis (7.9\xa0months) was more likely to reflect clinical practice. The committee noted that the difference in overall survival between patients having everolimus and those having best supportive care was 8.2\xa0months in the manufacturer's revised RPSFT analysis and 5.2\xa0months in the ERG's revised RPSFT analysis. The committee accepted that the ERG's estimate of overall survival for patients having best supportive care using the RPSFT analysis was higher than seen in clinical practice, but the incremental difference in overall survival for everolimus compared with best supportive care (5.2\xa0months) was more plausible than that derived by the manufacturer, and it was based on all of the available data.\n\nThe ERG reviewed the manufacturer's updated RPSFT analysis, which incorporated the revised patient access scheme. The ERG was satisfied that the model appropriately incorporated the conditions of the revised scheme. The ERG was also satisfied that the other changes made to the manufacturer's model had been satisfactorily incorporated (adopting the assumptions used in the ERG's RPSFT analysis). The ERG expressed concern that the hazard ratio for overall survival between treatment arms had wide confidence intervals and therefore this was the major source of uncertainty in the model.\n\nThe committee concluded that, because of the errors identified in the manufacturer's analysis, the ERG's probabilistic analysis was the most plausible.\n\n, 4.9, 4.10, 4.12\n\nIncorporation of health-related quality of life benefits and utility values\n\nThe committee noted that the utility estimates in the model were neither directly obtained nor mapped from the RECORD‑1 trial. The committee noted that the estimates of utility for each of the disease states were similar. The committee accepted that a larger decrement in utility may be plausible when a person moves from a 'stable disease' health state to a 'progressed disease' health state. The committee agreed that, although the utility estimates were subject to some uncertainty, the utility assumptions in the economic model were acceptable.\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo potential health-related benefits have been identified that were not included in the economic model.\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee noted that no subgroups of patients had been identified.\n\n\n\nWhat are the key factors in determining cost effectiveness?\n\nThe committee noted that the key factor in determining the cost effectiveness was the estimate of overall survival.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee considered the deterministic incremental cost-effectiveness ratio (ICER) of £49.300 per quality-adjusted life year (QALY) gained (derived by the manufacturer) and the mean probabilistic ICER of £51,700 per QALY gained (derived by the ERG).\n\n, 4.12\n\nAdditional factors taken into account (TA219)\n\nPatient access scheme\n\nThe manufacturer agreed a patient access scheme with the Department of Health in which the first treatment pack of everolimus is free to the NHS and following treatment packs cost £2,822 (that is, a 5% discount on the acquisition cost of everolimus). A revised patient access scheme was subsequently agreed, the details of which are confidential.\n\n\n\nEnd-of-life considerations\n\nThe committee concluded that everolimus for advanced RCC met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.\n\n\n\nEqualities considerations, social value judgements\n\nNo equality issues relating to population groups protected by equality legislation were highlighted when the scope for this appraisal was developed, or during the appraisal.\n\n\n\nCancer Drugs Fund reconsideration of TA219\n\nCurrent practice\n\nEverolimus remains a valuable treatment option for people with advanced RCC.\n\n\n\nEvidence for cost effectiveness\n\nThe committee concluded that the most plausible ICER for everolimus compared with best supportive care would be less than £30,000 per QALY gained including the revised patient access scheme.\n\n\n\nThe committee concluded that everolimus compared with axitinib is a cost-effective use of NHS resources.\n\n\n\nAdditional factors taken into account\n\nThe committee acknowledged that the Cancer Drugs Fund reconsideration submission included the patient access scheme as in everolimus with exemestane for treating advanced breast cancer after endocrine therapy.\n\n"}	https://www.nice.org.uk/guidance/ta432	Evidence-based recommendations on everolimus (Afinitor) for advanced renal cell carcinoma after previous treatment.
94fad285888a806d7e6f7e8d96f4c9f8962ce856	nice	Apremilast for treating active psoriatic arthritis	Apremilast for treating active psoriatic arthritis Evidence-based recommendations on apremilast (Otezla) for treating active psoriatic arthritis. # Recommendations Apremilast, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is recommended as an option for treating active psoriatic arthritis in adults only if: they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and their disease has not responded to adequate trials of at least 2 standard DMARDs, given either alone or in combination and the company provides apremilast with the discount agreed in the patient access scheme. Stop apremilast at 16 weeks if the psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis response Criteria (PsARC), defined as an improvement in at least 2 of the 4 PsARC criteria (including joint tenderness or swelling score) with no worsening in any criteria. If the disease has a Psoriasis Area and Severity Index (PASI) 75 response, a dermatologist should decide whether to continue treatment with apremilast after 16 weeks based on skin response. When using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate. This guidance is not intended to affect the position of patients whose treatment with apremilast was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Apremilast (Otezla, Celgene) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast down-regulates the inflammatory response by modulating the expression of inflammatory and anti-inflammatory cytokines and mediators associated with psoriatic arthritis (including tumour necrosis factor -alpha and interleukin -23). Marketing authorisation Apremilast 'alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy'. Adverse reactions The summary of product characteristics includes the following adverse reactions for apremilast: gastrointestinal (GI) disorders (most commonly diarrhoea and nausea); upper respiratory tract infections; headache; and tension headache. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Apremilast is an oral tablet. The recommended dosage is 30 mg twice daily after an initial titration schedule. A single 10-mg dose is given on the first day of treatment; this is titrated to 30 mg twice daily over 5 days (see the summary of product characteristics for the dose titration schedule). Price The price of apremilast is £550.00 for a 28-day pack (56×30-mg tablets) (excluding VAT; British National Formulary online, accessed September 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Celgene and a review of this submission by the evidence review group. This appraisal was a rapid review of the published NICE technology appraisal guidance on apremilast for treating psoriatic arthritis (TA372). It focused on cost‑effectiveness analyses using a patient access scheme agreement, which provides apremilast at a reduced cost. The discount is commercial in confidence. See the committee papers for full details of the rapid review evidence, and the history for full details of the evidence used for NICE's original technology appraisal guidance on apremilast for treating psoriatic arthritis. See section 4.24 onwards for the rapid review consideration.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of apremilast, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of apremilast by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical need and practice The committee heard from patient experts about the nature of psoriatic arthritis and their experiences of treatment. It heard that psoriatic arthritis is a lifelong condition that seriously affects people's quality of life. It can develop at a young age and affects all aspects of a person's life including education, work, self-care, and social and family life. The committee heard from the patient expert that skin symptoms can have a major psychological impact, and that joint symptoms can have an even greater impact on the psychological and functional aspects of living with the condition. The committee concluded that psoriatic arthritis substantially decreases quality of life. The committee considered the current treatment pathway for people with psoriatic arthritis. It heard from clinical experts that after taking non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, most people with non-responsive disease will have a tumour necrosis factor (TNF)‑alpha inhibitor, starting with the lowest cost drug as recommended in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. It heard from the clinical experts that use of more than 1 TNF‑alpha inhibitor is established practice in the NHS; if the disease fails to respond or loses response to the first TNF‑alpha inhibitor, or it causes adverse effects, a second TNF‑alpha inhibitor will often be used. The committee considered where apremilast would fit into this existing treatment pathway. It heard from the patient expert that when treatment with a TNF‑alpha inhibitor is contraindicated, or it is stopped because of loss of effectiveness or adverse effects (the clinical experts noted approximately 10% of patients per year stop TNF‑alpha inhibitor treatment), there may be no alternative treatments available. Therefore, patients and clinicians value having a range of treatment options available, and there is an unmet need for treatments that offer a different mechanism of action to the TNF‑alpha inhibitors or that are administered orally, as with apremilast (a PDE4 inhibitor). The committee was aware that apremilast had the same marketing authorisation as the currently recommended biological treatments, but that the company had stated that apremilast would be used before these treatments in clinical practice, based on its oral route of administration, safety profile compared with current biological and conventional DMARD treatments, no specific requirements in the marketing authorisation for regular monitoring, and a cheaper cost compared with current biological therapies. The committee was also aware of a written statement from the clinical expert that apremilast could be considered an alternative first- or second-line drug, because it was likely more effective than methotrexate. However, the written statement from the clinician had noted that placement in the pathway would also depend on treatment cost. The committee heard from the clinical experts that it would be useful to have an additional treatment option before TNF‑alpha inhibitors, because the psoriatic arthritis population is heterogeneous and some people cannot tolerate DMARD therapy, or their disease does not respond adequately to it. The committee concluded that it was possible that apremilast could be used as a treatment before TNF‑alpha inhibitors, but that any use or positioning of apremilast would need to be supported by clinical and cost‑effectiveness evidence, particularly because several effective treatment options are already recommended for psoriatic arthritis. The committee considered the most appropriate comparators for this appraisal. It was aware that in June 2015, NICE published guidance on ustekinumab for treating active psoriatic arthritis which, as an IL12/23 inhibitor, offered a different mechanism of action to the TNF‑alpha inhibitors. However, it accepted that current usage of this drug was likely to be low, both because it had only relatively recently received a positive recommendation, and also because the recommendation is more restrictive than the currently recommended TNF‑alpha inhibitors (ustekinumab is recommended as a treatment option only if treatment with TNF‑alpha inhibitors is contraindicated but would otherwise be considered, or if the person has had treatment with 1 or more TNF‑alpha inhibitors). The committee was also aware that certolizumab pegol (another TNF‑alpha inhibitor) is another possible treatment option for people with psoriatic arthritis; however, it heard from the clinical experts that it is rarely used in clinical practice. The committee concluded that the most appropriate comparators for this appraisal were the TNF‑alpha inhibitors adalimumab, etanercept, infliximab and golimumab (because they have a similar marketing authorisation to apremilast, and are the most commonly used treatments in clinical practice after the failure of a DMARD) and that ustekinumab could be considered as a comparator if it became relevant to consider making a recommendation specifically for a population for whom TNF‑alpha inhibitors are not appropriate. The committee heard from the clinical and patient experts that although methotrexate works well, some people fear the adverse effects associated with it (such as hair loss, nausea and lethargy) and the need for frequent blood tests. The experts stated that apremilast may be better tolerated, although it is associated with a higher incidence of diarrhoea initially compared with some DMARDs such as leflunomide. The clinical experts stated that there is no evidence on whether apremilast is better tolerated than TNF‑alpha inhibitors and that, in general, the TNF‑alpha inhibitors are well tolerated; apremilast is no better or worse than the TNF‑alpha inhibitors, and most patients do not experience unacceptable problems. The clinical experts also suggested that, as with any new treatment, apremilast would need extra monitoring because its long-term adverse events are unknown. The committee was aware of new evidence about the adverse effects of apremilast that the company had submitted in response to the appraisal consultation document, which provided further evidence about the adverse event profile for apremilast. The committee concluded that apremilast has an acceptable adverse event profile in people with active psoriatic arthritis. # Clinical effectiveness The committee considered the evidence presented by the company on the clinical effectiveness of apremilast. It noted that the main sources of evidence were the PSA-002, PSA-003 and PSA-004 trials that compared apremilast (20 mg and 30 mg) with placebo in patients with active psoriatic arthritis (3 or more swollen and tender joints for at least 6 months) that had not responded to treatment with up to 3 DMARDs or 1 TNF‑alpha inhibitor. The committee noted that the trials were well conducted and showed that apremilast is more effective than placebo after 16 weeks of treatment for a number of joint, skin and soft tissue outcomes; the primary outcome was ACR20, with a response experienced by 37% of people having apremilast compared with 19% having placebo (p≤0.0001). The clinical experts noted that apremilast was associated with a similar ACR20 response to methotrexate. The committee acknowledged that in response to the appraisal consultation document the company stated that it considered this opinion to be subjective, because little comparative evidence is available in this area. The committee also noted that apremilast was effective for associated problems such as dactylitis and enthesitis. The committee agreed that apremilast was a clinically effective treatment compared with placebo. The committee considered the more stringent ACR outcomes (ACR50 and ACR70) presented in the apremilast trials. It heard from the clinical experts that although ACR20 is an accepted outcome measure for treatments of psoriatic arthritis and was the primary outcome in the apremilast trials, people may still have painful and swollen joints and that people start to notice a benefit at ARC50 or ACR70. The committee agreed that there was a difference between apremilast and placebo but that the absolute differences were less than those seen for ACR20. The committee considered the evidence from the company's network meta-analysis that compared apremilast with TNF‑alpha inhibitors in the total population, and in the population who had not been treated with TNF‑alpha inhibitors. The committee heard from the evidence review group (ERG) that the methods used to identify both published and unpublished studies for the network meta-analysis were appropriate, and the studies were mostly well reported. The committee discussed the ERG's concerns that the placebo responses for some outcomes were high which made it difficult to compare the relative efficacies of apremilast with the different comparators. The committee noted that the results showed that apremilast had a clinical benefit compared with placebo. However, apremilast demonstrated less clinical benefit than any of the TNF‑alpha inhibitors, in either population. The committee concluded that apremilast is not as clinically effective as the TNF‑alpha inhibitors for treating psoriatic arthritis. The committee considered the HAQ‑DI outcome used by the company to calculate functional capacity and to assess disease progression. It heard from the ERG that there were uncertainties about the results from the apremilast trials because they were not blinded after 24 weeks and there were no stopping rules, which was likely to have influenced the HAQ‑DI results. The committee noted that the company had provided evidence to argue against this in its response to the appraisal consultation document; for example, the company stated that participants remained blinded to initial treatment and dose during the unblinded period. However, the committee remained concerned that, in comparison with more objective measures of disease progression such as radiographic assessments, there was a higher possibility of bias. The committee considered the lack of radiographic assessment in the apremilast trials. It heard from the clinical experts that it would be difficult to justify using apremilast early in the treatment pathway (before TNF‑alpha inhibitors) without evidence that it can prevent radiological progression, because there is evidence to show that TNF‑alpha inhibitors slow disease progression. The committee also heard from the patient experts that they want treatments that can stop the disease from progressing. It noted that the company had stated in its response to the appraisal consultation document that the relationship between radiographic progression and functional capacity was unclear, and that other measures such as disease activity were equally, if not more, important when considering the impact of disease on quality of life. The committee accepted that it may be necessary to interpret radiographic evidence with caution, and that disease activity outcomes play an important role in functional capacity. However, it noted that apremilast not only lacked radiographic evidence about disease progression, but had consistently shown the worst performance of any active comparator for all outcomes presented in the network meta-analyses. Because it is a new treatment, there is a lack of long-term clinical effectiveness data for apremilast. The committee concluded that the lack of radiographic evidence and the clinical-effectiveness evidence did not support the use of apremilast before TNF‑alpha inhibitors in clinical practice. # Cost effectiveness The committee considered the company's revised model which, as in the original base case, compared treatment sequences with and without apremilast, rather than comparing apremilast with a single comparator. This provided a revised base-case incremental cost‑effectiveness ratio (ICER) of approximately £19,500 per quality-adjusted life year (QALY) gained when adding apremilast to a treatment sequence of adalimumab, etanercept, and best supportive care. Apremilast remained cost effective (when assuming a maximum acceptable ICER of £30,000 per QALY gained) in exploratory analyses, including when varying apremilast HAQ-DI progression in relation to best supportive care (£22,700 to £29,100 per QALY gained). The committee accepted that the use of treatment sequences was a valid approach to modelling. The committee considered whether the structural and parameter assumptions in the company's treatment sequences in the revised base case reflected clinical practice. It noted that most analyses by the company compared treatment sequences that had a different number of active comparators before progression to best supportive care, with the base case comparing 3 active treatments for the apremilast group with 2 for the comparator group. The committee agreed that, in clinical practice, patients would likely receive more than the 2 active treatments patients were assumed to receive in the comparator group before they progressed to best supportive care. This was because there are a number of active comparators available for treating psoriatic arthritis, particularly since the positive recommendation for ustekinumab. The committee also considered that models comparing sequences, rather than more traditional direct comparisons, created additional uncertainty in the model. Treatment sequences of different lengths may exacerbate uncertainties in the model, which may also be less easily identifiable, because they are less likely to affect each arm equally than with direct comparisons or equal length sequences. The committee further understood from the assessment group analyses that, assuming all other things were equal, replacing apremilast in the intervention group of the company revised base case with any of the TNF‑alpha inhibitors would result in a QALY gain over the comparator sequence. The committee concluded that in order to prevent the model being confounded by any QALY gain occurring only because of one group in the model having an additional active treatment, in a selected and unrealistically short sequence, it was more informative to make inferences from modelling the same number of active comparators in each treatment sequence. The committee noted that the company had presented a limited exploratory analysis using treatment sequences of equal length in which apremilast was used instead of adalimumab in a sequence of adalimumab, etanercept, golimumab and best supportive care. However, the committee noted that this needed to be seen in the context of the ERG's multiple calculations using sequences with an equal number of active comparators, and also noted that the company considered this scenario to be of limited relevance. The committee also noted that the analyses should be consistent with the direct clinical and cost differences between the TNF‑alpha inhibitors and apremilast. The committee considered the company's assumptions about the improvement and progression of joint symptoms (measured using HAQ‑DI). It noted that these were key drivers of the economic model and that people whose disease continued to respond to treatment at the end of the trial period retained the same HAQ‑DI score (that is, apremilast was assumed to halt HAQ‑DI progression while people remained on treatment, therefore zero HAQ‑DI progression was applied). The committee noted that the company's rationale for assuming that apremilast halts disease progression was based on acceptance in previous NICE appraisals for psoriatic arthritis that TNF‑alpha inhibitors halt disease progression. The committee was aware that the assumption that TNF‑alpha inhibitors halt disease progression was supported radiographically and also by clinical practice evidence over a number of years. However, there was uncertainty about whether this assumption was equally relevant for apremilast, which has a different mechanism of action and limited evidence of use in clinical practice because it is a relatively new treatment. The committee also noted that people who progressed to best supportive care were assumed to experience subsequent natural progression of their disease, resulting in an increase (worsening) in HAQ‑DI score over time of 0.006 every 28 days, up to a maximum score of 3. The committee noted that this score appeared high but heard from the clinical experts that, although it is not possible to know if people would experience a linear progression of disease, the clinical experts considered that the increase in HAQ‑DI over time is likely to be within the same range as that used by the company. The committee heard from the ERG that experience with rheumatoid arthritis shows that HAQ‑DI does not have a linear trajectory; the rate of progression of the disease slows down over time. However, the committee also noted comments from the company in response to the appraisal consultation document that the linearity of HAQ‑DI progression was hypothetical and that the appraisal for ustekinumab for treating active psoriatic arthritis had assumed linear progression. The committee also noted that patients with the best HAQ‑DI responses would be likely to remain in the trials, making the HAQ‑DI appear to improve over time. The committee acknowledged that there is a lack of evidence to inform these model assumptions, and this added uncertainty to the model. However, the assumption that apremilast completely halts HAQ‑DI progression represented a best-case scenario that was not supported by clinical evidence (see sections 4.8, 4.9 and 4.10). The committee considered the use of HAQ‑DI and PASI scores mapped to EQ‑5D to produce utility values of health in the company's original base case. The committee noted that the utility values in the company's revised base case were derived from the apremilast trial. Although this reflected the preferences of the committee as expressed in the appraisal consultation document, the committee noted that this had little impact on results compared with the values used in the original base case. The committee was also surprised at the estimates of utility, which appeared very low and similar to technologies for end of life conditions. However, the committee agreed that the company had used a legitimate source for utility values by using the available trial data, and accepted the utility values for its decision-making. The committee discussed the costs included in the model, particularly the monitoring costs for apremilast treatment. It noted that in response to the appraisal consultation document the company had stated that monitoring costs for apremilast should not be included because there were no specific requirements for screening or regular monitoring, but that it had updated its revised base case to include an equal level of monitoring for all active treatments. The committee heard from the clinical experts that, as with any new drug, apremilast would initially need more monitoring compared with the current standard of care. It therefore concluded that the revised model had correctly accounted for monitoring costs for apremilast. The committee considered the assumption of different trial periods for apremilast (16 weeks) and TNF‑alpha inhibitors (12 weeks) for PsARC responses. The committee heard from the ERG that the use of different time points could favour apremilast and that, if the trial period for TNF‑alpha inhibitors were also increased to 16 weeks, the PsARC responses may increase. The clinical experts agreed that using different trial periods could influence the results. The committee acknowledged that the company had carried out a scenario analysis altering the length of the apremilast trial period to 24 weeks but leaving the TNF‑alpha inhibitor response at 12 weeks. The committee concluded that the longer trial period of apremilast could have given a relatively optimistic case for apremilast compared with other comparators. The committee considered the company's assumptions for placebo responses in the original and revised model. It noted that in the original model, the placebo response rate was discounted from best supportive care, but not from the absolute response rates of apremilast or the TNF‑alpha inhibitors used in the model. However, in the revised base case, the company had included a placebo response for best supportive care. The committee agreed that inclusion of placebo response rates in the model was necessary and accepted this revision to the model. The committee noted that the company's original base case results were based on uncertain assumptions. It appreciated that the company had attempted to address this uncertainty by making several changes in its revised model (including equal levels of monitoring for apremilast and TNF‑alpha inhibitors, a placebo response for best supportive care, and utility values derived from the apremilast trial), and also by presenting several exploratory analyses. However, most ICERs presented by the company were based on treatment sequences with an unequal number of treatments, which was not the committee's preference (see sections 4.11 and 4.19). The committee therefore went on to consider the exploratory analyses presented by the ERG. The committee noted that the ERG had based its analyses on the revised company base case and, therefore, as in the company revised base case, it accounted for several uncertainties in the original base case. Also, the ERG had used the committee's preferred treatment sequences, with an equal number of active comparators before progression to best supportive care, for its exploratory analyses. The committee concluded that the exploratory analyses presented by the ERG were the most appropriate for decision-making. The committee considered the results for apremilast as a treatment before TNF‑alpha inhibitor therapy, using its preferred exploratory analyses from the ERG (see sections 4.11 and 4.17). The committee noted that all the ERG's sequences in which apremilast was the first treatment in a sequence (after DMARDs) resulted in cost savings but also a QALY loss, resulting in ICERs that reflected 'savings per QALY lost'. For example, when comparing a sequence of apremilast, adalimumab, etanercept and best supportive care with adalimumab, etanercept, golimumab, and best supportive care, and when using the committees preferred assumption of some HAQ-DI progression for apremilast (at half the rate of that for best supportive care) there was a cost saving of £6,739 in the apremilast sequence, but a QALY loss of −0.368, resulting in an ICER of £18,300 saved per QALY lost. The committee considered this to be the most plausible scenario because it used its preferred assumptions, and also because the results were consistent with the clinical and cost data; that is, when compared with TNF‑alpha inhibitors, apremilast cost less but was also the least effective active treatment. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The committee was aware that psoriatic arthritis is a chronic and progressive condition, that patients want treatments that stop disease progression (see section 4.10), and that apremilast was the least effective treatment in the company analyses. Taking all of the above into account, the committee agreed that the ICER for apremilast was not high enough to compensate for the clinical effectiveness that would be lost. It therefore concluded that apremilast was not a cost‑effective option compared with TNF‑alpha inhibitors for people with psoriatic arthritis that has responded inadequately to DMARDs. The committee considered whether there was any evidence to consider apremilast as a treatment after TNF‑alpha inhibitor therapy, or for people who could not take TNF‑alpha inhibitors. It noted that evidence in this area was limited. The available clinical effectiveness evidence for apremilast was mostly for a population who had not previously had TNF‑alpha inhibitors. The cost‑effectiveness evidence was limited because the company had rejected this possible positioning of apremilast, even though such comparisons (particularly with ustekinumab) were listed in the final scope issued by NICE. The company had presented 2 direct comparisons of apremilast with best supportive care, and when assuming apremilast HAQ‑DI progression at a rate half that of best supportive care, the ICER for apremilast was £21,700 per QALY gained. The committee noted, however, that the company had not explored the analyses further because it did not consider best supportive care to be an appropriate comparator. Following the publication of ustekinumab for treating active psoriatic arthritis, and given the range of other treatments available for psoriatic arthritis, there are a number of other possible treatments used after TNF‑alpha inhibitors that would be available before best supportive care, and these had not been explored as comparators. The committee also considered the ERG's scenarios for apremilast used after TNF‑alpha inhibitors, which included the committee's preferred model assumption of the same number of active treatments in each sequence. The committee was aware of the ERG's comments about the validity of its exploratory analyses and agreed that as these were the only scenarios presented for apremilast used after TNF‑alpha inhibitors, they should be taken into account in its decision-making. The committee noted that in all the ERG's exploratory analyses the apremilast treatment sequence resulted in cost savings but a QALY loss, resulting in ICERs that reflected 'savings per QALY lost'. For example, a treatment sequence in which apremilast replaced golimumab in a sequence of adalimumab, etanercept, golimumab and best supportive care, assuming HAQ-DI progression at a rate equal to half of best supportive care, resulted in a cost saving of £5,343 and a QALY loss of −0.362, with an ICER of £14,800 saved per QALY lost. The committee agreed that this was the most plausible scenario that had been presented because it used the committee's preferred assumptions about treatment sequences with an equal number of treatments and some HAQ-DI progression for apremilast, the results were consistent with the clinical and cost data (that is, when compared with TNF‑alpha inhibitors, apremilast cost less but was also the least effective active treatment), and also because of the limited evidence presented by the company. The committee agreed that the ICER for apremilast was not high enough to compensate for the clinical effectiveness that would be lost. It therefore concluded that apremilast could not be recommended as a treatment after TNF‑alpha inhibitors. It was unable to make recommendations for its use when people cannot take TNF‑alpha inhibitors, because of a lack of evidence for its use in these circumstances. The committee discussed whether apremilast is considered innovative. It heard from clinical and patient experts that apremilast may provide an additional treatment option for patients, because of its different mode of action and oral formulation. However, given its conclusion on clinical efficacy (see sections 4.6 to 4.8) the committee considered that apremilast was not a step-change in treatment. The committee concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations, and that there was no need to change its conclusions on that basis. The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant for its consideration of the cost effectiveness of any of the technologies in this appraisal. # Rapid review ## Positioning of apremilast The committee noted that the company's rapid review submission had presented a base case for apremilast as a pre-TNF‑alpha inhibitor treatment only, despite the committee previously stating that the clinical evidence did not support the use of apremilast before the more effective TNF‑alpha inhibitors (section 4.10). The committee had also previously accepted that it was possible that in clinical practice, apremilast might be used before TNF‑alpha inhibitors (section 4.3); for example, some patients may prefer an oral treatment and may therefore be willing to accept some reduced effectiveness. However, the committee agreed that any recommendation it made would be on the basis of whether apremilast could be considered a cost‑effective treatment option alongside all other existing treatment options; it was not producing a treatment sequencing guideline. The committee discussed whether the company had presented enough analyses to fully consider the likely impact of apremilast, should it be recommended. It noted that the company had not explored the full treatment pathway in its rapid review submission, with most analyses limited to a maximum of 3 treatments in a sequence. However, the committee appreciated that the company had updated several assumptions in its base case to address committee concerns (for example, the base case now included an equal rather than uneven number of active treatments in each arm), and had also presented several new analyses which contributed to reducing the uncertainties outlined in the previous NICE technology appraisal. These included the addition of direct head-to-head comparisons with several comparators from the scope, scenarios where apremilast was positioned after TNF‑alpha inhibitors, and the addition of the scope comparator ustekinumab. The committee agreed that, in addition to the base case presented, it would have also preferred to see a company base case for apremilast as a post-TNF‑alpha inhibitor treatment. However, it concluded that the company and ERG exploratory analyses helped to reduce uncertainty in the cost‑effectiveness results. ## HAQ-DI The committee was aware that HAQ-DI was a principle uncertainty in the original company model for the previous NICE technology appraisal. It noted and appreciated that although there was a lack of evidence to support the exact value, the company had modelled some HAQ-DI progression for apremilast (at a rate of 50% of best supportive care) in its revised analyses. Both the company and the ERG had also attempted to explore this uncertainty by using different rates of HAQ-DI progression for apremilast, and the committee heard from the company that it now had access to 3-year clinical trial data for apremilast, showing that HAQ-DI had been maintained for patients using apremilast. The committee concluded that the company had taken the correct approach by including some HAQ-DI progression for apremilast in its base case and that, in the absence of more robust evidence, the value used of 50% of the rate of best supportive care was a pragmatic assumption. ## Modelled response to treatment The committee noted that the modelled response to treatment was binary, with modelled patients achieving either response or no response, using PsARC (psoriatic arthritis response criteria, which assesses several joint and skin outcomes). The committee considered whether this binary categorisation would accurately capture response to treatment, which may be more nuanced in clinical practice. It heard from the company that disease progression for psoriatic arthritis is driven by swollen joints. The committee also noted that the company had explored using ACR20 as a measure of response to treatment in its analyses, and this did not have a substantial effect on results. The committee concluded that the modelled response to treatment was imperfect, but appropriate for decision-making. ## Declining effectiveness assumption The committee noted that any TNF‑alpha inhibitor given in a modelled treatment sequence after previous TNF‑alpha inhibitor treatment was assumed to be less effective. The committee heard that the evidence for this was indirect. The committee concluded that although there was uncertainty about the declining effectiveness assumption for TNF‑alpha inhibitors, it was plausible that the effectiveness of a TNF‑alpha inhibitor could be affected by the use of a prior TNF‑alpha inhibitor. The company also highlighted that this assumption did not affect any head-to-head analyses. The committee accepted this assumption for decision-making. ## Most plausible ICERs The committee discussed whether it could identify a most plausible ICER. It noted that the base-case ICER with the apremilast patient access scheme was £39,052 saved per QALY lost. The committee also considered the sensitivity and scenario analyses presented by both the company and the ERG. All showed that, as in the company's base case, using apremilast resulted in cost savings but a QALY loss. All were over £20,000 saved per QALY lost, and most were also over £30,000 saved per QALY lost. The committee agreed that the analyses that produced ICERs of less than £30,000 saved per QALY lost were not the most realistic scenarios. It agreed that the inclusion of the apremilast patient access scheme had increased the cost savings such that they were at a more acceptable level given the QALYs that would be lost. ## Biosimilars The committee was aware that biosimilars for the comparators infliximab and etanercept are now available, and that the company had not included biosimilar infliximab despite it being a comparator in the scope. The committee considered what effect the inclusion of biosimilars could have had on the cost‑effectiveness results. It heard from the ERG that it had done some informal analyses in the context of the company base case (comparing a sequence of apremilast, adalimumab, etanercept and best supportive care with adalimumab, etanercept, golimumab, and best supportive care). Adding biosimilar etanercept to the base case did not substantially change cost‑effectiveness results. Importantly, the committee was also aware that in direct head-to-head comparisons, apremilast demonstrated the highest cost‑effectiveness results when compared with infliximab (the ICER was over £40,000 saved per QALY lost without the apremilast patient access scheme), so although the inclusion of biosimilar infliximab would worsen (that is, lower) the ICER for apremilast, the overall interpretation of the result was likely to be the same. The committee concluded that it would have preferred to have seen the inclusion of biosimilar infliximab, but that the cost‑effectiveness results were still appropriate for decision-making. ## Recommendation The committee agreed that, because apremilast is a less effective treatment than the currently available treatment options (see section 4.8), it was particularly important to consider the possible consequences of a positive recommendation for individual patients. It stated that the addition of apremilast to the existing treatment pathway would mean patients would have access to an additional treatment with a different mechanism of action. Furthermore, the committee agreed that some patients may be willing to accept a certain level of reduced effectiveness because apremilast, unlike the TNF‑alpha inhibitors and ustekinumab, is taken orally. The committee therefore agreed that apremilast could improve patient choice while also offering the opportunity of cost savings for the NHS (with cost savings at a more acceptable level given the QALY gain that would be lost). It concluded that apremilast could be recommended as a cost‑effective use of NHS resources. The committee emphasised that apremilast should be seen as just one option in the context of a range of existing treatment options. The committee was aware that NICE technology appraisal guidance on etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis recommend that the least costly treatment option should be used first. However, the committee agreed that apremilast should not be used based on cost alone, because all clinical-effectiveness results showed it to be the least effective treatment. The committee agreed that the intention of its recommendation was to improve individual patient and clinician choice while also offering the chance of cost savings for the NHS. Apremilast in routine NHS practice should not be a barrier for access to existing treatments; patients and their clinicians should still have the choice of the full range of treatments, including the more expensive and more effective TNF‑alpha inhibitors, if they are more clinically appropriate. The committee concluded that the decision to use apremilast should not be made based on cost alone, and that individual patient factors, including patient needs and preferences, should also be taken into consideration. ## Starting and stopping rules The committee noted several comments from consultation on the appraisal consultation document regarding the apremilast recommendation compared with previous NICE recommendations for TNF‑alpha inhibitors, specifically etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis. There was concern during consultation that inconsistent wording might imply that apremilast should be used at a different point in the pathway to the TNF‑alpha inhibitors, which was not the committee's intention (see section 4.31). The committee therefore went on to discuss aligning the apremilast recommendation to the starting (see section 4.33) and stopping rules (see section 4.34) in previous psoriatic arthritis appraisals. The committee was aware that NICE technology appraisal guidance on etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis included treatment eligibility criteria, outlining that patients should have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints, and to have previously had at least 2 standard DMARDs (administered either individually or in combination). The committee considered whether to add these treatment eligibility criteria to its recommendations for apremilast. It agreed that aligning apremilast recommendation with the recommendations for TNF‑alpha inhibitors would help to avoid any confusion about apremilast's intended position in the treatment pathway. The committee concluded that the treatment eligibility criteria included in the previous appraisals should also be specified in the recommendation for apremilast. The committee noted comments from consultation on the appraisal consultation document that it is important to ensure access to more effective treatments is not delayed after an inadequate response to apremilast. It was aware that NICE technology appraisal guidance on etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis include a stopping rule stating that treatment should be stopped in patients whose disease has not demonstrated an adequate response to treatment at 12 weeks. The committee noted that, for apremilast, the clinical trial data primary outcomes and the company model had measured response to treatment at 16 weeks. The committee concluded that its recommendation should specify that if an adequate response to apremilast is not observed at 16 weeks, treatment with apremilast should be stopped and other treatments considered. # Summary of appraisal committee's key conclusions TA433 Appraisal title: Apremilast for treating active psoriatic arthritis Section Key conclusion Apremilast, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is recommended as an option for treating active psoriatic arthritis in adults only if: they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and their disease has not responded to adequate trials of at least 2 standard DMARDs, given either alone or in combination and the company provides apremilast with the discount agreed in the patient access scheme. Treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis response Criteria (PsARC) at 16 weeks. Apremilast is a clinically effective treatment compared with placebo. Evidence from the company's network meta-analysis that compared apremilast with TNF alpha inhibitors in the total population, and also in people who had not had TNF alpha inhibitors, showed that apremilast was not as clinically effective as the TNF alpha inhibitors for treating psoriatic arthritis. The base-case ICER with the apremilast patient access scheme was £39,052 saved per QALY lost. All exploratory analyses presented by both the company and the ERG also showed that using apremilast resulted in cost savings but a QALY loss. The committee agreed that some patients may be willing to accept a certain level of reduced effectiveness because apremilast, unlike the TNF‑alpha inhibitors and ustekinumab, is administered orally, and that patients would have access to an additional treatment with a different mechanism of action. The choice to use apremilast should not be made based on cost alone, because all clinical effectiveness results showed it to be the least effective treatment. Current practice Clinical need of patients, including the availability of alternative treatments Psoriatic arthritis is a lifelong condition that seriously affects people's quality of life. There is an unmet need for treatments that offer a different mechanism of action to the TNF‑alpha inhibitors or that are administered orally, as with apremilast (a PDE4 inhibitor). The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Apremilast may provide an additional treatment option for patients, because of its different mode of action and oral formulation. However, the committee considered that apremilast was not a step-change in treatment. What is the position of the treatment in the pathway of care for the condition? The committee concluded that it was possible that apremilast could be used as a treatment before TNF‑alpha inhibitors, for example some people may prefer an oral treatment and may therefore be willing to accept some reduced effectiveness, but that any use or positioning of apremilast would need to be supported by clinical- and cost‑effectiveness evidence. Adverse reactions Apremilast has an acceptable adverse event profile in people with active psoriatic arthritis. Evidence for clinical effectiveness Availability, nature and quality of evidence The main sources of evidence were the PSA-002, PSA-003 and PSA-004 trials that compared apremilast (20 mg and 30 mg) with placebo. The methods used to identify both published and unpublished studies for the company's network meta-analysis were appropriate and the studies were mostly well reported. Relevance to general clinical practice in the NHS Treatment with a DMARD such as methotrexate, followed by TNF‑alpha inhibitors in people who can take them, is established practice in the NHS but that there is an unmet need for treatments that have a different mechanism of action to TNF‑alpha inhibitors. Uncertainties generated by the evidence Placebo responses for some outcomes were high, which made it difficult to compare the relative efficacies of apremilast with the different comparators. There were uncertainties about the PSA-002, PSA-003 and PSA-004 results because the trials were not blinded after 24 weeks and there were no stopping rules. The committee also considered the lack of radiographic assessment in the trials. Because it is a new treatment, there is a lack of long-term clinical-effectiveness data for apremilast. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No specific committee consideration. Estimate of the size of the clinical effectiveness including strength of supporting evidence Apremilast is a clinically effective treatment compared with placebo. Evidence from the company's network meta-analysis that compared apremilast with TNF‑alpha inhibitors in the total population, and also in people who had not had TNF‑alpha inhibitors, showed that apremilast was not as clinically effective as the TNF‑alpha inhibitors for treating psoriatic arthritis. Evidence for cost effectiveness Availability and nature of evidence The company base case compared treatment sequences with and without apremilast. The committee accepted that the use of treatment sequences was a valid approach to modelling. Uncertainties around and plausibility of assumptions and inputs in the economic model The company had not explored the full treatment pathway in its rapid review submission, with most analyses limited to a maximum of 3 treatments in a sequence. However, the committee appreciated that the company had updated several assumptions in its base case to address committee concerns, and had also presented several new analyses which contributed to reducing the uncertainties outlined in the previous appraisal of apremilast in this indication. The committee agreed that, in addition to the base case presented, it would have also preferred to see a company base case for apremilast as a post-TNF‑alpha inhibitor treatment. However, it concluded that the company and ERG exploratory analyses helped to reduce uncertainty in the cost‑effectiveness results. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The utility values in the company's revised base case were derived from the apremilast trial. The committee was surprised at the estimates of utility, which appeared very low and similar to technologies for end of life conditions. However, it agreed that the company had used a legitimate source for utility values by using the available trial data, and accepted the utility values for decision-making. The committee did not hear that there were any additional gains in health-related quality of life over those already included in the QALY calculations. Are there specific groups of people for whom the technology is particularly cost effective? No specific committee consideration. What are the key drivers of cost effectiveness? HAQ‑DI was a principle driver of the economic model. Although there was a lack of evidence to support the exact value, the company had modelled some HAQ-DI progression for apremilast (at a rate of 50% of best supportive care) in its revised analyses. Both the company and the ERG had also attempted to explore this uncertainty by using different rates of HAQ-DI progression for apremilast. Most likely cost‑effectiveness estimate (given as an ICER) The base-case ICER with the apremilast patient access scheme was £39,052 saved per QALY lost. The committee also considered the sensitivity and scenario analyses presented by both the company and the ERG. All showed that, as in the company's base case, using apremilast resulted in cost savings but a QALY loss. All company and ERG ICERs were over £20,000 saved per QALY lost. Most company and ERG ICERs were also over £30,000 saved per QALY lost. The committee agreed that the analyses that were under £30,000 saved per QALY lost were not the most realistic scenarios and agreed that the addition of the apremilast patient access scheme had increased the cost savings for apremilast so that they were at a more acceptable level given the QALYs that would be lost. Additional factors taken into account Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast. The level of the discount is commercial in confidence. End-of-life considerations Not applicable. Equalities considerations and social value judgements Not applicable.	{'Recommendations': "Apremilast, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is recommended as an option for treating active psoriatic arthritis in adults only if:\n\nthey have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and\n\ntheir disease has not responded to adequate trials of at least 2 standard DMARDs, given either alone or in combination and\n\nthe company provides apremilast with the discount agreed in the patient access scheme.\n\nStop apremilast at 16\xa0weeks if the psoriatic arthritis has not shown an adequate\xa0response using the Psoriatic Arthritis\xa0response Criteria (PsARC), defined as an improvement in at least 2 of the 4 PsARC criteria (including joint tenderness or swelling score) with no worsening in any criteria. If the disease has a Psoriasis Area and Severity Index (PASI) 75\xa0response, a dermatologist should decide whether to continue treatment with apremilast after 16\xa0weeks based on skin\xa0response.\n\nWhen using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's\xa0responses to components of the PsARC and make any adjustments they consider appropriate.\n\nThis guidance is not intended to affect the position of patients whose treatment with apremilast was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.", 'The technology': "Description of the technology\n\nApremilast (Otezla, Celgene) is a small-molecule\xa0inhibitor of phosphodiesterase 4 (PDE4). Apremilast down-regulates the inflammatory\xa0response by modulating the expression of inflammatory and anti-inflammatory cytokines and mediators associated with psoriatic arthritis (including tumour necrosis factor [TNF]-alpha and interleukin [IL]-23).\n\nMarketing authorisation\n\nApremilast 'alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate\xa0response or who have been intolerant to a prior DMARD therapy'.\n\nAdverse reactions\n\nThe summary of product characteristics includes the following adverse reactions for apremilast: gastrointestinal (GI) disorders (most commonly diarrhoea and nausea); upper respiratory tract infections; headache; and tension headache. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nApremilast is an oral tablet. The recommended dosage is 30\xa0mg twice daily after an initial titration schedule. A single 10-mg dose is given on the first day of treatment; this is titrated to 30\xa0mg twice daily over 5\xa0days (see the summary of product characteristics for the dose titration schedule).\n\nPrice\n\nThe price of apremilast is £550.00 for a 28-day pack (56×30-mg tablets) (excluding VAT; British National Formulary online, accessed September 2016).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Celgene and a review of this submission by the evidence review group. This appraisal was a rapid review of the published NICE technology appraisal guidance on apremilast for treating psoriatic arthritis (TA372). It focused on cost‑effectiveness analyses using a patient access scheme agreement, which provides apremilast at a reduced cost. The discount is commercial in confidence. See the committee papers for full details of the rapid review evidence, and the history for full details of the evidence used for NICE's original technology appraisal guidance on apremilast for treating psoriatic arthritis. See section\xa04.24 onwards for the rapid review consideration.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of apremilast, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of apremilast by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and practice\n\nThe committee heard from patient experts about the nature of psoriatic arthritis and their experiences of treatment. It heard that psoriatic arthritis is a lifelong condition that seriously affects people's quality of life. It can develop at a young age and affects all aspects of a person's life including education, work, self-care, and social and family life. The committee heard from the patient expert that skin symptoms can have a major psychological impact, and that joint symptoms can have an even greater impact on the psychological and functional aspects of living with the condition. The committee concluded that psoriatic arthritis substantially decreases quality of life.\n\nThe committee considered the current treatment pathway for people with psoriatic arthritis. It heard from clinical experts that after taking non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, most people with non-responsive disease will have a tumour necrosis factor (TNF)‑alpha\xa0inhibitor, starting with the lowest cost drug as recommended in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis and golimumab for the treatment of psoriatic arthritis. It heard from the clinical experts that use of more than 1\xa0TNF‑alpha inhibitor is established practice in the NHS; if the disease fails to respond or loses\xa0response to the first TNF‑alpha inhibitor, or it causes adverse effects, a second TNF‑alpha inhibitor will often be used. The committee considered where apremilast would fit into this existing treatment pathway. It heard from the patient expert that when treatment with a TNF‑alpha inhibitor is contraindicated, or it is stopped because of loss of effectiveness or adverse effects (the clinical experts noted approximately 10% of patients per year stop TNF‑alpha inhibitor treatment), there may be no alternative treatments available. Therefore, patients and clinicians value having a range of treatment options available, and there is an unmet need for treatments that offer a different mechanism of action to the TNF‑alpha inhibitors or that are administered orally, as with apremilast (a PDE4\xa0inhibitor).\n\nThe committee was aware that apremilast had the same marketing authorisation as the currently recommended biological treatments, but that the company had stated that apremilast would be used before these treatments in clinical practice, based on its oral route of administration, safety profile compared with current biological and conventional DMARD treatments, no specific requirements in the marketing authorisation for regular monitoring, and a cheaper cost compared with current biological therapies. The committee was also aware of a written statement from the clinical expert that apremilast could be considered an alternative first- or second-line drug, because it was likely more effective than methotrexate. However, the written statement from the clinician had noted that placement in the pathway would also depend on treatment cost. The committee heard from the clinical experts that it would be useful to have an additional treatment option before TNF‑alpha inhibitors, because the psoriatic arthritis population is heterogeneous and some people cannot tolerate DMARD therapy, or their disease does not respond adequately to it. The committee concluded that it was possible that apremilast could be used as a treatment before TNF‑alpha inhibitors, but that any use or positioning of apremilast would need to be supported by clinical and cost‑effectiveness evidence, particularly because several effective treatment options are already recommended for psoriatic arthritis.\n\nThe committee considered the most appropriate comparators for this appraisal. It was aware that in June 2015, NICE published guidance on ustekinumab for treating active psoriatic arthritis which, as an IL12/23\xa0inhibitor, offered a different mechanism of action to the TNF‑alpha inhibitors. However, it accepted that current usage of this drug was likely to be low, both because it had only relatively recently received a positive recommendation, and also because the recommendation is more restrictive than the currently recommended TNF‑alpha inhibitors (ustekinumab is recommended as a treatment option only if treatment with TNF‑alpha inhibitors is contraindicated but would otherwise be considered, or if the person has had treatment with 1 or more TNF‑alpha inhibitors). The committee was also aware that certolizumab pegol (another TNF‑alpha inhibitor) is another possible treatment option for people with psoriatic arthritis; however, it heard from the clinical experts that it is rarely used in clinical practice. The committee concluded that the most appropriate comparators for this appraisal were the TNF‑alpha inhibitors adalimumab, etanercept, infliximab and golimumab (because they have a similar marketing authorisation to apremilast, and are the most commonly used treatments in clinical practice after the failure of a DMARD) and that ustekinumab could be considered as a comparator if it became relevant to consider making a recommendation specifically for a population for whom TNF‑alpha inhibitors are not appropriate.\n\nThe committee heard from the clinical and patient experts that although methotrexate works well, some people fear the adverse effects associated with it (such as hair loss, nausea and lethargy) and the need for frequent blood tests. The experts stated that apremilast may be better tolerated, although it is associated with a higher incidence of diarrhoea initially compared with some DMARDs such as leflunomide. The clinical experts stated that there is no evidence on whether apremilast is better tolerated than TNF‑alpha inhibitors and that, in general, the TNF‑alpha inhibitors are well tolerated; apremilast is no better or worse than the TNF‑alpha inhibitors, and most patients do not experience unacceptable problems. The clinical experts also suggested that, as with any new treatment, apremilast would need extra monitoring because its long-term adverse events are unknown. The committee was aware of new evidence about the adverse effects of apremilast that the company had submitted in\xa0response to the appraisal consultation document, which provided further evidence about the adverse event profile for apremilast. The committee concluded that apremilast has an acceptable adverse event profile in people with active psoriatic arthritis.\n\n# Clinical effectiveness\n\nThe committee considered the evidence presented by the company on the clinical effectiveness of apremilast. It noted that the main sources of evidence were the PSA-002, PSA-003 and PSA-004 trials that compared apremilast (20\xa0mg and 30\xa0mg) with placebo in patients with active psoriatic arthritis (3 or more swollen and tender joints for at least 6\xa0months) that had not responded to treatment with up to 3\xa0DMARDs or 1\xa0TNF‑alpha inhibitor. The committee noted that the trials were well conducted and showed that apremilast is more effective than placebo after 16\xa0weeks of treatment for a number of joint, skin and soft tissue outcomes; the primary outcome was ACR20, with a\xa0response experienced by 37% of people having apremilast compared with 19% having placebo (p≤0.0001). The clinical experts noted that apremilast was associated with a similar ACR20\xa0response to methotrexate. The committee acknowledged that in\xa0response to the appraisal consultation document the company stated that it considered this opinion to be subjective, because little comparative evidence is available in this area. The committee also noted that apremilast was effective for associated problems such as dactylitis and enthesitis. The committee agreed that apremilast was a clinically effective treatment compared with placebo.\n\nThe committee considered the more stringent ACR outcomes (ACR50 and ACR70) presented in the apremilast trials. It heard from the clinical experts that although ACR20 is an accepted outcome measure for treatments of psoriatic arthritis and was the primary outcome in the apremilast trials, people may still have painful and swollen joints and that people start to notice a benefit at ARC50 or ACR70. The committee agreed that there was a difference between apremilast and placebo but that the absolute differences were less than those seen for ACR20.\n\nThe committee considered the evidence from the company's network meta-analysis that compared apremilast with TNF‑alpha inhibitors in the total population, and in the population who had not been treated with TNF‑alpha inhibitors. The committee heard from the evidence review group (ERG) that the methods used to identify both published and unpublished studies for the network meta-analysis were appropriate, and the studies were mostly well reported. The committee discussed the ERG's concerns that the placebo\xa0responses for some outcomes were high which made it difficult to compare the relative efficacies of apremilast with the different comparators. The committee noted that the results showed that apremilast had a clinical benefit compared with placebo. However, apremilast demonstrated less clinical benefit than any of the TNF‑alpha inhibitors, in either population. The committee concluded that apremilast is not as clinically effective as the TNF‑alpha inhibitors for treating psoriatic arthritis.\n\nThe committee considered the HAQ‑DI outcome used by the company to calculate functional capacity and to assess disease progression. It heard from the ERG that there were uncertainties about the results from the apremilast trials because they were not blinded after 24\xa0weeks and there were no stopping rules, which was likely to have influenced the HAQ‑DI results. The committee noted that the company had provided evidence to argue against this in its\xa0response to the appraisal consultation document; for example, the company stated that participants remained blinded to initial treatment and dose during the unblinded period. However, the committee remained concerned that, in comparison with more objective measures of disease progression such as radiographic assessments, there was a higher possibility of bias.\n\nThe committee considered the lack of radiographic assessment in the apremilast trials. It heard from the clinical experts that it would be difficult to justify using apremilast early in the treatment pathway (before TNF‑alpha inhibitors) without evidence that it can prevent radiological progression, because there is evidence to show that TNF‑alpha inhibitors slow disease progression. The committee also heard from the patient experts that they want treatments that can stop the disease from progressing. It noted that the company had stated in its\xa0response to the appraisal consultation document that the relationship between radiographic progression and functional capacity was unclear, and that other measures such as disease activity were equally, if not more, important when considering the impact of disease on quality of life. The committee accepted that it may be necessary to interpret radiographic evidence with caution, and that disease activity outcomes play an important role in functional capacity. However, it noted that apremilast not only lacked radiographic evidence about disease progression, but had consistently shown the worst performance of any active comparator for all outcomes presented in the network meta-analyses. Because it is a new treatment, there is a lack of long-term clinical effectiveness data for apremilast. The committee concluded that the lack of radiographic evidence and the clinical-effectiveness evidence did not support the use of apremilast before TNF‑alpha inhibitors in clinical practice.\n\n# Cost effectiveness\n\nThe committee considered the company's revised model which, as in the original base case, compared treatment sequences with and without apremilast, rather than comparing apremilast with a single comparator. This provided a revised base-case incremental cost‑effectiveness ratio (ICER) of approximately £19,500 per quality-adjusted life year (QALY) gained when adding apremilast to a treatment sequence of adalimumab, etanercept, and best supportive care. Apremilast remained cost effective (when assuming a maximum acceptable ICER of £30,000 per QALY gained) in exploratory analyses, including when varying apremilast HAQ-DI progression in relation to best supportive care (£22,700 to £29,100 per QALY gained). The committee accepted that the use of treatment sequences was a valid approach to modelling.\n\nThe committee considered whether the structural and parameter assumptions in the company's treatment sequences in the revised base case reflected clinical practice. It noted that most analyses by the company compared treatment sequences that had a different number of active comparators before progression to best supportive care, with the base case comparing 3\xa0active treatments for the apremilast group with 2 for the comparator group. The committee agreed that, in clinical practice, patients would likely receive more than the 2 active treatments patients were assumed to receive in the comparator group before they progressed to best supportive care. This was because there are a number of active comparators available for treating psoriatic arthritis, particularly since the positive recommendation for ustekinumab. The committee also considered that models comparing sequences, rather than more traditional direct comparisons, created additional uncertainty in the model. Treatment sequences of different lengths may exacerbate uncertainties in the model, which may also be less easily identifiable, because they are less likely to affect each arm equally than with direct comparisons or equal length sequences. The committee further understood from the assessment group analyses that, assuming all other things were equal, replacing apremilast in the intervention group of the company revised base case with any of the TNF‑alpha inhibitors would result in a QALY gain over the comparator sequence. The committee concluded that in order to prevent the model being confounded by any QALY gain occurring only because of one group in the model having an additional active treatment, in a selected and unrealistically short sequence, it was more informative to make inferences from modelling the same number of active comparators in each treatment sequence.\n\nThe committee noted that the company had presented a limited exploratory analysis using treatment sequences of equal length in which apremilast was used instead of adalimumab in a sequence of adalimumab, etanercept, golimumab and best supportive care. However, the committee noted that this needed to be seen in the context of the ERG's multiple calculations using sequences with an equal number of active comparators, and also noted that the company considered this scenario to be of limited relevance. The committee also noted that the analyses should be consistent with the direct clinical and cost differences between the TNF‑alpha inhibitors and apremilast.\n\nThe committee considered the company's assumptions about the improvement and progression of joint symptoms (measured using HAQ‑DI). It noted that these were key drivers of the economic model and that people whose disease continued to respond to treatment at the end of the trial period retained the same HAQ‑DI score (that is, apremilast was assumed to halt HAQ‑DI progression while people remained on treatment, therefore zero HAQ‑DI progression was applied). The committee noted that the company's rationale for assuming that apremilast halts disease progression was based on acceptance in previous NICE appraisals for psoriatic arthritis that TNF‑alpha inhibitors halt disease progression. The committee was aware that the assumption that TNF‑alpha inhibitors halt disease progression was supported radiographically and also by clinical practice evidence over a number of years. However, there was uncertainty about whether this assumption was equally relevant for apremilast, which has a different mechanism of action and limited evidence of use in clinical practice because it is a relatively new treatment. The committee also noted that people who progressed to best supportive care were assumed to experience subsequent natural progression of their disease, resulting in an increase (worsening) in HAQ‑DI score over time of 0.006 every 28\xa0days, up to a maximum score of\xa03. The committee noted that this score appeared high but heard from the clinical experts that, although it is not possible to know if people would experience a linear progression of disease, the clinical experts considered that the increase in HAQ‑DI over time is likely to be within the same range as that used by the company. The committee heard from the ERG that experience with rheumatoid arthritis shows that HAQ‑DI does not have a linear trajectory; the rate of progression of the disease slows down over time. However, the committee also noted comments from the company in\xa0response to the appraisal consultation document that the linearity of HAQ‑DI progression was hypothetical and that the appraisal for ustekinumab for treating active psoriatic arthritis had assumed linear progression. The committee also noted that patients with the best HAQ‑DI\xa0responses would be likely to remain in the trials, making the HAQ‑DI appear to improve over time. The committee acknowledged that there is a lack of evidence to inform these model assumptions, and this added uncertainty to the model. However, the assumption that apremilast completely halts HAQ‑DI progression represented a best-case scenario that was not supported by clinical evidence (see sections\xa04.8, 4.9 and 4.10).\n\nThe committee considered the use of HAQ‑DI and PASI scores mapped to EQ‑5D to produce utility values of health in the company's original base case. The committee noted that the utility values in the company's revised base case were derived from the apremilast trial. Although this reflected the preferences of the committee as expressed in the appraisal consultation document, the committee noted that this had little impact on results compared with the values used in the original base case. The committee was also surprised at the estimates of utility, which appeared very low and similar to technologies for end of life conditions. However, the committee agreed that the company had used a legitimate source for utility values by using the available trial data, and accepted the utility values for its decision-making.\n\nThe committee discussed the costs included in the model, particularly the monitoring costs for apremilast treatment. It noted that in\xa0response to the appraisal consultation document the company had stated that monitoring costs for apremilast should not be included because there were no specific requirements for screening or regular monitoring, but that it had updated its revised base case to include an equal level of monitoring for all active treatments. The committee heard from the clinical experts that, as with any new drug, apremilast would initially need more monitoring compared with the current standard of care. It therefore concluded that the revised model had correctly accounted for monitoring costs for apremilast.\n\nThe committee considered the assumption of different trial periods for apremilast (16\xa0weeks) and TNF‑alpha inhibitors (12\xa0weeks) for PsARC\xa0responses. The committee heard from the ERG that the use of different time points could favour apremilast and that, if the trial period for TNF‑alpha inhibitors were also increased to 16\xa0weeks, the PsARC\xa0responses may increase. The clinical experts agreed that using different trial periods could influence the results. The committee acknowledged that the company had carried out a scenario analysis altering the length of the apremilast trial period to 24\xa0weeks but leaving the TNF‑alpha inhibitor\xa0response at 12\xa0weeks. The committee concluded that the longer trial period of apremilast could have given a relatively optimistic case for apremilast compared with other comparators.\n\nThe committee considered the company's assumptions for placebo\xa0responses in the original and revised model. It noted that in the original model, the placebo\xa0response rate was discounted from best supportive care, but not from the absolute\xa0response rates of apremilast or the TNF‑alpha inhibitors used in the model. However, in the revised base case, the company had included a placebo\xa0response for best supportive care. The committee agreed that inclusion of placebo\xa0response rates in the model was necessary and accepted this revision to the model.\n\nThe committee noted that the company's original base case results were based on uncertain assumptions. It appreciated that the company had attempted to address this uncertainty by making several changes in its revised model (including equal levels of monitoring for apremilast and TNF‑alpha inhibitors, a placebo\xa0response for best supportive care, and utility values derived from the apremilast trial), and also by presenting several exploratory analyses. However, most ICERs presented by the company were based on treatment sequences with an unequal number of treatments, which was not the committee's preference (see sections\xa04.11 and 4.19). The committee therefore went on to consider the exploratory analyses presented by the ERG. The committee noted that the ERG had based its analyses on the revised company base case and, therefore, as in the company revised base case, it accounted for several uncertainties in the original base case. Also, the ERG had used the committee's preferred treatment sequences, with an equal number of active comparators before progression to best supportive care, for its exploratory analyses. The committee concluded that the exploratory analyses presented by the ERG were the most appropriate for decision-making.\n\nThe committee considered the results for apremilast as a treatment before TNF‑alpha inhibitor therapy, using its preferred exploratory analyses from the ERG (see sections\xa04.11 and 4.17). The committee noted that all the ERG's sequences in which apremilast was the first treatment in a sequence (after DMARDs) resulted in cost savings but also a QALY loss, resulting in ICERs that reflected 'savings per QALY lost'. For example, when comparing a sequence of apremilast, adalimumab, etanercept and best supportive care with adalimumab, etanercept, golimumab, and best supportive care, and when using the committees preferred assumption of some HAQ-DI progression for apremilast (at half the rate of that for best supportive care) there was a cost saving of £6,739 in the apremilast sequence, but a QALY loss of −0.368, resulting in an ICER of £18,300 saved per QALY lost. The committee considered this to be the most plausible scenario because it used its preferred assumptions, and also because the results were consistent with the clinical and cost data; that is, when compared with TNF‑alpha inhibitors, apremilast cost less but was also the least effective active treatment. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The committee was aware that psoriatic arthritis is a chronic and progressive condition, that patients want treatments that stop disease progression (see section\xa04.10), and that apremilast was the least effective treatment in the company analyses. Taking all of the above into account, the committee agreed that the ICER for apremilast was not high enough to compensate for the clinical effectiveness that would be lost. It therefore concluded that apremilast was not a cost‑effective option compared with TNF‑alpha inhibitors for people with psoriatic arthritis that has responded inadequately to DMARDs.\n\nThe committee considered whether there was any evidence to consider apremilast as a treatment after TNF‑alpha inhibitor therapy, or for people who could not take TNF‑alpha inhibitors. It noted that evidence in this area was limited. The available clinical effectiveness evidence for apremilast was mostly for a population who had not previously had TNF‑alpha inhibitors. The cost‑effectiveness evidence was limited because the company had rejected this possible positioning of apremilast, even though such comparisons (particularly with ustekinumab) were listed in the final scope issued by NICE. The company had presented 2 direct comparisons of apremilast with best supportive care, and when assuming apremilast HAQ‑DI progression at a rate half that of best supportive care, the ICER for apremilast was £21,700 per QALY gained. The committee noted, however, that the company had not explored the analyses further because it did not consider best supportive care to be an appropriate comparator. Following the publication of ustekinumab for treating active psoriatic arthritis, and given the range of other treatments available for psoriatic arthritis, there are a number of other possible treatments used after TNF‑alpha inhibitors that would be available before best supportive care, and these had not been explored as comparators. The committee also considered the ERG's scenarios for apremilast used after TNF‑alpha inhibitors, which included the committee's preferred model assumption of the same number of active treatments in each sequence. The committee was aware of the ERG's comments about the validity of its exploratory analyses and agreed that as these were the only scenarios presented for apremilast used after TNF‑alpha inhibitors, they should be taken into account in its decision-making. The committee noted that in all the ERG's exploratory analyses the apremilast treatment sequence resulted in cost savings but a QALY loss, resulting in ICERs that reflected 'savings per QALY lost'. For example, a treatment sequence in which apremilast replaced golimumab in a sequence of adalimumab, etanercept, golimumab and best supportive care, assuming HAQ-DI progression at a rate equal to half of best supportive care, resulted in a cost saving of £5,343 and a QALY loss of −0.362, with an ICER of £14,800 saved per QALY lost. The committee agreed that this was the most plausible scenario that had been presented because it used the committee's preferred assumptions about treatment sequences with an equal number of treatments and some HAQ-DI progression for apremilast, the results were consistent with the clinical and cost data (that is, when compared with TNF‑alpha inhibitors, apremilast cost less but was also the least effective active treatment), and also because of the limited evidence presented by the company. The committee agreed that the ICER for apremilast was not high enough to compensate for the clinical effectiveness that would be lost. It therefore concluded that apremilast could not be recommended as a treatment after TNF‑alpha inhibitors. It was unable to make recommendations for its use when people cannot take TNF‑alpha inhibitors, because of a lack of evidence for its use in these circumstances.\n\nThe committee discussed whether apremilast is considered innovative. It heard from clinical and patient experts that apremilast may provide an additional treatment option for patients, because of its different mode of action and oral formulation. However, given its conclusion on clinical efficacy (see sections\xa04.6 to 4.8) the committee considered that apremilast was not a step-change in treatment. The committee concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations, and that there was no need to change its conclusions on that basis.\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant for its consideration of the cost effectiveness of any of the technologies in this appraisal.\n\n# Rapid review\n\n## Positioning of apremilast\n\nThe committee noted that the company's rapid review submission had presented a base case for apremilast as a pre-TNF‑alpha inhibitor treatment only, despite the committee previously stating that the clinical evidence did not support the use of apremilast before the more effective TNF‑alpha inhibitors (section\xa04.10). The committee had also previously accepted that it was possible that in clinical practice, apremilast might be used before TNF‑alpha inhibitors (section\xa04.3); for example, some patients may prefer an oral treatment and may therefore be willing to accept some reduced effectiveness. However, the committee agreed that any recommendation it made would be on the basis of whether apremilast could be considered a cost‑effective treatment option alongside all other existing treatment options; it was not producing a treatment sequencing guideline. The committee discussed whether the company had presented enough analyses to fully consider the likely impact of apremilast, should it be recommended. It noted that the company had not explored the full treatment pathway in its rapid review submission, with most analyses limited to a maximum of 3 treatments in a sequence. However, the committee appreciated that the company had updated several assumptions in its base case to address committee concerns (for example, the base case now included an equal rather than uneven number of active treatments in each arm), and had also presented several new analyses which contributed to reducing the uncertainties outlined in the previous NICE technology appraisal. These included the addition of direct head-to-head comparisons with several comparators from the scope, scenarios where apremilast was positioned after TNF‑alpha inhibitors, and the addition of the scope comparator ustekinumab. The committee agreed that, in addition to the base case presented, it would have also preferred to see a company base case for apremilast as a post-TNF‑alpha inhibitor treatment. However, it concluded that the company and ERG exploratory analyses helped to reduce uncertainty in the cost‑effectiveness results.\n\n## HAQ-DI\n\nThe committee was aware that HAQ-DI was a principle uncertainty in the original company model for the previous NICE technology appraisal. It noted and appreciated that although there was a lack of evidence to support the exact value, the company had modelled some HAQ-DI progression for apremilast (at a rate of 50% of best supportive care) in its revised analyses. Both the company and the ERG had also attempted to explore this uncertainty by using different rates of HAQ-DI progression for apremilast, and the committee heard from the company that it now had access to 3-year clinical trial data for apremilast, showing that HAQ-DI had been maintained for patients using apremilast. The committee concluded that the company had taken the correct approach by including some HAQ-DI progression for apremilast in its base case and that, in the absence of more robust evidence, the value used of 50% of the rate of best supportive care was a pragmatic assumption.\n\n## Modelled\xa0response to treatment\n\nThe committee noted that the modelled\xa0response to treatment was binary, with modelled patients achieving either\xa0response or no\xa0response, using PsARC (psoriatic arthritis\xa0response criteria, which assesses several joint and skin outcomes). The committee considered whether this binary categorisation would accurately capture\xa0response to treatment, which may be more nuanced in clinical practice. It heard from the company that disease progression for psoriatic arthritis is driven by swollen joints. The committee also noted that the company had explored using ACR20 as a measure of\xa0response to treatment in its analyses, and this did not have a substantial effect on results. The committee concluded that the modelled\xa0response to treatment was imperfect, but appropriate for decision-making.\n\n## Declining effectiveness assumption\n\nThe committee noted that any TNF‑alpha inhibitor given in a modelled treatment sequence after previous TNF‑alpha inhibitor treatment was assumed to be less effective. The committee heard that the evidence for this was indirect. The committee concluded that although there was uncertainty about the declining effectiveness assumption for TNF‑alpha inhibitors, it was plausible that the effectiveness of a TNF‑alpha inhibitor could be affected by the use of a prior TNF‑alpha inhibitor. The company also highlighted that this assumption did not affect any head-to-head analyses. The committee accepted this assumption for decision-making.\n\n## Most plausible ICERs\n\nThe committee discussed whether it could identify a most plausible ICER. It noted that the base-case ICER with the apremilast patient access scheme was £39,052 saved per QALY lost. The committee also considered the sensitivity and scenario analyses presented by both the company and the ERG. All showed that, as in the company's base case, using apremilast resulted in cost savings but a QALY loss. All were over £20,000 saved per QALY lost, and most were also over £30,000 saved per QALY lost. The committee agreed that the analyses that produced ICERs of less than £30,000 saved per QALY lost were not the most realistic scenarios. It agreed that the inclusion of the apremilast patient access scheme had increased the cost savings such that they were at a more acceptable level given the QALYs that would be lost.\n\n## Biosimilars\n\nThe committee was aware that biosimilars for the comparators infliximab and etanercept are now available, and that the company had not included biosimilar infliximab despite it being a comparator in the scope. The committee considered what effect the inclusion of biosimilars could have had on the cost‑effectiveness results. It heard from the ERG that it had done some informal analyses in the context of the company base case (comparing a sequence of apremilast, adalimumab, etanercept and best supportive care with adalimumab, etanercept, golimumab, and best supportive care). Adding biosimilar etanercept to the base case did not substantially change cost‑effectiveness results. Importantly, the committee was also aware that in direct head-to-head comparisons, apremilast demonstrated the highest cost‑effectiveness results when compared with infliximab (the ICER was over £40,000 saved per QALY lost without the apremilast patient access scheme), so although the inclusion of biosimilar infliximab would worsen (that is, lower) the ICER for apremilast, the overall interpretation of the result was likely to be the same. The committee concluded that it would have preferred to have seen the inclusion of biosimilar infliximab, but that the cost‑effectiveness results were still appropriate for decision-making.\n\n## Recommendation\n\nThe committee agreed that, because apremilast is a less effective treatment than the currently available treatment options (see section\xa04.8), it was particularly important to consider the possible consequences of a positive recommendation for individual patients. It stated that the addition of apremilast to the existing treatment pathway would mean patients would have access to an additional treatment with a different mechanism of action. Furthermore, the committee agreed that some patients may be willing to accept a certain level of reduced effectiveness because apremilast, unlike the TNF‑alpha inhibitors and ustekinumab, is taken orally. The committee therefore agreed that apremilast could improve patient choice while also offering the opportunity of cost savings for the NHS (with cost savings at a more acceptable level given the QALY gain that would be lost). It concluded that apremilast could be recommended as a cost‑effective use of NHS resources.\n\nThe committee emphasised that apremilast should be seen as just one option in the context of a range of existing treatment options. The committee was aware that NICE technology appraisal guidance on etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis recommend that the least costly treatment option should be used first. However, the committee agreed that apremilast should not be used based on cost alone, because all clinical-effectiveness results showed it to be the least effective treatment. The committee agreed that the intention of its recommendation was to improve individual patient and clinician choice while also offering the chance of cost savings for the NHS. Apremilast in routine NHS practice should not be a barrier for access to existing treatments; patients and their clinicians should still have the choice of the full range of treatments, including the more expensive and more effective TNF‑alpha inhibitors, if they are more clinically appropriate. The committee concluded that the decision to use apremilast should not be made based on cost alone, and that individual patient factors, including patient needs and preferences, should also be taken into consideration.\n\n## Starting and stopping rules\n\nThe committee noted several comments from consultation on the appraisal consultation document regarding the apremilast recommendation compared with previous NICE recommendations for TNF‑alpha inhibitors, specifically etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis. There was concern during consultation that inconsistent wording might imply that apremilast should be used at a different point in the pathway to the TNF‑alpha inhibitors, which was not the committee's intention (see section\xa04.31). The committee therefore went on to discuss aligning the apremilast recommendation to the starting (see section\xa04.33) and stopping rules (see section\xa04.34) in previous psoriatic arthritis appraisals.\n\nThe committee was aware that NICE technology appraisal guidance on etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis included treatment eligibility criteria, outlining that patients should have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints, and to have previously had at least 2 standard DMARDs (administered either individually or in combination). The committee considered whether to add these treatment eligibility criteria to its recommendations for apremilast. It agreed that aligning apremilast recommendation with the recommendations for TNF‑alpha inhibitors would help to avoid any confusion about apremilast's intended position in the treatment pathway. The committee concluded that the treatment eligibility criteria included in the previous appraisals should also be specified in the recommendation for apremilast.\n\nThe committee noted comments from consultation on the appraisal consultation document that it is important to ensure access to more effective treatments is not delayed after an inadequate\xa0response to apremilast. It was aware that NICE technology appraisal guidance on etanercept, infliximab and adalimumab and golimumab for the treatment of psoriatic arthritis include a stopping rule stating that treatment should be stopped in patients whose disease has not demonstrated an adequate\xa0response to treatment at 12\xa0weeks. The committee noted that, for apremilast, the clinical trial data primary outcomes and the company model had measured\xa0response to treatment at 16\xa0weeks. The committee concluded that its recommendation should specify that if an adequate\xa0response to apremilast is not observed at 16\xa0weeks, treatment with apremilast should be stopped and other treatments considered.\n\n# Summary of appraisal committee's key conclusions\n\nTA433\n\nAppraisal title: Apremilast for treating active psoriatic arthritis\n\nSection\n\nKey conclusion\n\nApremilast, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is recommended as an option for treating active psoriatic arthritis in adults only if:\n\nthey have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and\n\ntheir disease has not responded to adequate trials of at least 2 standard DMARDs, given either alone or in combination and\n\nthe company provides apremilast with the discount agreed in the patient access scheme.\n\nTreatment should be discontinued in people whose psoriatic arthritis has not shown an adequate\xa0response using the Psoriatic Arthritis\xa0response Criteria (PsARC) at 16\xa0weeks.\n\nApremilast is a clinically effective treatment compared with placebo. Evidence from the company's network meta-analysis that compared apremilast with TNF alpha\xa0inhibitors in the total population, and also in people who had not had TNF alpha\xa0inhibitors, showed that apremilast was not as clinically effective as the TNF alpha\xa0inhibitors for treating psoriatic arthritis.\n\nThe base-case ICER with the apremilast patient access scheme was £39,052 saved per QALY lost. All exploratory analyses presented by both the company and the ERG also showed that using apremilast resulted in cost savings but a QALY loss.\n\nThe committee agreed that some patients may be willing to accept a certain level of reduced effectiveness because apremilast, unlike the TNF‑alpha inhibitors and ustekinumab, is administered orally, and that patients would have access to an additional treatment with a different mechanism of action. The choice to use apremilast should not be made based on cost alone, because all clinical effectiveness results showed it to be the least effective treatment.\n\n, 4.6, 4.8, 4.28, 4.30, 4.31, 4.33, 4.34\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nPsoriatic arthritis is a lifelong condition that seriously affects people's quality of life. There is an unmet need for treatments that offer a different mechanism of action to the TNF‑alpha inhibitors or that are administered orally, as with apremilast (a PDE4\xa0inhibitor).\n\n, 4.2\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nApremilast may provide an additional treatment option for patients, because of its different mode of action and oral formulation. However, the committee considered that apremilast was not a step-change in treatment.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that it was possible that apremilast could be used as a treatment before TNF‑alpha inhibitors, for example some people may prefer an oral treatment and may therefore be willing to accept some reduced effectiveness, but that any use or positioning of apremilast would need to be supported by clinical- and cost‑effectiveness evidence.\n\n, 4.3, 4.24\n\n\n\n\n\n\n\n\n\nAdverse reactions\n\nApremilast has an acceptable adverse event profile in people with active psoriatic arthritis.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe main sources of evidence were the PSA-002, PSA-003 and PSA-004 trials that compared apremilast (20\xa0mg and 30\xa0mg) with placebo. The methods used to identify both published and unpublished studies for the company's network meta-analysis were appropriate and the studies were mostly well reported.\n\n, 4.8\n\nRelevance to general clinical practice in the NHS\n\nTreatment with a DMARD such as methotrexate, followed by TNF‑alpha inhibitors in people who can take them, is established practice in the NHS but that there is an unmet need for treatments that have a different mechanism of action to TNF‑alpha inhibitors.\n\n, 4.24\n\nUncertainties generated by the evidence\n\nPlacebo\xa0responses for some outcomes were high, which made it difficult to compare the relative efficacies of apremilast with the different comparators.\n\nThere were uncertainties about the PSA-002, PSA-003 and PSA-004 results because the trials were not blinded after 24\xa0weeks and there were no stopping rules. The committee also considered the lack of radiographic assessment in the trials.\n\nBecause it is a new treatment, there is a lack of long-term clinical-effectiveness data for apremilast.\n\n, 4.9, 4.10\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo specific committee consideration.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nApremilast is a clinically effective treatment compared with placebo.\n\nEvidence from the company's network meta-analysis that compared apremilast with TNF‑alpha inhibitors in the total population, and also in people who had not had TNF‑alpha inhibitors, showed that apremilast was not as clinically effective as the TNF‑alpha inhibitors for treating psoriatic arthritis.\n\n, 4.8\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company base case compared treatment sequences with and without apremilast. The committee accepted that the use of treatment sequences was a valid approach to modelling.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe company had not explored the full treatment pathway in its rapid review submission, with most analyses limited to a maximum of 3 treatments in a sequence. However, the committee appreciated that the company had updated several assumptions in its base case to address committee concerns, and had also presented several new analyses which contributed to reducing the uncertainties outlined in the previous appraisal of apremilast in this indication.\n\nThe committee agreed that, in addition to the base case presented, it would have also preferred to see a company base case for apremilast as a post-TNF‑alpha inhibitor treatment. However, it concluded that the company and ERG exploratory analyses helped to reduce uncertainty in the cost‑effectiveness results.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe utility values in the company's revised base case were derived from the apremilast trial. The committee was surprised at the estimates of utility, which appeared very low and similar to technologies for end of life conditions. However, it agreed that the company had used a legitimate source for utility values by using the available trial data, and accepted the utility values for decision-making.\n\nThe committee did not hear that there were any additional gains in health-related quality of life over those already included in the QALY calculations.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific committee consideration.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nHAQ‑DI was a principle driver of the economic model. Although there was a lack of evidence to support the exact value, the company had modelled some HAQ-DI progression for apremilast (at a rate of 50% of best supportive care) in its revised analyses. Both the company and the ERG had also attempted to explore this uncertainty by using different rates of HAQ-DI progression for apremilast.\n\n, 4.25\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe base-case ICER with the apremilast patient access scheme was £39,052 saved per QALY lost. The committee also considered the sensitivity and scenario analyses presented by both the company and the ERG. All showed that, as in the company's base case, using apremilast resulted in cost savings but a QALY loss. All company and ERG ICERs were over £20,000 saved per QALY lost. Most company and ERG ICERs were also over £30,000 saved per QALY lost. The committee agreed that the analyses that were under £30,000 saved per QALY lost were not the most realistic scenarios and agreed that the addition of the apremilast patient access scheme had increased the cost savings for apremilast so that they were at a more acceptable level given the QALYs that would be lost.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast. The level of the discount is commercial in confidence.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNot applicable.\n\n–"}	https://www.nice.org.uk/guidance/ta433	Evidence-based recommendations on apremilast (Otezla) for treating active psoriatic arthritis.
93247180e6c996e03c77816e7d9a3ef0c35cf17b	nice	Molecular testing strategies for Lynch syndrome in people with colorectal cancer	Molecular testing strategies for Lynch syndrome in people with colorectal cancer Evidence-based recommendations on using immunohistochemistry or microsatellite instability testing to guide further testing for Lynch syndrome in people with colorectal cancer. # Recommendations Offer testing to all people with colorectal cancer, when first diagnosed, using immunohistochemistry for mismatch repair proteins or microsatellite instability testing to identify tumours with deficient DNA mismatch repair, and to guide further sequential testing for Lynch syndrome (see 1.2 and 1.3). Do not wait for the results before starting treatment. If using immunohistochemistry, follow the steps in table 1. Table 1 Steps in the immunohistochemistry testing strategy Step 1 Do an immunohistochemistry 4‑panel test for MLH1, MSH2, MSH6 and PMS2. Step 2 If the MLH1 immunohistochemistry result is abnormal, use sequential BRAF V600E and MLH1 promoter hypermethylation testing to differentiate sporadic and Lynch syndrome-associated colorectal cancers. First do a BRAF V600E test. If the MSH2, MSH6 or PMS2 immunohistochemistry results are abnormal, confirm Lynch syndrome by genetic testing of germline DNA. Step 3 If the BRAF V600E test is negative, do an MLH1 promoter hypermethylation test. Step 4 If the MLH1 promoter hypermethylation test is negative, confirm Lynch syndrome by genetic testing of germline DNA. If using microsatellite instability testing, follow the steps in table 2. Table 2 Steps in the microsatellite instability testing strategy Step 1 Do a microsatellite instability test. Step 2 If the microsatellite instability test result is positive, use sequential BRAF V600E and MLH1 promoter hypermethylation testing to differentiate sporadic and Lynch syndrome-associated colorectal cancers. First do a BRAF V600E test. Step 3 If the BRAF V600E test is negative, do an MLH1 promoter hypermethylation test. Step 4 If the MLH1 promoter hypermethylation test is negative, confirm Lynch syndrome by genetic testing of germline DNA. Healthcare professionals should ensure that people are informed of the possible implications of test results for both themselves and their relatives, and ensure that relevant support and information is available. Discussion of genetic testing should be done by a healthcare professional with appropriate training. Laboratories doing microsatellite instability testing or immunohistochemistry for mismatch repair proteins should take part in a recognised external quality assurance programme.# Clinical need and practice # The problem addressed Testing colorectal tumours using either microsatellite instability (MSI) or immunohistochemistry (IHC) testing for mismatch repair (MMR) proteins can identify people in whom the cancer may have occurred because of Lynch syndrome. Further testing for people at risk of Lynch syndrome can confirm this diagnosis. As well as colorectal cancer, people with Lynch syndrome have an increased risk of other cancers (such as endometrial, ovarian, stomach, small intestine, hepatobiliary tract, urinary tract, brain and skin cancer). After a diagnosis of Lynch syndrome, for some cancer sites, risk-reducing strategies can be offered to prevent or allow early diagnosis of associated cancers. Currently, testing for Lynch syndrome is typically offered to people considered to be at high risk of having Lynch syndrome. Risk factors include a family history of cancer and age younger than 50 years at the onset of colorectal cancer. Expanding testing to all people with colorectal cancer may increase the detection of Lynch syndrome and, because Lynch syndrome is an inherited condition, identify families who could benefit from cascade genetic testing to determine if other family members have Lynch syndrome. This could lead to increased surveillance and consequently improved patient outcomes through earlier diagnosis and treatment, if cancer is present. The purpose of this assessment is to evaluate the clinical and cost effectiveness of using molecular testing strategies, which involve MSI testing and IHC for MMR proteins, to assess how likely it is that a person with colorectal cancer has Lynch syndrome. This assessment considers the use of the molecular testing strategies to identify people who are at risk of Lynch syndrome for genetic testing and, if Lynch syndrome is confirmed, direct cascade testing for relatives. # The condition Lynch syndrome is an inherited genetic condition caused by mutation in 1 of 4 DNA MMR genes: MLH1, MSH2, MSH6 or PMS2. Mutations in another non‑MMR gene, known as EPCAM, which is next to the MSH2 gene, can also cause Lynch syndrome. MMR genes encode proteins that are involved in recognising and repairing errors in DNA sequence, which occur when DNA is replicated during cell division. Mutations in MMR genes can lead to impaired functioning of the MMR system and a failure to repair DNA errors. Over time, this allows mutations to accumulate, potentially leading to cancer. Lynch syndrome accounts for about 3.3% of colorectal tumours, and the condition is estimated to lead to over 1,100 colorectal cancers a year in the UK. An estimated 175,000 people in the UK have Lynch syndrome, a large proportion of whom will be unaware that they have the condition. In addition to colorectal cancer, people with Lynch syndrome are also at increased risk of other cancers. # The diagnostic and care pathways ## Diagnosis In current practice, testing for Lynch syndrome in people with colorectal cancer is usually targeted using criteria based on family history and age of cancer onset to determine people at high risk. There is currently no NICE guidance on the population to be tested or the testing strategy for Lynch syndrome. The guidelines of the British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) for colorectal cancer screening and surveillance in moderate and high risk groups (2010) recommend that people with a lifetime risk of between 10% and 100% of developing colorectal cancer are referred to a regional genetics centre for genetic counselling and appropriate mutation analysis. In 2009, after a review of Lynch syndrome testing, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group's report on genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives recommended offering laboratory testing to all such people with colorectal cancer, regardless of age or family history. The 2013 European revised guidelines for the clinical management of Lynch syndrome (HNPCC) also recommended systematic testing of all people with colorectal cancer (or at least all those up to the age of 70) for loss of MMR function by testing for MSI in tumour DNA or IHC for MMR proteins. The Royal College of Pathologists includes MMR protein IHC as a core dataset item for people under the age of 50 diagnosed with colorectal cancer. The Independent Cancer Taskforce also recommended in its report, Achieving world-class outcomes – a strategy for England 2015–2020, that all people under the age of 50 be offered a genetic test for Lynch syndrome when bowel cancer is diagnosed. ## Treating colorectal cancer in people with Lynch syndrome The NICE guideline on colorectal cancer provides recommendations on treating colorectal cancer. Clinicians in the NHS also use the European Society for Medical Oncology (ESMO) guidelines for diagnosis, treatment and follow-up of early colon cancer to guide treatment decisions. The 2013 European HNPCC's revised guidelines for managing Lynch syndrome also note the substantial risk of a second colorectal cancer after partial colectomy and that the quality of life after partial or subtotal colectomy are similar. Therefore, the option of subtotal colectomy, including its advantages and disadvantages, should be discussed with all people with Lynch syndrome and colorectal cancer, especially younger patients. ## Management and surveillance of Lynch syndrome The 2013 European HNPCC's revised guidelines for managing Lynch syndrome recommend that people with a Lynch syndrome mutation take aspirin because this can reduce the incidence of cancer in Lynch syndrome mutation carriers. The 2013 European HNPCC's revised guidelines for managing Lynch syndrome recommend that people with a Lynch syndrome mutation have a colonoscopy every 1 to 2 years. The BSG and ACPGBI's guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (2010) recommend that people with a Lynch syndrome mutation are offered total colonic surveillance at least every 2 years from the age of 25.# The diagnostic tests The assessment compared tumour testing strategies involving microsatellite instability (MSI) testing, immunohistochemistry (IHC) testing (both with and without further testing to exclude sporadic colorectal cancers), and comprehensive mismatch repair (MMR) gene mutation testing with a single comparator. Comprehensive MMR gene mutation testing was also used as the reference standard for assessing the accuracy of the tumour testing strategies. # The interventions ## Microsatellite instability testing Microsatellites are repetitive sequences of DNA that are at increased risk of copying errors during replication. In tumours of people without an effective DNA MMR system, errors in copying microsatellite sequences cause them to vary in length. This is known as MSI. MSI testing can, therefore, be used to assess whether the DNA MMR system is working effectively by detecting the size of microsatellite regions in tumour samples from people diagnosed with colorectal cancer. Deficiencies in DNA MMR show that a person's cancer may have developed because they have Lynch syndrome. MSI testing is a polymerase chain reaction (PCR) based method that amplifies DNA at several microsatellite sites from a person's tumour tissue sample and also a healthy tissue sample. MSI tests can differ in the panel of microsatellite marker sites they assess, both in terms of their number and genetic location. ## Immunohistochemistry testing IHC uses antibodies to detect decreased or abnormal expression of MMR proteins in colorectal tumour tissue samples. Absent or reduced nuclear staining of 1 or more MMR proteins suggests that there may be a pathogenic mutation in a gene encoding these proteins. MMR proteins detected by IHC are MLH1, MSH2, MSH6 and PMS2. Laboratories may differ in the source of the antibodies used to carry out these tests. ## Tests for sporadic colorectal cancer Although deficient DNA MMR systems (identified with MSI testing or IHC) indicate that a person may have Lynch syndrome, they can also be seen in sporadic colorectal cancers (that is, cancers not caused by Lynch syndrome). Sporadic colorectal cancers can show loss of MLH1 protein expression caused by changes in the MLH1 gene promoter. MLH1 promoter hypermethylation testing can be used to directly test for these changes, or BRAF V600E mutation testing can be used, because this mutation is associated with MLH1 promoter hypermethylation. Using these tests can identify sporadic colorectal tumours that are MSI positive or have abnormal MLH1 protein expression in people who are not at risk for Lynch syndrome, and therefore prevent unnecessary further genetic testing. ## Comprehensive mismatch repair gene mutation testing Comprehensive screening for constitutional mutations in the MMR genes, and also possibly the EPCAM gene, is the gold standard for diagnosing Lynch syndrome. This involves gene sequencing to detect point mutations and small insertions or deletions in these genes, and also multiplex ligation-dependent probe amplification to detect larger structural changes to genes, such as deletions, duplications or rearrangements. Comprehensive screening for constitutional mutations in MMR genes can identify novel sequence variations in these genes that are of unknown significance, that is, it is unknown whether they are pathological or non-pathological. It can therefore be uncertain as to whether people with such sequence variants should be diagnosed as having Lynch syndrome or not. # The comparator The comparator used in this assessment is no testing to identify Lynch syndrome. That is, all people diagnosed with colorectal cancer are assumed not to have Lynch syndrome.# Evidence The diagnostics advisory committee (section 7) considered several sources of evidence on molecular testing strategies for Lynch syndrome in people with colorectal cancer. Full details of all the evidence are in the committee papers. # Clinical effectiveness ## Diagnostic accuracy Ten diagnostic accuracy studies that met the inclusion criteria for the systematic review were identified, 1 of which was based in the UK (Barnetson et al. 2006). One of these studies (Poynter et al. 2008) had 2 distinct samples that were treated separately in the review, so although there were 10 included studies, there were 11 included populations or datasets. Four of the included studies were single-gate studies recruiting population-based samples, that is, they recruited people with colorectal cancer regardless of their risk factors for Lynch syndrome. One study (Poynter et al. 2008) reported data from 2 separate populations; 1 seemed to be an unselected population with colorectal cancer and 1 was in people at high risk of Lynch syndrome. The other 3 studies with population-based samples (Barnetson et al. 2006; Limburg et al. 2011; Southey et al. 2005) included populations with colorectal cancer but specified age limits in their inclusion criteria. These were people younger than 55, younger than 50 and younger than 45 years respectively. The ages of participants in Poynter et al. (2008) were not reported. A further 4 studies (Caldes et al. 2004; Mueller et al. 2009; Overbeek et al. 2007; Shia et al. 2005), plus the second population in Poynter et al. (2008), were all classified as single-gate studies that recruited high-risk populations. The remaining 2 studies recruited patients with colorectal cancer who were known to have Lynch syndrome (Hendriks et al. 2003; Okkels et al. 2012) and are referred to as reference standard positive studies. Studies based on high-risk populations and people known to have Lynch syndrome were only used to inform sensitivity estimates for the index tests. Quality appraisal of the included studies was done using the QUADAS‑2 tool. The external assessment group (EAG) commented that no evidence was found to show that the included studies were at high risk of bias. The EAG noted that the index tests included in the assessment are highly susceptible to spectrum bias. In particular, the increased presence of mismatch repair (MMR) mutation carriers in a study population (for example, because of the age of the study population) could change the apparent sensitivity and specificity of the index tests. Significant methodological and clinical heterogeneity across studies was also noted; in particular, the reference standard differed between studies. Because of the methodological and clinical heterogeneity seen, the EAG did not consider meta-analyses to be appropriate, and results were presented as a narrative summary. Most of the included studies assessed microsatellite instability (MSI) testing and immunohistochemistry (IHC); however, because none of the studies directly compared MSI testing and IHC, results were reported separately for each of the index tests. All of the included studies, except Limburg et al. (2011) and Okkels et al. (2012), assessed MSI testing. There were several differences in the MSI testing procedures used in the included studies. These included variations in the number and types of markers in the panels of MSI markers used and also differences in the categorisation of test results; tumours were categorised using either 2 categories (MSI positive or negative) or 3 categories (MSI‑High , MSI‑Low or microsatellite stable ). Studies also varied in the thresholds used to categorise MSI. Sensitivity and specificity values were calculated based on a positive MSI test result for Lynch syndrome being MSI‑H alone or either MSI‑H or MSI‑L, as shown in table 3. Table 3 Accuracy estimates for MSI testing Study Test positive: MSI‑H Test negative: MSI‑L or MSS Test positive: MSI‑H or MSI‑L Test negative: MSS Sensitivity (%; 95% CI) Specificity (%; 95% CI) Sensitivity (%; 95% CI) Specificity (%; 95% CI) Single-gate, population-based samples Poynter et al. 2008a to 100.0 to 65.1 to 100.0 to 33.4 Barnetson et al. 2006 to 82.7 to 95.2 to 99.2 to 88.2 Southey et al. 2005 to 90.3 to 95.9 to 99.9 to 73.7 Single-gate, high-risk samples Caldes et al. 2004b to 91.3 to 91.3 Mueller et al. 2009 to 98.9 to 99.2 Overbeek et al. 2007b to 98.2 to 98.2 Poynter et al. 2008 to 95.6 to 99.4 Shia et al. 2005b to 100.0 to 100.0 Reference standard positive study Hendriks et al. 2003 to 97.5 to 99.0 a Population-based sample. b MSI‑L not defined. Abbreviations: CI, confidence interval; MSI, microsatellite instability; MSI‑H, microsatellite instability high; MSI‑L, microsatellite instability low; MSS, microsatellite stable. Secondary analyses were carried out if data allowed, with unclassified variants (variations in the sequence of MMR genes that are of unknown clinical significance) considered as positive reference standard results for Lynch syndrome (as opposed to negative reference standard results, as in primary analyses). The EAG noted that results were similar to those obtained when unclassified variants were considered as negative. IHC for MMR proteins was carried out in all of the 10 included studies, although 2 of the studies did not have enough data to be included in the IHC analyses: the high-risk samples in Poynter et al. (2008) and Mueller et al. (2009). The accuracy estimates from included studies are shown in table 4. The proteins targeted by the tests used and the way results were reported differed between the studies. In 7 studies (Barnetson et al. 2006; Limburg et al. 2011; Southey et al. 2005; Caldes et al. 2004; Overbeek et al. 2007; Shia et al. 2005; Hendriks et al. 2003), an overall result was given, that is, when abnormal staining of any of the MMR proteins assessed was classed as a positive IHC result. All of these 7 studies assessed MLH1, MSH2 and MSH6 proteins. Southey et al. (2005) and Overbeek et al. (2007) also assessed PMS2. So, for these 2 studies, an abnormal PMS2 result would also be included as a positive index test result. Table 4 Accuracy estimates for overall IHC testing Study Sensitivity (%; 95% CI) Specificity (%; 95% CI) LR+ (95% CI) LR− (95% CI) PPV (%; 95% CI) NVP (%; 95% CI) Single-gate, population-based samples Barnetson et al. 2006 (76.6 to 97.9) NE – a – a – a – a Limburg et al. 2011 (42.1 to 99.6) (86.3 to 95.7) (5.7 to 19.7) (0.02 to 0.95) (13.3 to 59.0) (96.0 to 100.0) Southey et al. 2005 (81.5 to 100.0) (65.1 to 91.2) (2.8 to 9.5) (NE) (48.2 to 85.7) (89.4 to 100.0) Single-gate, high-risk samples Caldes et al. 2004 (81.7 to 99.9) Overbeek et al. 2007 (52.9 to 97.7) Shia et al. 2005 (60.6 to 93.4) Reference standard positive study sample Hendriks et al. 2003 (77.5 to 98.2) a Analysis not done because overall IHC results were only available for reference standard positive participants. Abbreviations: IHC, immunohistochemistry; LR+, positive likelihood ratio; LR−, negative likelihood ratio; NE, not estimable; NPV, negative predictive value; PPV, positive predictive value. Only 2 studies (Caldes et al. 2004; Hendriks et al. 2003) had enough data to be included in the secondary analyses (in which unclassified variants were considered as positive reference standard results for Lynch syndrome). Only sensitivity estimates could be made because Caldes et al. included people at high risk of Lynch syndrome and Hendriks et al. included people known to have Lynch syndrome. Caldes et al. showed a reduction in sensitivity (75.0%; 95% confidence interval 57.8 to 87.9) compared with the primary analyses in which unclassified variants were categorised as negative reference standard tests (96.4%; 95% CI 81.7 to 99.9). For Hendriks et al., sensitivity was only slightly reduced from 91.7% (95% CI 77.5 to 98.2) to 88.6% (95% CI 76.0 to 95.0). No end-to-end studies meeting the inclusion criteria for the systematic review were identified. # Cost effectiveness ## Systematic review of cost effectiveness Nine separate studies reporting the cost effectiveness of using MSI and IHC testing in strategies to identify Lynch syndrome in people with colorectal cancer met the inclusion criteria for the systematic review of existing economic evaluations. One study was reported in 2 papers (Snowsill et al. 2014; Snowsill et al. 2015). Seven of the included studies were based in US populations, 1 in Germany and 1 in the UK. The modelling approach used by the studies was similar. Most included a decision tree to model the diagnosis of Lynch syndrome, and a longer-term Markov or individual patient simulation model to estimate the costs and benefits associated with the outcomes of the diagnostic model. Conclusions on which were the most cost-effective strategies varied across these studies and depended on the maximum acceptable incremental cost-effectiveness ratio (ICER) and comparators used in the analysis. No single strategy was consistently most cost effective. When a universal genetic testing strategy was assessed by the studies, strategies that used tumour-based tests, such as IHC or MSI, to select the population having full genetic testing seemed to improve the cost-effectiveness estimates. Most studies agreed that the effectiveness of colonoscopy screening, number of relatives and prevalence of Lynch syndrome were the parameters that had the greatest effect on the cost effectiveness of the testing strategies assessed. ## Modelling approach An economic model was developed to assess the cost effectiveness of molecular testing strategies for Lynch syndrome in people with colorectal cancer. This was based on a previously constructed model, as described in Snowsill et al. (2014 and 2015). The model included: a decision tree model to investigate the short-term outcomes of strategies to identify people with Lynch syndrome and an individual patient simulation model to assess the long-term implications of strategies to identify and manage Lynch syndrome; the model considers longer-term outcomes for both colorectal and endometrial cancer. The decision tree started with people diagnosed with colorectal cancer (called 'probands') who could have 1 of 10 diagnostic strategies for Lynch syndrome, as described in table 5. As a result of these diagnostic strategies, probands were either diagnosed as LS‑positive, LS‑negative or LS‑assumed (if they refused genetic testing). People who were diagnosed as LS‑positive or LS‑assumed were offered 2‑yearly colonoscopies, which they could either accept or decline. People diagnosed as LS‑negative had standard colorectal cancer follow‑up and surveillance. Decision tree models were also included for relatives of probands. Those diagnosed as LS‑positive were offered testing (which they could accept or decline). Relatives who tested positive for Lynch syndrome, or who declined testing, were offered surveillance (which they could either accept or decline). First-degree relatives of probands diagnosed as LS‑assumed were also offered surveillance. No further action was taken for the relatives of probands who did not have Lynch syndrome. Table 5 Diagnostic strategies for probands Strategy number Description No systematic testing to identify LS (all probands assumed to not have LS). IHC 4‑panel test for MLH1, MSH2, MSH6 and PMS2, then genetic testing if the IHC result is abnormal for 1 of them. IHC 4‑panel test for MLH1, MSH2, MSH6 and PMS2, then: genetic testing for abnormal MSH2, MSH6 or PMS2 IHC results, or BRAF V600E testing for an abnormal MLH1 IHC result, if negative for V600E (a 'wild type' result) then genetic testing is carried out. IHC 4‑panel test for MLH1, MSH2, MSH6 and PMS2, then: genetic testing for abnormal MSH2, MSH6 or PMS2 IHC results, or MLH1 promoter hypermethylation testing for an abnormal MLH1 IHC result, if negative then genetic testing is carried out. IHC 4‑panel test for MLH1, MSH2, MSH6 and PMS2, then: genetic testing for abnormal MSH2, MSH6 or PMS2 IHC results, or BRAF V600E testing for an abnormal MLH1 IHC result, if negative then MLH1 promoter hypermethylation testing is done, if the MLH1 promoter hypermethylation test is negative, genetic testing is carried out. MSI test, if positive then genetic testing is done. MSI test, if positive then BRAF V600E testing, if negative for V600E (a 'wild type' result) then genetic testing is done. MSI test, if positive then MLH1 promoter hypermethylation testing, if the MLH1 promoter hypermethylation test is negative, then genetic testing is done. MSI test, if positive then BRAF V600E testing, if negative for V600E then an MLH1 promoter hypermethylation test is done, if the MLH1 promoter hypermethylation test is negative, then genetic testing is done. Universal genetic testing (that is, the first and only test for all probands). Abbreviations: IHC, immunohistochemistry; MSI, microsatellite instability; LS, Lynch syndrome. The longer-term model included outcomes relating to surveillance and treatment for both colorectal cancer and gynaecological (endometrial) cancer. Longer-term outcomes were modelled for all probands and relatives (regardless of the diagnostic path they follow) using an individual patient sampling model to simulate 240,000 patients, distributed across 24 groups, representing all combinations of the following variables: whether the person was a proband or relative whether the person had Lynch syndrome whether the person had been diagnosed with Lynch syndrome and accepted or declined surveillance sex. Patients were simulated for 1 year at a time in the model, with the events that happened to them during that year, as well as the life years and quality-adjusted life years (QALYs) they accumulated, being determined by the health state they were in. Estimates of test accuracy were taken from available literature identified through the diagnostic-accuracy and cost-effectiveness literature reviews. To estimate the accuracy of MSI and IHC testing, results from studies included in the clinical-effectiveness review were pooled using a multilevel mixed-effects logistic regression analysis. For MSI testing, the results from Barnetson et al. (2006), the population-based sample from Poynter et al. (2008) and Southey et al. (2005) were pooled, and for IHC testing, the results from Limburg et al. (2011) and Southey et al. (2005) were pooled. Diagnostic-accuracy data for BRAF V600E and MLH1 promoter methylation testing were taken from Ladabaum et al. (2015). This study pooled values from studies reporting test accuracy, with included studies using various types of previous testing for Lynch syndrome (including MSI and IHC testing). Test accuracy parameters used in modelling are shown in table 6. Table 6 Test accuracy parameters used in modelling Test Parameter Parameter value (95% CI) MSI Base case: MSI test positive=MSI‑H Sensitivity (0.426 to 0.993) Specificity (0.638 to 0.937) MSI Scenario analysis: MSI test positive=MSI‑L and MSI‑H Sensitivity (0.893 to 0.994) Specificity (0.304 to 0.833) IHC Sensitivity (0.694 to 0.996) Specificity (0.790 to 0.940) BRAF V600E Sensitivity (0.600 to 0.990) Specificity (0.600 to 0.870) MLH1 promoter methylation Sensitivity (0.790 to 0.980) Specificity (0.590 to 0.860) Diagnostic genetic testing for probands Sensitivity MLH1, MSH2, MSH6: 0.90 PMS2: 0.67 Specificity Predictive testing for relatives Sensitivity Specificity Abbreviations: CI, confidence interval; IHC, immunohistochemistry; MSI, microsatellite instability; MSI‑H, microsatellite instability high; MSI‑L, microsatellite instability low. Estimates of parameter values relating to acceptance of tests, colorectal cancer surveillance, stage of cancer at diagnosis, gynaecological surveillance and chemoprevention were taken from identified literature, registry data and clinical expert opinion. Costs of preliminary tumour testing, genetic tests (for both probands and relatives), and genetic counselling were sourced from the UK Genetic Testing Network (2016), Health and Social Care Unit Costs and from personal communication with providers. Further relevant costs came from NHS references costs (2014/15 and updated to 2016/17 prices), identified literature, the British national formulary (BNF 2016) and the NHS drug tariff. Utilities associated with colorectal cancer, endometrial cancer and prophylactic hysterectomy were taken from published literature identified by systematic searches. Disutilities associated with genetic testing used in the model were as previously reported in Snowsill et al. (2014). The key assumptions applied in the base-case analysis were: MSI‑L was considered a negative result. The sensitivity of MSI and IHC testing did not depend on which MMR gene is mutated. All people who accepted genetic testing had testing for all 4 MMR genes, unless they followed a strategy that used IHC, in which case they had either BRAF V600E or MLH1 promoter hypermethylation testing and only MLH1 and PMS2 were tested. The average number of relatives per proband was 6 (2.5 of whom were first-degree relatives). Surveillance colonoscopies reduced the incidence of colorectal cancer by 61%, and the incidence of metachronous colorectal cancer by 47%. Surveillance colonoscopies improved the proportion of people in whom colorectal cancer was diagnosed at an early stage (stage I or II) from 44.6% to 79.1%. Colorectal surveillance colonoscopies occurred every 2 years. Gynaecological surveillance reduced endometrial cancer mortality by 10%. People taking aspirin had a reduced incidence of colorectal and endometrial cancer that lasted for 10 years. Disutility was only applied to people with stage IV colorectal cancer. No disutility arising from prophylactic hysterectomy was assumed. Initial acceptance of colonoscopic surveillance was 97% for probands and relatives who tested positive for Lynch syndrome mutation, and 70% for probands and relatives who were assumed to have Lynch syndrome. The base-case analysis included 238,175 simulated individuals and represents an annual cohort of 34,025 probands with colorectal cancer and 204,150 relatives. Pairwise ICERs were calculated for all strategies compared with no testing (strategy 1). Only strategy 10 (universal genetic testing) had an ICER above £20,000 per QALY gained, with ICERs for strategies 2 to 9 all below £14,000 per QALY gained. Comparative (fully incremental) ICERs were also calculated for all strategies. Strategies involving MSI testing were either dominated (that is, they were less effective and more expensive than another option) or extendedly dominated (that is, a combination of other options were more effective and less expensive) by other strategies. The ICER for strategy 3 (IHC plus BRAF V600E) was £37,495 per QALY gained and the ICER for strategy 5 (IHC plus BRAF V600E and MLH1 promoter methylation) was £11,008 per QALY gained. Subgroup analyses were carried out by restricting the age of probands, who have Lynch syndrome testing strategies, included in the model. The age groups were: under 50 years, under 60 years, under 70 years, and 70 years or over. When the proband population was restricted to people under 50 years, all the strategies had ICERs of less than £13,000 per QALY gained compared with no testing (strategy 1). Strategies 3 (IHC plus BRAF V600E; £19,903) and 5 (IHC plus BRAF V600E and MLH1 promoter methylation; £8,090) had ICERs under £20,000 per QALY gained in the fully incremental analysis. When the proband population was restricted to people under 60 years, all the strategies had ICERs of less than £17,000 per QALY gained compared with no testing (strategy 1). Only strategy 5 (IHC plus BRAF V600E and MLH1 promoter methylation; £9,156) had an ICER below £20,000 per QALY gained in the fully incremental analysis. When the proband population was restricted to people under 70 years, all the strategies had ICERs of less than £20,000 per QALY gained compared with no testing (strategy 1), except for strategy 10 (universal genetic testing), which had an ICER of £20,528 per QALY gained. Only strategy 5 (IHC plus BRAF V600E and MLH1 promoter methylation; £9,912) had an ICER below £20,000 per QALY gained in the fully incremental analysis. When the proband population was restricted to people 70 years or over, strategies 5 (IHC plus BRAF V600E and MLH1 promoter methylation), 7 (MSI plus BRAF V600E) and 9 (MSI plus BRAF V600E and MLH1 promoter methylation) had ICERs less than £20,000 per QALY gained compared with no testing (strategy 1). Strategies 5 (£18,839) and 9 (£18,766) had ICERs below £20,000 per QALY gained in the fully incremental analysis. If both MSI‑L and MSI‑H test results were assumed to indicate Lynch syndrome (in the base-case analysis, only MSI‑H is indicative), this effectively lowered the threshold for a positive MSI test result. Only strategies involving MSI testing (strategies 6 to 9) were affected, with ICERs for testing compared with no testing increased relative to the base-case analysis. As for the base-case analysis, strategy 5 was the only strategy with an ICER below £20,000 cost per QALY gained (unchanged at £11,008) in the fully incremental analysis. If aspirin was not included as a risk-reducing component in the model (as it was in the base-case analysis), this resulted in a marginal increase in ICER values, and strategy 5 remained the optimal strategy with an ICER of £11,659 per QALY gained in the fully incremental analysis. In the base-case analysis, if gynaecological surveillance was accepted, it reduced the risk of mortality from endometrial cancer. Two scenarios were considered: 1 assuming that gynaecological surveillance has no benefit (but still has a cost) and another that removed gynaecological surveillance from the model (no cost and no benefit). For both scenarios, strategy 5 remained the optimal strategy and the only strategy with an ICER below £20,000 per QALY gained in the fully incremental analysis. In the base-case analysis, the quality of life for people with colorectal cancer, except Dukes' stage D, was assumed to be similar to the general population (that is, a disutility value of 0). In this scenario analysis, increased disutility values for all colorectal cancer stages were used and values were based on Ness et al. (1999). When compared with the base-case analysis, ICER values for all strategies compared with no testing were reduced. Strategy 5 remained the optimal strategy, with an ICER of £9,775 per QALY gained in the fully incremental analysis. If colonoscopic surveillance was assumed to have no effect on colorectal cancer incidence, ICERs for all strategies were increased compared with no testing (strategy 1), with only 3 strategies remaining, marginally, below £20,000 per QALY gained. Strategy 5 remained the only strategy with an ICER below £20,000 per QALY gained in the fully incremental analysis; however, this value increased to £19,194 per QALY gained (from £11,008 per QALY gained in the base case). Deterministic sensitivity analyses were carried out for several parameters in the model. The ICERs for the testing strategies were sensitive to several parameters. When sensitivity and specificity values for all tumour tests (MSI, IHC, BRAF V600E and MLH1 promoter methylation) were both reduced to their lower 95% confidence interval values, the ICER for strategy 5 compared with no testing increased to £16,036 per QALY gained. Altering diagnostic accuracy can also affect which strategy is optimal. When sensitivity was reduced for all tumour tests, strategy 4 became the optimal strategy (IHC followed by MLH1 promoter methylation). When sensitivity values were increased for all tumour tests (to their upper 95% confidence interval values), MSI testing strategies became optimal, despite MSI testing still having lower sensitivity and specificity values than IHC testing. In addition, when the cost of IHC was doubled, or the cost of MSI testing halved (both relative to base-case values), strategy 7 (MSI followed by BRAF V600E) became the optimal strategy. Decreasing the acceptance by probands of both genetic counselling and testing after counselling (set at 90% and 92.5% respectively in the base-case analysis) to 50%, increased the ICER for strategy 5 compared with no testing to £17,767 per QALY gained (from £11,008 per QALY gained). Increasing the incidence of colorectal cancer in people with Lynch syndrome in the model decreased the ICER for strategy 5 compared with no testing to £6,689 per QALY gained, whereas decreasing the incidence of colorectal cancer increased this value to £19,300 per QALY gained. In the base-case analysis, people who were diagnosed as LS‑assumed because they declined genetic testing were considered as positive for Lynch syndrome. If all LS‑assumed probands, and their relatives, were instead considered to be negative for Lynch syndrome, the ICER for strategy 5 compared with no testing decreased to £5,225 per QALY gained. Six relatives per proband were assumed in the base-case analysis. If only probands were included in the model (that is, no relatives included), the ICERs for all strategies increased, with strategy 5 compared with no testing increasing to £17,921 per QALY gained. Increasing the number of relatives per proband to 12 decreased the ICERs slightly, with strategy 5 compared with no testing decreasing to £10,068 per QALY gained. If the costs of colonoscopy used in the base-case analysis were doubled, all ICERs for strategies compared with no testing increased; for example, for strategy 5, this increased to £16,630 per QALY gained. Reducing the acceptance of colonoscopy surveillance by people with confirmed Lynch syndrome causing mutations from 97% (as in the base-case analysis) to 70% increased the ICERs for strategies compared with no testing (for example, to £12,632 per QALY gained for strategy 5). In the base-case analysis, disutility associated with prophylactic hysterectomy and bilateral salpingo-oophorectomy was assumed to be 0. Increasing the disutility value to 0.04 for 1 year increased the ICERs for all strategies compared with no testing, with the value for strategy 5 increasing to £14,441 per QALY gained.# Committee discussion The committee discussed current practice for assessing the risk of Lynch syndrome in people with colorectal cancer. It heard that testing is usually only carried out in people with colorectal cancer who are under 50 years at the time of diagnosis. The committee heard from clinical experts that guidelines to target testing for Lynch syndrome, such as the Amsterdam criteria and Revised Bethesda Guidelines, are often not used in current practice because they were developed to identify research populations. Also, required information, such as a detailed family history, is often not available and there are concerns over the sensitivity of these methods to detect Lynch syndrome. The committee also heard that the provision of testing for Lynch syndrome and other inherited colorectal cancers varies widely, with an estimated 50% of centres providing tests to assess the risk of Lynch syndrome in people under the age of 50 who have been diagnosed with colorectal cancer. The committee discussed the effect that a diagnosis of Lynch syndrome may have on people with colorectal cancer and their families. It heard from a patient expert that many people are unaware that their colorectal cancer could be hereditary and therefore do not ask questions about whether they should have further genetic testing, unless this issue is raised by their clinician. It also heard that people who are diagnosed with Lynch syndrome often find that the diagnosis is of benefit to both themselves and their family. The diagnosis can help a person to be placed on an appropriate pathway for colorectal cancer treatment and make decisions about further surveillance. Family members can also have genetic testing and surveillance to reduce their risk of developing cancer. The committee also heard that good communication between healthcare professionals and patients is needed so that people get their test results as soon as possible, which can reduce their anxiety. The committee concluded that assessing the risk of Lynch syndrome in people with colorectal cancer could have substantial benefits for patients and their families. # Clinical effectiveness The committee reviewed the available evidence on the clinical effectiveness of using immunohistochemistry (IHC) testing of tumour tissue for mismatch repair (MMR) proteins and microsatellite instability (MSI) to identify tumours with deficient DNA mismatch repair in people with colorectal cancer to assess their risk of having Lynch syndrome. The committee discussed the generalisability of data from the studies, which were identified in the clinical review, to the decision problem. It noted that estimates for sensitivity values were taken from all the studies in the review, which included colorectal cancer patients who were identified as being at high risk of Lynch syndrome and age-limited patient populations that would be expected to have a higher prevalence of Lynch syndrome. The committee heard from the external assessment group (EAG) that the incidence of MSI in sporadic colorectal cancer increases with age and that this may alter test accuracy values in different age groups. The committee concluded that although there were differences in the trial populations in identified studies and the population of people with colorectal cancer in the UK, the effect of this on test accuracy was likely to be minimal. The committee considered the evidence available on the diagnostic accuracy of MSI and IHC testing for MMR proteins. It noted that no identified studies directly compared MSI and IHC testing. It heard from the clinical experts that, in their experience, these tests are comparable in diagnostic accuracy. The committee noted that the tests appeared to be accurate enough for detecting MSI or abnormal expression of MMR proteins, but noted that these findings alone are not enough to diagnose Lynch syndrome without second-line tumour-based testing and subsequent genetic testing. Further, it heard that external quality assurance programmes are used to ensure the accuracy and consistency of testing between laboratories. The committee also heard that both tests are used in current practice in the NHS, and that the choice of test used is often determined by locally available services and expertise. The committee concluded that these tests are broadly comparable in accuracy. The committee discussed the issue of unclassified variants, that is, when genetic testing identifies variations in the sequence of MMR genes that are of unknown clinical significance. This can affect whether results from the reference standard test are classified as positive or negative. The committee noted that relatively few studies identified in the clinical review had enough data to allow alternative analyses when unclassified variants were considered as positive reference standard results for Lynch syndrome. The clinical experts commented that in practice, unclassified variants are investigated further by asking for additional clinical information and testing before a diagnosis is given. The committee also heard that there are ongoing efforts to classify sequence variants in MMR genes and that the number of unclassified variants is therefore decreasing. The committee concluded that unclassified variants are unlikely to have a large effect on diagnosing Lynch syndrome in clinical practice. # Cost effectiveness The committee considered the cost effectiveness of the different testing strategies to identify Lynch syndrome in people with colorectal cancer. It noted that 10 strategies had been modelled, each using different combinations of tumour-based tests and genetic testing (see table 5). The committee discussed the assumptions about the effectiveness of aspirin as a risk-reducing strategy for people with Lynch syndrome that were made in the economic model. It heard from the EAG that in the model, the effect of aspirin in reducing the risk of colorectal and endometrial cancer was assumed to occur instantaneously and last for 10 years, after which time the effect was assumed to stop instantaneously. However, the committee heard from the clinical experts that the Colorectal adenoma/carcinoma prevention programme 2 (CaPP2) trial of aspirin prophylaxis in Lynch syndrome reported that there is a lag time in the protective effect after starting therapy and that its effects can continue after people stop taking aspirin. The committee noted that the scenario analysis without the costs and effects of aspirin prophylaxis showed no substantial effect on overall results. The committee concluded that the effect of the assumptions about aspirin prophylaxis was likely to be small. The committee discussed the effect estimates of colonoscopic surveillance used in the model. It noted that a study used to estimate the effectiveness of colonoscopic surveillance in people with Lynch syndrome in the model was about 15 years old and questioned whether this represents current practice in the NHS. The committee heard from the clinical experts that recent technological developments in this area and the introduction of standards by the Joint Advisory Group on Gastrointestinal Endoscopy have improved the effectiveness of colonoscopic surveillance. Data from cancer screening programmes have also shown that colonoscopic surveillance can lead to the detection of colorectal cancer at an earlier stage, which could improve patient outcomes. The committee also noted that the effectiveness of colonoscopic surveillance is likely to be influenced not only by the effectiveness of the test, but also by patient uptake and were reassured by the clinical experts that uptake of surveillance was high among people with Lynch syndrome. The committee concluded that colonoscopic surveillance is likely to reduce the risk of cancer developing in people with Lynch syndrome, and that consequently the effect estimate used in the base-case analysis was appropriate. The committee considered the results of the base-case analysis, which suggested that strategies that began with IHC for MMR proteins were more cost effective than those that began with MSI testing, and that overall, strategy 5 appeared to be the most cost effective. The committee discussed the extent to which the results of the model were driven by the sensitivity and specificity parameter values used in the model. It noted that in the base-case analysis, MSI testing was assumed to be both less sensitive and less specific than IHC testing. The committee considered that, given the perceived equivalence of MSI and IHC testing and the absence of direct comparative data, there was not enough evidence to conclude that testing strategies that begin with MSI testing are not cost effective compared with IHC testing for MMR proteins. The committee discussed the scenario analysis in which MSI‑Low (MSI‑L) was classified as a positive result for Lynch syndrome and noted that only MSH‑High (MSI‑H) was considered a positive result in the base case. It heard from the clinical experts that in current practice, both MSI‑L and MSI‑H results are generally considered indicative of Lynch syndrome. The results of the scenario analysis suggested that including MSI‑L as a positive result did not affect the cost effectiveness of the MSI‑based testing strategies. The committee concluded that both MSI‑L and MSI‑H should be considered as positive results. The committee discussed the role of BRAF V600E and MLH1 promoter hypermethylation testing in the modelled strategies. It heard from the clinical experts that some tumours that test positive for MSI, or that have abnormal MLH1 protein expression, are sporadic colorectal cancers. Further, it heard that BRAF V600E and MLH1 promoter hypermethylation testing, particularly in combination, can be used to identify sporadic colorectal cancers and so reduce the number of people who are referred for genetic testing for Lynch syndrome. In addition, the clinical experts advised that testing strategies that aim to decrease the number of false-positive diagnoses for Lynch syndrome reduce the number of people having unnecessary colonoscopic surveillance. The committee concluded that strategies 5 and 9, which include tests to identify sporadic colorectal cancers, after first having MSI or IHC testing, are likely to be the most cost-effective options. The committee discussed the cost effectiveness of the testing strategies in different age groups. It noted that the age-restricted subgroup analysis had little effect on the overall conclusions, but that referral straight to genetic testing was unlikely to be cost effective in older age groups. The committee heard from the clinical experts that although the prevalence of Lynch syndrome is much higher in younger people with colorectal cancer, it can still cause colorectal cancer in older people. It also heard that despite the lower prevalence of Lynch syndrome in older people, the greater number of colorectal cancer diagnoses in these age groups could mean that the absolute number of people who could benefit from a Lynch syndrome diagnosis may be similar to that in younger age groups. Therefore, the committee considered that there is no clinical reason to treat age groups differently. The committee concluded that all people, regardless of their age, with colorectal cancer should have tumour-based testing to assess the risk of Lynch syndrome. The committee considered the joint effect of parameter uncertainty used in the model, and noted that this had not been explored in a probabilistic sensitivity analysis. It heard from the EAG that the univariate deterministic sensitivity analyses did not result in large changes to the incremental cost-effective ratios (ICERs) or the net health benefit values, and that it was unlikely that negative net health benefit values would be seen in a probabilistic sensitivity analysis. The committee considered that parameter uncertainty had been explored sufficiently, and that further analyses were unlikely to substantially change the overall results of the economic modelling. Therefore, the committee concluded that testing all people with colorectal cancer using strategies 5 (IHC plus BRAF V600E and MLH1 promoter methylation) and 9 (MSI plus BRAF V600E and MLH1 promoter methylation) would be a cost-effective use of NHS resource. # Other considerations The committee discussed the timing of testing for Lynch syndrome in people who have been diagnosed with colorectal cancer. It heard from the clinical experts that a person's MMR tumour or gene status may be used to determine treatment options for colorectal cancer, for example, to direct surgical decisions or chemotherapy, although the clinical utility of using tumour testing to guide the selection of chemotherapy is not fully understood at present. However, it noted that it is very unlikely that definitive genetic testing will be completed before treatment for colorectal cancer begins. The committee therefore concluded that testing for Lynch syndrome should be started as soon as colorectal cancer is diagnosed, but should not delay the start of treatment. The committee discussed which tissue samples should be used for testing. It heard from the clinical experts that there is good correlation between results for tissue from biopsies and tissue from resections. The committee concluded that clinical judgement should be used to determine the tumour material to be tested, and that tissue from a biopsy, resected colorectal tumour or polyp can be used. The committee also noted that people with Lynch syndrome may develop more than 1 colorectal cancer at the same time. It heard from the clinical experts that some of these cancers may differ in DNA mismatch repair functionality because people with Lynch syndrome can get sporadic colorectal cancers. The committee concluded that testing for Lynch syndrome should be considered for each individual cancer. The committee noted that Lynch syndrome is not the only inherited condition that increases the risk of colorectal cancer. It heard from the clinical experts that other inherited causes of colorectal cancer include familial adenomatous polyposis. The clinical experts also emphasised that it is important that these additional inherited conditions are considered if someone is found not to have Lynch syndrome but the clinician suspects that the person's family history suggests that a genetic cause is likely. The committee concluded that clinical judgement should be used to determine whether a referral to clinical genetics is appropriate when Lynch syndrome has been ruled out by tumour-based testing, but other genetic causes are suspected. The committee considered ongoing developments in genetic testing technologies. It noted that in the future, broad-range genetic sequencing or specific cancer panels using next-generation sequencing technology may be considered for diagnosing Lynch and other inherited colorectal cancer syndromes. The committee concluded that these advances may identify alternative and more rapid methods for diagnosing Lynch syndrome. # Research considerations The committee discussed the value of developing research recommendations for tumour testing for Lynch syndrome. It considered that further research was unlikely to change its recommendations on molecular testing strategies for Lynch syndrome in people diagnosed with colorectal cancer. The committee heard that good communication between colorectal cancer multidisciplinary teams and genetics or pathology laboratories is important for implementing tumour-based testing for Lynch syndrome to ensure that testing and reporting of results is coordinated. The committee noted that similar systems are embedded in breast cancer care pathways, in which reflex testing for human epidermal growth factor receptor 2 (HER2) and BRCA are done as part of the first assessment. The committee therefore wished to encourage centres adopting Lynch syndrome testing strategies to audit and publish their clinical and diagnostic outcomes to ensure that assessment of Lynch syndrome is timely and appropriate. The committee heard from the clinical experts that centres already offering tumour-based testing for Lynch syndrome often carry out both MSI and IHC testing on samples. The committee encouraged these centres to publish their previously generated comparative results.	{'Recommendations': 'Offer testing to all people with colorectal cancer, when first diagnosed, using immunohistochemistry for mismatch repair proteins or microsatellite instability testing to identify tumours with deficient DNA mismatch repair, and to guide further sequential testing for Lynch syndrome (see\xa01.2 and\xa01.3). Do not wait for the results before starting treatment.\n\nIf using immunohistochemistry, follow the steps in table\xa01.\n\nTable 1 Steps in the immunohistochemistry testing strategy\n\nStep\xa01\n\nDo an immunohistochemistry 4‑panel test for MLH1, MSH2, MSH6 and PMS2.\n\nStep\xa02\n\nIf the MLH1 immunohistochemistry result is abnormal, use sequential BRAF\xa0V600E and MLH1 promoter hypermethylation testing to differentiate sporadic and Lynch syndrome-associated colorectal cancers. First do a BRAF\xa0V600E test.\n\nIf the MSH2, MSH6 or PMS2 immunohistochemistry results are abnormal, confirm Lynch syndrome by genetic testing of germline DNA.\n\nStep\xa03\n\nIf the BRAF\xa0V600E test is negative, do an MLH1 promoter hypermethylation test.\n\nStep\xa04\n\nIf the MLH1 promoter hypermethylation test is negative, confirm Lynch syndrome by genetic testing of germline DNA.\n\nIf using microsatellite instability testing, follow the steps in table\xa02.\n\nTable 2 Steps in the microsatellite instability testing strategy\n\nStep\xa01\n\nDo a microsatellite instability test.\n\nStep\xa02\n\nIf the microsatellite instability test result is positive, use sequential BRAF\xa0V600E and MLH1 promoter hypermethylation testing to differentiate sporadic and Lynch syndrome-associated colorectal cancers. First do a BRAF\xa0V600E test.\n\nStep\xa03\n\nIf the BRAF\xa0V600E test is negative, do an MLH1 promoter hypermethylation test.\n\nStep\xa04\n\nIf the MLH1 promoter hypermethylation test is negative, confirm Lynch syndrome by genetic testing of germline DNA.\n\nHealthcare professionals should ensure that people are informed of the possible implications of test results for both themselves and their relatives, and ensure that relevant support and information is available. Discussion of genetic testing should be done by a healthcare professional with appropriate training.\n\nLaboratories doing microsatellite instability testing or immunohistochemistry for mismatch repair proteins should take part in a recognised external quality assurance programme.', 'Clinical need and practice': "# The problem addressed\n\nTesting colorectal tumours using either microsatellite instability (MSI) or immunohistochemistry (IHC) testing for mismatch repair (MMR) proteins can identify people in whom the cancer may have occurred because of Lynch syndrome. Further testing for people at risk of Lynch syndrome can confirm this diagnosis. As well as colorectal cancer, people with Lynch syndrome have an increased risk of other cancers (such as endometrial, ovarian, stomach, small intestine, hepatobiliary tract, urinary tract, brain and skin cancer). After a diagnosis of Lynch syndrome, for some cancer sites, risk-reducing strategies can be offered to prevent or allow early diagnosis of associated cancers.\n\nCurrently, testing for Lynch syndrome is typically offered to people considered to be at high risk of having Lynch syndrome. Risk factors include a family history of cancer and age younger than 50\xa0years at the onset of colorectal cancer. Expanding testing to all people with colorectal cancer may increase the detection of Lynch syndrome and, because Lynch syndrome is an inherited condition, identify families who could benefit from cascade genetic testing to determine if other family members have Lynch syndrome. This could lead to increased surveillance and consequently improved patient outcomes through earlier diagnosis and treatment, if cancer is present.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of using molecular testing strategies, which involve MSI testing and IHC for MMR proteins, to assess how likely it is that a person with colorectal cancer has Lynch syndrome. This assessment considers the use of the molecular testing strategies to identify people who are at risk of Lynch syndrome for genetic testing and, if Lynch syndrome is confirmed, direct cascade testing for relatives.\n\n# The condition\n\nLynch syndrome is an inherited genetic condition caused by mutation in 1 of 4\xa0DNA MMR genes: MLH1, MSH2, MSH6 or PMS2. Mutations in another non‑MMR gene, known as EPCAM, which is next to the MSH2 gene, can also cause Lynch syndrome.\n\nMMR genes encode proteins that are involved in recognising and repairing errors in DNA sequence, which occur when DNA is replicated during cell division. Mutations in MMR genes can lead to impaired functioning of the MMR system and a failure to repair DNA errors. Over time, this allows mutations to accumulate, potentially leading to cancer.\n\nLynch syndrome accounts for about 3.3% of colorectal tumours, and the condition is estimated to lead to over 1,100\xa0colorectal cancers a year in the UK. An estimated 175,000\xa0people in the UK have Lynch syndrome, a large proportion of whom will be unaware that they have the condition. In addition to colorectal cancer, people with Lynch syndrome are also at increased risk of other cancers.\n\n# The diagnostic and care pathways\n\n## Diagnosis\n\nIn current practice, testing for Lynch syndrome in people with colorectal cancer is usually targeted using criteria based on family history and age of cancer onset to determine people at high risk.\n\nThere is currently no NICE guidance on the population to be tested or the testing strategy for Lynch syndrome. The guidelines of the British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) for colorectal cancer screening and surveillance in moderate and high risk groups (2010) recommend that people with a lifetime risk of between 10% and 100% of developing colorectal cancer are referred to a regional genetics centre for genetic counselling and appropriate mutation analysis.\n\nIn 2009, after a review of Lynch syndrome testing, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group's report on genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives recommended offering laboratory testing to all such people with colorectal cancer, regardless of age or family history. The 2013 European revised guidelines for the clinical management of Lynch syndrome (HNPCC) also recommended systematic testing of all people with colorectal cancer (or at least all those up to the age of\xa070) for loss of MMR function by testing for MSI in tumour DNA or IHC for MMR proteins.\n\nThe Royal College of Pathologists includes MMR protein IHC as a core dataset item for people under the age of\xa050 diagnosed with colorectal cancer. The Independent Cancer Taskforce also recommended in its report, Achieving world-class outcomes – a strategy for England 2015–2020, that all people under the age of\xa050 be offered a genetic test for Lynch syndrome when bowel cancer is diagnosed.\n\n## Treating colorectal cancer in people with Lynch syndrome\n\nThe NICE guideline on colorectal cancer provides recommendations on treating colorectal cancer. Clinicians in the NHS also use the European Society for Medical Oncology (ESMO) guidelines for diagnosis, treatment and follow-up of early colon cancer to guide treatment decisions.\n\nThe 2013 European HNPCC's revised guidelines for managing Lynch syndrome also note the substantial risk of a second colorectal cancer after partial colectomy and that the quality of life after partial or subtotal colectomy are similar. Therefore, the option of subtotal colectomy, including its advantages and disadvantages, should be discussed with all people with Lynch syndrome and colorectal cancer, especially younger patients.\n\n## Management and surveillance of Lynch syndrome\n\nThe 2013 European HNPCC's revised guidelines for managing Lynch syndrome recommend that people with a Lynch syndrome mutation take aspirin because this can reduce the incidence of cancer in Lynch syndrome mutation carriers.\n\nThe 2013 European HNPCC's revised guidelines for managing Lynch syndrome recommend that people with a Lynch syndrome mutation have a colonoscopy every 1\xa0to\xa02\xa0years. The BSG and ACPGBI's guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (2010) recommend that people with a Lynch syndrome mutation are offered total colonic surveillance at least every 2\xa0years from the age of\xa025.", 'The diagnostic tests': "The assessment compared tumour testing strategies involving microsatellite instability (MSI) testing, immunohistochemistry (IHC) testing (both with and without further testing to exclude sporadic colorectal cancers), and comprehensive mismatch repair (MMR) gene mutation testing with a single comparator. Comprehensive MMR gene mutation testing was also used as the reference standard for assessing the accuracy of the tumour testing strategies.\n\n# The interventions\n\n## Microsatellite instability testing\n\nMicrosatellites are repetitive sequences of DNA that are at increased risk of copying errors during replication. In tumours of people without an effective DNA MMR system, errors in copying microsatellite sequences cause them to vary in length. This is known as MSI.\n\nMSI testing can, therefore, be used to assess whether the DNA MMR system is working effectively by detecting the size of microsatellite regions in tumour samples from people diagnosed with colorectal cancer. Deficiencies in DNA MMR show that a person's cancer may have developed because they have Lynch syndrome.\n\nMSI testing is a polymerase chain reaction (PCR) based method that amplifies DNA at several microsatellite sites from a person's tumour tissue sample and also a healthy tissue sample. MSI tests can differ in the panel of microsatellite marker sites they assess, both in terms of their number and genetic location.\n\n## Immunohistochemistry testing\n\nIHC uses antibodies to detect decreased or abnormal expression of MMR proteins in colorectal tumour tissue samples. Absent or reduced nuclear staining of 1\xa0or more MMR proteins suggests that there may be a pathogenic mutation in a gene encoding these proteins.\n\nMMR proteins detected by IHC are MLH1, MSH2, MSH6 and PMS2. Laboratories may differ in the source of the antibodies used to carry out these tests.\n\n## Tests for sporadic colorectal cancer\n\nAlthough deficient DNA MMR systems (identified with MSI testing or IHC) indicate that a person may have Lynch syndrome, they can also be seen in sporadic colorectal cancers (that is, cancers not caused by Lynch syndrome). Sporadic colorectal cancers can show loss of MLH1 protein expression caused by changes in the MLH1 gene promoter. MLH1 promoter hypermethylation testing can be used to directly test for these changes, or BRAF\xa0V600E mutation testing can be used, because this mutation is associated with MLH1 promoter hypermethylation. Using these tests can identify sporadic colorectal tumours that are MSI positive or have abnormal MLH1 protein expression in people who are not at risk for Lynch syndrome, and therefore prevent unnecessary further genetic testing.\n\n## Comprehensive mismatch repair gene mutation testing\n\nComprehensive screening for constitutional mutations in the MMR genes, and also possibly the EPCAM gene, is the gold standard for diagnosing Lynch syndrome. This involves gene sequencing to detect point mutations and small insertions or deletions in these genes, and also multiplex ligation-dependent probe amplification to detect larger structural changes to genes, such as deletions, duplications or rearrangements.\n\nComprehensive screening for constitutional mutations in MMR genes can identify novel sequence variations in these genes that are of unknown significance, that is, it is unknown whether they are pathological or non-pathological. It can therefore be uncertain as to whether people with such sequence variants should be diagnosed as having Lynch syndrome or not.\n\n# The comparator\n\nThe comparator used in this assessment is no testing to identify Lynch syndrome. That is, all people diagnosed with colorectal cancer are assumed not to have Lynch syndrome.", 'Evidence': "The diagnostics advisory committee (section\xa07) considered several sources of evidence on molecular testing strategies for Lynch syndrome in people with colorectal cancer. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\n## Diagnostic accuracy\n\nTen diagnostic accuracy studies that met the inclusion criteria for the systematic review were identified, 1\xa0of which was based in the UK (Barnetson et\xa0al. 2006). One of these studies (Poynter et\xa0al. 2008) had 2\xa0distinct samples that were treated separately in the review, so although there were 10\xa0included studies, there were 11\xa0included populations or datasets.\n\nFour of the included studies were single-gate studies recruiting population-based samples, that is, they recruited people with colorectal cancer regardless of their risk factors for Lynch syndrome. One study (Poynter et\xa0al. 2008) reported data from 2\xa0separate populations; 1\xa0seemed to be an unselected population with colorectal cancer and 1\xa0was in people at high risk of Lynch syndrome. The other 3\xa0studies with population-based samples (Barnetson et\xa0al. 2006; Limburg et\xa0al. 2011; Southey et\xa0al. 2005) included populations with colorectal cancer but specified age limits in their inclusion criteria. These were people younger than\xa055, younger than\xa050 and younger than 45\xa0years respectively. The ages of participants in Poynter et\xa0al. (2008) were not reported.\n\nA further 4\xa0studies (Caldes et\xa0al. 2004; Mueller et\xa0al. 2009; Overbeek et\xa0al. 2007; Shia et\xa0al. 2005), plus the second population in Poynter et\xa0al. (2008), were all classified as single-gate studies that recruited high-risk populations. The remaining 2\xa0studies recruited patients with colorectal cancer who were known to have Lynch syndrome (Hendriks et\xa0al. 2003; Okkels et\xa0al. 2012) and are referred to as reference standard positive studies. Studies based on high-risk populations and people known to have Lynch syndrome were only used to inform sensitivity estimates for the index tests.\n\nQuality appraisal of the included studies was done using the QUADAS‑2 tool. The external assessment group (EAG) commented that no evidence was found to show that the included studies were at high risk of bias.\n\nThe EAG noted that the index tests included in the assessment are highly susceptible to spectrum bias. In particular, the increased presence of mismatch repair (MMR) mutation carriers in a study population (for example, because of the age of the study population) could change the apparent sensitivity and specificity of the index tests. Significant methodological and clinical heterogeneity across studies was also noted; in particular, the reference standard differed between studies.\n\nBecause of the methodological and clinical heterogeneity seen, the EAG did not consider meta-analyses to be appropriate, and results were presented as a narrative summary. Most of the included studies assessed microsatellite instability (MSI) testing and immunohistochemistry (IHC); however, because none of the studies directly compared MSI testing and IHC, results were reported separately for each of the index tests.\n\nAll of the included studies, except Limburg et\xa0al. (2011) and Okkels et\xa0al. (2012), assessed MSI testing. There were several differences in the MSI testing procedures used in the included studies. These included variations in the number and types of markers in the panels of MSI markers used and also differences in the categorisation of test results; tumours were categorised using either 2\xa0categories (MSI positive or negative) or 3\xa0categories (MSI‑High [MSI‑H], MSI‑Low [MSI‑L] or microsatellite stable [MSS]). Studies also varied in the thresholds used to categorise MSI.\n\nSensitivity and specificity values were calculated based on a positive MSI test result for Lynch syndrome being MSI‑H alone or either MSI‑H or MSI‑L, as shown in table\xa03.\n\nTable\xa03 Accuracy estimates for MSI testing\n\nStudy\n\nTest positive: MSI‑H\n\nTest negative: MSI‑L or MSS\n\nTest positive: MSI‑H or MSI‑L Test negative: MSS\n\nSensitivity\n\n(%; 95%\xa0CI)\n\nSpecificity\n\n(%; 95%\xa0CI)\n\nSensitivity\n\n(%; 95%\xa0CI)\n\nSpecificity\n\n(%; 95%\xa0CI)\n\nSingle-gate, population-based samples\n\nPoynter et\xa0al. 2008a\n\n\n\nto 100.0\n\n\n\nto 65.1\n\n\n\nto 100.0\n\n\n\nto 33.4\n\nBarnetson et\xa0al. 2006\n\n\n\nto 82.7\n\n\n\nto 95.2\n\n\n\nto 99.2\n\n\n\nto 88.2\n\nSouthey et\xa0al. 2005\n\n\n\nto 90.3\n\n\n\nto 95.9\n\n\n\nto 99.9\n\n\n\nto 73.7\n\nSingle-gate, high-risk samples\n\nCaldes et\xa0al. 2004b\n\n\n\nto 91.3\n\n–\n\n\n\nto 91.3\n\n–\n\nMueller et\xa0al. 2009\n\n\n\nto 98.9\n\n–\n\n\n\nto 99.2\n\n–\n\nOverbeek et\xa0al. 2007b\n\n\n\nto 98.2\n\n–\n\n\n\nto 98.2\n\n–\n\nPoynter et\xa0al. 2008\n\n\n\nto 95.6\n\n–\n\n\n\nto 99.4\n\n–\n\nShia et\xa0al. 2005b\n\n\n\nto 100.0\n\n–\n\n\n\nto 100.0\n\n–\n\nReference standard positive study\n\nHendriks et\xa0al. 2003\n\n\n\nto 97.5\n\n–\n\n\n\nto 99.0\n\n–\n\na Population-based sample.\n\nb MSI‑L not defined.\n\nAbbreviations: CI, confidence interval; MSI, microsatellite instability; MSI‑H, microsatellite instability high; MSI‑L, microsatellite instability low; MSS, microsatellite stable.\n\nSecondary analyses were carried out if data allowed, with unclassified variants (variations in the sequence of MMR genes that are of unknown clinical significance) considered as positive reference standard results for Lynch syndrome (as opposed to negative reference standard results, as in primary analyses). The EAG noted that results were similar to those obtained when unclassified variants were considered as negative.\n\nIHC for MMR proteins was carried out in all of the 10\xa0included studies, although 2\xa0of the studies did not have enough data to be included in the IHC analyses: the high-risk samples in Poynter et\xa0al. (2008) and Mueller et\xa0al. (2009).\n\nThe accuracy estimates from included studies are shown in table\xa04. The proteins targeted by the tests used and the way results were reported differed between the studies. In 7\xa0studies (Barnetson et\xa0al. 2006; Limburg et\xa0al. 2011; Southey et\xa0al. 2005; Caldes et\xa0al. 2004; Overbeek et\xa0al. 2007; Shia et\xa0al. 2005; Hendriks et\xa0al. 2003), an overall result was given, that is, when abnormal staining of any of the MMR proteins assessed was classed as a positive IHC result. All of these 7\xa0studies assessed MLH1, MSH2 and MSH6 proteins. Southey et\xa0al. (2005) and Overbeek et\xa0al. (2007) also assessed PMS2. So, for these 2\xa0studies, an abnormal PMS2 result would also be included as a positive index test result.\n\nTable 4 Accuracy estimates for overall IHC testing\n\nStudy\n\nSensitivity\n\n(%; 95%\xa0CI)\n\nSpecificity\n\n(%; 95%\xa0CI)\n\nLR+\n\n(95%\xa0CI)\n\nLR−\n\n(95%\xa0CI)\n\nPPV\n\n(%; 95%\xa0CI)\n\nNVP\n\n(%; 95%\xa0CI)\n\nSingle-gate, population-based samples\n\nBarnetson et\xa0al. 2006\n\n\n\n(76.6 to 97.9)\n\nNE\n\n– a\n\n– a\n\n– a\n\n– a\n\nLimburg et\xa0al. 2011\n\n\n\n(42.1 to 99.6)\n\n\n\n(86.3 to 95.7)\n\n\n\n(5.7 to 19.7)\n\n\n\n(0.02 to 0.95)\n\n(13.3 to 59.0)\n\n(96.0 to 100.0)\n\nSouthey et\xa0al. 2005\n\n\n\n(81.5 to 100.0)\n\n\n\n(65.1 to 91.2)\n\n(2.8 to 9.5)\n\n(NE)\n\n(48.2 to 85.7)\n\n(89.4 to 100.0)\n\nSingle-gate, high-risk samples\n\nCaldes et\xa0al. 2004\n\n\n\n(81.7 to 99.9)\n\n–\n\n–\n\n–\n\n–\n\n–\n\nOverbeek et\xa0al. 2007\n\n\n\n(52.9 to 97.7)\n\n–\n\n–\n\n–\n\n–\n\n–\n\nShia et\xa0al. 2005\n\n\n\n(60.6 to 93.4)\n\n–\n\n–\n\n–\n\n–\n\n–\n\nReference standard positive study sample\n\nHendriks et\xa0al. 2003\n\n\n\n(77.5 to 98.2)\n\n–\n\n–\n\n–\n\n–\n\n–\n\na Analysis not done because overall IHC results were only available for reference standard positive participants.\n\nAbbreviations: IHC, immunohistochemistry; LR+, positive likelihood ratio; LR−, negative likelihood ratio; NE, not estimable; NPV, negative predictive value; PPV, positive predictive value.\n\nOnly 2\xa0studies (Caldes et\xa0al. 2004; Hendriks et\xa0al. 2003) had enough data to be included in the secondary analyses (in which unclassified variants were considered as positive reference standard results for Lynch syndrome). Only sensitivity estimates could be made because Caldes et\xa0al. included people at high risk of Lynch syndrome and Hendriks et\xa0al. included people known to have Lynch syndrome. Caldes et\xa0al. showed a reduction in sensitivity (75.0%; 95% confidence interval [CI] 57.8 to 87.9) compared with the primary analyses in which unclassified variants were categorised as negative reference standard tests (96.4%; 95% CI 81.7 to 99.9). For Hendriks et al., sensitivity was only slightly reduced from 91.7% (95% CI 77.5 to 98.2) to 88.6% (95% CI 76.0 to\xa095.0).\n\nNo end-to-end studies meeting the inclusion criteria for the systematic review were identified.\n\n# Cost effectiveness\n\n## Systematic review of cost effectiveness\n\nNine separate studies reporting the cost effectiveness of using MSI and IHC testing in strategies to identify Lynch syndrome in people with colorectal cancer met the inclusion criteria for the systematic review of existing economic evaluations. One study was reported in 2\xa0papers (Snowsill et\xa0al. 2014; Snowsill et\xa0al. 2015). Seven of the included studies were based in US populations, 1\xa0in Germany and 1\xa0in the UK.\n\nThe modelling approach used by the studies was similar. Most included a decision tree to model the diagnosis of Lynch syndrome, and a longer-term Markov or individual patient simulation model to estimate the costs and benefits associated with the outcomes of the diagnostic model. Conclusions on which were the most cost-effective strategies varied across these studies and depended on the maximum acceptable incremental cost-effectiveness ratio (ICER) and comparators used in the analysis. No single strategy was consistently most cost effective.\n\nWhen a universal genetic testing strategy was assessed by the studies, strategies that used tumour-based tests, such as IHC or MSI, to select the population having full genetic testing seemed to improve the cost-effectiveness estimates. Most studies agreed that the effectiveness of colonoscopy screening, number of relatives and prevalence of Lynch syndrome were the parameters that had the greatest effect on the cost effectiveness of the testing strategies assessed.\n\n## Modelling approach\n\nAn economic model was developed to assess the cost effectiveness of molecular testing strategies for Lynch syndrome in people with colorectal cancer. This was based on a previously constructed model, as described in Snowsill et\xa0al. (2014 and 2015).\n\nThe model included:\n\na decision tree model to investigate the short-term outcomes of strategies to identify people with Lynch syndrome and\n\nan individual patient simulation model to assess the long-term implications of strategies to identify and manage Lynch syndrome; the model considers longer-term outcomes for both colorectal and endometrial cancer.\n\nThe decision tree started with people diagnosed with colorectal cancer (called 'probands') who could have 1\xa0of 10\xa0diagnostic strategies for Lynch syndrome, as described in table\xa05. As a result of these diagnostic strategies, probands were either diagnosed as LS‑positive, LS‑negative or LS‑assumed (if they refused genetic testing). People who were diagnosed as LS‑positive or LS‑assumed were offered 2‑yearly colonoscopies, which they could either accept or decline. People diagnosed as LS‑negative had standard colorectal cancer follow‑up and surveillance.\n\nDecision tree models were also included for relatives of probands. Those diagnosed as LS‑positive were offered testing (which they could accept or decline). Relatives who tested positive for Lynch syndrome, or who declined testing, were offered surveillance (which they could either accept or decline). First-degree relatives of probands diagnosed as LS‑assumed were also offered surveillance. No further action was taken for the relatives of probands who did not have Lynch syndrome.\n\nTable\xa05 Diagnostic strategies for probands\n\nStrategy number\n\nDescription\n\n\n\nNo systematic testing to identify LS (all probands assumed to not have LS).\n\n\n\nIHC\xa04‑panel test for MLH1, MSH2, MSH6 and PMS2, then genetic testing if the IHC result is abnormal for 1\xa0of them.\n\n\n\nIHC\xa04‑panel test for MLH1, MSH2, MSH6 and PMS2, then:\n\ngenetic testing for abnormal MSH2, MSH6 or PMS2 IHC results, or\n\nBRAF\xa0V600E testing for an abnormal MLH1 IHC result, if negative for V600E (a 'wild type' result) then genetic testing is carried out.\n\n\n\nIHC\xa04‑panel test for MLH1, MSH2, MSH6 and PMS2, then:\n\ngenetic testing for abnormal MSH2, MSH6 or PMS2 IHC results, or\n\nMLH1 promoter hypermethylation testing for an abnormal MLH1 IHC result, if negative then genetic testing is carried out.\n\n\n\nIHC\xa04‑panel test for MLH1, MSH2, MSH6 and PMS2, then:\n\ngenetic testing for abnormal MSH2, MSH6 or PMS2 IHC results, or\n\nBRAF\xa0V600E testing for an abnormal MLH1 IHC result, if negative then MLH1 promoter hypermethylation testing is done, if the MLH1 promoter hypermethylation test is negative, genetic testing is carried out.\n\n\n\nMSI test, if positive then genetic testing is done.\n\n\n\nMSI test, if positive then BRAF\xa0V600E testing, if negative for V600E (a 'wild type' result) then genetic testing is done.\n\n\n\nMSI test, if positive then MLH1 promoter hypermethylation testing, if the MLH1 promoter hypermethylation test is negative, then genetic testing is done.\n\n\n\nMSI test, if positive then BRAF\xa0V600E testing, if negative for V600E then an MLH1 promoter hypermethylation test is done, if the MLH1 promoter hypermethylation test is negative, then genetic testing is done.\n\n\n\nUniversal genetic testing (that is, the first and only test for all probands).\n\nAbbreviations: IHC, immunohistochemistry; MSI, microsatellite instability; LS, Lynch syndrome.\n\nThe longer-term model included outcomes relating to surveillance and treatment for both colorectal cancer and gynaecological (endometrial) cancer. Longer-term outcomes were modelled for all probands and relatives (regardless of the diagnostic path they follow) using an individual patient sampling model to simulate 240,000\xa0patients, distributed across 24\xa0groups, representing all combinations of the following variables:\n\nwhether the person was a proband or relative\n\nwhether the person had Lynch syndrome\n\nwhether the person had been diagnosed with Lynch syndrome and accepted or declined surveillance\n\nsex.\n\nPatients were simulated for 1\xa0year at a time in the model, with the events that happened to them during that year, as well as the life years and quality-adjusted life years (QALYs) they accumulated, being determined by the health state they were in.\n\nEstimates of test accuracy were taken from available literature identified through the diagnostic-accuracy and cost-effectiveness literature reviews. To estimate the accuracy of MSI and IHC testing, results from studies included in the clinical-effectiveness review were pooled using a multilevel mixed-effects logistic regression analysis. For MSI testing, the results from Barnetson et\xa0al. (2006), the population-based sample from Poynter et\xa0al. (2008) and Southey et\xa0al. (2005) were pooled, and for IHC testing, the results from Limburg et\xa0al. (2011) and Southey et\xa0al. (2005) were pooled.\n\nDiagnostic-accuracy data for BRAF\xa0V600E and MLH1 promoter methylation testing were taken from Ladabaum et\xa0al. (2015). This study pooled values from studies reporting test accuracy, with included studies using various types of previous testing for Lynch syndrome (including MSI and IHC testing). Test accuracy parameters used in modelling are shown in table\xa06.\n\nTable\xa06 Test accuracy parameters used in modelling\n\nTest\n\nParameter\n\nParameter value (95% CI)\n\nMSI\n\nBase case: MSI test positive=MSI‑H\n\nSensitivity\n\n(0.426 to 0.993)\n\nSpecificity\n\n(0.638 to 0.937)\n\nMSI\n\nScenario analysis: MSI test positive=MSI‑L and MSI‑H\n\nSensitivity\n\n(0.893 to 0.994)\n\nSpecificity\n\n(0.304 to 0.833)\n\nIHC\n\nSensitivity\n\n(0.694 to 0.996)\n\nSpecificity\n\n(0.790 to 0.940)\n\nBRAF\xa0V600E\n\nSensitivity\n\n(0.600 to 0.990)\n\nSpecificity\n\n(0.600 to 0.870)\n\nMLH1 promoter methylation\n\nSensitivity\n\n(0.790 to 0.980)\n\nSpecificity\n\n(0.590 to 0.860)\n\nDiagnostic genetic testing for probands\n\nSensitivity\n\nMLH1, MSH2, MSH6: 0.90\n\nPMS2: 0.67\n\nSpecificity\n\n\n\nPredictive testing for relatives\n\nSensitivity\n\n\n\nSpecificity\n\n\n\nAbbreviations: CI, confidence interval; IHC, immunohistochemistry; MSI, microsatellite instability; MSI‑H, microsatellite instability high; MSI‑L, microsatellite instability low.\n\nEstimates of parameter values relating to acceptance of tests, colorectal cancer surveillance, stage of cancer at diagnosis, gynaecological surveillance and chemoprevention were taken from identified literature, registry data and clinical expert opinion.\n\nCosts of preliminary tumour testing, genetic tests (for both probands and relatives), and genetic counselling were sourced from the UK Genetic Testing Network (2016), Health and Social Care Unit Costs and from personal communication with providers. Further relevant costs came from NHS references costs (2014/15 and updated to 2016/17 prices), identified literature, the British national formulary (BNF 2016) and the NHS drug tariff.\n\nUtilities associated with colorectal cancer, endometrial cancer and prophylactic hysterectomy were taken from published literature identified by systematic searches. Disutilities associated with genetic testing used in the model were as previously reported in Snowsill et\xa0al. (2014).\n\nThe key assumptions applied in the base-case analysis were:\n\nMSI‑L was considered a negative result.\n\nThe sensitivity of MSI and IHC testing did not depend on which MMR gene is mutated.\n\nAll people who accepted genetic testing had testing for all 4\xa0MMR genes, unless they followed a strategy that used IHC, in which case they had either BRAF\xa0V600E or MLH1 promoter hypermethylation testing and only MLH1 and PMS2 were tested.\n\nThe average number of relatives per proband was\xa06 (2.5\xa0of whom were first-degree relatives).\n\nSurveillance colonoscopies reduced the incidence of colorectal cancer by 61%, and the incidence of metachronous colorectal cancer by 47%.\n\nSurveillance colonoscopies improved the proportion of people in whom colorectal cancer was diagnosed at an early stage (stage\xa0I or\xa0II) from 44.6% to 79.1%.\n\nColorectal surveillance colonoscopies occurred every 2\xa0years.\n\nGynaecological surveillance reduced endometrial cancer mortality by\xa010%.\n\nPeople taking aspirin had a reduced incidence of colorectal and endometrial cancer that lasted for 10\xa0years.\n\nDisutility was only applied to people with stage\xa0IV colorectal cancer.\n\nNo disutility arising from prophylactic hysterectomy was assumed.\n\nInitial acceptance of colonoscopic surveillance was 97% for probands and relatives who tested positive for Lynch syndrome mutation, and 70% for probands and relatives who were assumed to have Lynch syndrome.\n\nThe base-case analysis included 238,175\xa0simulated individuals and represents an annual cohort of 34,025\xa0probands with colorectal cancer and 204,150\xa0relatives.\n\nPairwise ICERs were calculated for all strategies compared with no testing (strategy\xa01). Only strategy\xa010 (universal genetic testing) had an ICER above £20,000 per QALY gained, with ICERs for strategies 2\xa0to\xa09 all below £14,000 per QALY gained. Comparative (fully incremental) ICERs were also calculated for all strategies. Strategies involving MSI testing were either dominated (that is, they were less effective and more expensive than another option) or extendedly dominated (that is, a combination of other options were more effective and less expensive) by other strategies. The ICER for strategy\xa03 (IHC plus BRAF\xa0V600E) was £37,495 per QALY gained and the ICER for strategy\xa05 (IHC plus BRAF\xa0V600E and MLH1 promoter methylation) was £11,008 per QALY gained.\n\nSubgroup analyses were carried out by restricting the age of probands, who have Lynch syndrome testing strategies, included in the model. The age groups were: under 50\xa0years, under 60\xa0years, under 70\xa0years, and 70\xa0years or over.\n\nWhen the proband population was restricted to people under 50\xa0years, all the strategies had ICERs of less than £13,000 per QALY gained compared with no testing (strategy\xa01). Strategies\xa03 (IHC plus BRAF\xa0V600E; £19,903) and\xa05 (IHC plus BRAF\xa0V600E and MLH1 promoter methylation; £8,090) had ICERs under £20,000 per QALY gained in the fully incremental analysis.\n\nWhen the proband population was restricted to people under 60\xa0years, all the strategies had ICERs of less than £17,000 per QALY gained compared with no testing (strategy\xa01). Only strategy\xa05 (IHC plus BRAF\xa0V600E and MLH1 promoter methylation; £9,156) had an ICER below £20,000 per QALY gained in the fully incremental analysis.\n\nWhen the proband population was restricted to people under 70\xa0years, all the strategies had ICERs of less than £20,000 per QALY gained compared with no testing (strategy\xa01), except for strategy\xa010 (universal genetic testing), which had an ICER of £20,528 per QALY gained. Only strategy\xa05 (IHC plus BRAF\xa0V600E and MLH1 promoter methylation; £9,912) had an ICER below £20,000 per QALY gained in the fully incremental analysis.\n\nWhen the proband population was restricted to people 70\xa0years or over, strategies\xa05 (IHC plus BRAF\xa0V600E and MLH1 promoter methylation), 7\xa0(MSI plus BRAF\xa0V600E) and 9\xa0(MSI plus BRAF\xa0V600E and MLH1 promoter methylation) had ICERs less than £20,000 per QALY gained compared with no testing (strategy\xa01). Strategies\xa05 (£18,839) and\xa09 (£18,766) had ICERs below £20,000 per QALY gained in the fully incremental analysis.\n\nIf both MSI‑L and MSI‑H test results were assumed to indicate Lynch syndrome (in the base-case analysis, only MSI‑H is indicative), this effectively lowered the threshold for a positive MSI test result. Only strategies involving MSI testing (strategies\xa06 to\xa09) were affected, with ICERs for testing compared with no testing increased relative to the base-case analysis. As for the base-case analysis, strategy\xa05 was the only strategy with an ICER below £20,000 cost per QALY gained (unchanged at £11,008) in the fully incremental analysis.\n\nIf aspirin was not included as a risk-reducing component in the model (as it was in the base-case analysis), this resulted in a marginal increase in ICER values, and strategy\xa05 remained the optimal strategy with an ICER of £11,659 per QALY gained in the fully incremental analysis.\n\nIn the base-case analysis, if gynaecological surveillance was accepted, it reduced the risk of mortality from endometrial cancer. Two scenarios were considered: 1\xa0assuming that gynaecological surveillance has no benefit (but still has a cost) and another that removed gynaecological surveillance from the model (no cost and no benefit). For both scenarios, strategy\xa05 remained the optimal strategy and the only strategy with an ICER below £20,000 per QALY gained in the fully incremental analysis.\n\nIn the base-case analysis, the quality of life for people with colorectal cancer, except Dukes' stage\xa0D, was assumed to be similar to the general population (that is, a disutility value of\xa00). In this scenario analysis, increased disutility values for all colorectal cancer stages were used and values were based on Ness et\xa0al. (1999). When compared with the base-case analysis, ICER values for all strategies compared with no testing were reduced. Strategy\xa05 remained the optimal strategy, with an ICER of £9,775 per QALY gained in the fully incremental analysis.\n\nIf colonoscopic surveillance was assumed to have no effect on colorectal cancer incidence, ICERs for all strategies were increased compared with no testing (strategy\xa01), with only 3\xa0strategies remaining, marginally, below £20,000 per QALY gained. Strategy\xa05 remained the only strategy with an ICER below £20,000 per QALY gained in the fully incremental analysis; however, this value increased to £19,194 per QALY gained (from £11,008 per QALY gained in the base case).\n\nDeterministic sensitivity analyses were carried out for several parameters in the model. The ICERs for the testing strategies were sensitive to several parameters. When sensitivity and specificity values for all tumour tests (MSI, IHC, BRAF\xa0V600E and MLH1 promoter methylation) were both reduced to their lower 95% confidence interval values, the ICER for strategy\xa05 compared with no testing increased to £16,036 per QALY gained.\n\nAltering diagnostic accuracy can also affect which strategy is optimal. When sensitivity was reduced for all tumour tests, strategy\xa04 became the optimal strategy (IHC followed by MLH1 promoter methylation). When sensitivity values were increased for all tumour tests (to their upper 95% confidence interval values), MSI testing strategies became optimal, despite MSI testing still having lower sensitivity and specificity values than IHC testing. In addition, when the cost of IHC was doubled, or the cost of MSI testing halved (both relative to base-case values), strategy\xa07 (MSI followed by BRAF\xa0V600E) became the optimal strategy.\n\nDecreasing the acceptance by probands of both genetic counselling and testing after counselling (set at 90% and 92.5% respectively in the base-case analysis) to 50%, increased the ICER for strategy\xa05 compared with no testing to £17,767 per QALY gained (from £11,008 per QALY gained).\n\nIncreasing the incidence of colorectal cancer in people with Lynch syndrome in the model decreased the ICER for strategy\xa05 compared with no testing to £6,689 per QALY gained, whereas decreasing the incidence of colorectal cancer increased this value to £19,300 per QALY gained.\n\nIn the base-case analysis, people who were diagnosed as LS‑assumed because they declined genetic testing were considered as positive for Lynch syndrome. If all LS‑assumed probands, and their relatives, were instead considered to be negative for Lynch syndrome, the ICER for strategy\xa05 compared with no testing decreased to £5,225 per QALY gained.\n\nSix relatives per proband were assumed in the base-case analysis. If only probands were included in the model (that is, no relatives included), the ICERs for all strategies increased, with strategy\xa05 compared with no testing increasing to £17,921 per QALY gained. Increasing the number of relatives per proband to\xa012 decreased the ICERs slightly, with strategy 5\xa0compared with no testing decreasing to £10,068 per QALY gained.\n\nIf the costs of colonoscopy used in the base-case analysis were doubled, all ICERs for strategies compared with no testing increased; for example, for strategy\xa05, this increased to £16,630 per QALY gained. Reducing the acceptance of colonoscopy surveillance by people with confirmed Lynch syndrome causing mutations from 97% (as in the base-case analysis) to 70% increased the ICERs for strategies compared with no testing (for example, to £12,632 per QALY gained for strategy\xa05).\n\nIn the base-case analysis, disutility associated with prophylactic hysterectomy and bilateral salpingo-oophorectomy was assumed to be\xa00. Increasing the disutility value to 0.04 for 1\xa0year increased the ICERs for all strategies compared with no testing, with the value for strategy\xa05 increasing to £14,441 per QALY gained.", 'Committee discussion': "The committee discussed current practice for assessing the risk of Lynch syndrome in people with colorectal cancer. It heard that testing is usually only carried out in people with colorectal cancer who are under 50\xa0years at the time of diagnosis. The committee heard from clinical experts that guidelines to target testing for Lynch syndrome, such as the Amsterdam criteria and Revised Bethesda Guidelines, are often not used in current practice because they were developed to identify research populations. Also, required information, such as a detailed family history, is often not available and there are concerns over the sensitivity of these methods to detect Lynch syndrome. The committee also heard that the provision of testing for Lynch syndrome and other inherited colorectal cancers varies widely, with an estimated 50% of centres providing tests to assess the risk of Lynch syndrome in people under the age of\xa050 who have been diagnosed with colorectal cancer.\n\nThe committee discussed the effect that a diagnosis of Lynch syndrome may have on people with colorectal cancer and their families. It heard from a patient expert that many people are unaware that their colorectal cancer could be hereditary and therefore do not ask questions about whether they should have further genetic testing, unless this issue is raised by their clinician. It also heard that people who are diagnosed with Lynch syndrome often find that the diagnosis is of benefit to both themselves and their family. The diagnosis can help a person to be placed on an appropriate pathway for colorectal cancer treatment and make decisions about further surveillance. Family members can also have genetic testing and surveillance to reduce their risk of developing cancer. The committee also heard that good communication between healthcare professionals and patients is needed so that people get their test results as soon as possible, which can reduce their anxiety. The committee concluded that assessing the risk of Lynch syndrome in people with colorectal cancer could have substantial benefits for patients and their families.\n\n# Clinical effectiveness\n\nThe committee reviewed the available evidence on the clinical effectiveness of using immunohistochemistry (IHC) testing of tumour tissue for mismatch repair (MMR) proteins and microsatellite instability (MSI) to identify tumours with deficient DNA mismatch repair in people with colorectal cancer to assess their risk of having Lynch syndrome.\n\nThe committee discussed the generalisability of data from the studies, which were identified in the clinical review, to the decision problem. It noted that estimates for sensitivity values were taken from all the studies in the review, which included colorectal cancer patients who were identified as being at high risk of Lynch syndrome and age-limited patient populations that would be expected to have a higher prevalence of Lynch syndrome. The committee heard from the external assessment group (EAG) that the incidence of MSI in sporadic colorectal cancer increases with age and that this may alter test accuracy values in different age groups. The committee concluded that although there were differences in the trial populations in identified studies and the population of people with colorectal cancer in the UK, the effect of this on test accuracy was likely to be minimal.\n\nThe committee considered the evidence available on the diagnostic accuracy of MSI and IHC testing for MMR proteins. It noted that no identified studies directly compared MSI and IHC testing. It heard from the clinical experts that, in their experience, these tests are comparable in diagnostic accuracy. The committee noted that the tests appeared to be accurate enough for detecting MSI or abnormal expression of MMR proteins, but noted that these findings alone are not enough to diagnose Lynch syndrome without second-line tumour-based testing and subsequent genetic testing. Further, it heard that external quality assurance programmes are used to ensure the accuracy and consistency of testing between laboratories. The committee also heard that both tests are used in current practice in the NHS, and that the choice of test used is often determined by locally available services and expertise. The committee concluded that these tests are broadly comparable in accuracy.\n\nThe committee discussed the issue of unclassified variants, that is, when genetic testing identifies variations in the sequence of MMR genes that are of unknown clinical significance. This can affect whether results from the reference standard test are classified as positive or negative. The committee noted that relatively few studies identified in the clinical review had enough data to allow alternative analyses when unclassified variants were considered as positive reference standard results for Lynch syndrome. The clinical experts commented that in practice, unclassified variants are investigated further by asking for additional clinical information and testing before a diagnosis is given. The committee also heard that there are ongoing efforts to classify sequence variants in MMR genes and that the number of unclassified variants is therefore decreasing. The committee concluded that unclassified variants are unlikely to have a large effect on diagnosing Lynch syndrome in clinical practice.\n\n# Cost effectiveness\n\nThe committee considered the cost effectiveness of the different testing strategies to identify Lynch syndrome in people with colorectal cancer. It noted that 10\xa0strategies had been modelled, each using different combinations of tumour-based tests and genetic testing (see table\xa05).\n\nThe committee discussed the assumptions about the effectiveness of aspirin as a risk-reducing strategy for people with Lynch syndrome that were made in the economic model. It heard from the EAG that in the model, the effect of aspirin in reducing the risk of colorectal and endometrial cancer was assumed to occur instantaneously and last for 10\xa0years, after which time the effect was assumed to stop instantaneously. However, the committee heard from the clinical experts that the Colorectal adenoma/carcinoma prevention programme\xa02 (CaPP2) trial of aspirin prophylaxis in Lynch syndrome reported that there is a lag time in the protective effect after starting therapy and that its effects can continue after people stop taking aspirin. The committee noted that the scenario analysis without the costs and effects of aspirin prophylaxis showed no substantial effect on overall results. The committee concluded that the effect of the assumptions about aspirin prophylaxis was likely to be small.\n\nThe committee discussed the effect estimates of colonoscopic surveillance used in the model. It noted that a study used to estimate the effectiveness of colonoscopic surveillance in people with Lynch syndrome in the model was about 15\xa0years old and questioned whether this represents current practice in the NHS. The committee heard from the clinical experts that recent technological developments in this area and the introduction of standards by the Joint Advisory Group on Gastrointestinal Endoscopy have improved the effectiveness of colonoscopic surveillance. Data from cancer screening programmes have also shown that colonoscopic surveillance can lead to the detection of colorectal cancer at an earlier stage, which could improve patient outcomes. The committee also noted that the effectiveness of colonoscopic surveillance is likely to be influenced not only by the effectiveness of the test, but also by patient uptake and were reassured by the clinical experts that uptake of surveillance was high among people with Lynch syndrome. The committee concluded that colonoscopic surveillance is likely to reduce the risk of cancer developing in people with Lynch syndrome, and that consequently the effect estimate used in the base-case analysis was appropriate.\n\nThe committee considered the results of the base-case analysis, which suggested that strategies that began with IHC for MMR proteins were more cost effective than those that began with MSI testing, and that overall, strategy\xa05 appeared to be the most cost effective. The committee discussed the extent to which the results of the model were driven by the sensitivity and specificity parameter values used in the model. It noted that in the base-case analysis, MSI testing was assumed to be both less sensitive and less specific than IHC testing. The committee considered that, given the perceived equivalence of MSI and IHC testing and the absence of direct comparative data, there was not enough evidence to conclude that testing strategies that begin with MSI testing are not cost effective compared with IHC testing for MMR proteins.\n\nThe committee discussed the scenario analysis in which MSI‑Low (MSI‑L) was classified as a positive result for Lynch syndrome and noted that only MSH‑High (MSI‑H) was considered a positive result in the base case. It heard from the clinical experts that in current practice, both MSI‑L and MSI‑H results are generally considered indicative of Lynch syndrome. The results of the scenario analysis suggested that including MSI‑L as a positive result did not affect the cost effectiveness of the MSI‑based testing strategies. The committee concluded that both MSI‑L and MSI‑H should be considered as positive results.\n\nThe committee discussed the role of BRAF\xa0V600E and MLH1 promoter hypermethylation testing in the modelled strategies. It heard from the clinical experts that some tumours that test positive for MSI, or that have abnormal MLH1 protein expression, are sporadic colorectal cancers. Further, it heard that BRAF\xa0V600E and MLH1 promoter hypermethylation testing, particularly in combination, can be used to identify sporadic colorectal cancers and so reduce the number of people who are referred for genetic testing for Lynch syndrome. In addition, the clinical experts advised that testing strategies that aim to decrease the number of false-positive diagnoses for Lynch syndrome reduce the number of people having unnecessary colonoscopic surveillance. The committee concluded that strategies\xa05 and\xa09, which include tests to identify sporadic colorectal cancers, after first having MSI or IHC testing, are likely to be the most cost-effective options.\n\nThe committee discussed the cost effectiveness of the testing strategies in different age groups. It noted that the age-restricted subgroup analysis had little effect on the overall conclusions, but that referral straight to genetic testing was unlikely to be cost effective in older age groups. The committee heard from the clinical experts that although the prevalence of Lynch syndrome is much higher in younger people with colorectal cancer, it can still cause colorectal cancer in older people. It also heard that despite the lower prevalence of Lynch syndrome in older people, the greater number of colorectal cancer diagnoses in these age groups could mean that the absolute number of people who could benefit from a Lynch syndrome diagnosis may be similar to that in younger age groups. Therefore, the committee considered that there is no clinical reason to treat age groups differently. The committee concluded that all people, regardless of their age, with colorectal cancer should have tumour-based testing to assess the risk of Lynch syndrome.\n\nThe committee considered the joint effect of parameter uncertainty used in the model, and noted that this had not been explored in a probabilistic sensitivity analysis. It heard from the EAG that the univariate deterministic sensitivity analyses did not result in large changes to the incremental cost-effective ratios (ICERs) or the net health benefit values, and that it was unlikely that negative net health benefit values would be seen in a probabilistic sensitivity analysis. The committee considered that parameter uncertainty had been explored sufficiently, and that further analyses were unlikely to substantially change the overall results of the economic modelling. Therefore, the committee concluded that testing all people with colorectal cancer using strategies\xa05 (IHC plus BRAF\xa0V600E and MLH1 promoter methylation) and\xa09 (MSI plus BRAF\xa0V600E and MLH1 promoter methylation) would be a cost-effective use of NHS resource.\n\n# Other considerations\n\nThe committee discussed the timing of testing for Lynch syndrome in people who have been diagnosed with colorectal cancer. It heard from the clinical experts that a person's MMR tumour or gene status may be used to determine treatment options for colorectal cancer, for example, to direct surgical decisions or chemotherapy, although the clinical utility of using tumour testing to guide the selection of chemotherapy is not fully understood at present. However, it noted that it is very unlikely that definitive genetic testing will be completed before treatment for colorectal cancer begins. The committee therefore concluded that testing for Lynch syndrome should be started as soon as colorectal cancer is diagnosed, but should not delay the start of treatment.\n\nThe committee discussed which tissue samples should be used for testing. It heard from the clinical experts that there is good correlation between results for tissue from biopsies and tissue from resections. The committee concluded that clinical judgement should be used to determine the tumour material to be tested, and that tissue from a biopsy, resected colorectal tumour or polyp can be used. The committee also noted that people with Lynch syndrome may develop more than 1\xa0colorectal cancer at the same time. It heard from the clinical experts that some of these cancers may differ in DNA mismatch repair functionality because people with Lynch syndrome can get sporadic colorectal cancers. The committee concluded that testing for Lynch syndrome should be considered for each individual cancer.\n\nThe committee noted that Lynch syndrome is not the only inherited condition that increases the risk of colorectal cancer. It heard from the clinical experts that other inherited causes of colorectal cancer include familial adenomatous polyposis. The clinical experts also emphasised that it is important that these additional inherited conditions are considered if someone is found not to have Lynch syndrome but the clinician suspects that the person's family history suggests that a genetic cause is likely. The committee concluded that clinical judgement should be used to determine whether a referral to clinical genetics is appropriate when Lynch syndrome has been ruled out by tumour-based testing, but other genetic causes are suspected.\n\nThe committee considered ongoing developments in genetic testing technologies. It noted that in the future, broad-range genetic sequencing or specific cancer panels using next-generation sequencing technology may be considered for diagnosing Lynch and other inherited colorectal cancer syndromes. The committee concluded that these advances may identify alternative and more rapid methods for diagnosing Lynch syndrome.\n\n# Research considerations\n\nThe committee discussed the value of developing research recommendations for tumour testing for Lynch syndrome. It considered that further research was unlikely to change its recommendations on molecular testing strategies for Lynch syndrome in people diagnosed with colorectal cancer.\n\nThe committee heard that good communication between colorectal cancer multidisciplinary teams and genetics or pathology laboratories is important for implementing tumour-based testing for Lynch syndrome to ensure that testing and reporting of results is coordinated. The committee noted that similar systems are embedded in breast cancer care pathways, in which reflex testing for human epidermal growth factor receptor\xa02 (HER2) and BRCA are done as part of the first assessment. The committee therefore wished to encourage centres adopting Lynch syndrome testing strategies to audit and publish their clinical and diagnostic outcomes to ensure that assessment of Lynch syndrome is timely and appropriate.\n\nThe committee heard from the clinical experts that centres already offering tumour-based testing for Lynch syndrome often carry out both MSI and IHC testing on samples. The committee encouraged these centres to publish their previously generated comparative results."}	https://www.nice.org.uk/guidance/dg27	Evidence-based recommendations on using immunohistochemistry or microsatellite instability testing to guide further testing for Lynch syndrome in people with colorectal cancer.
ce2e72caad79af6217d1e0f19ab037611a9a1b50	nice	Lateral interbody fusion in the lumbar spine for low back pain	Lateral interbody fusion in the lumbar spine for low back pain Evidence-based recommendations on lateral interbody fusion in the lumbar spine for low back pain in adults. This involves removing the damaged disc and fixing parts of the spine together, to relieve pain. # Recommendations Current evidence on the safety of lateral (including extreme, extra and direct lateral) interbody fusion in the lumbar spine for low back pain shows there are serious but well-recognised complications. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. This procedure should only be done by surgeons with specific training in the technique, who should carry out their initial procedures with an experienced mentor. Clinicians should enter details about all patients having lateral interbody fusion in the lumbar spine for low back pain onto the British Spine Registry.# Indications and current treatments Chronic low back pain may result from degenerative changes in the intervertebral discs or spinal facet joints. Conservative treatments include analgesics, non‑steroidal anti-inflammatory medication and manual therapy. For people with severe, life-limiting, chronic low back pain that does not respond to conservative treatments, surgery may be appropriate. This may include bony fusion of vertebrae (to immobilise segments of the vertebral column thought to be responsible for back pain, using either a posterior or anterior approach) or inserting a prosthetic intervertebral disc (which preserves lumbar mobility to reduce the risk of degenerative changes in adjacent intervertebral disc spaces). Other surgical alternatives include non‑rigid stabilisation techniques.# The procedure The aim of lateral interbody fusion in the lumbar spine is to achieve spinal fusion by a side or lateral approach, to avoid the major muscle groups in the back (posterior approach) or the organs and blood vessels in the abdomen (anterior approach). The procedure is done with the patient under general anaesthesia. A probe is inserted laterally through the psoas muscle, under fluoroscopic guidance, to lie alongside the affected disc. A posterior incision is also sometimes made, to allow access for manipulation of the probe. Nerve monitoring is recommended by many specialists. Dilators are inserted around the probe and a retractor is positioned to give the surgeon direct access to the spine. A discectomy is carried out and a cage implant inserted to hold the vertebrae in position. A bone graft (usually from the hip) is inserted between the 2 vertebrae, sometimes with additional support from screws, plates or rods. The procedure may be done at more than 1 level during the same operation. A recent variation of this procedure is oblique lateral interbody fusion, which involves retroperitoneal access anterior to the psoas. It may take a few months before patients are able to return to their normal activities after the procedure. There are a number of different devices used for this procedure.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of 237 articles on lateral lumbar interbody fusion, the weighted average for the rate of fusion in all patients was 94% (n=907 patients; 22 study arms). In the systematic review of 237 articles, the weighted average for improvement in pain, measured on a visual analogue scale, was 60% (n=2,097 patients; 41 study arms). In a non-randomised comparative study of 202 patients treated by extreme lateral interbody fusion (LIF) or open anterior lumbar interbody fusion (ALIF), low back pain scores, measured on a scale of 0–10, improved from 7.5 at baseline in both groups (n=95) to 2.4 and 2.6 respectively at 12‑month follow-up (n=61; p<0.001 compared with baseline; p=not significant for between group comparison). Mean leg pain, measured on a scale of 0–10, improved from 5.8 in the extreme LIF group and 5.4 in the ALIF group at baseline (n=95) to 1.6 and 2.0 respectively at 12‑month follow-up (n=61), in the same study (p<0.001 compared with baseline; p value not significant for between group comparison). In the systematic review of 237 articles, the weighted average for improvement in disability, measured on the Oswestry Disability Index (ODI), was 48% (n=1,234 patients; 29 study arms). In the non-randomised comparative study of 202 patients treated by extreme LIF or ALIF, the ODI improved from 59% at baseline in both groups (n=95) to 23% and 24% respectively at 12‑month follow-up (n=61; p<0.001 compared with baseline; p value not significant for between group comparison). In a case series of 160 patients, the ODI improved from 44% at baseline to 23.5% at the last follow-up (mean follow-up 18.5 months; p value not reported). In the systematic review of 237 articles, the weighted average for patient satisfaction was 89% (n=491 patients; 9 study arms); 85% of patients said that they would have the procedure again if their outcome had been known in advance. In a randomised controlled trial (RCT) and non‑randomised comparative study of 55 patients treated by extreme LIF or transforaminal interbody fusion (TLIF), 91% and 80% of patients respectively were satisfied with their outcome at 24‑month follow-up (p=0.393) and 100% and 90% of patients respectively would be willing to have the same procedure had their outcome been known in advance (p=0.210). In a non-randomised comparative study of 208 patients treated by extreme LIF or ALIF, 95% (198/208) of patients were satisfied with the procedure and reported improvement; 10 patients did not improve or worsened (radiological and clinical results were similar in both groups). In the RCT and non‑randomised comparative study of 55 patients treated by extreme LIF or TLIF, mean quality-of-life scores for the SF‑36 physical component improved from 37.7 and 39.5 respectively at baseline to 61.4 and 64.9 at 24‑month follow-up (p<0.05 compared with baseline). Mean quality-of-life scores for the SF‑36 mental component improved from 51 and 52.2 respectively at baseline to 67.2 and 69.2 at 24‑month follow-up (p<0.05 compared with baseline). In the case series of 160 patients, the SF‑36 physical component score improved from 30.9 at baseline to 43.2 at the last follow-up (mean follow-up 18.5 months; p value not reported). The specialist advisers listed the key efficacy outcomes as patient reported outcome measures, including reduced pain, and radiological outcomes, including fusion of the lumbar spine and restoration of the disc height.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of 237 articles, the weighted averages for thigh side effects, hip flexion weakness and motor neural deficits were 26% (n=2,772), 21% (n=1,360 patients; 22 study arms) and 3% (n=1,568 patients; 14 study arms) respectively. In a systematic review of 34 studies, neurological adverse events (transient motor weakness, hypoaesthesia, transient or persistent thigh symptoms, injury to lumbosacral plexus, injury to femoral nerve) were reported. These occurred in 9% (209/2,342) of patients treated by extreme lateral interbody fusion (LIF) compared with 5% (27/544) of patients treated by anterior lumbar interbody fusion (ALIF) when Food and Drug Administration (FDA) reports were excluded (p=0.0015) and in 9% (130/1,379) of patients treated by ALIF when FDA reports were included (p=0.605). In the extreme LIF group, 43% (90/209) of the neurological adverse events resolved within 3 months of the procedure, 16% (33/209) lasted between 3 months and 2 years or throughout the last follow-up; there was no information on the remaining 41% (86/209) of complications. Sensory deficit was reported in 27% (585/2,160) of patients treated by lateral lumbar interbody fusion (LLIF) compared with 20% (380/1,885) of patients treated by minimally-invasive transforaminal lumbar interbody fusion (MI‑LIF, p<0.0001) in a systematic review of 96 studies (n=9,714 patients). Temporary neurological deficit was reported in 9% (278/2,957) of patients treated by LLIF and 2% (30/1,349) of patients treated by MI-LIF (p<0.0001). Permanent neurological deficit was reported in 3% (62/2,525) and 1% (14/1,382) of patients respectively (p=0.002), in the same study. Postoperative hip flexion weakness was reported in 31% (9/29) of patients treated by extreme LIF and in no patients treated by transforaminal interbody fusion (TLIF) in a randomised controlled trial (RCT) and non-randomised comparative study of 55 patients (p<0.001); all resolved within 6 months. Postoperative distal motor weakness was reported in 3.5% (1/29) and 0% (0/26) of patients respectively (p=1.00) and sensory deficit was reported in 10% (3/29) and 8% (2/26) of patients respectively (p=1.00), in the same study; all resolved within 12 months. A partial and transient injury to the L5 nerve root during implant insertion at level L4–5 was reported in 1 patient treated by extreme LIF in a non-randomised comparative study of 208 patients; intraoperative nerve monitoring was not yet being used. The weighted average for reoperations was 6% (n=2,080 patients; 24 study arms) in the systematic review of 237 articles. A secondary surgical procedure (revisions, supplemental fixations, reoperations) was reported in 2% (40/2,342) of patients treated by extreme LIF compared with 5% (25/544) of patients treated by ALIF when FDA reports were excluded (p=0.0002) and in 9% (121/1,379) of patients treated by ALIF when FDA reports were included (p<0.0001) in the systematic review of 34 studies. Laceration of the abdominal aorta was reported in 1 patient in a case series of 900 patients; this was repaired through an exploratory laparotomy. Segmental vessel lacerations were reported in less than 1% (4/900) of patients in the same study; all were ligated under direct visualisation without further extension of the incision and no clinical sequelae. Major vascular injury was reported in a case report; a detachable retractor blade caused extensive damage to the iliac veins, the patient had massive blood loss and died a few weeks later from multiple organ failure secondary to septic shock. Lumbar artery pseudoaneurysm, which was successfully treated by embolisation, was reported in 1 patient in a case report. Wound-related complications (psoas haematoma, infection) were reported in less than 1% (15/2,342) of patients treated by extreme LIF, in less than 1% (7/544) of patients treated by ALIF when FDA reports were excluded (p=0.1438) and in 2% (26/1,379) of patients treated by ALIF when FDA reports were included (p=0.00067) in the systematic review of 34 studies. Gastrointestinal complications (ileus, gastric volvulus, bowel injury) were reported in 1% (25/2,342) of patients treated by extreme LIF, in less than 1% (3/544) of patients treated by ALIF when FDA reports were excluded (p=0.2771) and in 8% (116/1,379) of patients treated by ALIF when FDA reports were included (p<0.0001) in the systematic review of 34 studies. Ileus was reported in 7% (2/29) of patients treated by extreme LIF and in no patients treated by TLIF in the RCT and non‑randomised comparative study of 55 patients. Bowel perforation after extreme LIF was described in a case report: the patient had a temporary colostomy for 3 months before making a full recovery. Renal complications (urinary tract infection or urinary retention) were reported in 1% (12/2,342) of patients treated by extreme LIF, in no patients treated by ALIF when FDA reports were excluded (p=0.09) and in 1% (10/1,379) of patients treated by ALIF when FDA reports were included (p=0.4214) in the systematic review of 34 studies. Vertebral body fracture or remote compression fracture was reported in 1% (18/2,342) of patients treated by extreme LIF, in no patients treated by ALIF when FDA reports were excluded (p=0.0274) and in less than 1% (3/1,379) of patients treated by ALIF when FDA reports were included (p=0.0262) in the systematic review of 34 studies. Hardware failure (cage subsidence or breakage, intraoperative pedicle fracture, implant bone interface failure) was reported in 1% (31/2,342) of patients treated by extreme LIF, in 3% (17/544) of patients treated by ALIF when FDA reports were excluded (p=0.0065) and in 3% (47/1,379) of patients treated by ALIF when FDA reports were included (p<0.0001) in the systematic review of 34 studies. Graft migration and graft subsidence at 24‑month follow-up were reported in 0% (0/29) and 3% (1/29) of patients treated by extreme LIF and in 5% (1/21) and 10% (2/21) of patients treated by TLIF respectively in the RCT and non‑randomised comparative study of 55 patients. Complex regional pain syndrome was reported in 1 patient in a case report. The symptoms were treated conservatively and resolved within 8 weeks. Lumbar post-sympathectomy syndrome was reported in 5% (4/88) of patients treated by extreme LIF in the non‑randomised comparative study of 208 patients (at level L4/5 in 3 patients and at level L5/6 in 1 patient). In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers noted that spinal cord injury was an anecdotal adverse event. They considered that kidney injury was a theoretical adverse event.# Further information Patient commentary was sought but none was received. For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2342-7	{'Recommendations': 'Current evidence on the safety of lateral (including extreme, extra and direct lateral) interbody fusion in the lumbar spine for low back pain shows there are serious but well-recognised complications. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should only be done by surgeons with specific training in the technique, who should carry out their initial procedures with an experienced mentor.\n\nClinicians should enter details about all patients having lateral interbody fusion in the lumbar spine for low back pain onto the British Spine Registry.', 'Indications and current treatments': 'Chronic low back pain may result from degenerative changes in the intervertebral discs or spinal facet joints. Conservative treatments include analgesics, non‑steroidal anti-inflammatory medication and manual therapy.\n\nFor people with severe, life-limiting, chronic low back pain that does not respond to conservative treatments, surgery may be appropriate. This may include bony fusion of vertebrae (to immobilise segments of the vertebral column thought to be responsible for back pain, using either a posterior or anterior approach) or inserting a prosthetic intervertebral disc (which preserves lumbar mobility to reduce the risk of degenerative changes in adjacent intervertebral disc spaces). Other surgical alternatives include non‑rigid stabilisation techniques.', 'The procedure': 'The aim of lateral interbody fusion in the lumbar spine is to achieve spinal fusion by a side or lateral approach, to avoid the major muscle groups in the back (posterior approach) or the organs and blood vessels in the abdomen (anterior approach).\n\nThe procedure is done with the patient under general anaesthesia. A probe is inserted laterally through the psoas muscle, under fluoroscopic guidance, to lie alongside the affected disc. A posterior incision is also sometimes made, to allow access for manipulation of the probe. Nerve monitoring is recommended by many specialists. Dilators are inserted around the probe and a retractor is positioned to give the surgeon direct access to the spine. A discectomy is carried out and a cage implant inserted to hold the vertebrae in position. A bone graft (usually from the hip) is inserted between the 2\xa0vertebrae, sometimes with additional support from screws, plates or rods. The procedure may be done at more than\xa01 level during the same operation. A recent variation of this procedure is oblique lateral interbody fusion, which involves retroperitoneal access anterior to the psoas. It may take a few months before patients are able to return to their normal activities after the procedure.\n\nThere are a number of different devices used for this procedure.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of 237\xa0articles on lateral lumbar interbody fusion, the weighted average for the rate of fusion in all patients was 94% (n=907\xa0patients; 22\xa0study arms).\n\nIn the systematic review of 237\xa0articles, the weighted average for improvement in pain, measured on a visual analogue scale, was 60% (n=2,097\xa0patients; 41\xa0study arms). In a non-randomised comparative study of 202\xa0patients treated by extreme lateral interbody fusion (LIF) or open anterior lumbar interbody fusion (ALIF), low back pain scores, measured on a scale of 0–10, improved from 7.5 at baseline in both groups (n=95) to 2.4 and 2.6 respectively at 12‑month follow-up (n=61; p<0.001 compared with baseline; p=not significant for between group comparison). Mean leg pain, measured on a scale of 0–10, improved from 5.8 in the extreme LIF group and 5.4 in the ALIF group at baseline (n=95) to 1.6 and 2.0 respectively at 12‑month follow-up (n=61), in the same study (p<0.001 compared with baseline; p value not significant for between group comparison).\n\nIn the systematic review of 237\xa0articles, the weighted average for improvement in disability, measured on the Oswestry Disability Index (ODI), was 48% (n=1,234\xa0patients; 29\xa0study arms). In the non-randomised comparative study of 202\xa0patients treated by extreme LIF or ALIF, the ODI improved from 59% at baseline in both groups (n=95) to 23% and 24% respectively at 12‑month follow-up (n=61; p<0.001 compared with baseline; p\xa0value not significant for between group comparison). In a case series of 160\xa0patients, the ODI improved from 44% at baseline to 23.5% at the last follow-up (mean follow-up 18.5\xa0months; p\xa0value not reported).\n\nIn the systematic review of 237\xa0articles, the weighted average for patient satisfaction was 89% (n=491\xa0patients; 9\xa0study arms); 85% of patients said that they would have the procedure again if their outcome had been known in advance. In a randomised controlled trial (RCT) and non‑randomised comparative study of 55\xa0patients treated by extreme LIF or transforaminal interbody fusion (TLIF), 91% and 80% of patients respectively were satisfied with their outcome at 24‑month follow-up (p=0.393) and 100% and 90% of patients respectively would be willing to have the same procedure had their outcome been known in advance (p=0.210). In a non-randomised comparative study of 208\xa0patients treated by extreme LIF or ALIF, 95% (198/208) of patients were satisfied with the procedure and reported improvement; 10\xa0patients did not improve or worsened (radiological and clinical results were similar in both groups).\n\nIn the RCT and non‑randomised comparative study of 55\xa0patients treated by extreme LIF or TLIF, mean quality-of-life scores for the SF‑36 physical component improved from 37.7 and 39.5 respectively at baseline to 61.4 and 64.9 at 24‑month follow-up (p<0.05 compared with baseline). Mean quality-of-life scores for the SF‑36 mental component improved from 51 and 52.2 respectively at baseline to 67.2 and 69.2 at 24‑month follow-up (p<0.05 compared with baseline). In the case series of 160\xa0patients, the SF‑36 physical component score improved from 30.9 at baseline to 43.2 at the last follow-up (mean follow-up 18.5\xa0months; p\xa0value not reported).\n\nThe specialist advisers listed the key efficacy outcomes as patient reported outcome measures, including reduced pain, and radiological outcomes, including fusion of the lumbar spine and restoration of the disc height.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of 237\xa0articles, the weighted averages for thigh side effects, hip flexion weakness and motor neural deficits were 26% (n=2,772), 21% (n=1,360\xa0patients; 22\xa0study arms) and 3% (n=1,568\xa0patients; 14\xa0study arms) respectively. In a systematic review of 34\xa0studies, neurological adverse events (transient motor weakness, hypoaesthesia, transient or persistent thigh symptoms, injury to lumbosacral plexus, injury to femoral nerve) were reported. These occurred in 9% (209/2,342) of patients treated by extreme lateral interbody fusion (LIF) compared with 5% (27/544) of patients treated by anterior lumbar interbody fusion (ALIF) when Food and Drug Administration (FDA) reports were excluded (p=0.0015) and in 9% (130/1,379) of patients treated by ALIF when FDA reports were included (p=0.605). In the extreme LIF group, 43% (90/209) of the neurological adverse events resolved within 3\xa0months of the procedure, 16% (33/209) lasted between 3\xa0months and 2\xa0years or throughout the last follow-up; there was no information on the remaining 41% (86/209) of complications.\n\nSensory deficit was reported in 27% (585/2,160) of patients treated by lateral lumbar interbody fusion (LLIF) compared with 20% (380/1,885) of patients treated by minimally-invasive transforaminal lumbar interbody fusion (MI‑LIF, p<0.0001) in a systematic review of 96\xa0studies (n=9,714\xa0patients). Temporary neurological deficit was reported in 9% (278/2,957) of patients treated by LLIF and 2% (30/1,349) of patients treated by MI-LIF (p<0.0001). Permanent neurological deficit was reported in 3% (62/2,525) and 1% (14/1,382) of patients respectively (p=0.002), in the same study.\n\nPostoperative hip flexion weakness was reported in 31% (9/29) of patients treated by extreme LIF and in no patients treated by transforaminal interbody fusion (TLIF) in a randomised controlled trial (RCT) and non-randomised comparative study of 55\xa0patients (p<0.001); all resolved within 6\xa0months. Postoperative distal motor weakness was reported in 3.5% (1/29) and 0% (0/26) of patients respectively (p=1.00) and sensory deficit was reported in 10% (3/29) and 8% (2/26) of patients respectively (p=1.00), in the same study; all resolved within 12\xa0months.\n\nA partial and transient injury to the L5 nerve root during implant insertion at level L4–5 was reported in 1\xa0patient treated by extreme LIF in a non-randomised comparative study of 208\xa0patients; intraoperative nerve monitoring was not yet being used.\n\nThe weighted average for reoperations was 6% (n=2,080\xa0patients; 24\xa0study arms) in the systematic review of 237\xa0articles. A secondary surgical procedure (revisions, supplemental fixations, reoperations) was reported in 2% (40/2,342) of patients treated by extreme LIF compared with 5% (25/544) of patients treated by ALIF when FDA reports were excluded (p=0.0002) and in 9% (121/1,379) of patients treated by ALIF when FDA reports were included (p<0.0001) in the systematic review of 34\xa0studies.\n\nLaceration of the abdominal aorta was reported in 1\xa0patient in a case series of 900\xa0patients; this was repaired through an exploratory laparotomy. Segmental vessel lacerations were reported in less than\xa01% (4/900) of patients in the same study; all were ligated under direct visualisation without further extension of the incision and no clinical sequelae. Major vascular injury was reported in a case report; a detachable retractor blade caused extensive damage to the iliac veins, the patient had massive blood loss and died a few weeks later from multiple organ failure secondary to septic shock. Lumbar artery pseudoaneurysm, which was successfully treated by embolisation, was reported in 1\xa0patient in a case report.\n\nWound-related complications (psoas haematoma, infection) were reported in less than\xa01% (15/2,342) of patients treated by extreme LIF, in less than\xa01% (7/544) of patients treated by ALIF when FDA reports were excluded (p=0.1438) and in 2% (26/1,379) of patients treated by ALIF when FDA reports were included (p=0.00067) in the systematic review of 34\xa0studies.\n\nGastrointestinal complications (ileus, gastric volvulus, bowel injury) were reported in 1% (25/2,342) of patients treated by extreme LIF, in less than\xa01% (3/544) of patients treated by ALIF when FDA reports were excluded (p=0.2771) and in 8% (116/1,379) of patients treated by ALIF when FDA reports were included (p<0.0001) in the systematic review of 34\xa0studies. Ileus was reported in 7% (2/29) of patients treated by extreme LIF and in no patients treated by TLIF in the RCT and non‑randomised comparative study of 55\xa0patients. Bowel perforation after extreme LIF was described in a case report: the patient had a temporary colostomy for 3\xa0months before making a full recovery.\n\nRenal complications (urinary tract infection or urinary retention) were reported in 1% (12/2,342) of patients treated by extreme LIF, in no patients treated by ALIF when FDA reports were excluded (p=0.09) and in 1% (10/1,379) of patients treated by ALIF when FDA reports were included (p=0.4214) in the systematic review of 34\xa0studies.\n\nVertebral body fracture or remote compression fracture was reported in 1% (18/2,342) of patients treated by extreme LIF, in no patients treated by ALIF when FDA reports were excluded (p=0.0274) and in less than\xa01% (3/1,379) of patients treated by ALIF when FDA reports were included (p=0.0262) in the systematic review of 34\xa0studies.\n\nHardware failure (cage subsidence or breakage, intraoperative pedicle fracture, implant bone interface failure) was reported in 1% (31/2,342) of patients treated by extreme LIF, in 3% (17/544) of patients treated by ALIF when FDA reports were excluded (p=0.0065) and in 3% (47/1,379) of patients treated by ALIF when FDA reports were included (p<0.0001) in the systematic review of 34\xa0studies. Graft migration and graft subsidence at 24‑month follow-up were reported in 0% (0/29) and 3% (1/29) of patients treated by extreme LIF and in 5% (1/21) and 10% (2/21) of patients treated by TLIF respectively in the RCT and non‑randomised comparative study of 55\xa0patients.\n\nComplex regional pain syndrome was reported in 1\xa0patient in a case report. The symptoms were treated conservatively and resolved within 8\xa0weeks. Lumbar post-sympathectomy syndrome was reported in 5% (4/88) of patients treated by extreme LIF in the non‑randomised comparative study of 208\xa0patients (at level L4/5 in 3\xa0patients and at level L5/6 in 1\xa0patient).\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers noted that spinal cord injury was an anecdotal adverse event. They considered that kidney injury was a theoretical adverse event.', 'Further information': 'Patient commentary was sought but none was received.\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2342-7'}	https://www.nice.org.uk/guidance/ipg574	Evidence-based recommendations on lateral interbody fusion in the lumbar spine for low back pain in adults. This involves removing the damaged disc and fixing parts of the spine together, to relieve pain.
0d5afe13cdb0884c5ed9e0ee970e4f573b1b6951	nice	Trabecular stent bypass microsurgery for open-angle glaucoma	Trabecular stent bypass microsurgery for open-angle glaucoma Evidence-based recommendations on trabecular stent bypass microsurgery for open-angle glaucoma. This involves inserting a hollow metal tube (stent) into the eye, to improve drainage of fluid from the eye. # Recommendations Current evidence on the safety of trabecular stent bypass microsurgery for open-angle glaucoma raises no major safety concerns. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Trabecular stent bypass microsurgery for open-angle glaucoma should only be done by clinicians with specific training in the procedure.# Indications and current treatments Open-angle glaucoma is a chronic condition associated with elevated intraocular pressure and leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness. Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.# The procedure Trabecular stent bypass microsurgery aims to reduce intraocular pressure by creating a bypass channel between the anterior chamber and Schlemm's canal to improve drainage of aqueous humor. This procedure is often combined with phacoemulsification and intraocular lens insertion for the concomitant treatment of cataracts. Using local anaesthesia, a small corneal incision is made and viscoelastic is inserted into the anterior chamber. Under gonioscopic guidance and using a special applicator, a stent is slid through the trabecular meshwork (a small slit may be necessary) and into Schlemm's canal. The position of the stent is verified, then the applicator and viscoelastic are removed. Either 1 or multiple stents may be inserted during the same procedure.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. In a systematic review and meta-analysis of 2,143 patients from 32 studies, comparing stent insertion combined with phacoemulsification against phacoemulsification alone in patients with glaucoma and cataract, there was a statistically significant decrease in intraocular pressure (IOP) from baseline in the combined group compared against the phacoemulsification-only group at a follow‑up of 12 to 58 months (standardised mean deviation −0.46, 95% confidence interval −0.87 to −0.06, 4 randomised controlled trials , I2=47%, p=0.128). In a systematic review and meta-analysis of 248 patients (5 studies) with mild to moderate glaucoma treated by stent insertion alone, there was a statistically significant reduction in IOP from baseline after implantation of 1 stent at a follow‑up of 6 to 18 months (SMD −1.95, 95% CI −3.41 to −0.49, 3 studies; I2=96%, p=0.000) and of 3 stents at 6‑month follow‑up (SMD −4.26, 95% CI −5.18 to −3.33, 1 study). But there was not a statistically significant reduction in IOP from baseline after implantation of 2 stents at 6 to 12 months (SMD −3.08, 95% CI −6.90 to 0.74, 2 studies; I2=98%, p=0.000). In the same study there was a 22% reduction in IOP from baseline after 1‑stent insertion at 18‑month follow‑up (1 study), and at 6‑month follow‑up there was a 30% reduction in IOP after 2‑stent implantation (2 studies) and a 41% reduction after 3‑stent insertion (1 study). In the systematic review and meta-analysis of 2,143 patients there was a statistically significant reduction in the number of topical glaucoma medications used after the procedure in the combined group compared against the phacoemulsification-only group (SMD −0.65, 95% CI −1.18 to −0.12, 3 studies; I2=58%, p=0.092). There was a weighted mean reduction in topical glaucoma medications per patient of 1.33 from baseline after insertion of 1 stent combined with phacoemulsification (3 RCTs), of 1.1 from baseline after insertion of 2 stents combined with phacoemulsification (1 RCT) and of 1.01 after phacoemulsification alone (3 RCTs). In an RCT of 239 patients comparing stent insertion combined with phacoemulsification (n=116) against phacoemulsification alone (n=123) in patients with open-angle glaucoma not controlled on 1 medication, the proportions of eyes with corrected distance visual acuity of 20/40 or better in the combined group were 45% (49 eyes) before the procedure and 94% (99 eyes) at 12‑month follow‑up. In the phacoemulsification-only group, the proportions were 44% (53 eyes) before the procedure and 90% (101 eyes) 12 months after the procedure. In an RCT of 192 patients comparing implantation of 2 stents (n=94) against medical therapy (n=98), the proportions of eyes with best corrected visual acuity (BCVA) of 20/40 or better in the stent group were 84% before the procedure and 79% at 12‑month follow‑up. In the medical therapy group, the proportions were 87% before the procedure and 84% at 12‑month follow‑up. In the RCT of 192 patients, the vertical cup‑to‑disc ratio had not changed from baseline (change within ±0.2) in 97% (90/93) of patients in the stent group at 1‑year follow‑up, and was worse than baseline (increase of more than 0.2) in 1 patient (n=93). In the medication group, the vertical cup‑to‑disc ratio had not changed from baseline in 99% (88/89) of patients in the stent group at 1‑year follow‑up and was better than baseline (decrease of more than 0.2) in 1 patient (n=89). In an RCT of 119 patients comparing implantation of 1 stent (n=38) against implantation of 2 stents (n=41) or 3 stents (n=40), the mean cup‑to‑disc ratios at 18‑month follow‑up were the same as preoperative values. In an RCT of 100 patients comparing stent insertion combined with phacoemulsification (n=50) against phacoemulsification alone (n=50) in patients with open-angle glaucoma and cataract, the successful stent implantation rate was 96% (48/50). In a prospective case series of 19 patients treated by stent implantation and phacoemulsification, the stent was successfully implanted in all eyes (19/19). The specialist advisers listed the following key efficacy outcomes: IOP reduction, glaucoma medication use and quality of life.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview. Severe loss of corrected distance visual acuity (CDVA) was reported in 1 patient each in the combined group and in the phacoemulsification-only group in a randomised controlled trial (RCT) of 239 patients with open-angle glaucoma not controlled on 1 medication comparing stent insertion combined with phacoemulsification (n=116) against phacoemulsification alone (n=123). In the combined group, the loss of CDVA occurred after a stroke; in the phacoemulsification-only group, it occurred after macular traction, macular hole and macular oedema treated with vitrectomy. In the same study, CDVA worse than 20/40 was reported in 7 eyes in the combined group and in 9 eyes in the phacoemulsification group at 24‑month follow‑up. The causes reported were onset or progression of macular disease (n=6), posterior capsule opacification (n=2) and dry eye (n=2). Blurry vision or visual disturbance were also reported in 3% (4/116) of eyes in the combined group and in 7% (8/117) of eyes in the phacoemulsification-only group. Increase in intraocular pressure (IOP) above 10 mmHg after the procedure was reported in 48% of patients in the combined group of 1 of the 32 studies included in a systematic review and meta-analysis of 2,143 patients with glaucoma and cataract comparing stent insertion combined with phacoemulsification against phacoemulsification alone. In the same systematic review, rise in IOP above 30 mmHg after the procedure was reported in 15% of patients in the combined group in 1 of the studies. Elevated IOP was reported in 10% of patients in 1 of the 5 studies included in a systematic review and meta-analysis of 248 patients treated by stent insertion alone. Cystoid macular oedema was reported in 1% of patients in the combined group of 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Macular oedema was reported in 2% (1/50) of patients in the combined group and in 4% (2/50) of patients in the phacoemulsification-only group in an RCT of 100 patients comparing stent insertion combined with phacoemulsification (n=50) against phacoemulsification alone (n=50), during the first year of follow‑up. Optic disc haemorrhage was reported in 1 patient in each of the combined groups in the RCTs of 239 patients and 100 patients, within 24 months and 1 year of follow‑up respectively. Hyphema was reported in 2 to 4% of patients in 3 of the studies included in the systematic review and meta-analysis of 2,143 patients, and in 3% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients. Subconjunctival haemorrhage was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients, and in 1% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients. Anterior chamber collapse was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Hypotony was reported in 3% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients. Intraocular inflammation was reported in 1% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients. Cataract progression was reported in 3% (4/119) of patients (2 in the 1‑stent group and 2 in the 3‑stent group) in an RCT comparing implantation of 1 stent (n=38) against implantation of 2 stents (n=41) or 3 stents (n=40) in patients with primary open-angle glaucoma not controlled on ocular hypotensive medication; the patients were treated by cataract surgery. Goniosynechiae or iris synechiae each were reported in 1% of patients in 1 of the studies included in the systematic review and meta-analysis of 248 patients. Focal peripheral anterior synechiae were reported in 30% (15/50) of patients in the combined group and in 4% (2/50) of patients in the phacoemulsification-only group in the RCT of 100 patients within 2 years of follow‑up. Vitreous wick incarcerated in paracentesis was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Vitreomacular traction was reported in 2% (1/50) of patients in each group in the RCT of 100 patients within 2 years of the procedure. Posterior capsule opacification was reported in 3% and 1% of patients and in 6% (7/116) of eyes in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients, in the systematic review and meta-analysis of 248 patients and in the RCT of 239 patients respectively, within 24 months of the procedure. Epiretinal membrane was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta-analysis of 2,143 patients. Iris atrophy was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta‑analysis of 2,143 patients. Uveitis (iritis) was reported in 2% of patients and in 1 (n=116) eye treated by stent insertion and phacoemulsification in the systematic review and meta-analysis of 2,143 patients and in the RCT of 239 patients respectively. Dry eye was reported in 2% of patients in the combined group in 1 of the studies included in the systematic review and meta‑analysis of 2,143 patients. Soreness or discomfort was reported in 1 patient in an RCT of 192 patients comparing implantation of 2 stents (n=94) against medical therapy (n=98); this was treated with non-steroidal anti-inflammatory medications. Descemet folds were reported in 1 patient in each group at 1‑month follow‑up in the RCT of 100 patients; they resolved before the 3‑month follow‑up visit. In the systematic review and meta-analysis of 2,143 patients, stent malposition was reported in 2 to 18% of patients in 6 studies, stent occlusion was reported in 4 to 15% of patients in 4 studies and blockage of the opening of the stent lumen was reported in 15% of patients in 1 study. In the systematic review and meta-analysis of 248 patients, a need to reposition the stent was reported in 2% of patients in 1 study, stent not visible upon gonioscopy was reported in 13% of patients in 1 study, and stent replacement was reported in 5% of patients in 1 study. Secondary surgical interventions were needed in 4% (5/116) of eyes in the combined group and in 5% (6/117) of eyes in the phacoemulsification-only group in the RCT of 239 patients, within 24 months of follow‑up (including patients who had more than 1 surgical re‑intervention). In the combined group of 116 patients, the secondary surgical interventions were stent repositioning (3% ), stent removal and replacement (1 patient), Nd:YAG laser for stent obstruction (1 patient), trabeculoplasty (1 patient) and focal argon laser photocoagulation (1 patient). Secondary glaucoma surgery was reported in 1 patient in the combined group and in 2 patients in the phacoemulsification-only group in the RCT of 100 patients during the second year of follow‑up. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: stent dislocation. They considered that the following was a theoretical adverse event: stent movement during MRI scan.# Further information For related NICE guidance, see the NICE website. Patient commentary was sought but none was received. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2344-1	{'Recommendations': 'Current evidence on the safety of trabecular stent bypass microsurgery for open-angle glaucoma raises no major safety concerns. Evidence on efficacy is adequate in quality and quantity. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nTrabecular stent bypass microsurgery for open-angle glaucoma should only be done by clinicians with specific training in the procedure.', 'Indications and current treatments': 'Open-angle glaucoma is a chronic condition associated with elevated intraocular pressure and leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.\n\nTreatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.', 'The procedure': "Trabecular stent bypass microsurgery aims to reduce intraocular pressure by creating a bypass channel between the anterior chamber and Schlemm's canal to improve drainage of aqueous humor.\n\nThis procedure is often combined with phacoemulsification and intraocular lens insertion for the concomitant treatment of cataracts. Using local anaesthesia, a small corneal incision is made and viscoelastic is inserted into the anterior chamber. Under gonioscopic guidance and using a special applicator, a stent is slid through the trabecular meshwork (a small slit may be necessary) and into Schlemm's canal. The position of the stent is verified, then the applicator and viscoelastic are removed.\n\nEither 1\xa0or multiple stents may be inserted during the same procedure.", 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nIn a systematic review and meta-analysis of 2,143\xa0patients from 32\xa0studies, comparing stent insertion combined with phacoemulsification against phacoemulsification alone in patients with glaucoma and cataract, there was a statistically significant decrease in intraocular pressure (IOP) from baseline in the combined group compared against the phacoemulsification-only group at a follow‑up of 12\xa0to\xa058\xa0months (standardised mean deviation [SMD] −0.46, 95% confidence interval [CI] −0.87 to −0.06, 4\xa0randomised controlled trials [RCTs], I2=47%, p=0.128). In a systematic review and meta-analysis of 248\xa0patients (5\xa0studies) with mild to moderate glaucoma treated by stent insertion alone, there was a statistically significant reduction in IOP from baseline after implantation of 1\xa0stent at a follow‑up of 6\xa0to\xa018\xa0months (SMD −1.95, 95% CI −3.41 to −0.49, 3\xa0studies; I2=96%, p=0.000) and of 3\xa0stents at 6‑month follow‑up (SMD −4.26, 95% CI −5.18 to −3.33, 1\xa0study). But there was not a statistically significant reduction in IOP from baseline after implantation of 2\xa0stents at 6\xa0to\xa012\xa0months (SMD −3.08, 95% CI −6.90 to 0.74, 2\xa0studies; I2=98%, p=0.000). In the same study there was a 22% reduction in IOP from baseline after 1‑stent insertion at 18‑month follow‑up (1\xa0study), and at 6‑month follow‑up there was a 30% reduction in IOP after 2‑stent implantation (2\xa0studies) and a 41% reduction after 3‑stent insertion (1\xa0study).\n\nIn the systematic review and meta-analysis of 2,143\xa0patients there was a statistically significant reduction in the number of topical glaucoma medications used after the procedure in the combined group compared against the phacoemulsification-only group (SMD −0.65, 95% CI −1.18 to −0.12, 3\xa0studies; I2=58%, p=0.092). There was a weighted mean reduction in topical glaucoma medications per patient of\xa01.33 from baseline after insertion of 1\xa0stent combined with phacoemulsification (3\xa0RCTs), of\xa01.1 from baseline after insertion of 2\xa0stents combined with phacoemulsification (1\xa0RCT) and of\xa01.01 after phacoemulsification alone (3\xa0RCTs).\n\nIn an RCT of 239\xa0patients comparing stent insertion combined with phacoemulsification (n=116) against phacoemulsification alone (n=123) in patients with open-angle glaucoma not controlled on 1\xa0medication, the proportions of eyes with corrected distance visual acuity of 20/40 or better in the combined group were 45% (49\xa0eyes) before the procedure and 94% (99\xa0eyes) at 12‑month follow‑up. In the phacoemulsification-only group, the proportions were 44% (53\xa0eyes) before the procedure and 90% (101\xa0eyes) 12\xa0months after the procedure. In an RCT of 192\xa0patients comparing implantation of 2\xa0stents (n=94) against medical therapy (n=98), the proportions of eyes with best corrected visual acuity (BCVA) of 20/40 or better in the stent group were 84% before the procedure and 79% at 12‑month follow‑up. In the medical therapy group, the proportions were 87% before the procedure and 84% at 12‑month follow‑up.\n\nIn the RCT of 192\xa0patients, the vertical cup‑to‑disc ratio had not changed from baseline (change within ±0.2) in 97% (90/93) of patients in the stent group at 1‑year follow‑up, and was worse than baseline (increase of more than\xa00.2) in 1\xa0patient (n=93). In the medication group, the vertical cup‑to‑disc ratio had not changed from baseline in 99% (88/89) of patients in the stent group at 1‑year follow‑up and was better than baseline (decrease of more than\xa00.2) in 1\xa0patient (n=89). In an RCT of 119\xa0patients comparing implantation of 1\xa0stent (n=38) against implantation of 2\xa0stents (n=41) or 3\xa0stents (n=40), the mean cup‑to‑disc ratios at 18‑month follow‑up were the same as preoperative values.\n\nIn an RCT of 100\xa0patients comparing stent insertion combined with phacoemulsification (n=50) against phacoemulsification alone (n=50) in patients with open-angle glaucoma and cataract, the successful stent implantation rate was 96% (48/50). In a prospective case series of 19\xa0patients treated by stent implantation and phacoemulsification, the stent was successfully implanted in all eyes (19/19).\n\nThe specialist advisers listed the following key efficacy outcomes: IOP reduction, glaucoma medication use and quality of life.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures overview.\n\nSevere loss of corrected distance visual acuity (CDVA) was reported in 1\xa0patient each in the combined group and in the phacoemulsification-only group in a randomised controlled trial (RCT) of 239\xa0patients with open-angle glaucoma not controlled on 1\xa0medication comparing stent insertion combined with phacoemulsification (n=116) against phacoemulsification alone (n=123). In the combined group, the loss of CDVA occurred after a stroke; in the phacoemulsification-only group, it occurred after macular traction, macular hole and macular oedema treated with vitrectomy. In the same study, CDVA worse than 20/40 was reported in 7\xa0eyes in the combined group and in 9\xa0eyes in the phacoemulsification group at 24‑month follow‑up. The causes reported were onset or progression of macular disease (n=6), posterior capsule opacification (n=2) and dry eye (n=2). Blurry vision or visual disturbance were also reported in 3% (4/116) of eyes in the combined group and in 7% (8/117) of eyes in the phacoemulsification-only group.\n\nIncrease in intraocular pressure (IOP) above 10\xa0mmHg after the procedure was reported in 48% of patients in the combined group of 1\xa0of the 32\xa0studies included in a systematic review and meta-analysis of 2,143\xa0patients with glaucoma and cataract comparing stent insertion combined with phacoemulsification against phacoemulsification alone. In the same systematic review, rise in IOP above 30\xa0mmHg after the procedure was reported in 15% of patients in the combined group in 1\xa0of the studies. Elevated IOP was reported in 10% of patients in 1\xa0of the 5\xa0studies included in a systematic review and meta-analysis of 248\xa0patients treated by stent insertion alone.\n\nCystoid macular oedema was reported in 1% of patients in the combined group of 1\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients. Macular oedema was reported in 2% (1/50) of patients in the combined group and in 4% (2/50) of patients in the phacoemulsification-only group in an RCT of 100\xa0patients comparing stent insertion combined with phacoemulsification (n=50) against phacoemulsification alone (n=50), during the first year of follow‑up.\n\nOptic disc haemorrhage was reported in 1\xa0patient in each of the combined groups in the RCTs of 239\xa0patients and 100\xa0patients, within 24\xa0months and 1\xa0year of follow‑up respectively.\n\nHyphema was reported in 2\xa0to\xa04% of patients in 3\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients, and in 3% of patients in 1\xa0of the studies included in the systematic review and meta-analysis of 248\xa0patients.\n\nSubconjunctival haemorrhage was reported in 2% of patients in the combined group in 1\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients, and in 1% of patients in 1\xa0of the studies included in the systematic review and meta-analysis of 248\xa0patients.\n\nAnterior chamber collapse was reported in 2% of patients in the combined group in 1\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients. Hypotony was reported in 3% of patients in 1\xa0of the studies included in the systematic review and meta-analysis of 248\xa0patients.\n\nIntraocular inflammation was reported in 1% of patients in 1\xa0of the studies included in the systematic review and meta-analysis of 248\xa0patients.\n\nCataract progression was reported in 3% (4/119) of patients (2\xa0in the 1‑stent group and 2\xa0in the 3‑stent group) in an RCT comparing implantation of 1\xa0stent (n=38) against implantation of 2\xa0stents (n=41) or 3\xa0stents (n=40) in patients with primary open-angle glaucoma not controlled on ocular hypotensive medication; the patients were treated by cataract surgery.\n\nGoniosynechiae or iris synechiae each were reported in 1% of patients in 1\xa0of the studies included in the systematic review and meta-analysis of 248\xa0patients. Focal peripheral anterior synechiae were reported in 30% (15/50) of patients in the combined group and in 4% (2/50) of patients in the phacoemulsification-only group in the RCT of 100\xa0patients within 2\xa0years of follow‑up.\n\nVitreous wick incarcerated in paracentesis was reported in 2% of patients in the combined group in 1\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients.\n\nVitreomacular traction was reported in 2% (1/50) of patients in each group in the RCT of 100\xa0patients within 2\xa0years of the procedure.\n\nPosterior capsule opacification was reported in 3% and 1% of patients and in 6% (7/116) of eyes in the combined group in 1\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients, in the systematic review and meta-analysis of 248\xa0patients and in the RCT of 239\xa0patients respectively, within 24\xa0months of the procedure.\n\nEpiretinal membrane was reported in 2% of patients in the combined group in 1\xa0of the studies included in the systematic review and meta-analysis of 2,143\xa0patients.\n\nIris atrophy was reported in 2% of patients in the combined group in 1\xa0of the studies included in the systematic review and meta‑analysis of 2,143\xa0patients.\n\nUveitis (iritis) was reported in 2% of patients and in 1\xa0(n=116) eye treated by stent insertion and phacoemulsification in the systematic review and meta-analysis of 2,143\xa0patients and in the RCT of 239\xa0patients respectively.\n\nDry eye was reported in 2% of patients in the combined group in 1\xa0of the studies included in the systematic review and meta‑analysis of 2,143\xa0patients. Soreness or discomfort was reported in 1\xa0patient in an RCT of 192\xa0patients comparing implantation of 2\xa0stents (n=94) against medical therapy (n=98); this was treated with non-steroidal anti-inflammatory medications.\n\nDescemet folds were reported in 1\xa0patient in each group at 1‑month follow‑up in the RCT of 100\xa0patients; they resolved before the 3‑month follow‑up visit.\n\nIn the systematic review and meta-analysis of 2,143\xa0patients, stent malposition was reported in 2\xa0to\xa018% of patients in 6\xa0studies, stent occlusion was reported in 4\xa0to\xa015% of patients in 4\xa0studies and blockage of the opening of the stent lumen was reported in 15% of patients in 1\xa0study.\n\nIn the systematic review and meta-analysis of 248\xa0patients, a need to reposition the stent was reported in 2% of patients in 1\xa0study, stent not visible upon gonioscopy was reported in 13% of patients in 1\xa0study, and stent replacement was reported in 5% of patients in 1\xa0study.\n\nSecondary surgical interventions were needed in 4% (5/116) of eyes in the combined group and in 5% (6/117) of eyes in the phacoemulsification-only group in the RCT of 239\xa0patients, within 24\xa0months of follow‑up (including patients who had more than 1\xa0surgical re‑intervention). In the combined group of 116\xa0patients, the secondary surgical interventions were stent repositioning (3% [3/116]), stent removal and replacement (1\xa0patient), Nd:YAG laser for stent obstruction (1\xa0patient), trabeculoplasty (1\xa0patient) and focal argon laser photocoagulation (1\xa0patient). Secondary glaucoma surgery was reported in 1\xa0patient in the combined group and in 2\xa0patients in the phacoemulsification-only group in the RCT of 100\xa0patients during the second year of follow‑up.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: stent dislocation. They considered that the following was a theoretical adverse event: stent movement during MRI scan.', 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2344-1'}	https://www.nice.org.uk/guidance/ipg575	Evidence-based recommendations on trabecular stent bypass microsurgery for open-angle glaucoma. This involves inserting a hollow metal tube (stent) into the eye, to improve drainage of fluid from the eye.
2ba351facb2a4743758ff822557cc4c6999390de	nice	Healthcare-associated infections: prevention and control in primary and community care	Healthcare-associated infections: prevention and control in primary and community care This guideline covers preventing and controlling healthcare-associated infections in children, young people and adults in primary and community care settings. It provides a blueprint for the infection prevention and control precautions that should be applied by everyone involved in delivering NHS care and treatment. # Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Standard principles Recommendation 1.1.1.2 in the section on general advice, and recommendations 1.1.3.1,1.1.3.3, 1.1.3.4, 1.1.3.6, 1.1.3.10 and 1.1.3.11 in the section on use of personal protective equipment, are in accordance with the following health and safety legislation (current at the time of publication, March 2012): Health and Safety at Work Act 1974 Management of Health and Safety at Work Regulations 1999 Health and Safety Regulations 2002, Control of Substances Hazardous to Health Regulations 2002, Personal Protective Equipment Regulations 2002 Health and Social Care Act 2008. ## General advice Everyone involved in providing care should be: educated about the standard principles of infection prevention and control and trained in hand decontamination, the use of personal protective equipment, and the safe use and disposal of sharps. Wherever care is delivered, healthcare workers must have available appropriate supplies of materials for hand decontamination sharps containers personal protective equipment. Educate patients and carers about: the benefits of effective hand decontamination the correct techniques and timing of hand decontamination when it is appropriate to use liquid soap and water or handrub the availability of hand decontamination facilities their role in maintaining standards of healthcare workers' hand decontamination. ## Hand decontamination Hands must be decontaminated in all of the following circumstances: immediately before every episode of direct patient contact or care, including aseptic procedures immediately after every episode of direct patient contact or care immediately after any exposure to body fluids immediately after any other activity or contact with a patient's surroundings that could potentially result in hands becoming contaminated immediately after removal of gloves. Decontaminate hands preferably with a handrub (conforming to the British standard BS EN 1500:2013 ), except in the following circumstances, when liquid soap and water must be used: when hands are visibly soiled or potentially contaminated with body fluids or in clinical situations where there is potential for the spread of alcohol-resistant organisms (such as Clostridium difficile or other organisms that cause diarrhoeal illness). Healthcare workers should ensure that their hands can be decontaminated throughout the duration of clinical work by: being bare below the elbow when delivering direct patient care (for the purposes of this guideline, bare below the elbow means: not wearing false nails, nail polish, a wristwatch or stoned rings; wearing short-sleeved garments or being able to roll or push up sleeves) removing wrist and hand jewellery making sure that fingernails are short, clean and free of nail polish covering cuts and abrasions with waterproof dressings. An effective handwashing technique involves three stages: preparation, washing and rinsing, and drying. Preparation requires wetting hands under tepid running water before applying liquid soap or an antimicrobial preparation. The handwash solution must come into contact with all of the surfaces of the hand. The hands must be rubbed together vigorously for a minimum of 10–15 seconds, paying particular attention to the tips of the fingers, the thumbs and the areas between the fingers. Hands should be rinsed thoroughly before drying with good quality paper towels. When decontaminating hands using an alcohol handrub, hands should be free from dirt and organic material. The handrub solution must come into contact with all surfaces of the hand. The hands must be rubbed together vigorously, paying particular attention to the tips of the fingers, the thumbs and the areas between the fingers, until the solution has evaporated and the hands are dry. An emollient hand cream should be applied regularly to protect skin from the drying effects of regular hand decontamination. If a particular soap, antimicrobial hand wash or alcohol product causes skin irritation an occupational health team should be consulted. ## Use of personal protective equipment Selection of protective equipment must be based on an assessment of the risk of transmission of microorganisms to the patient, and the risk of contamination of the healthcare worker's clothing and skin by patients' blood, body fluids, secretions or excretions. Gloves used for direct patient care: must conform to current EU legislation (CE marked as medical gloves for single use under BS EN 455 Parts 1–4 and in accordance with the following health and safety legislation : Health and Safety at Work Act 1974, Management of Health and Safety at Work Regulations 1999, Health and Safety Regulations 2002, Control of Substances Hazardous to Health Regulations 2002, Personal Protective Equipment Regulations 2002 and Health and Social Care Act 2008) and should be appropriate for the task. Gloves must be worn for invasive procedures, contact with sterile sites and non-intact skin or mucous membranes, and all activities that have been assessed as carrying a risk of exposure to blood, body fluids, secretions or excretions, or to sharp or contaminated instruments. Gloves mustbe worn as single-use items. They must be put on immediately before an episode of patient contact or treatment and removed as soon as the activity is completed. Gloves must be changed between caring for different patients, and between different care or treatment activities for the same patient. Ensure that gloves used for direct patient care that have been exposed to body fluids are disposed of correctly, in accordance with current national legislation (for guidance see NHS England's document on Management and disposal of healthcare waste, HTM 07-01) or local policies (see section 1.1.5 on waste disposal). Alternatives to natural rubber latex gloves must be available for patients, carers and healthcare workers who have a documented sensitivity to natural rubber latex. Do not use polythene gloves for clinical interventions. When delivering direct patient care: wear a disposable plastic apron if there is a risk that clothing may be exposed to blood, body fluids, secretions or excretions or wear a long-sleeved fluid-repellent gown if there is a risk of extensive splashing of blood, body fluids, secretions or excretions onto skin or clothing. When using disposable plastic aprons or gowns: use them as single-use items, for one procedure or one episode of direct patient care and ensure they are disposed of correctly (see section 1.1.5 on waste disposal). Face masks and eye protection must be worn where there is a risk of blood, body fluids, secretions or excretions splashing into the face and eyes. Respiratory protective equipment, for example a particulate filter mask, must be used when clinically indicated. ## Safe use and disposal of sharps Sharps should not be passed directly from hand to hand, and handling should be kept to a minimum. Used standard needles: must not be bent or broken before disposal (however, it is acceptable to bend needles when they are part of an approved sharps safety device) must not be recapped.In dentistry, if recapping or disassembly is unavoidable, a risk assessment must be undertaken and appropriate safety devices should be used (see the Health and Safety Regulations 2013). Used sharps must be discarded immediately by the person generating the sharps waste into a sharps container conforming to current standards (which at the time of publication Sharps containers: must be located in a safe position that avoids spillage, is at a height that allows the safe disposal of sharps, is away from public access areas and is out of the reach of children must not be used for any other purpose than the disposal of sharps must not be filled above the fill line must be disposed of when the fill line is reached should be temporarily closed when not in use.For guidance see NHS England's document on Management and disposal of healthcare waste (HTM 07-01). Use sharps safety devices if a risk assessment has indicated that they will provide safer systems of working for healthcare workers, carers and patients. Train and assess all users in the correct use and disposal of sharps and sharps safety devices. ## Waste disposal Healthcare waste must be segregated immediately by the person generating the waste into appropriate colour-coded storage or waste disposal bags or containers defined as being compliant with current national legislation (for guidance see NHS England's document on Management and disposal of healthcare waste, HTM 07-01) and local policies. Healthcare waste must be labelled, stored, transported and disposed of in accordance with current national legislation (for guidance see NHS England's document on Management and disposal of healthcare waste, HTM 07-01) and local policies. Educate patients and carers about the correct handling, storage and disposal of healthcare waste. # Long-term urinary catheters ## Education of patients, their carers and healthcare workers Patients and carers should be educated about and trained in techniques of hand decontamination, insertion of intermittent catheters where applicable, and catheter management before discharge from hospital. Community and primary healthcare workers must be trained in catheter insertion, including suprapubic catheter replacement and catheter maintenance. Follow-up training and ongoing support of patients and carers should be available for the duration of long-term catheterisation. ## Assessing the need for catheterisation Indwelling urinary catheters should be used only after alternative methods of management have been considered. The patient's clinical need for catheterisation should be reviewed regularly and the urinary catheter removed as soon as possible. Catheter insertion, changes and care should be documented. ## Catheter drainage options Following assessment, the best approach to catheterisation that takes account of clinical need, anticipated duration of catheterisation, patient preference and risk of infection should be selected. Intermittent catheterisation should be used in preference to an indwelling catheter if it is clinically appropriate and a practical option for the patient. Offer a choice of either single-use hydrophilic or gel reservoir catheters for intermittent self-catheterisation. Select the type and gauge of an indwelling urinary catheter based on an assessment of the patient's individual characteristics, including: age any allergy or sensitivity to catheter materials gender history of symptomatic urinary tract infection patient preference and comfort previous catheter history reason for catheterisation. In general, the catheter balloon should be inflated with 10 ml of sterile water in adults and 3–5 ml in children. In patients for whom it is appropriate, a catheter valve may be used as an alternative to a drainage bag. ## Catheter insertion All catheterisations carried out by healthcare workers should be aseptic procedures. After training, healthcare workers should be assessed for their competence to carry out these types of procedures. Intermittent self-catheterisation is a clean procedure. A lubricant for single-patient use is required for non-lubricated catheters. For urethral catheterisation, the meatus should be cleaned before insertion of the catheter, in accordance with local guidelines/policy. An appropriate lubricant from a single-use container should be used during catheter insertion to minimise urethral trauma and infection. ## Catheter maintenance Indwelling catheters should be connected to a sterile closed urinary drainage system or catheter valve. Healthcare workers should ensure that the connection between the catheter and the urinary drainage system is not broken except for good clinical reasons (for example changing the bag in line with the manufacturer's recommendations). Healthcare workers must decontaminate their hands and wear a new pair of clean, non-sterile gloves before manipulating a patient's catheter, and must decontaminate their hands after removing gloves. Patients managing their own catheters, and their carers, must be educated about the need for hand decontamination before and after manipulation of the catheter, in accordance with the recommendations in the section on standard principles. Urine samples must be obtained from a sampling port using an aseptic technique. Urinary drainage bags should be positioned below the level of the bladder, and should not be in contact with the floor. A link system should be used to facilitate overnight drainage, to keep the original system intact. The urinary drainage bag should be emptied frequently enough to maintain urine flow and prevent reflux, and should be changed when clinically indicated. The meatus should be washed daily with soap and water. To minimise the risk of blockages, encrustations and catheter-associated infections for patients with a long-term indwelling urinary catheter: develop a patient-specific care regimen consider approaches such as reviewing the frequency of planned catheter changes and increasing fluid intake document catheter blockages. Bladder instillations or washouts must not be used to prevent catheter-associated infections. Catheters should be changed only when clinically necessary or according to the manufacturer's current recommendations. When changing catheters in patients with a long-term indwelling urinary catheter: do not offer antibiotic prophylaxis routinely consider antibiotic prophylaxis for patients who: have a history of symptomatic urinary tract infection after catheter change or experience trauma (frank haematuria after catheterisation or two or more attempts of catheterisation) during catheterisation. At the time of publication (March 2012), no antibiotics have a UK marketing authorisation for this indication. Informed consent should be obtained and documented. # Enteral feeding ## Education of patients, their carers and healthcare workers Patients and carers should be educated about and trained in the techniques of hand decontamination, enteral feeding and the management of the administration system before being discharged from hospital. Healthcare workers should be trained in enteral feeding and management of the administration system. Follow-up training and ongoing support of patients and carers should be available for the duration of home enteral tube feeding. ## Preparation and storage of feeds Wherever possible pre-packaged, ready-to-use feeds should be used in preference to feeds requiring decanting, reconstitution or dilution. The system selected should require minimal handling to assemble, and be compatible with the patient's enteral feeding tube. Effective hand decontamination must be carried out before starting feed preparation. When decanting, reconstituting or diluting feeds, a clean working area should be prepared and equipment dedicated for enteral feed use only should be used. Feeds should be mixed using cooled boiled water or freshly opened sterile water and a no-touch technique. Feeds should be stored according to the manufacturer's instructions and, where applicable, food hygiene legislation. Where ready-to-use feeds are not available, feeds may be prepared in advance, stored in a refrigerator, and used within 24 hours. ## Administration of feeds Use minimal handling and an aseptic technique to connect the administration system to the enteral feeding tube. Ready-to-use feeds may be given for a whole administration session, up to a maximum of 24 hours. Reconstituted feeds should be administered over a maximum 4-hour period. Administration sets and feed containers are for single use and must be discarded after each feeding session. ## Care of insertion site and enteral feeding tube The stoma should be washed daily with water and dried thoroughly. To prevent blockages, flush the enteral feeding tube before and after feeding or administering medications using single-use syringes or single-patient-use (reusable) syringes according to the manufacturer's instructions. Use: freshly drawn tap water for patients who are not immunosuppressed either cooled freshly boiled water or sterile water from a freshly opened container for patients who are immunosuppressed. # Vascular access devices ## Education of patients, their carers and healthcare workers Before discharge from hospital, patients and their carers should be taught any techniques they may need to use to prevent infection and safely manage a vascular access device. Healthcare workers caring for a patient with a vascular access device should be trained, and assessed as competent, in using and consistently adhering to the infection prevention practices described in this guideline. Follow-up training and support should be available to patients with a vascular access device and their carers. ## General asepsis Hands must be decontaminated (see section 1.1.2 on hand decontamination) before accessing or dressing a vascular access device. An aseptic technique must be used for vascular access device catheter site care and when accessing the system (the Aseptic Non Touch Technique (ANTT™) is an example of an aseptic technique for vascular access device maintenance which is widely used in acute and community settings and represents a possible framework for establishing standardised guidance on aseptic technique. ## Vascular access device site care Decontaminate the skin at the insertion site with chlorhexidine gluconate in 70% alcohol before inserting a peripheral vascular access device or a peripherally inserted central catheter.In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. Use a sterile transparent semipermeable membrane dressing to cover the vascular access device insertion site. Consider a sterile gauze dressing covered with a sterile transparent semipermeable membrane dressing only if the patient has profuse perspiration, or if the vascular access device insertion site is bleeding or oozing. If a gauze dressing is used: change it every 24 hours, or sooner if it is soiled and replace it with a sterile transparent semipermeable membrane dressing as soon as possible. Change the transparent semipermeable membrane dressing covering a central venous access device insertion site every 7 days, or sooner if the dressing is no longer intact or moisture collects under it. Leave the transparent semipermeable membrane dressing applied to a peripheral cannula insertion site in situ for the life of the cannula, provided that the integrity of the dressing is retained. Dressings used on tunnelled or implanted central venous catheter sites should be replaced every 7 days until the insertion site has healed, unless there is an indication to change them sooner. Healthcare workers should ensure that catheter-site care is compatible with catheter materials (tubing, hubs, injection ports, luer connectors and extensions) and carefully check compatibility with the manufacturer's recommendations. Decontaminate the central venous catheter insertion site and surrounding skin during dressing changes using chlorhexidine gluconate in 70% alcohol, and allow to air dry. Consider using an aqueous solution of chlorhexidine gluconate if the manufacturer's recommendations prohibit the use of alcohol with their catheter. In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. Individual sachets of antiseptic solution or individual packages of antiseptic-impregnated swabs or wipes should be used to disinfect the dressing site. ## General principles for management of vascular access devices Decontaminate the injection port or vascular access device catheter hub before and after accessing the system using chlorhexidine gluconate in 70% alcohol. Consider using an aqueous solution of chlorhexidine gluconate if the manufacturer's recommendations prohibit the use of alcohol with their catheter. In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. In-line filters should not be used routinely for infection prevention. Antibiotic lock solutions should not be used routinely to prevent catheter-related bloodstream infections (CRBSI). Systemic antimicrobial prophylaxis should not be used routinely to prevent catheter colonisation or CRBSI, either before insertion or during the use of a central venous catheter. Preferably, a single lumen catheter should be used to administer parenteral nutrition. If a multilumen catheter is used, one port must be exclusively dedicated for total parenteral nutrition, and all lumens must be handled with the same meticulous attention to aseptic technique. Preferably, a sterile 0.9 percent sodium chloride injection should be used to flush and lock catheter lumens. When recommended by the manufacturer, implanted ports or opened-ended catheter lumens should be flushed and locked with heparin sodium flush solutions. Systemic anticoagulants should not be used routinely to prevent CRBSI. If needleless devices are used, the manufacturer's recommendations for changing the needleless components should be followed. When needleless devices are used, healthcare workers should ensure that all components of the system are compatible and secured, to minimise leaks and breaks in the system. When needleless devices are used, the risk of contamination should be minimised by decontaminating the access port with either alcohol or an alcoholic solution of chlorhexidine gluconate before and after using it to access the system.In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. In general, administration sets in continuous use need not be replaced more frequently than at 72-hour intervals unless they become disconnected, or a catheter-related infection is suspected or documented. Administration sets for blood and blood components should be changed every 12 hours, or according to the manufacturer's recommendations. Administration sets used for total parenteral nutrition infusions should generally be changed every 24 hours. If the solution contains only glucose and amino acids, administration sets in continuous use do not need to be replaced more frequently than every 72 hours. Avoid the use of multidose vials, in order to prevent the contamination of infusates. # Terms used in this guidance ## Aseptic technique An aseptic technique ensures that only uncontaminated equipment and fluids come into contact with susceptible body sites. It should be used during any clinical procedure that bypasses the body's natural defences. Using the principles of asepsis minimises the spread of organisms from one person to another. ## Direct patient care 'Hands on' or face-to-face contact with patients. Any physical aspect of the healthcare of a patient, including treatments, self-care and administration of medication. ## Hand decontamination The use of handrub or handwashing to reduce the number of bacteria on the hands. In this guideline this term is interchangeable with 'hand hygiene'. ## Handrub A preparation applied to the hands to reduce the number of viable microorganisms. This guideline refers to handrubs compliant with British standards (BS EN1500; standard for efficacy of hygienic handrubs using a reference of 60% isopropyl alcohol). ## Healthcare worker Any person employed by the health service, social services, a local authority or an agency to provide care for a sick, disabled or elderly person. ## Healthcare waste In this guideline, healthcare waste refers to any waste produced by, and as a consequence of, healthcare activities. ## Personal protective equipment Equipment that is intended to be worn or held by a person to protect them from risks to their health and safety while at work. Examples include gloves, aprons, and eye and face protection.# Recommendations for research The GDG has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Standard principles of infection prevention and control What are the barriers to compliance with the standard principles of infection prevention and control that patients and carers experience in their own homes? ## Why this is important Recent changes to the delivery of healthcare mean that care is increasingly delivered within a patient's home environment. Infection prevention in this setting is just as important as in hospital. There are currently approximately 6 million unpaid carers in the UK, a number that is likely to increase with an aging population. The association between carer training and infection rates is unknown. No evidence of surveillance of healthcare-associated infections in the community is currently available in the UK. A qualitative study is needed to investigate the themes surrounding the barriers to patient and carer compliance with the standard principles of infection prevention in their own homes. It would be important to assess whether lack of awareness or knowledge is a barrier. If patients and carers have received education, this should be assessed to see if this was applicable to the patient's home setting. Areas of low compliance in the home environment need to be identified. The findings could have far-reaching implications for discharge planning and duty of care. # Hand decontamination When clean running water is not available, what is the clinical and cost effectiveness of using wipes, gels, handrubs or other products to remove visible contamination? ## Why this is important Community healthcare workers often encounter challenges in carrying out hand decontamination when there is no access to running water. This particularly affects ambulance service staff, who often provide emergency care at locations where running water is not available. No evidence from randomised controlled trials is available on the most effective way for community-based healthcare workers to remove physical contamination, such as blood, from their hands in the absence of running water. In recent years, hand decontamination products that can be used without running water, such as gels, handrubs and wipes, have become available. However, their efficacy and suitability in actual clinical practice for use with visibly dirty hands has not been determined. A randomised controlled trial is required to compare hand wipes (alcohol and antiseptic), hand gels and other hand decontamination products that can be used without running water, to determine the most effective way to remove physical dirt in the absence of running water, in order to make a recommendation for their use in real situations. The primary outcome measure should be colony-forming units on the basis of the adenosine triphosphate (ATP) surface test. # Intermittent urinary catheters: catheter selection For patients performing intermittent self-catheterisation over the long term, what is the clinical and cost effectiveness of single-use non-coated versus single-use hydrophilic versus single-use gel reservoir versus reusable non-coated catheters with regard to the following outcomes: symptomatic urinary tract infections, urinary tract infection-associated bacteraemia, mortality, patient comfort and preference, quality of life, and clinical symptoms of urethral damage? ## Why this is important Long-term (more than 28 days) intermittent self-catheterisation is performed by many people living in the community. It is important that the choice between intermittent catheters is informed by robust evidence on clinical and cost effectiveness. The cost-effectiveness model developed for this guideline combined evidence of clinical effectiveness, costs and quality of life with respect to symptomatic urinary tract infection and associated complications. The results of the analysis showed that reusable non-coated catheters were the most cost-effective option for intermittent self-catheterisation. However, the clinical evidence informing this model was of low to very low quality. Currently, non-coated catheters are considered to be single-use devices. In order to make an 'off-licence' recommendation for the use of these catheters, better quality evidence is needed. A four-arm randomised controlled trial is required. The trial population should be diverse, including wheelchair users, people with spinal cord injuries and people over 16 who regularly self-catheterise. The primary outcome measures should be incidence of symptomatic urinary tract infections, urinary tract infection-associated bacteraemia, mortality, patient comfort and preference, quality of life, clinical symptoms of urethral damage, and costs. # Indwelling urinary catheters: catheter selection For patients using a long-term indwelling urinary catheter, what is the clinical and cost effectiveness of impregnated versus hydrophilic versus silicone catheters in reducing symptomatic urinary tract infections, encrustations and/or blockages? ## Why this is important Long-term indwelling catheters (both urethral and suprapubic) are commonly used in both hospital and community care settings. Long-term catheterisation carries a significant risk of symptomatic urinary tract infection, which can lead to more serious complications. Several different types of impregnated and hydrophilic long-term indwelling catheters on the market claim to be more effective than non-coated catheters, but are also more expensive. The clinical evidence review for the guideline revealed an absence of evidence for the effectiveness of indwelling catheters over the long term. A comparison of impregnated (for example, with silver), hydrophilic and silicone catheters is needed. The primary outcome measures should be symptomatic urinary tract infections, encrustations, blockages, cost/resource use and quality of life. Secondary outcome measures should include the mean number of days the catheter remains in situ (mean dwell time) and patient comfort. # Indwelling urinary catheters: antibiotic prophylaxis When recatheterising patients who have a long-term indwelling urinary catheter, what is the clinical and cost effectiveness of single-dose antibiotic prophylaxis in reducing symptomatic urinary tract infections in patients with a history of urinary tract infections associated with catheter change? ## Why this is important The immediate clinical and economic impact of urinary tract infection is so great that patients at risk of infection are sometimes offered the option to receive prophylactic antibiotics. However, the widespread use of antibiotics, including their prophylactic use, has been identified as a major factor in the increasing levels of antibiotic resistance observed across England and Wales. There is currently an absence of evidence about the short-term and long-term effects of prophylactic antibiotic use during catheter change. The GDG identified this as an important area for research to establish the benefits and harms of this practice in order to develop future guidance (the recommendation on this topic in the current guideline was based on GDG consensus). A randomised controlled trial or cohort trial comparing single-dose antibiotic prophylaxis with selected major antibiotic groups is needed. The primary outcome measures should be symptomatic urinary tract infection, cost and quality of life. This is an important area for patients as it could minimise the inappropriate use of antibiotics # Vascular access devices: skin decontamination What is the clinical and cost effectiveness of 2% chlorhexidine in alcohol versus 0.5% chlorhexidine in alcohol versus 2% chlorhexidine aqueous solution versus 0.5% chlorhexidine aqueous solution for cleansing skin (before insertion of peripheral vascular access devices and during dressing changes of all VADs) in reducing VAD-related bacteraemia and VAD site infections? ## Why this is important The effective management of VADs is important for reducing phlebitis and bacteraemia. In the community, compliance is improved when a single solution is used for all aspects of VAD-related skin care. There is no direct evidence comparing different percentages of chlorhexidine in aqueous and alcohol solutions, and little evidence on the use of such solutions in the community. A randomised controlled trial is required to compare the clinical and cost effectiveness of the different solutions available. The trial should enrol patients in the community with a VAD. The protocol would need to use the same skin preparation technique regardless of solution, and could also investigate the effects of decontamination technique and drying time. The primary outcome measures should be rate of VAD-related bacteraemia, rate of VAD site infections, mortality, cost and quality of life. Secondary outcome measures should include visual infusion phlebitis (VIP) score, insertion times and skin irritation.# Context A wide variety of healthcare is delivered in primary and community care settings. Healthcare-associated infections arise across a wide range of clinical conditions and can affect patients of all ages. Healthcare workers, family members and carers are also at risk of acquiring infections when caring for patients. Healthcare-associated infections can occur in otherwise healthy individuals, especially if invasive procedures or devices are used. For example, indwelling urinary catheters are the most common cause of urinary tract infections, and bloodstream infections are associated with vascular access devices. Healthcare-associated infections are caused by a wide range of microorganisms. These are often carried by the patients themselves, and have taken advantage of a route into the body provided by an invasive device or procedure. Healthcare-associated infections can exacerbate existing or underlying conditions, delay recovery and adversely affect quality of life. Patient safety has become a cornerstone of care, and preventing healthcare-associated infections remains a priority. It is estimated that 300,000 patients a year in England acquire a healthcare-associated infection as a result of care within the NHS. In 2007, meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infections and Clostridium difficile infections were recorded as the underlying cause of, or a contributory factor in, approximately 9000 deaths in hospital and primary care in England. Healthcare-associated infections are estimated to cost the NHS approximately £1 billion a year, and £56 million of this is estimated to be incurred after patients are discharged from hospital. In addition to increased costs, each one of these infections means additional use of NHS resources, greater patient discomfort and a decrease in patient safety. A no-tolerance attitude is now prevalent in relation to avoidable healthcare-associated infections. In 2012, this guideline updated and replaced the clinical guideline on infection control: prevention of healthcare-associated infection in primary and community care (CG2). We updated and replaced the recommendations to reflect the many changes that have happened in the NHS to help ensure patients' interests are at the centre of all activities. These changes include the launch of the NHS Constitution for England, which defines the rights and pledges that every patient can expect regarding their care. The Care Quality Commission (CQC), the independent regulator of all health and adult social care in England, which helps to ensure that health and social care is safe and monitors how providers comply with established standards. In addition, the legal framework that underpins the guidance has changed since 2003. The 2012 guidance was also needed to reflect the fact that, due to the rapid turnover of patients in acute care settings, complex care is increasingly being delivered in the community. New standards for the care of patients and the management of devices are needed to prevent related healthcare-associated infections that could reinforce the principles of asepsis. The 2012 guideline also addressed areas in which clinical practice for preventing healthcare-associated infections in primary and community care have changed, where the risk of healthcare-associated infections is greatest or where the evidence has changed (see update information for more details). Where high-quality evidence is lacking, the Guideline Development Group (GDG) highlighted areas for further research. This guideline assumes that all providers of healthcare in primary and community care settings are compliant with current code of practice on preventing and controlling infections. It aims to help build on advice given in the code and elsewhere to improve the quality of care and practice in these areas over and above current standards. The GDG recognises the important contribution that surveillance makes to monitoring infection, but it is not within the scope of this guideline to make specific recommendations about this subject. Medical Device Regulations The Medical devices regulations implement the EC Medical Devices Directives into UK law. They place obligations on manufacturers to ensure that their devices (including medical gloves, needles and other devices discussed in this guideline) are safe and fit for their intended purpose before they are CE marked and placed on the market in any EC member state. Guidance on the MHRA's adverse incident reporting system is available for reporting adverse incidents involving medical devices.	{'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Standard principles\n\nRecommendation 1.1.1.2 in the section on general advice, and recommendations 1.1.3.1,1.1.3.3, 1.1.3.4, 1.1.3.6, 1.1.3.10 and 1.1.3.11 in the section on use of personal protective equipment, are in accordance with the following health and safety legislation (current at the time of publication, March 2012):\n\nHealth and Safety at Work Act 1974\n\nManagement of Health and Safety at Work Regulations 1999\n\nHealth and Safety Regulations 2002,\n\nControl of Substances Hazardous to Health Regulations 2002,\n\nPersonal Protective Equipment Regulations 2002\n\nHealth and Social Care Act 2008.\n\n## General advice\n\nEveryone involved in providing care should be:\n\neducated about the standard principles of infection prevention and control and\n\ntrained in hand decontamination, the use of personal protective equipment, and the safe use and disposal of sharps. \n\nWherever care is delivered, healthcare workers must have available appropriate supplies of\n\nmaterials for hand decontamination\n\nsharps containers\n\npersonal protective equipment. [new 2012]\n\nEducate patients and carers about:\n\nthe benefits of effective hand decontamination\n\nthe correct techniques and timing of hand decontamination\n\nwhen it is appropriate to use liquid soap and water or handrub\n\nthe availability of hand decontamination facilities\n\ntheir role in maintaining standards of healthcare workers' hand decontamination. [new 2012]\n\n## Hand decontamination\n\nHands must be decontaminated in all of the following circumstances:\n\nimmediately before every episode of direct patient contact or care, including aseptic procedures\n\nimmediately after every episode of direct patient contact or care\n\nimmediately after any exposure to body fluids\n\nimmediately after any other activity or contact with a patient's surroundings that could potentially result in hands becoming contaminated\n\nimmediately after removal of gloves. [new 2012]\n\nDecontaminate hands preferably with a handrub (conforming to the British standard BS EN 1500:2013 [current at time of publication, March 2012]), except in the following circumstances, when liquid soap and water must be used:\n\nwhen hands are visibly soiled or potentially contaminated with body fluids or\n\nin clinical situations where there is potential for the spread of alcohol-resistant organisms (such as Clostridium difficile or other organisms that cause diarrhoeal illness). [new 2012]\n\nHealthcare workers should ensure that their hands can be decontaminated throughout the duration of clinical work by:\n\nbeing bare below the elbow when delivering direct patient care (for the purposes of this guideline, bare below the elbow means: not wearing false nails, nail polish, a wristwatch or stoned rings; wearing short-sleeved garments or being able to roll or push up sleeves)\n\nremoving wrist and hand jewellery\n\nmaking sure that fingernails are short, clean and free of nail polish\n\ncovering cuts and abrasions with waterproof dressings. [new 2012]\n\nAn effective handwashing technique involves three stages: preparation, washing and rinsing, and drying. Preparation requires wetting hands under tepid running water before applying liquid soap or an antimicrobial preparation. The handwash solution must come into contact with all of the surfaces of the hand. The hands must be rubbed together vigorously for a minimum of 10–15\xa0seconds, paying particular attention to the tips of the fingers, the thumbs and the areas between the fingers. Hands should be rinsed thoroughly before drying with good quality paper towels. \n\nWhen decontaminating hands using an alcohol handrub, hands should be free from dirt and organic material. The handrub solution must come into contact with all surfaces of the hand. The hands must be rubbed together vigorously, paying particular attention to the tips of the fingers, the thumbs and the areas between the fingers, until the solution has evaporated and the hands are dry. \n\nAn emollient hand cream should be applied regularly to protect skin from the drying effects of regular hand decontamination. If a particular soap, antimicrobial hand wash or alcohol product causes skin irritation an occupational health team should be consulted. \n\n## Use of personal protective equipment\n\nSelection of protective equipment must be based on an assessment of the risk of transmission of microorganisms to the patient, and the risk of contamination of the healthcare worker's clothing and skin by patients' blood, body fluids, secretions or excretions. \n\nGloves used for direct patient care:\n\nmust conform to current EU legislation (CE marked as medical gloves for single use under BS EN 455 Parts 1–4 and in accordance with the following health and safety legislation [current at the time of publication, March 2012]: Health and Safety at Work Act 1974, Management of Health and Safety at Work Regulations 1999, Health and Safety Regulations 2002, Control of Substances Hazardous to Health Regulations 2002, Personal Protective Equipment Regulations 2002 and Health and Social Care Act 2008) and\n\nshould be appropriate for the task. [new 2012]\n\nGloves must be worn for invasive procedures, contact with sterile sites and non-intact skin or mucous membranes, and all activities that have been assessed as carrying a risk of exposure to blood, body fluids, secretions or excretions, or to sharp or contaminated instruments.\n\nGloves mustbe worn as single-use items. They must be put on immediately before an episode of patient contact or treatment and removed as soon as the activity is completed. Gloves must be changed between caring for different patients, and between different care or treatment activities for the same patient. \n\nEnsure that gloves used for direct patient care that have been exposed to body fluids are disposed of correctly, in accordance with current national legislation (for guidance see NHS England's document on Management and disposal of healthcare waste, HTM 07-01) or local policies (see section 1.1.5 on waste disposal). [new 2012]\n\nAlternatives to natural rubber latex gloves must be available for patients, carers and healthcare workers who have a documented sensitivity to natural rubber latex. \n\nDo not use polythene gloves for clinical interventions. [new 2012]\n\nWhen delivering direct patient care:\n\nwear a disposable plastic apron if there is a risk that clothing may be exposed to blood, body fluids, secretions or excretions or\n\nwear a long-sleeved fluid-repellent gown if there is a risk of extensive splashing of blood, body fluids, secretions or excretions onto skin or clothing. \n\nWhen using disposable plastic aprons or gowns:\n\nuse them as single-use items, for one procedure or one episode of direct patient care and\n\nensure they are disposed of correctly (see section 1.1.5 on waste disposal). \n\nFace masks and eye protection must be worn where there is a risk of blood, body fluids, secretions or excretions splashing into the face and eyes. \n\nRespiratory protective equipment, for example a particulate filter mask, must be used when clinically indicated. \n\n## Safe use and disposal of sharps\n\nSharps should not be passed directly from hand to hand, and handling should be kept to a minimum. [2003, amended 2012]\n\nUsed standard needles:\n\nmust not be bent or broken before disposal (however, it is acceptable to bend needles when they are part of an approved sharps safety device)\n\nmust not be recapped.In dentistry, if recapping or disassembly is unavoidable, a risk assessment must be undertaken and appropriate safety devices should be used (see the Health and Safety [Sharp Instruments in Healthcare] Regulations 2013). [new 2012]\n\nUsed sharps must be discarded immediately by the person generating the sharps waste into a sharps container conforming to current standards (which at the time of publication [March 2012} was BS EN ISO 23907:2012). [new 2012]\n\nSharps containers:\n\nmust be located in a safe position that avoids spillage, is at a height that allows the safe disposal of sharps, is away from public access areas and is out of the reach of children\n\nmust not be used for any other purpose than the disposal of sharps\n\nmust not be filled above the fill line\n\nmust be disposed of when the fill line is reached\n\nshould be temporarily closed when not in use.For guidance see NHS England's document on Management and disposal of healthcare waste (HTM 07-01). [new 2012]\n\nUse sharps safety devices if a risk assessment has indicated that they will provide safer systems of working for healthcare workers, carers and patients. [new 2012]\n\nTrain and assess all users in the correct use and disposal of sharps and sharps safety devices. [new 2012]\n\n## Waste disposal\n\nHealthcare waste must be segregated immediately by the person generating the waste into appropriate colour-coded storage or waste disposal bags or containers defined as being compliant with current national legislation (for guidance see NHS England's document on Management and disposal of healthcare waste, HTM 07-01) and local policies. [new 2012]\n\nHealthcare waste must be labelled, stored, transported and disposed of in accordance with current national legislation (for guidance see NHS England's document on Management and disposal of healthcare waste, HTM 07-01) and local policies. [new 2012]\n\nEducate patients and carers about the correct handling, storage and disposal of healthcare waste. [new 2012]\n\n# Long-term urinary catheters\n\n## Education of patients, their carers and healthcare workers\n\nPatients and carers should be educated about and trained in techniques of hand decontamination, insertion of intermittent catheters where applicable, and catheter management before discharge from hospital. \n\nCommunity and primary healthcare workers must be trained in catheter insertion, including suprapubic catheter replacement and catheter maintenance. \n\nFollow-up training and ongoing support of patients and carers should be available for the duration of long-term catheterisation. \n\n## Assessing the need for catheterisation\n\nIndwelling urinary catheters should be used only after alternative methods of management have been considered. \n\nThe patient's clinical need for catheterisation should be reviewed regularly and the urinary catheter removed as soon as possible. \n\nCatheter insertion, changes and care should be documented. \n\n## Catheter drainage options\n\nFollowing assessment, the best approach to catheterisation that takes account of clinical need, anticipated duration of catheterisation, patient preference and risk of infection should be selected. \n\nIntermittent catheterisation should be used in preference to an indwelling catheter if it is clinically appropriate and a practical option for the patient. \n\nOffer a choice of either single-use hydrophilic or gel reservoir catheters for intermittent self-catheterisation. [new 2012]\n\nSelect the type and gauge of an indwelling urinary catheter based on an assessment of the patient's individual characteristics, including:\n\nage\n\nany allergy or sensitivity to catheter materials\n\ngender\n\nhistory of symptomatic urinary tract infection\n\npatient preference and comfort\n\nprevious catheter history\n\nreason for catheterisation. [new 2012]\n\nIn general, the catheter balloon should be inflated with 10\xa0ml of sterile water in adults and 3–5\xa0ml in children. \n\nIn patients for whom it is appropriate, a catheter valve may be used as an alternative to a drainage bag. \n\n## Catheter insertion\n\nAll catheterisations carried out by healthcare workers should be aseptic procedures. After training, healthcare workers should be assessed for their competence to carry out these types of procedures. \n\nIntermittent self-catheterisation is a clean procedure. A lubricant for single-patient use is required for non-lubricated catheters. \n\nFor urethral catheterisation, the meatus should be cleaned before insertion of the catheter, in accordance with local guidelines/policy. \n\nAn appropriate lubricant from a single-use container should be used during catheter insertion to minimise urethral trauma and infection. \n\n## Catheter maintenance\n\nIndwelling catheters should be connected to a sterile closed urinary drainage system or catheter valve. \n\nHealthcare workers should ensure that the connection between the catheter and the urinary drainage system is not broken except for good clinical reasons (for example changing the bag in line with the manufacturer's recommendations). \n\nHealthcare workers must decontaminate their hands and wear a new pair of clean, non-sterile gloves before manipulating a patient's catheter, and must decontaminate their hands after removing gloves. \n\nPatients managing their own catheters, and their carers, must be educated about the need for hand decontamination before and after manipulation of the catheter, in accordance with the recommendations in the section on standard principles. [2003, amended 2012]\n\nUrine samples must be obtained from a sampling port using an aseptic technique. \n\nUrinary drainage bags should be positioned below the level of the bladder, and should not be in contact with the floor. \n\nA link system should be used to facilitate overnight drainage, to keep the original system intact. \n\nThe urinary drainage bag should be emptied frequently enough to maintain urine flow and prevent reflux, and should be changed when clinically indicated. \n\nThe meatus should be washed daily with soap and water. \n\nTo minimise the risk of blockages, encrustations and catheter-associated infections for patients with a long-term indwelling urinary catheter:\n\ndevelop a patient-specific care regimen\n\nconsider approaches such as reviewing the frequency of planned catheter changes and increasing fluid intake\n\ndocument catheter blockages. [new 2012]\n\nBladder instillations or washouts must not be used to prevent catheter-associated infections. \n\nCatheters should be changed only when clinically necessary or according to the manufacturer's current recommendations. \n\nWhen changing catheters in patients with a long-term indwelling urinary catheter:\n\ndo not offer antibiotic prophylaxis routinely\n\nconsider antibiotic prophylaxis for patients who:\n\n\n\nhave a history of symptomatic urinary tract infection after catheter change or\n\nexperience trauma (frank haematuria after catheterisation or two or more attempts of catheterisation) during catheterisation. At the time of publication (March 2012), no antibiotics have a UK marketing authorisation for this indication. Informed consent should be obtained and documented. [new 2012]\n\n\n\n# Enteral feeding\n\n## Education of patients, their carers and healthcare workers\n\nPatients and carers should be educated about and trained in the techniques of hand decontamination, enteral feeding and the management of the administration system before being discharged from hospital. \n\nHealthcare workers should be trained in enteral feeding and management of the administration system. \n\nFollow-up training and ongoing support of patients and carers should be available for the duration of home enteral tube feeding. \n\n## Preparation and storage of feeds\n\nWherever possible pre-packaged, ready-to-use feeds should be used in preference to feeds requiring decanting, reconstitution or dilution. \n\nThe system selected should require minimal handling to assemble, and be compatible with the patient's enteral feeding tube. \n\nEffective hand decontamination must be carried out before starting feed preparation. \n\nWhen decanting, reconstituting or diluting feeds, a clean working area should be prepared and equipment dedicated for enteral feed use only should be used. \n\nFeeds should be mixed using cooled boiled water or freshly opened sterile water and a no-touch technique. \n\nFeeds should be stored according to the manufacturer's instructions and, where applicable, food hygiene legislation. \n\nWhere ready-to-use feeds are not available, feeds may be prepared in advance, stored in a refrigerator, and used within 24\xa0hours. \n\n## Administration of feeds\n\nUse minimal handling and an aseptic technique to connect the administration system to the enteral feeding tube. [new 2012]\n\nReady-to-use feeds may be given for a whole administration session, up to a maximum of 24\xa0hours. Reconstituted feeds should be administered over a maximum 4-hour period. \n\nAdministration sets and feed containers are for single use and must be discarded after each feeding session. \n\n## Care of insertion site and enteral feeding tube\n\nThe stoma should be washed daily with water and dried thoroughly. \n\nTo prevent blockages, flush the enteral feeding tube before and after feeding or administering medications using single-use syringes or single-patient-use (reusable) syringes according to the manufacturer's instructions. Use:\n\nfreshly drawn tap water for patients who are not immunosuppressed\n\neither cooled freshly boiled water or sterile water from a freshly opened container for patients who are immunosuppressed. [new 2012]\n\n# Vascular access devices\n\n## Education of patients, their carers and healthcare workers\n\nBefore discharge from hospital, patients and their carers should be taught any techniques they may need to use to prevent infection and safely manage a vascular access device. [2003, amended 2012]\n\nHealthcare workers caring for a patient with a vascular access device should be trained, and assessed as competent, in using and consistently adhering to the infection prevention practices described in this guideline. [2003, amended 2012]\n\nFollow-up training and support should be available to patients with a vascular access device and their carers. [2003, amended 2012]\n\n## General asepsis\n\nHands must be decontaminated (see section 1.1.2 on hand decontamination) before accessing or dressing a vascular access device. [new 2012]\n\nAn aseptic technique must be used for vascular access device catheter site care and when accessing the system (the Aseptic Non Touch Technique (ANTT™) is an example of an aseptic technique for vascular access device maintenance which is widely used in acute and community settings and represents a possible framework for establishing standardised guidance on aseptic technique. [new 2012]\n\n## Vascular access device site care\n\nDecontaminate the skin at the insertion site with chlorhexidine gluconate in 70% alcohol before inserting a peripheral vascular access device or a peripherally inserted central catheter.In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. [new 2012]\n\nUse a sterile transparent semipermeable membrane dressing to cover the vascular access device insertion site. [new 2012]\n\nConsider a sterile gauze dressing covered with a sterile transparent semipermeable membrane dressing only if the patient has profuse perspiration, or if the vascular access device insertion site is bleeding or oozing. If a gauze dressing is used:\n\nchange it every 24\xa0hours, or sooner if it is soiled and\n\nreplace it with a sterile transparent semipermeable membrane dressing as soon as possible. [new 2012]\n\nChange the transparent semipermeable membrane dressing covering a central venous access device insertion site every 7\xa0days, or sooner if the dressing is no longer intact or moisture collects under it. \n\nLeave the transparent semipermeable membrane dressing applied to a peripheral cannula insertion site in situ for the life of the cannula, provided that the integrity of the dressing is retained. [new 2012]\n\nDressings used on tunnelled or implanted central venous catheter sites should be replaced every 7\xa0days until the insertion site has healed, unless there is an indication to change them sooner. \n\nHealthcare workers should ensure that catheter-site care is compatible with catheter materials (tubing, hubs, injection ports, luer connectors and extensions) and carefully check compatibility with the manufacturer's recommendations. \n\nDecontaminate the central venous catheter insertion site and surrounding skin during dressing changes using chlorhexidine gluconate in 70% alcohol, and allow to air dry. Consider using an aqueous solution of chlorhexidine gluconate if the manufacturer's recommendations prohibit the use of alcohol with their catheter. In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. [new 2012]\n\nIndividual sachets of antiseptic solution or individual packages of antiseptic-impregnated swabs or wipes should be used to disinfect the dressing site. \n\n## General principles for management of vascular access devices\n\nDecontaminate the injection port or vascular access device catheter hub before and after accessing the system using chlorhexidine gluconate in 70% alcohol. Consider using an aqueous solution of chlorhexidine gluconate if the manufacturer's recommendations prohibit the use of alcohol with their catheter. In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. [new 2012]\n\nIn-line filters should not be used routinely for infection prevention. \n\nAntibiotic lock solutions should not be used routinely to prevent catheter-related bloodstream infections (CRBSI). \n\nSystemic antimicrobial prophylaxis should not be used routinely to prevent catheter colonisation or CRBSI, either before insertion or during the use of a central venous catheter. \n\nPreferably, a single lumen catheter should be used to administer parenteral nutrition. If a multilumen catheter is used, one port must be exclusively dedicated for total parenteral nutrition, and all lumens must be handled with the same meticulous attention to aseptic technique. \n\nPreferably, a sterile 0.9\xa0percent sodium chloride injection should be used to flush and lock catheter lumens. \n\nWhen recommended by the manufacturer, implanted ports or opened-ended catheter lumens should be flushed and locked with heparin sodium flush solutions. \n\nSystemic anticoagulants should not be used routinely to prevent CRBSI. \n\nIf needleless devices are used, the manufacturer's recommendations for changing the needleless components should be followed. \n\nWhen needleless devices are used, healthcare workers should ensure that all components of the system are compatible and secured, to minimise leaks and breaks in the system. \n\nWhen needleless devices are used, the risk of contamination should be minimised by decontaminating the access port with either alcohol or an alcoholic solution of chlorhexidine gluconate before and after using it to access the system.In 2012, an MHRA safety alert for chlorhexidine was issued related to the risk of adverse events. \n\nIn general, administration sets in continuous use need not be replaced more frequently than at 72-hour intervals unless they become disconnected, or a catheter-related infection is suspected or documented. \n\nAdministration sets for blood and blood components should be changed every 12\xa0hours, or according to the manufacturer's recommendations. \n\nAdministration sets used for total parenteral nutrition infusions should generally be changed every 24\xa0hours. If the solution contains only glucose and amino acids, administration sets in continuous use do not need to be replaced more frequently than every 72\xa0hours. \n\nAvoid the use of multidose vials, in order to prevent the contamination of infusates. [new 2012]\n\n# Terms used in this guidance\n\n## Aseptic technique\n\nAn aseptic technique ensures that only uncontaminated equipment and fluids come into contact with susceptible body sites. It should be used during any clinical procedure that bypasses the body's natural defences. Using the principles of asepsis minimises the spread of organisms from one person to another.\n\n## Direct patient care\n\n'Hands on' or face-to-face contact with patients. Any physical aspect of the healthcare of a patient, including treatments, self-care and administration of medication.\n\n## Hand decontamination\n\nThe use of handrub or handwashing to reduce the number of bacteria on the hands. In this guideline this term is interchangeable with 'hand hygiene'.\n\n## Handrub\n\nA preparation applied to the hands to reduce the number of viable microorganisms. This guideline refers to handrubs compliant with British standards (BS EN1500; standard for efficacy of hygienic handrubs using a reference of 60% isopropyl alcohol).\n\n## Healthcare worker\n\nAny person employed by the health service, social services, a local authority or an agency to provide care for a sick, disabled or elderly person.\n\n## Healthcare waste\n\nIn this guideline, healthcare waste refers to any waste produced by, and as a consequence of, healthcare activities.\n\n## Personal protective equipment\n\nEquipment that is intended to be worn or held by a person to protect them from risks to their health and safety while at work. Examples include gloves, aprons, and eye and face protection.", 'Recommendations for research': "The GDG has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Standard principles of infection prevention and control\n\nWhat are the barriers to compliance with the standard principles of infection prevention and control that patients and carers experience in their own homes?\n\n## Why this is important\n\nRecent changes to the delivery of healthcare mean that care is increasingly delivered within a patient's home environment. Infection prevention in this setting is just as important as in hospital. There are currently approximately 6\xa0million unpaid carers in the UK, a number that is likely to increase with an aging population. The association between carer training and infection rates is unknown. No evidence of surveillance of healthcare-associated infections in the community is currently available in the UK.\n\nA qualitative study is needed to investigate the themes surrounding the barriers to patient and carer compliance with the standard principles of infection prevention in their own homes. It would be important to assess whether lack of awareness or knowledge is a barrier. If patients and carers have received education, this should be assessed to see if this was applicable to the patient's home setting. Areas of low compliance in the home environment need to be identified. The findings could have far-reaching implications for discharge planning and duty of care.\n\n# Hand decontamination\n\nWhen clean running water is not available, what is the clinical and cost effectiveness of using wipes, gels, handrubs or other products to remove visible contamination?\n\n## Why this is important\n\nCommunity healthcare workers often encounter challenges in carrying out hand decontamination when there is no access to running water. This particularly affects ambulance service staff, who often provide emergency care at locations where running water is not available. No evidence from randomised controlled trials is available on the most effective way for community-based healthcare workers to remove physical contamination, such as blood, from their hands in the absence of running water. In recent years, hand decontamination products that can be used without running water, such as gels, handrubs and wipes, have become available. However, their efficacy and suitability in actual clinical practice for use with visibly dirty hands has not been determined. A randomised controlled trial is required to compare hand wipes (alcohol and antiseptic), hand gels and other hand decontamination products that can be used without running water, to determine the most effective way to remove physical dirt in the absence of running water, in order to make a recommendation for their use in real situations. The primary outcome measure should be colony-forming units on the basis of the adenosine triphosphate (ATP) surface test.\n\n# Intermittent urinary catheters: catheter selection\n\nFor patients performing intermittent self-catheterisation over the long term, what is the clinical and cost effectiveness of single-use non-coated versus single-use hydrophilic versus single-use gel reservoir versus reusable non-coated catheters with regard to the following outcomes: symptomatic urinary tract infections, urinary tract infection-associated bacteraemia, mortality, patient comfort and preference, quality of life, and clinical symptoms of urethral damage?\n\n## Why this is important\n\nLong-term (more than 28\xa0days) intermittent self-catheterisation is performed by many people living in the community. It is important that the choice between intermittent catheters is informed by robust evidence on clinical and cost effectiveness.\n\nThe cost-effectiveness model developed for this guideline combined evidence of clinical effectiveness, costs and quality of life with respect to symptomatic urinary tract infection and associated complications. The results of the analysis showed that reusable non-coated catheters were the most cost-effective option for intermittent self-catheterisation. However, the clinical evidence informing this model was of low to very low quality. Currently, non-coated catheters are considered to be single-use devices. In order to make an 'off-licence' recommendation for the use of these catheters, better quality evidence is needed.\n\nA four-arm randomised controlled trial is required. The trial population should be diverse, including wheelchair users, people with spinal cord injuries and people over 16 who regularly self-catheterise. The primary outcome measures should be incidence of symptomatic urinary tract infections, urinary tract infection-associated bacteraemia, mortality, patient comfort and preference, quality of life, clinical symptoms of urethral damage, and costs.\n\n# Indwelling urinary catheters: catheter selection\n\nFor patients using a long-term indwelling urinary catheter, what is the clinical and cost effectiveness of impregnated versus hydrophilic versus silicone catheters in reducing symptomatic urinary tract infections, encrustations and/or blockages?\n\n## Why this is important\n\nLong-term indwelling catheters (both urethral and suprapubic) are commonly used in both hospital and community care settings. Long-term catheterisation carries a significant risk of symptomatic urinary tract infection, which can lead to more serious complications. Several different types of impregnated and hydrophilic long-term indwelling catheters on the market claim to be more effective than non-coated catheters, but are also more expensive.\n\nThe clinical evidence review for the guideline revealed an absence of evidence for the effectiveness of indwelling catheters over the long term. A comparison of impregnated (for example, with silver), hydrophilic and silicone catheters is needed. The primary outcome measures should be symptomatic urinary tract infections, encrustations, blockages, cost/resource use and quality of life. Secondary outcome measures should include the mean number of days the catheter remains in situ (mean dwell time) and patient comfort.\n\n# Indwelling urinary catheters: antibiotic prophylaxis\n\nWhen recatheterising patients who have a long-term indwelling urinary catheter, what is the clinical and cost effectiveness of single-dose antibiotic prophylaxis in reducing symptomatic urinary tract infections in patients with a history of urinary tract infections associated with catheter change?\n\n## Why this is important\n\nThe immediate clinical and economic impact of urinary tract infection is so great that patients at risk of infection are sometimes offered the option to receive prophylactic antibiotics. However, the widespread use of antibiotics, including their prophylactic use, has been identified as a major factor in the increasing levels of antibiotic resistance observed across England and Wales. There is currently an absence of evidence about the short-term and long-term effects of prophylactic antibiotic use during catheter change. The GDG identified this as an important area for research to establish the benefits and harms of this practice in order to develop future guidance (the recommendation on this topic in the current guideline was based on GDG consensus).\n\nA randomised controlled trial or cohort trial comparing single-dose antibiotic prophylaxis with selected major antibiotic groups is needed. The primary outcome measures should be symptomatic urinary tract infection, cost and quality of life. This is an important area for patients as it could minimise the inappropriate use of antibiotics\n\n# Vascular access devices: skin decontamination\n\nWhat is the clinical and cost effectiveness of 2% chlorhexidine in alcohol versus 0.5% chlorhexidine in alcohol versus 2% chlorhexidine aqueous solution versus 0.5% chlorhexidine aqueous solution for cleansing skin (before insertion of peripheral vascular access devices [VADs] and during dressing changes of all VADs) in reducing VAD-related bacteraemia and VAD site infections?\n\n## Why this is important\n\nThe effective management of VADs is important for reducing phlebitis and bacteraemia. In the community, compliance is improved when a single solution is used for all aspects of VAD-related skin care. There is no direct evidence comparing different percentages of chlorhexidine in aqueous and alcohol solutions, and little evidence on the use of such solutions in the community. A randomised controlled trial is required to compare the clinical and cost effectiveness of the different solutions available. The trial should enrol patients in the community with a VAD. The protocol would need to use the same skin preparation technique regardless of solution, and could also investigate the effects of decontamination technique and drying time. The primary outcome measures should be rate of VAD-related bacteraemia, rate of VAD site infections, mortality, cost and quality of life. Secondary outcome measures should include visual infusion phlebitis (VIP) score, insertion times and skin irritation.", 'Context': "A wide variety of healthcare is delivered in primary and community care settings. Healthcare-associated infections arise across a wide range of clinical conditions and can affect patients of all ages. Healthcare workers, family members and carers are also at risk of acquiring infections when caring for patients.\n\nHealthcare-associated infections can occur in otherwise healthy individuals, especially if invasive procedures or devices are used. For example, indwelling urinary catheters are the most common cause of urinary tract infections, and bloodstream infections are associated with vascular access devices.\n\nHealthcare-associated infections are caused by a wide range of microorganisms. These are often carried by the patients themselves, and have taken advantage of a route into the body provided by an invasive device or procedure. Healthcare-associated infections can exacerbate existing or underlying conditions, delay recovery and adversely affect quality of life.\n\nPatient safety has become a cornerstone of care, and preventing healthcare-associated infections remains a priority. It is estimated that 300,000 patients a year in England acquire a healthcare-associated infection as a result of care within the NHS. In 2007, meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infections and Clostridium difficile infections were recorded as the underlying cause of, or a contributory factor in, approximately 9000 deaths in hospital and primary care in England.\n\nHealthcare-associated infections are estimated to cost the NHS approximately £1\xa0billion a year, and £56\xa0million of this is estimated to be incurred after patients are discharged from hospital. In addition to increased costs, each one of these infections means additional use of NHS resources, greater patient\n\ndiscomfort and a decrease in patient safety. A no-tolerance attitude is now prevalent in relation to avoidable healthcare-associated infections.\n\nIn 2012, this guideline updated and replaced the clinical guideline on infection control: prevention of healthcare-associated infection in primary and community care (CG2). We updated and replaced the recommendations to reflect the many changes that have happened in the NHS to help ensure patients' interests are at the centre of all activities. These changes include the launch of the NHS Constitution for England, which defines the rights and pledges that every patient can expect regarding their care. The Care Quality Commission (CQC), the independent regulator of all health and adult social care in England, which helps to ensure that health and social care is safe and monitors how providers comply with established standards. In addition, the legal framework that underpins the guidance has changed since 2003.\n\nThe 2012 guidance was also needed to reflect the fact that, due to the rapid turnover of patients in acute care settings, complex care is increasingly being delivered in the community. New standards for the care of patients and the management of devices are needed to prevent related healthcare-associated infections that could reinforce the principles of asepsis.\n\nThe 2012 guideline also addressed areas in which clinical practice for preventing healthcare-associated infections in primary and community care have changed, where the risk of healthcare-associated infections is greatest or where the evidence has changed (see update information for more details). Where high-quality evidence is lacking, the Guideline Development Group (GDG) highlighted areas for further research.\n\nThis guideline assumes that all providers of healthcare in primary and community care settings are compliant with current code of practice on preventing and controlling infections. It aims to help build on advice given in the code and elsewhere to improve the quality of care and practice in these areas over and above current standards.\n\nThe GDG recognises the important contribution that surveillance makes to monitoring infection, but it is not within the scope of this guideline to make specific recommendations about this subject.\n\nMedical Device Regulations\n\nThe Medical devices regulations implement the EC Medical Devices Directives into UK law. They place obligations on manufacturers to ensure that their devices (including medical gloves, needles and other devices discussed in this guideline) are safe and fit for their intended purpose before they are CE marked and placed on the market in any EC member state. Guidance on the MHRA's adverse incident reporting system is available for reporting adverse incidents involving medical devices."}	https://www.nice.org.uk/guidance/cg139	This guideline covers preventing and controlling healthcare-associated infections in children, young people and adults in primary and community care settings. It provides a blueprint for the infection prevention and control precautions that should be applied by everyone involved in delivering NHS care and treatment.
32b2811236f47face766b1f4b5bb72aae50c5fee	nice	HumiGard for preventing inadvertent perioperative hypothermia	HumiGard for preventing inadvertent perioperative hypothermia Evidence-based recommendations on HumiGard for preventing inadvertent perioperative hypothermia. # Recommendations HumiGard shows promise for preventing hypothermia during abdominal surgery. There is, however, insufficient robust evidence to support the case for routine adoption, particularly on using HumiGard to avoid important adverse outcomes and on how it affects resource use in open and laparoscopic surgery. Research is recommended on HumiGard compared with standard insufflation gases in patients having laparoscopic or open surgery alongside general measures to reduce the risk of perioperative hypothermia described in section 2.5. Research should report on the comparative rate of surgical site infections and other complications associated with hypothermia and normothermia, as well as related resource use.# The technology # Description of the technology HumiGard (Fisher and Paykel Healthcare) is designed to humidify and heat carbon dioxide (CO2) gas, which is routinely used to fill the peritoneal cavity during laparoscopic abdominal surgery. The intention is to reduce the negative effects associated with the use of dry, unwarmed CO2 gas, namely tissue desiccation and intra-operative hypothermia. HumiGard is designed to be used both independently and in addition to other warming measures that are applied to the external body surfaces and extremities, such as forced air warming. HumiGard comprises a humidifier and consumable tubing set. It humidifies and warms the CO2 by passing the gas over a reservoir of water. The heated, humidified gas is then passed along a sterile tube for delivery into the abdominal cavity through a needle cannula. HumiGard can also be applied to open surgical wounds using a bespoke patient interface diffuser to effectively immerse the open surgical wound cavity in warmed, humidified CO2 gas. HumiGard received a class IIa CE mark in April 2013. It is indicated for use in laparoscopic or open abdominal surgery when CO2 insufflation gas is used. The list prices (excluding VAT) for the components of HumiGard are as follows. Capital costs: MR860AEU humidifier: £895. Consumables: For laparoscopic surgery: ST310 humidified and heated tubing kit: £75 per patient. For open surgery: ST310 humidified and heated tubing kit plus VITA diffuser (ST300 DF): £99 per patient. The claimed benefits of HumiGard in the case for adoption presented by the company are: Decreased incidence of intra-operative and post-operative hypothermia through less evaporative cooling. Decreased incidence of surgical site infections because of improved intra-operative temperature maintenance. Improved post-operative recovery and faster discharge. Reduced overall costs as a result of better patient outcomes including fewer surgical site infections, less time spent in hospital for surgery, and less time in post-operative recovery. # Current management The NICE guideline on hypothermia recommends that all patients intended for surgery be assessed for risk of perioperative hypothermia. All patients should receive warmed intravenous fluids and blood products; patients identified as being at higher risk should be warmed intraoperatively using a forced air warming device, as should any patient having anaesthesia for more than 30 minutes. Regular temperature measurement is recommended before, during and after surgery, and forced air warming is recommended for any patient whose core temperature drops below 36°C. NICE's hypothermia guideline relates to the general prevention of hypothermia during surgery and does not make any specific recommendations about the warming of insufflation gas. Unwarmed, dry insufflation gas is used routinely in laparoscopic surgery. NICE medical technologies guidance on the Inditherm patient warming mattress recommends this device as a cost-effective alternative to forced air warming.# Clinical evidence # Summary of clinical evidence The key clinical outcomes for HumiGard presented in the decision problem were: incidence of hypothermia during and after surgery (defined as a core body temperature of less than 36°C) incidence of surgical site infections length of stay in post-operative recovery total length of hospital stay device-related adverse events patient-reported pain. The company carried out separate literature searches for laparoscopic and open surgery, encompassing both published and unpublished studies. Its submission included 24 studies, 20 involving laparoscopic surgery and 4 involving open surgery. The company used a checklist to determine if studies were generalisable and presented 16 (of the total 24) involving other humidification devices. The external assessment centre (EAC) considered that humidification systems other than HumiGard were beyond the scope of the evaluation and that those 16 studies should be excluded. The EAC's independent literature searches did not identify any additional studies on HumiGard. It judged that 7 studies provided relevant evidence: 5 on laparoscopic surgery (Herrmann and De Wilde 2015, Manwaring et al. 2008, Sammour et al. 2010, Yu et al. 2013 and Mason et al. 2016) and 2 on open surgery (Frey et al. 2012 and Weinberg et al. 2014). ## Laparoscopic surgery Hermann and De Wilde (2015) reported on a double-blind randomised controlled trial that compared HumiGard with unwarmed, dry CO2 gas in patients aged 18 years or over with benign uterine diseases having gynaecological laparoscopic surgery. Randomisation led to 52 patients receiving warm (35±2°C), humidified (98% humidity) CO2 with HumiGard and 52 patients receiving standard room temperature, dry (0% humidity) CO2. The primary outcome was post-operative pain at 2, 4, 6, 24 and 48 hours as measured by a visual analogue scale (VAS). Secondary outcome measures were morphine consumption and demand and post-operative, patient-controlled analgesia, including rejected boli delivery (not delivered when request was made within 10 minutes of the previous bolus), temperature change during surgery, length of time spent in the recovery room and length of inpatient stay. The results showed a significant difference in total shoulder tip pain (p=0.037), which was one of a number pain outcomes and differences in some indicators of morphine consumption. There were no other statistically significant difference in any of the other outcome measures specified in the scope. Manwaring et al. (2008) reported on a randomised controlled trial that compared HumiGard with unwarmed, dry CO2 gas in women aged 18 to 55 years having gynaecologic laparoscopic surgery. Randomisation led to 30 patients receiving warmed, humidified CO2 with HumiGard, and 30 patients receiving standard room temperature, dry CO2. The primary outcome was shoulder tip pain at 4 hours after surgery. Secondary outcome measures were time in recovery room, nausea, post-operative temperature and pelvic pain. The results showed a significant difference in change in core temperature from theatre to recovery (p=0.027) but no other statistically significant difference in the other outcome measures specified in the scope. Sammour et al. (2010) reported a double-blind randomised controlled trial that compared HumiGard with unwarmed, dry CO2 gas in patients aged 15 years or older having elective laparoscopic colonic resection. Randomisation led to 41 patients receiving warm (37°C), humidified (98% humidity) CO2 with HumiGard, and 41 patients receiving room temperature, dry CO2. The primary outcome was total opiate analgesia used during inpatient stay. Secondary outcome measures were post-operative pain (measured on a VAS) at 2, 4, 8 and 12 hours and 1, 2, 3, 7, 14, 30 and 60 days after the operation. Other secondary outcome measures were intra-operative core temperature, cytokine response and length of inpatient stay. Six patients in the HumiGard group and 2 in the control group were excluded from the analysis with reasons given. The results showed that HumiGard had a significant effect on post-operative pain at rest on day 1 (p=0.01) and post-operative pain on moving on day 1 (p=0.018). The results showed no statistically significant difference in the other outcome measures specified in the scope. Yu et al. (2013) reported on a double-blind randomised controlled trial that compared HumiGard with unwarmed, dry CO2 gas in children aged 8 to 14 years having an acute laparoscopic appendectomy. Randomisation led to 95 patients receiving warm (37°C), humidified (98% humidity) CO2 with HumiGard and 95 patients receiving room temperature, dry CO2. The primary outcome was post-operative pain (analgesic use) in the recovery room and at days 1 and 2 after the operation. Secondary outcome measures were pain intensity scores, intra-operative core temperature and post-operative recovery and return to normal activities. Two patients in the HumiGard group and 3 in the control group were excluded from the analysis with reasons given. The authors provided only graphical data for pain perceived at rest and on moving (VAS), but no differences were reported between the groups at any of the time points studied (0, 2, 4, 6, 8, 10, 12, 24 and 48 hours). The results showed no statistically significant difference in the other outcome measures specified in the scope. Mason et al. (2016) was a retrospective cohort trial, done in a single UK centre, including patients having laparoscopic colorectal resections. The trial included 246 consecutive patients (mean age 68 years) with equal numbers having HumiGard or standard care. Outcome measures included incidence of surgical site infections, incidence of post-operative pneumonia, perioperative hypothermia, number of bed days, length of time in theatre recovery and cost. Body temperature was routinely measured tympanically on arrival to the post-anaesthetic recovery suite. The measurement of temperature intraoperatively was not standardised and therefore could not be included in the analysis. The results showed significant differences in perioperative hypothermia (p≤0.001), post-operative hypothermia on arrival in the recovery suite (p<0.001) and incidence of surgical site infections when hypothermic (p=0.02). There was a significant difference in overall incidence of surgical site infections (p=0.04) but not in length of hospital stay. The EAC concluded that the clinical evidence on HumiGard for laparoscopic surgery was of relatively good quality: there are 4 randomised controlled trials and 1 retrospective cohort study in appropriate patients, all of which compared HumiGard with standard unwarmed, dry CO2 gas. However, the EAC also concluded that the cohort study (Mason et al. 2016) should be interpreted with caution, because of possible confounding factors arising from its design and uncertainty about the significance of its findings because of an incomplete description of regression and model development methods, regression diagnostics, any missing data and choice of final model. ## Open surgery Frey et al. (2012) reported on a randomised controlled trial that compared HumiGard with no insufflation in patients over 18 years (mean age 63.5 years) having elective open colonic surgery. Randomisation led to 42 patients receiving warm (37°C), humidified (100% humidity) CO2 gas with HumiGard and 41 patients receiving no insufflation. The primary outcome was intra-operative core and wound temperature and the secondary outcome measure was length of hospital stay. Two patients in the HumiGard group and 2 in the control group were excluded from the analysis with reasons given. The results showed significant benefits for the HumiGard group in terms of the proportion of patients with core temperature <36.0°C at end of surgery (p=0.005), the proportion of patients with core temperature <36.5°C at end of surgery (p=0.001), reduced core temperature at end of surgery (p≤0.001), reduced core temperature during surgery (p≤0.001), reduced wound area temperature during surgery (p≤0.001) and reduced wound edge temperature during surgery (p≤0.001). The results showed no statistically significant difference between the groups for length of stay. Weinberg et al. (2014) reported on a prospective pilot randomised controlled trial published as an abstract that compared HumiGard and standard care (predetermined temperatures for infused fluid, ambient air and heating mattress temperature) with standard care alone in adult patients having primary orthotopic liver transplantation. No details were provided regarding number of patients in each group, but 22 patients were randomised to the intervention or control. The primary outcome was intra-operative core temperature before reperfusion and at completion of surgery. No secondary outcomes were reported. The core temperature immediately before reperfusion (°C, nasopharyngeal probe) was significantly higher in the HumiGard group (p=0.02). No statistically significant differences were reported for core temperature on wound closure (°C, nasopharyngeal probe), core temperature immediately before reperfusion (°C, pulmonary artery catheter), core temperature on wound closure (°C, pulmonary artery catheter), core temperature immediately before reperfusion (°C, bladder probe) and core temperature on wound closure (°C, bladder probe). The clinical evidence submitted for open surgery was based on 2 small randomised controlled trials, 1 of which was a small pilot study published in abstract form only. The EAC concluded that there was insufficient information to critically appraise the Weinberg et al. (2014) abstract and Frey et al. (2012) was of reasonable quality. ## Adverse events Two randomised controlled trials involving laparoscopic abdominal surgery (Herrmann and De Wilde 2015, Sammour et al. 2010), included device-related adverse events as an outcome measure. Both studies reported no adverse events associated with the use of HumiGard. The other 3 studies on laparoscopic surgery did not report device-related adverse events. None of the studies on open abdominal surgery reported device-related adverse events. # Committee considerations The committee noted that there is good evidence that perioperative hypothermia is associated with poor patient outcomes, such as surgical site infections. Experts were in agreement and advised the committee that maintaining perioperative normothermia is now an established aim of clinical practice. The committee considered that the clinical evidence supported the effectiveness of HumiGard in reducing hypothermia during laparoscopic and open abdominal surgery, noting that the evidence base was more substantial for laparoscopic surgery than for open surgery. The committee also noted the lack of high quality direct comparisons supporting the use of HumiGard to avoid the adverse outcomes of hypothermia following surgery. The committee noted that only 1 of the included studies involved children, and that in this study outcomes did not improve. The clinical experts advised that heat loss is partly determined by the ratio of body surface area to body mass. Because this is larger in children, overheating through the use of warming strategies can also be a concern. The committee concluded that there was insufficient evidence to recommend the use of HumiGard in children. The committee heard from the clinical experts that total length of hospital stay after abdominal surgery has been reduced through the implementation of enhanced recovery programmes. Historically, length of stay after colorectal surgery was 7 to 9 days but this has now been reduced to approximately 4 to 5 days through the use of such programmes. This change makes it difficult to demonstrate how a single technology such as HumiGard affects total length of stay but the committee accepted that interventions which reduce surgical site infections would be beneficial. The committee heard from the clinical experts that wound orientation is unlikely to affect the use and effectiveness of HumiGard. The committee was also advised that the presence of intra-abdominal sepsis would not be a barrier to its safe use.# NHS considerations # System impact During abdominal surgery, HumiGard is used in combination with other warming measures (such as forced air warming) in patients at high risk of developing hypothermia. This includes patients having surgical procedures with anaesthesia for more than 30 minutes. During laparoscopic surgery, HumiGard replaces standard insufflation equipment. For open surgery, HumiGard is connected to standard sources of theatre-piped gas. If piped gas is unavailable, the company is able to provide a gas supply stand that delivers CO2 to HumiGard. Clinical experts with experience in the use of HumiGard stated that minimal training is needed to introduce it into clinical practice. ## Committee considerations The committee was informed by the clinical experts that HumiGard can be set up in approximately 1 minute. The committee heard from 2 expert advisers that HumiGard has become a well-accepted part of standard theatre practice in their centres. One expert adviser added that HumiGard has been introduced as a part of their enhanced recovery programme and subsequently adopted by every theatre in the hospital. The committee heard from the clinical experts that they had experienced no safety issues with HumiGard.# Cost considerations # Cost evidence The company identified 2 studies that incorporated a cost-effectiveness analysis. The external assessment centre (EAC) judged that the company's search strategy was highly sensitive and well-constructed, and that the selection criteria reflected the NICE scope. The EAC carried out its own economic search and found no additional studies. Both of the identified studies were published as conference abstracts and compared HumiGard with standard care in the UK. The company provided unpublished, academic-in-confidence draft manuscripts relating to both abstracts. The abstract by Jenks et al. (2015) reported on a cost-utility analysis using a decision analytic model of HumiGard compared with standard care open or laparoscopic colorectal surgery. This showed that HumiGard dominated standard care in both open and laparoscopic surgery (that is, it was both less costly and more effective than standard care). The full manuscript by Jenks et al. provided further detail on the study and was available to the EAC. Effectiveness data for open surgery were derived from Frey et al. (2012; section 3.9). Data on the probability of complications related to hypothermia were taken from a published retrospective study (Billeter et al. 2014) and linked to the data from Frey et al. (2012). The effectiveness data for laparoscopic surgery were taken from a retrospective cohort study reported in a conference abstract (Noor et al. 2015). The costs of myocardial infarction, stroke, sepsis and pneumonia were taken from NHS reference costs 2013/14. The cost of surgical site infections was derived from the NICE quality standard. The results presented in the full manuscript matched those reported in the abstract. The study by Mason et al. 2016 (section 3.7) also reported a cost-benefit analysis of HumiGard compared with standard care in patients having laparoscopic colorectal surgery. The EAC was unable to replicate the cost analysis from this study. ## Cost model The company presented a de novo economic model adapted from Jenks et al. estimating mean cost savings per patient in open and laparoscopic colorectal surgery. The model assumed a 70:30 split for the use of HumiGard in laparoscopic and open surgery respectively. It comprised 2 decision trees incorporating complications associated with hypothermia and related NHS costs for each kind of surgery. The model runs over 1 year; horizons up to 5 years were reported in scenario analyses, but because these extend post-myocardial infarction and stroke costs they affect only open surgery. The model was based on 3 studies: Noor et al. 2015 (laparoscopic surgery: incidence of surgical site infections and pneumonia), Frey et al. 2012 (open surgery: proportion of patients with hypothermia at the end of surgery) and Billeter et al. 2014 (open surgery: incidence of myocardial infarction, stroke, sepsis, pneumonia, surgical site infection and mortality). The company's scenario analyses included exploring the use of alternative sources of clinical effectiveness, a univariate deterministic sensitivity analysis and a probabilistic analysis of the base-case results. For open surgery, it used 3 alternative sources for the proportion of patients experiencing complications (Kurz et al. 1996, Flores-Maldonado et al. 2001, Anannamcharoen et al. 2012). For laparoscopic surgery, the company presented 2 scenario analyses that used data on the proportion of patients with hypothermia linked with complications associated with open surgery (Billeter et al. 2014). The first of these used data from Mason et al. (2016) whereas the second used data from Sammour et al. (2010). The analyses showed that the costs for treating stroke (£2,715 to £13,858) and surgical site infections (£2,100 to £10,500) had the largest effects on the results. The company's base case showed that, overall, HumiGard costs £419 per patient compared with £724 per patient for standard care. The company therefore estimated that using HumiGard would save £305 per patient. Most cost savings (69%) come from fewer surgical site infections after laparoscopic surgery (with cost savings of £20 per patient in open surgery and £428 per patient in laparoscopic surgery). Sensitivity analyses showed that HumiGard becomes cost incurring when the absolute difference in infection risk is 0.3% (for example, 4.7% versus 5%). For open surgery, using data from Frey et al. (2012), HumiGard was associated with a modest additional cost (using complication data from Billeter et al. 2014 or Flores-Maldonado et al. 2001). The company's probabilistic sensitivity analysis found that HumiGard was cost saving in 97.4% of iterations and the average probabilistic cost savings were £302 per patient. The company noted that the results of its probabilistic sensitivity analysis have a skewed distribution and stated that this is because of the distribution of costs of complications within the model (which have a gamma distribution bounded by 0, but no upper limit). ## Additional work by the external assessment centre The EAC re-ran the company's base case and univariate sensitivity analyses for open and laparoscopic surgery separately, and conducted additional analyses using its preferred estimates. The main changes to the company's model were: including updated NHS reference costs for pneumonia, acute myocardial infarction and sepsis annuitising the capital cost of HumiGard re-estimating the costs of 'post-myocardial infarction' to reflect current drug prices using alternative costs of treating stroke and surgical site infections using a 5-year time horizon and including data on hypothermia from the randomised control trial in laparoscopic surgery linked to data on complications from the retrospective cohort study (laparoscopic surgery only). The EAC re-ran univariate sensitivity analyses for open and laparoscopic surgery, including updated costs for adverse events and a discount rate for HumiGard of 3.5% over 5 years. In addition to this for laparoscopic surgery, the EAC took hypothermia data from Sammour et al. (2010) and risk of complications data from Billeter et al. (2014). The EAC considered that because stroke and myocardial infarction have long-term resource implications, a longer time horizon was preferable. However, the model incorporates this by simply adding in additional costs to later years, so the EAC also conducted analyses using a 1-year time horizon. Additional EAC sensitivity analyses included an alternative estimate for the cost of treating surgical site infections (£5,164, based on Jenks et al. 2015) and laparoscopic surgery complication data from Noor et al. (2015). For open surgery, the results of the EAC's analysis suggest that HumiGard is cost saving compared with standard care, with an average saving per patient of £209. This is a larger cost saving than that identified in the company's model because of the longer (5-year) time horizon. The probability that HumiGard is cost saving was 98% in the sensitivity analysis. The results for a 1-year time horizon were broadly similar to those reported by the company (an average cost saving of £28 per patient). For laparoscopic surgery, the EAC concluded that savings were lower than in the company model (an average of £77 per patient) because the EAC used data from Sammour et al. (2010) rather than Mason et al. (2016). The probabilistic analysis found that HumiGard was cost saving in 67.5% of iterations. Using a 1-year time horizon, HumiGard was associated with a small additional cost of £11 per patient. The committee was uncertain about assumptions and parameters in the cost modelling which could not be addressed by the evidence presented. The committee noted that the effect of hypothermia on the risk of stroke during abdominal surgery, the incidence of surgical site infection and the cost of a surgical site infection to the NHS were parameters associated with most uncertainty. The EAC was asked to make further changes to the model to better inform the economic analysis (sections 5.15 to 5.19). The committee was advised by clinical experts that the risk of stroke during abdominal surgery is very low. In the context of elective colorectal surgery, the experts estimated it to be less than 1%. Hospital Episode Statistics data were presented to the committee on perioperative stroke rates for England. The data represented selected abdominal procedures that were done in April 2014 and were followed by a primary diagnosis of a stroke at any time during the 2014/15 financial year. The relevant procedures were selected following expert advice. The stroke rates were 0.4% for laparoscopic surgery and 0.6% for open surgery. The EAC reviewed the NICE guideline on hypothermia to identify additional data on the associated complications. The guideline cited a study by Frank et al. (1997), as well as 2 studies (Kurz 1996 and Flores-Maldonado 2001) used in the company's model (section 5.6). Nevertheless, following the review, the EAC re-affirmed its view that Billeter et al. (2014) was most relevant to the decision problem. The EAC used 2 sources (Sammour et al. 2010 and Mason et al. 2016) of clinical-effectiveness data to better characterise the remaining uncertainties in further cost analyses for laparoscopic surgery. The EAC used data in a personal communication from Mason et al. (2016) to calculate adjusted risks for hypothermia and surgical site infections, taking into account the population characteristics in each study arm. The EAC also used data in a personal communication from Sammour et al. (2010) to assess hypothermia risk with and without HumiGard. The EAC used a range of additional analyses to assess how different stroke rates, surgical site infection costs and sources of effectiveness data affect HumiGard's potential cost savings. For open surgery (using data from Frey et al. 2012 data on hypothermia risk and Billeter et al. 2014 data on risk of complications), HumiGard appears to be associated with a cost saving for scenarios when the difference in risk of stroke between hypothermic and normothermic patients is greater than 0.75% to 1.25% (depending on the cost of surgical site infections). At a stroke risk difference below this range, HumiGard is associated with a modest increase in mean cost per patient. For laparoscopic surgery (using data from Billeter et al. 2014 and Sammour et al. 2010), HumiGard is cost saving only if the difference in stroke risk between hypothermic and normothermic patients is greater than 1.75% to 2.25% (depending on the cost of surgical site infections). Additional analyses using the data from Mason et al. (2016; and the updated predicted risk data calculated by the EAC) suggest that HumiGard is cost saving regardless of the cost of surgical site infections and stroke risk when using a range of complications data from Billeter et al. (2014), but cost saving or cost neutral when using only direct data on surgical site infection complications. However, the EAC was unable to fully appraise these models because of incomplete information from Mason et al. (2016). # Committee considerations The committee was informed by the clinical experts that the 5.5% stroke risk extrapolated from Billeter et al. (2014) in the company's cost model was an overestimate of the risk in current UK NHS practice, and that this is more likely to be less than 1%. The committee concluded that this distinction is likely to be very influential in the outcome of cost modelling. The committee was informed by the EAC that reducing the stroke risk to 0% in the cost model would make the use of HumiGard cost incurring. The committee concluded that the use of HumiGard was unlikely to reduce stroke rates for patients having abdominal surgery in the NHS. The committee was informed that the NHS costs associated with surgical site infections were uncertain and that published estimates vary. The committee noted that the average cost used in the EAC cost analysis was reflective of current practice. Expert advice stated that surgical site infection costs vary considerably in colorectal surgery.# Conclusions The committee concluded that there is good evidence to support the use of measures to prevent hypothermia during abdominal surgery and that, in this regard, HumiGard shows promise. However, it considered that there is insufficient evidence to demonstrate that HumiGard has a substantial effect on reducing adverse outcomes for patients having abdominal surgery. The committee concluded that the cost consequences of using HumiGard in abdominal surgery are very uncertain, and that further research is needed on resource use. The committee recommended conducting research in collaboration with the company and with clinical and academic partners. NICE will update this guidance if new and substantive evidence becomes available.Andrew DillonChief executiveFebruary 2017	{'Recommendations': 'HumiGard shows promise for preventing hypothermia during abdominal surgery. There is, however, insufficient robust evidence to support the case for routine adoption, particularly on using HumiGard to avoid important adverse outcomes and on how it affects resource use in open and laparoscopic surgery.\n\nResearch is recommended on HumiGard compared with standard insufflation\xa0gases in patients having laparoscopic or open surgery alongside general measures to reduce the risk of perioperative hypothermia described in section 2.5. Research should report on the comparative rate of surgical site infections and other complications associated with hypothermia and normothermia, as well as related resource use.', 'The technology': "# Description of the technology\n\nHumiGard (Fisher and Paykel Healthcare) is designed to humidify and heat carbon dioxide (CO2)\xa0gas, which is routinely used to fill the peritoneal cavity during laparoscopic abdominal surgery. The intention is to reduce the negative effects associated with the use of dry, unwarmed CO2\xa0gas, namely tissue desiccation and intra-operative hypothermia. HumiGard is designed to be used both independently and in addition to other warming measures that are applied to the external body surfaces and extremities, such as forced air warming. HumiGard comprises a humidifier and consumable tubing set. It humidifies and warms the CO2 by passing the\xa0gas over a reservoir of water. The heated, humidified\xa0gas is then passed along a sterile tube for delivery into the abdominal cavity through a needle cannula. HumiGard can also be applied to open surgical wounds using a bespoke patient interface diffuser to effectively immerse the open surgical wound cavity in warmed, humidified CO2\xa0gas.\n\nHumiGard received a class IIa CE mark in April 2013. It is indicated for use in laparoscopic or open abdominal surgery when CO2 insufflation\xa0gas is used.\n\nThe list prices (excluding VAT) for the components of HumiGard are as follows.\n\nCapital costs:\n\n\n\nMR860AEU humidifier: £895.\n\n\n\nConsumables:\n\n\n\nFor laparoscopic surgery: ST310\xa0humidified and heated tubing kit: £75 per\xa0patient.\n\nFor open surgery: ST310\xa0humidified and heated tubing kit plus VITA diffuser (ST300\xa0DF): £99 per\xa0patient.\n\n\n\nThe claimed benefits of HumiGard in the case for adoption presented by the company are:\n\nDecreased incidence of intra-operative and post-operative hypothermia through less evaporative cooling.\n\nDecreased incidence of surgical site infections because of improved intra-operative temperature maintenance.\n\nImproved post-operative recovery and faster discharge.\n\nReduced overall costs as a result of better patient outcomes including fewer surgical site infections, less time spent in hospital for surgery, and less time in post-operative recovery.\n\n# Current management\n\nThe NICE guideline on hypothermia recommends that all patients intended for surgery be assessed for risk of perioperative hypothermia. All patients should receive warmed intravenous fluids and blood products; patients identified as being at higher risk should be warmed intraoperatively using a forced air warming device, as should any patient having anaesthesia for more than 30\xa0minutes. Regular temperature measurement is recommended before, during and after surgery, and forced air warming is recommended for any patient whose core temperature drops below 36°C.\n\nNICE's hypothermia guideline relates to the general prevention of hypothermia during surgery and does not make any specific recommendations about the warming of insufflation\xa0gas. Unwarmed, dry insufflation\xa0gas is used routinely in laparoscopic surgery.\n\nNICE medical technologies guidance on the Inditherm patient warming mattress recommends this device as a cost-effective alternative to forced air warming.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe key clinical outcomes for HumiGard presented in the decision problem were:\n\nincidence of hypothermia during and after surgery (defined as a core body temperature of less than 36°C)\n\nincidence of surgical site infections\n\nlength of stay in post-operative recovery\n\ntotal length of hospital stay\n\ndevice-related adverse events\n\npatient-reported pain.\n\nThe company carried out separate literature searches for laparoscopic and open surgery, encompassing both published and unpublished studies. Its submission included 24 studies, 20\xa0involving laparoscopic surgery and 4 involving open surgery. The company used a checklist to determine if studies were generalisable and presented 16 (of the total 24) involving other humidification devices. The external assessment centre (EAC) considered that humidification systems other than HumiGard were beyond the scope of the evaluation and that those 16 studies should be excluded. The EAC's independent literature searches did not identify any additional studies on HumiGard. It judged that 7 studies provided relevant evidence: 5 on laparoscopic surgery (Herrmann and De Wilde 2015, Manwaring et\xa0al. 2008, Sammour et\xa0al. 2010, Yu et\xa0al. 2013 and Mason et\xa0al. 2016) and 2 on open surgery (Frey et\xa0al. 2012 and Weinberg et\xa0al. 2014).\n\n## Laparoscopic surgery\n\nHermann and De Wilde (2015) reported on a double-blind randomised controlled trial that compared HumiGard with unwarmed, dry CO2\xa0gas in patients aged 18\xa0years or over with benign uterine diseases having gynaecological laparoscopic surgery. Randomisation led to 52 patients receiving warm (35±2°C), humidified (98% humidity) CO2 with HumiGard and 52 patients receiving standard room temperature, dry (0% humidity) CO2. The primary outcome was post-operative pain at 2, 4, 6, 24 and 48\xa0hours as measured by a visual analogue scale (VAS). Secondary outcome measures were morphine consumption and demand and post-operative, patient-controlled analgesia, including rejected boli delivery (not delivered when request was made within 10\xa0minutes of the previous bolus), temperature change during surgery, length of time spent in the recovery room and length of inpatient stay. The results showed a significant difference in total shoulder tip pain (p=0.037), which was one of a number pain outcomes and differences in some indicators of morphine consumption. There were no other statistically significant difference in any of the other outcome measures specified in the scope.\n\nManwaring et\xa0al. (2008) reported on a randomised controlled trial that compared HumiGard with unwarmed, dry CO2\xa0gas in women aged 18 to 55\xa0years having gynaecologic laparoscopic surgery. Randomisation led to 30\xa0patients receiving warmed, humidified CO2 with HumiGard, and 30\xa0patients receiving standard room temperature, dry CO2. The primary outcome was shoulder tip pain at 4\xa0hours after surgery. Secondary outcome measures were time in recovery room, nausea, post-operative temperature and pelvic pain. The results showed a significant difference in change in core temperature from theatre to recovery (p=0.027) but no other statistically significant difference in the other outcome measures specified in the scope.\n\nSammour et\xa0al. (2010) reported a double-blind randomised controlled trial that compared HumiGard with unwarmed, dry CO2\xa0gas in patients aged 15\xa0years or older having elective laparoscopic colonic resection. Randomisation led to 41 patients receiving warm (37°C), humidified (98% humidity) CO2 with HumiGard, and 41 patients receiving room temperature, dry CO2. The primary outcome was total opiate analgesia used during inpatient stay. Secondary outcome measures were post-operative pain (measured on a VAS) at 2, 4, 8 and 12\xa0hours and 1, 2, 3, 7, 14, 30\xa0and 60\xa0days after the operation. Other secondary outcome measures were intra-operative core temperature, cytokine response and length of inpatient stay. Six patients in the HumiGard group and 2 in the control group were excluded from the analysis with reasons given. The results showed that HumiGard had a significant effect on post-operative pain at rest on day 1 (p=0.01) and post-operative pain on moving on day 1 (p=0.018). The results showed no statistically significant difference in the other outcome measures specified in the scope.\n\nYu et\xa0al. (2013) reported on a double-blind randomised controlled trial that compared HumiGard with unwarmed, dry CO2\xa0gas in children aged 8 to 14\xa0years having an acute laparoscopic appendectomy. Randomisation led to 95 patients receiving warm (37°C), humidified (98% humidity) CO2 with HumiGard and 95 patients receiving room temperature, dry CO2. The primary outcome was post-operative pain (analgesic use) in the recovery room and at days 1 and 2 after the operation. Secondary outcome measures were pain intensity scores, intra-operative core temperature and post-operative recovery and return to normal activities. Two patients in the HumiGard group and 3 in the control group were excluded from the analysis with reasons given. The authors provided only graphical data for pain perceived at rest and on moving (VAS), but no differences were reported between the groups at any of the time points studied (0, 2, 4, 6, 8, 10, 12, 24 and 48\xa0hours). The results showed no statistically significant difference in the other outcome measures specified in the scope.\n\nMason et\xa0al. (2016) was a retrospective cohort trial, done in a single UK centre, including patients having laparoscopic colorectal resections. The trial included 246 consecutive patients (mean age 68\xa0years) with equal numbers having HumiGard or standard care. Outcome measures included incidence of surgical site infections, incidence of post-operative pneumonia, perioperative hypothermia, number of bed days, length of time in theatre recovery and cost. Body temperature was routinely measured tympanically on arrival to the post-anaesthetic recovery suite. The measurement of temperature intraoperatively was not standardised and therefore could not be included in the analysis. The results showed significant differences in perioperative hypothermia (p≤0.001), post-operative hypothermia on arrival in the recovery suite (p<0.001) and incidence of surgical site infections when hypothermic (p=0.02). There was a significant difference in overall incidence of surgical site infections (p=0.04) but not in length of hospital stay.\n\nThe EAC concluded that the clinical evidence on HumiGard for laparoscopic surgery was of relatively good quality: there are 4 randomised controlled trials and 1 retrospective cohort study in appropriate patients, all of which compared HumiGard with standard unwarmed, dry CO2\xa0gas. However, the EAC also concluded that the cohort study (Mason et\xa0al. 2016) should be interpreted with caution, because of possible confounding factors arising from its design and uncertainty about the significance of its findings because of an incomplete description of regression and model development methods, regression diagnostics, any missing data and choice of final model.\n\n## Open surgery\n\nFrey et\xa0al. (2012) reported on a randomised controlled trial that compared HumiGard with no insufflation in patients over 18\xa0years (mean age 63.5\xa0years) having elective open colonic surgery. Randomisation led to 42 patients receiving warm (37°C), humidified (100% humidity) CO2\xa0gas with HumiGard and 41 patients receiving no insufflation. The primary outcome was intra-operative core and wound temperature and the secondary outcome measure was length of hospital stay. Two patients in the HumiGard group and 2 in the control group were excluded from the analysis with reasons given. The results showed significant benefits for the HumiGard group in terms of the proportion of patients with core temperature <36.0°C at end of surgery (p=0.005), the proportion of patients with core temperature <36.5°C at end of surgery (p=0.001), reduced core temperature at end of surgery (p≤0.001), reduced core temperature during surgery (p≤0.001), reduced wound area temperature during surgery (p≤0.001) and reduced wound edge temperature during surgery (p≤0.001). The results showed no statistically significant difference between the groups for length of stay.\n\nWeinberg et\xa0al. (2014) reported on a prospective pilot randomised controlled trial published as an abstract that compared HumiGard and standard care (predetermined temperatures for infused fluid, ambient air and heating mattress temperature) with standard care alone in adult patients having primary orthotopic liver transplantation. No details were provided regarding number of patients in each group, but 22 patients were randomised to the intervention or control. The primary outcome was intra-operative core temperature before reperfusion and at completion of surgery. No secondary outcomes were reported. The core temperature immediately before reperfusion (°C, nasopharyngeal probe) was significantly higher in the HumiGard group (p=0.02). No statistically significant differences were reported for core temperature on wound closure (°C, nasopharyngeal probe), core temperature immediately before reperfusion (°C, pulmonary artery catheter), core temperature on wound closure (°C, pulmonary artery catheter), core temperature immediately before reperfusion (°C, bladder probe) and core temperature on wound closure (°C, bladder probe).\n\nThe clinical evidence submitted for open surgery was based on 2 small randomised controlled trials, 1 of which was a small pilot study published in abstract form only. The EAC concluded that there was insufficient information to critically appraise the Weinberg et\xa0al. (2014) abstract and Frey et\xa0al. (2012) was of reasonable quality.\n\n## Adverse events\n\nTwo randomised controlled trials involving laparoscopic abdominal surgery (Herrmann and De Wilde 2015, Sammour et\xa0al. 2010), included device-related adverse events as an outcome measure. Both studies reported no adverse events associated with the use of HumiGard. The other 3 studies on laparoscopic surgery did not report device-related adverse events. None of the studies on open abdominal surgery reported device-related adverse events.\n\n# Committee considerations\n\nThe committee noted that there is good evidence that perioperative hypothermia is associated with poor patient outcomes, such as surgical site infections. Experts were in agreement and advised the committee that maintaining perioperative normothermia is now an established aim of clinical practice.\n\nThe committee considered that the clinical evidence supported the effectiveness of HumiGard in reducing hypothermia during laparoscopic and open abdominal surgery, noting that the evidence base was more substantial for laparoscopic surgery than for open surgery. The committee also noted the lack of high quality direct comparisons supporting the use of HumiGard to avoid the adverse outcomes of hypothermia following surgery.\n\nThe committee noted that only 1 of the included studies involved children, and that in this study outcomes did not improve. The clinical experts advised that heat loss is partly determined by the ratio of body surface area to body mass. Because this is larger in children, overheating through the use of warming strategies can also be a concern. The committee concluded that there was insufficient evidence to recommend the use of HumiGard in children.\n\nThe committee heard from the clinical experts that total length of hospital stay after abdominal surgery has been reduced through the implementation of enhanced recovery programmes. Historically, length of stay after colorectal surgery was 7 to 9 days but this has now been reduced to approximately 4 to 5 days through the use of such programmes. This change makes it difficult to demonstrate how a single technology such as HumiGard affects total length of stay but the committee accepted that interventions which reduce surgical site infections would be beneficial.\n\nThe committee heard from the clinical experts that wound orientation is unlikely to affect the use and effectiveness of HumiGard. The committee was also advised that the presence of intra-abdominal sepsis would not be a barrier to its safe use.", 'NHS considerations': '# System impact\n\nDuring abdominal surgery, HumiGard is used in combination with other warming measures (such as forced air warming) in patients at high risk of developing hypothermia. This includes patients having surgical procedures with anaesthesia for more than 30\xa0minutes. During laparoscopic surgery, HumiGard replaces standard insufflation equipment. For open surgery, HumiGard is connected to standard sources of theatre-piped\xa0gas. If piped\xa0gas is unavailable, the company is able to provide a\xa0gas supply stand that delivers CO2 to HumiGard. Clinical experts with experience in the use of HumiGard stated that minimal training is needed to introduce it into clinical practice.\n\n## Committee considerations\n\nThe committee was informed by the clinical experts that HumiGard can be set up in approximately 1 minute.\n\nThe committee heard from 2 expert advisers that HumiGard has become a well-accepted part of standard theatre practice in their centres. One expert adviser added that HumiGard has been introduced as a part of their enhanced recovery programme and subsequently adopted by every theatre in the hospital.\n\nThe committee heard from the clinical experts that they had experienced no safety issues with HumiGard.', 'Cost considerations': "# Cost evidence\n\nThe company identified 2 studies that incorporated a cost-effectiveness analysis. The external assessment centre (EAC) judged that the company's search strategy was highly sensitive and well-constructed, and that the selection criteria reflected the NICE scope. The EAC carried out its own economic search and found no additional studies.\n\nBoth of the identified studies were published as conference abstracts and compared HumiGard with standard care in the UK. The company provided unpublished, academic-in-confidence draft manuscripts relating to both abstracts.\n\nThe abstract by Jenks et\xa0al. (2015) reported on a cost-utility analysis using a decision analytic model of HumiGard compared with standard care open or laparoscopic colorectal surgery. This showed that HumiGard dominated standard care in both open and laparoscopic surgery (that is, it was both less costly and more effective than standard care). The full manuscript by Jenks et\xa0al. provided further detail on the study and was available to the EAC. Effectiveness data for open surgery were derived from Frey et\xa0al. (2012; section 3.9). Data on the probability of complications related to hypothermia were taken from a published retrospective study (Billeter et\xa0al. 2014) and linked to the data from Frey et\xa0al. (2012). The effectiveness data for laparoscopic surgery were taken from a retrospective cohort study reported in a conference abstract (Noor et\xa0al. 2015). The costs of myocardial infarction, stroke, sepsis and pneumonia were taken from NHS reference costs 2013/14. The cost of surgical site infections was derived from the NICE quality standard. The results presented in the full manuscript matched those reported in the abstract.\n\nThe study by Mason et\xa0al. 2016 (section 3.7) also reported a cost-benefit analysis of HumiGard compared with standard care in patients having laparoscopic colorectal surgery. The EAC was unable to replicate the cost analysis from this study.\n\n## Cost model\n\nThe company presented a de novo economic model adapted from Jenks et\xa0al. estimating mean cost savings per\xa0patient in open and laparoscopic colorectal surgery. The model assumed a 70:30\xa0split for the use of HumiGard in laparoscopic and open surgery respectively. It comprised 2 decision trees incorporating complications associated with hypothermia and related NHS costs for each kind of surgery. The model runs over 1 year; horizons up to 5\xa0years were reported in scenario analyses, but because these extend post-myocardial infarction and stroke costs they affect only open surgery. The model was based on 3 studies: Noor et\xa0al. 2015 (laparoscopic surgery: incidence of surgical site infections and pneumonia), Frey et\xa0al. 2012 (open surgery: proportion of patients with hypothermia at the end of surgery) and Billeter et\xa0al. 2014 (open surgery: incidence of myocardial infarction, stroke, sepsis, pneumonia, surgical site infection and mortality).\n\nThe company's scenario analyses included exploring the use of alternative sources of clinical effectiveness, a univariate deterministic sensitivity analysis and a probabilistic analysis of the base-case results. For open surgery, it used 3 alternative sources for the proportion of patients experiencing complications (Kurz et\xa0al. 1996, Flores-Maldonado et\xa0al. 2001, Anannamcharoen et\xa0al. 2012). For laparoscopic surgery, the company presented 2 scenario analyses that used data on the proportion of patients with hypothermia linked with complications associated with open surgery (Billeter et\xa0al. 2014). The first of these used data from Mason et\xa0al. (2016) whereas the second used data from Sammour et\xa0al. (2010). The analyses showed that the costs for treating stroke (£2,715 to £13,858) and surgical site infections (£2,100\xa0to £10,500) had the largest effects on the results.\n\nThe company's base case showed that, overall, HumiGard costs £419 per\xa0patient compared with £724 per\xa0patient for standard care. The company therefore estimated that using HumiGard would save £305 per\xa0patient. Most cost savings (69%) come from fewer surgical site infections after laparoscopic surgery (with cost savings of £20\xa0per\xa0patient in open surgery and £428 per\xa0patient in laparoscopic surgery).\n\nSensitivity analyses showed that HumiGard becomes cost incurring when the absolute difference in infection risk is 0.3% (for example, 4.7% versus 5%). For open surgery, using data from Frey et\xa0al. (2012), HumiGard was associated with a modest additional cost (using complication data from Billeter et\xa0al. 2014 or Flores-Maldonado et\xa0al. 2001).\n\nThe company's probabilistic sensitivity analysis found that HumiGard was cost saving in 97.4% of iterations and the average probabilistic cost savings were £302 per\xa0patient. The company noted that the results of its probabilistic sensitivity analysis have a skewed distribution and stated that this is because of the distribution of costs of complications within the model (which have a gamma distribution bounded by 0, but no upper\xa0limit).\n\n## Additional work by the external assessment centre\n\nThe EAC re-ran the company's base case and univariate sensitivity analyses for open and laparoscopic surgery separately, and conducted additional analyses using its preferred estimates. The main changes to the company's model were:\n\nincluding updated NHS reference costs for pneumonia, acute myocardial infarction and sepsis\n\nannuitising the capital cost of HumiGard\n\nre-estimating the costs of 'post-myocardial infarction' to reflect current drug prices\n\nusing alternative costs of treating stroke and surgical site infections\n\nusing a 5-year time horizon and including data on hypothermia from the randomised control trial in laparoscopic surgery linked to data on complications from the retrospective cohort study (laparoscopic surgery only).\n\nThe EAC re-ran univariate sensitivity analyses for open and laparoscopic surgery, including updated costs for adverse events and a discount rate for HumiGard of 3.5% over 5\xa0years. In addition to this for laparoscopic surgery, the EAC took hypothermia data from Sammour et\xa0al. (2010) and risk of complications data from Billeter et\xa0al. (2014). The EAC considered that because stroke and myocardial infarction have long-term resource implications, a longer time horizon was preferable. However, the model incorporates this by simply adding in additional costs to later\xa0years, so the EAC also conducted analyses using a 1-year time horizon. Additional EAC sensitivity analyses included an alternative estimate for the cost of treating surgical site infections (£5,164, based on Jenks et\xa0al. 2015) and laparoscopic surgery complication data from Noor et\xa0al. (2015).\n\nFor open surgery, the results of the EAC's analysis suggest that HumiGard is cost saving compared with standard care, with an average saving per\xa0patient of £209. This is a larger cost saving than that identified in the company's model because of the longer (5-year) time horizon. The probability that HumiGard is cost saving was 98% in the sensitivity analysis. The results for a 1-year time horizon were broadly similar to those reported by the company (an average cost saving of £28 per\xa0patient).\n\nFor laparoscopic surgery, the EAC concluded that savings were lower than in the company model (an average of £77 per\xa0patient) because the EAC used data from Sammour et\xa0al. (2010) rather than Mason et\xa0al. (2016). The probabilistic analysis found that HumiGard was cost saving in 67.5% of iterations. Using a 1-year time horizon, HumiGard was associated with a small additional cost of £11 per\xa0patient.\n\nThe committee was uncertain about assumptions and parameters in the cost modelling which could not be addressed by the evidence presented. The committee noted that the effect of hypothermia on the risk of stroke during abdominal surgery, the incidence of surgical site infection and the cost of a surgical site infection to the NHS were parameters associated with most uncertainty. The EAC was asked to make further changes to the model to better inform the economic analysis (sections 5.15 to 5.19).\n\nThe committee was advised by clinical experts that the risk of stroke during abdominal surgery is very low. In the context of elective colorectal surgery, the experts estimated it to be less than 1%. Hospital Episode Statistics data were presented to the committee on perioperative stroke rates for England. The data represented selected abdominal procedures that were done in April 2014 and were followed by a primary diagnosis of a stroke at any time during the 2014/15 financial year. The relevant procedures were selected following expert advice. The stroke rates were 0.4% for laparoscopic surgery and 0.6% for open surgery.\n\nThe EAC reviewed the NICE guideline on hypothermia to identify additional data on the associated complications. The guideline cited a study by Frank et\xa0al. (1997), as well as 2 studies (Kurz 1996 and Flores-Maldonado 2001) used in the company's model (section\xa05.6). Nevertheless, following the review, the EAC re-affirmed its view that Billeter et\xa0al. (2014) was most relevant to the decision problem.\n\nThe EAC used 2 sources (Sammour et\xa0al. 2010\xa0and Mason et\xa0al. 2016) of clinical-effectiveness data to better characterise the remaining uncertainties in further cost analyses for laparoscopic surgery. The EAC used data in a personal communication from Mason et\xa0al. (2016) to calculate adjusted risks for hypothermia and surgical site infections, taking into account the population characteristics in each study arm. The EAC also used data in a personal communication from Sammour et\xa0al. (2010) to assess hypothermia risk with and without HumiGard.\n\nThe EAC used a range of additional analyses to assess how different stroke rates, surgical site infection costs and sources of effectiveness data affect HumiGard's potential cost savings.\n\nFor open surgery (using data from Frey et\xa0al. 2012 data on hypothermia risk and Billeter et\xa0al. 2014 data on risk of complications), HumiGard appears to be associated with a cost saving for scenarios when the difference in risk of stroke between hypothermic and normothermic patients is greater than 0.75% to 1.25% (depending on the cost of surgical site infections). At a stroke risk difference below this range, HumiGard is associated with a modest increase in mean cost per\xa0patient.\n\nFor laparoscopic surgery (using data from Billeter et\xa0al. 2014 and Sammour et\xa0al. 2010), HumiGard is cost saving only if the difference in stroke risk between hypothermic and normothermic patients is greater than 1.75% to 2.25% (depending on the cost of surgical site infections). Additional analyses using the data from Mason et\xa0al. (2016; and the updated predicted risk data calculated by the EAC) suggest that HumiGard is cost saving regardless of the cost of surgical site infections and stroke risk when using a range of complications data from Billeter et\xa0al. (2014), but cost saving or cost neutral when using only direct data on surgical site infection complications. However, the EAC was unable to fully appraise these models because of incomplete information from Mason et\xa0al. (2016).\n\n# Committee considerations\n\nThe committee was informed by the clinical experts that the 5.5% stroke risk extrapolated from Billeter et\xa0al. (2014) in the company's cost model was an overestimate of the risk in current UK NHS practice, and that this is more likely to be less than 1%. The committee concluded that this distinction is likely to be very influential in the outcome of cost modelling. The committee was informed by the EAC that reducing the stroke risk to 0% in the cost model would make the use of HumiGard cost incurring. The committee concluded that the use of HumiGard was unlikely to reduce stroke rates for patients having abdominal surgery in the NHS.\n\nThe committee was informed that the NHS costs associated with surgical site infections were uncertain and that published estimates vary. The committee noted that the average cost used in the EAC cost analysis was reflective of current practice. Expert advice stated that surgical site infection costs vary considerably in colorectal surgery.", 'Conclusions': 'The committee concluded that there is good evidence to support the use of measures to prevent hypothermia during abdominal surgery and that, in this regard, HumiGard shows promise. However, it considered that there is insufficient evidence to demonstrate that HumiGard has a substantial effect on reducing adverse outcomes for patients having abdominal surgery.\n\nThe committee concluded that the cost consequences of using HumiGard in abdominal surgery are very uncertain, and that further research is needed on resource use.\n\nThe committee recommended conducting research in collaboration with the company and with clinical and academic partners. NICE will update this guidance if new and substantive evidence becomes available.Andrew DillonChief executiveFebruary 2017'}	https://www.nice.org.uk/guidance/mtg31	Evidence-based recommendations on HumiGard for preventing inadvertent perioperative hypothermia.
aa165b5a1ccbf1485a381ae2102bc214a35fe998	nice	Osteoporosis: assessing the risk of fragility fracture	Osteoporosis: assessing the risk of fragility fracture This guideline covers assessing the risk of fragility fracture in people aged 18 and over with osteoporosis. It aims to provide guidance on the selection and use of risk assessment tools in the care of adults at risk of fragility fractures in all NHS settings. # Introduction Osteoporosis is a disease characterised by low bone mass and structural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis leads to nearly 9 million fractures annually worldwide, and over 300,000 patients present with fragility fractures to hospitals in the UK each year. Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture, known as low-level (or 'low energy') trauma. The World Health Organization (WHO) has quantified this as forces equivalent to a fall from a standing height or less. Reduced bone density is a major risk factor for fragility fracture. Other factors that may affect the risk of fragility fracture include the use of oral or systemic glucocorticoids, age, sex, previous fractures and family history of osteoporosis. Because of increased bone loss after the menopause in women, and age-related bone loss in both women and men, the prevalence of osteoporosis increases markedly with age, from 2% at 50 years to more than 25% at 80 years in women. As the longevity of the population increases, so will the incidence of osteoporosis and fragility fracture. Fragility fractures occur most commonly in the spine (vertebrae), hip (proximal femur) and wrist (distal radius). They may also occur in the arm (humerus), pelvis, ribs and other bones. Osteoporotic fractures are defined as fractures associated with low bone mineral density (BMD) and include clinical spine, forearm, hip and shoulder fractures. Osteoporotic fragility fractures can cause substantial pain and severe disability, often leading to a reduced quality of life, and hip and vertebral fractures are associated with decreased life expectancy. Hip fracture nearly always requires hospitalisation, is fatal in 20% of cases and permanently disables 50% of those affected; only 30% of patients fully recover. Projections suggest that, in the UK, hip fracture incidence will rise from 70,000 per year in 2006 to 91,500 in 2015 and 101,000 in 2020. Direct medical costs from fragility fractures to the UK healthcare economy were estimated at £1.8 billion in 2000, with the potential to increase to £2.2 billion by 2025, and with most of these costs relating to hip fracture care. There are a number of therapies and treatments available for the prevention of fragility fractures in people who are thought to be at risk, or to prevent further fractures in those who have already had one or more fragility fractures. However, identifying who will benefit from preventative treatment is imprecise. A number of risk assessment tools are available to predict fracture incidence over a period of time, and these may be used to aid decision-making. These tools are limited in that they may not include all risk factors, or may lack details of some risk factors. Tools are dependent on the accuracy of the epidemiological data used to derive them and tools validated in other populations may not apply to the UK. Two tools, FRAX and QFracture, are available for use in the UK. It is not clear whether these tools are equally accurate and whether choice of tool should depend on circumstances. This short clinical guideline aims to provide guidance on the selection and use of risk assessment tools in the care of people who may be at risk of fragility fractures in all settings in which NHS care is received. Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporosis International 17: 1726–33. British Orthopaedic Association (2007). The care of patients with fragility fracture. Kanis JA, Oden A, Johnell O et al. (2001) The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporosis International 12: 417–27. Sernbo I, Johnell O (1993). Consequences of a hip fracture: a prospective study over 1 year. Osteoporosis International 3: 148–53. Department of Health. Hospital episode statistics (England) 2006. Burge RT, Worley D, Johansen A, et al. The cost of osteoporotic fractures in the UK: projections for 2000–2020. Journal of Medical Economics 4: 51–52.# Guidance People have the right to be involved in discussions and make informed decisions about their care, as described in your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # Targeting risk assessment Consider assessment of fracture risk: In all women aged 65 years and over and all men aged 75 years and over in women aged under 65 years and men aged under 75 years in the presence of risk factors, for example: previous fragility fracture current use or frequent recent use of oral or systemic glucocorticoids history of falls family history of hip fracture -ther causes of secondary osteoporosis low body mass index (BMI) (less than 18.5 kg/m2) smoking alcohol intake of more than 14 units per week for men and women. Do not routinely assess fracture risk in people aged under 50 years unless they have major risk factors (for example, current or frequent recent use of oral or systemic glucocorticoids, untreated premature menopause or previous fragility fracture), because they are unlikely to be at high risk. # Methods of risk assessment Estimate absolute risk when assessing risk of fracture (for example, the predicted risk of major osteoporotic or hip fracture over 10 years, expressed as a percentage). Use either FRAX (without a bone mineral density value if a dual-energy X-ray absorptiometry scan has not previously been undertaken) or QFracture, within their allowed age ranges, to estimate 10-year predicted absolute fracture risk when assessing risk of fracture. Above the upper age limits defined by the tools, consider people to be at high risk. Interpret the estimated absolute risk of fracture in people aged over 80 years with caution, because predicted 10-year fracture risk may underestimate their short-term fracture risk. Do not routinely measure BMD to assess fracture risk without prior assessment using FRAX (without a BMD value) or QFracture. Following risk assessment with FRAX (without a BMD value) or QFracture, consider measuring BMD with DXA in people whose fracture risk is in the region of an intervention threshold for a proposed treatment, and recalculate absolute risk using FRAX with the BMD value. Consider measuring BMD with DXA before starting treatments that may have a rapid adverse effect on bone density (for example, sex hormone deprivation for treatment for breast or prostate cancer). Measure BMD to assess fracture risk in people aged under 40 years who have a major risk factor, such as history of multiple fragility fracture, major osteoporotic fracture, or current or recent use of high-dose oral or high-dose systemic glucocorticoids (more than 7.5 mg prednisolone or equivalent per day for 3 months or longer). Consider recalculating fracture risk in the future: if the original calculated risk was in the region of the intervention threshold for a proposed treatment and only after a minimum of 2 years, or when there has been a change in the person's risk factors. Take into account that risk assessment tools may underestimate fracture risk in certain circumstances, for example if a person: has a history of multiple fractures has had previous vertebral fracture(s) has a high alcohol intake is taking high-dose oral or high-dose systemic glucocorticoids (more than 7.5 mg prednisolone or equivalent per day for 3 months or longer) has other causes of secondary osteoporosis. Take into account that fracture risk can be affected by factors that may not be included in the risk tool, for example living in a care home or taking drugs that may impair bone metabolism (such as anti-convulsants, selective serotonin reuptake inhibitors, thiazolidinediones, proton pump inhibitors and anti-retroviral drugs). # More information You can also see this guideline in the NICE Pathway on osteoporosis. To find out what NICE has said on topics related to this guideline, see our web page on diabetes and other endocrinal, nutritional and metabolic conditions. See also the guideline committee's discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee. Causes of secondary osteoporosis include endocrine (hypogonadism in either sex including untreated premature menopause and treatment with aromatase inhibitors or androgen deprivation therapy; hyperthyroidism; hyperparathyroidism; hyperprolactinaemia; Cushing's disease; diabetes), gastrointestinal (coeliac disease; inflammatory bowel disease; chronic liver disease; chronic pancreatitis; other causes of malabsorption), rheumatological (rheumatoid arthritis; other inflammatory arthropathies), haematological (multiple myeloma; haemoglobinopathies; systemic mastocytosis), respiratory (cystic fibrosis; chronic obstructive pulmonary disease), metabolic (homocystinuria), chronic renal disease and immobility(due for example to neurological injury or disease). FRAX can be used for people aged between 40 and 90 years, either with or without BMD values, as specified. QFracture can be used for people aged between 30 and 84 years. BMD values cannot be incorporated into the risk algorithm. An intervention threshold is the level of risk at which an intervention is recommended. People whose risk is in the region from just below to just above the threshold may be reclassified if BMD is added to assessment. It is out of the scope of this guideline to recommend intervention thresholds. Healthcare professionals should follow local protocols or other national guidelines for advice on intervention thresholds. An intervention threshold is the level of risk at which an intervention is recommended. It is out of the scope of this guideline to recommend intervention thresholds. Healthcare professionals should follow local protocols or other national guidelines for advice on intervention thresholds.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline. # Using GP practice lists to identify people at high risk What is the clinical and cost effectiveness of using GP practice lists to identify people at high risk of fracture, leading to formal risk assessment and possible treatment? ## Why this is important Fracture risk is currently assessed opportunistically. GP records are now universally computerised and contain information that may be useful in identifying patients at high risk of fracture (for example, age, record of prescriptions, major diagnoses and previous fracture). A study is needed to assess whether people at higher risk can be identified by using risk assessment tools to obtain an estimate of risk based on pre-existing information and inviting people at highest risk for a clinical assessment and risk-factor estimation. This could result in a more effective and efficient use of staff time and health service resources than an opportunistic approach. # FRAX and QFracture in adults receiving bone protective therapy What is the utility of FRAX and QFracture in adults receiving bone protective therapy? ## Why this is important Because of concerns about rare but serious side-effects of long-term anti-resorptive therapy, many physicians prescribe these drugs for a finite period of time, usually 3–5 years. Reassessment of fracture risk at the end of this treatment period is important, since some people remain at high risk of fracture and require continued treatment whereas others may benefit from a 'drug holiday' for 1 or more years. Neither FRAX nor QFracture has been examined in treated patients, and it is not known whether the ability of clinical risk factors with or without measurement of BMD to predict fracture risk is similar in untreated and treated patients. There is therefore a need for prospective studies to investigate the predictive power of these tools to assess fracture risk in patients after a period of bone protective therapy. # FRAX and QFracture in adults with secondary causes of osteoporosis What is the utility of FRAX and QFracture in detecting risk of fragility fracture in adults with secondary causes of osteoporosis? ## Why this is important If secondary osteoporosis is entered as a risk factor in FRAX, the algorithm assumes that the effect is mediated solely through effects on BMD. Input of BMD into the questionnaire in such patients will therefore generate the same fracture risk whether or not secondary osteoporosis is entered. However, it is likely that at least some causes of secondary osteoporosis (for example, inflammatory bowel disease) affect fracture risk by mechanisms that are partially independent of BMD and fracture risk may therefore be underestimated in such patients. There is therefore a need to investigate the accuracy of FRAX in predicting fracture risk in patients with causes of secondary osteoporosis other than rheumatoid arthritis and to establish whether their effect on fracture risk is mediated solely through effects on BMD. # BMD with FRAX What is the added prognostic value of BMD in the assessment of fracture risk with FRAX? ## Why this is important The 10-year fracture risk as estimated by FRAX is calculated using clinical risk factors with or without BMD. The clinical risk factors are routinely available, making calculation of fracture risk possible at the time of consultation. However, refinement of a patient's 10-year fracture risk using BMD requires assessment using DXA scanning equipment. Currently, there are no definitive studies in primary or secondary care evaluating whether the addition of BMD to FRAX improves the accuracy of the predicted fracture risk. There is a need for studies to examine whether adding BMD to FRAX results in the correct reclassification of patients from low risk to high risk (and vice-versa). Furthermore, studies are also needed to evaluate the clinical usefulness (net benefit) of adding BMD to FRAX; that is, how many more patients are correctly classified as high risk (true positives) and low risk (true negatives). # FRAX and QFracture in adults living in residential care What is the utility of FRAX and QFracture in detecting risk of fragility fracture in adults living in residential care? ## Why this is important Care home residents are at high risk of fragility fracture. This is probably related to increased age and frailty with multiple comorbidities, which increase fracture risk. There is also evidence that care home residents have lower BMD, with 70% assessed as having osteoporosis using densitometry criteria alone. However, tools such as FRAX and QFracture, which only estimate fracture risk up to the 9th decade and use 10-year fracture risk, may underestimate short-term risk in care home residents, who have a mean age of approximately 85 years and a life expectancy of less than 5 years. A study is required to assess whether care home residents should have targeted fracture risk assessment and whether residents at higher risk of fracture can be identified, using FRAX or QFracture. This could result in a more effective and efficient strategy for fracture prevention, targeting health service resources on those at the very highest fracture risk.# Finding more information and resources To find out what NICE has said on topics related to this guideline, see our web page on musculoskeletal conditions.	{'Introduction': "Osteoporosis is a disease characterised by low bone mass and structural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis leads to nearly 9\xa0million fractures annually worldwide, and over 300,000\xa0patients present with fragility fractures to hospitals in the UK each year.\n\nFragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture, known as low-level (or 'low energy') trauma. The World Health Organization (WHO) has quantified this as forces equivalent to a fall from a standing height or less. Reduced bone density is a major risk factor for fragility fracture. Other factors that may affect the risk of fragility fracture include the use of oral or systemic glucocorticoids, age, sex, previous fractures and family history of osteoporosis. Because of increased bone loss after the menopause in women, and age-related bone loss in both women and men, the prevalence of osteoporosis increases markedly with age, from 2% at 50\xa0years to more than 25% at 80\xa0years in women. As the longevity of the population increases, so will the incidence of osteoporosis and fragility fracture.\n\nFragility fractures occur most commonly in the spine (vertebrae), hip (proximal femur) and wrist (distal radius). They may also occur in the arm (humerus), pelvis, ribs and other bones. Osteoporotic fractures are defined as fractures associated with low bone mineral density (BMD) and include clinical spine, forearm, hip and shoulder fractures. Osteoporotic fragility fractures can cause substantial pain and severe disability, often leading to a reduced quality of life, and hip and vertebral fractures are associated with decreased life expectancy. Hip fracture nearly always requires hospitalisation, is fatal in 20% of cases and permanently disables 50% of those affected; only 30% of patients fully recover. Projections suggest that, in the UK, hip fracture incidence will rise from 70,000 per year in 2006 to 91,500 in 2015 and 101,000 in 2020.\n\nDirect medical costs from fragility fractures to the UK healthcare economy were estimated at £1.8\xa0billion in 2000, with the potential to increase to £2.2\xa0billion by 2025, and with most of these costs relating to hip fracture care.\n\nThere are a number of therapies and treatments available for the prevention of fragility fractures in people who are thought to be at risk, or to prevent further fractures in those who have already had one or more fragility fractures. However, identifying who will benefit from preventative treatment is imprecise. A number of risk assessment tools are available to predict fracture incidence over a period of time, and these may be used to aid decision-making. These tools are limited in that they may not include all risk factors, or may lack details of some risk factors. Tools are dependent on the accuracy of the epidemiological data used to derive them and tools validated in other populations may not apply to the UK. Two tools, FRAX and QFracture, are available for use in the UK. It is not clear whether these tools are equally accurate and whether choice of tool should depend on circumstances. This short clinical guideline aims to provide guidance on the selection and use of risk assessment tools in the care of people who may be at risk of fragility fractures in all settings in which NHS care is received.\n\n Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporosis International 17: 1726–33.\n\n British Orthopaedic Association (2007). The care of patients with fragility fracture.\n\n Kanis JA, Oden A, Johnell O et al. (2001) The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporosis International 12: 417–27.\n\n Sernbo I, Johnell O (1993). Consequences of a hip fracture: a prospective study over 1 year. Osteoporosis International 3: 148–53.\n\n Department of Health. Hospital episode statistics (England) 2006.\n\n Burge RT, Worley D, Johansen A, et al. The cost of osteoporotic fractures in the UK: projections for 2000–2020. Journal of Medical Economics 4: 51–52.", 'Guidance': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Targeting risk assessment\n\nConsider assessment of fracture risk:\n\nIn all women aged 65\xa0years and over and all men aged 75\xa0years and over\n\nin women aged under 65\xa0years and men aged under 75\xa0years in the presence of risk factors, for example:\n\n\n\nprevious fragility fracture\n\ncurrent use or frequent recent use of oral or systemic glucocorticoids\n\nhistory of falls\n\nfamily history of hip fracture\n\nother causes of secondary osteoporosis\n\nlow body mass index (BMI) (less than 18.5\xa0kg/m2)\n\nsmoking\n\nalcohol intake of more than 14\xa0units per week for men and women.\n\n\n\nDo not routinely assess fracture risk in people aged under 50\xa0years unless they have major risk factors (for example, current or frequent recent use of oral or systemic glucocorticoids, untreated premature menopause or previous fragility fracture), because they are unlikely to be at high risk.\n\n# Methods of risk assessment\n\nEstimate absolute risk when assessing risk of fracture (for example, the predicted risk of major osteoporotic or hip fracture over 10\xa0years, expressed as a percentage).\n\nUse either FRAX (without a bone mineral density [BMD] value if a dual-energy X-ray absorptiometry [DXA] scan has not previously been undertaken) or QFracture, within their allowed age ranges, to estimate 10-year predicted absolute fracture risk when assessing risk of fracture. Above the upper age limits defined by the tools, consider people to be at high risk.\n\nInterpret the estimated absolute risk of fracture in people aged over 80\xa0years with caution, because predicted 10-year fracture risk may underestimate their short-term fracture risk.\n\nDo not routinely measure BMD to assess fracture risk without prior assessment using FRAX (without a BMD value) or QFracture.\n\nFollowing risk assessment with FRAX (without a BMD value) or QFracture, consider measuring BMD with DXA in people whose fracture risk is in the region of an intervention threshold for a proposed treatment, and recalculate absolute risk using FRAX with the BMD value.\n\nConsider measuring BMD with DXA before starting treatments that may have a rapid adverse effect on bone density (for example, sex hormone deprivation for treatment for breast or prostate cancer).\n\nMeasure BMD to assess fracture risk in people aged under 40\xa0years who have a major risk factor, such as history of multiple fragility fracture, major osteoporotic fracture, or current or recent use of high-dose oral or high-dose systemic glucocorticoids (more than 7.5\xa0mg prednisolone or equivalent per day for 3\xa0months or longer).\n\nConsider recalculating fracture risk in the future:\n\nif the original calculated risk was in the region of the intervention threshold for a proposed treatment and only after a minimum of 2\xa0years, or\n\nwhen there has been a change in the person's risk factors.\n\nTake into account that risk assessment tools may underestimate fracture risk in certain circumstances, for example if a person:\n\nhas a history of multiple fractures\n\nhas had previous vertebral fracture(s)\n\nhas a high alcohol intake\n\nis taking high-dose oral or high-dose systemic glucocorticoids (more than 7.5\xa0mg prednisolone or equivalent per day for 3\xa0months or longer)\n\nhas other causes of secondary osteoporosis.\n\nTake into account that fracture risk can be affected by factors that may not be included in the risk tool, for example living in a care home or taking drugs that may impair bone metabolism (such as anti-convulsants, selective serotonin reuptake inhibitors, thiazolidinediones, proton pump inhibitors and anti-retroviral drugs).\n\n# More information\n\nYou can also see this guideline in the NICE Pathway on osteoporosis.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on diabetes and other endocrinal, nutritional and metabolic conditions.\n\nSee also the guideline committee's discussion and the evidence reviews (in the full guideline), and information about how the guideline was developed, including details of the committee.\n\n Causes of secondary osteoporosis include endocrine (hypogonadism in either sex including untreated premature menopause and treatment with aromatase inhibitors or androgen deprivation therapy; hyperthyroidism; hyperparathyroidism; hyperprolactinaemia; Cushing's disease; diabetes), gastrointestinal (coeliac disease; inflammatory bowel disease; chronic liver disease; chronic pancreatitis; other causes of malabsorption), rheumatological (rheumatoid arthritis; other inflammatory arthropathies), haematological (multiple myeloma; haemoglobinopathies; systemic mastocytosis), respiratory (cystic fibrosis; chronic obstructive pulmonary disease), metabolic (homocystinuria), chronic renal disease and immobility(due for example to neurological injury or disease).\n\n \n FRAX can be used for people aged between 40 and 90\xa0years, either with or without BMD values, as specified.\n\n \n QFracture can be used for people aged between 30 and 84\xa0years. BMD values cannot be incorporated into the risk algorithm.\n\n An intervention threshold is the level of risk at which an intervention is recommended. People whose risk is in the region from just below to just above the threshold may be reclassified if BMD is added to assessment. It is out of the scope of this guideline to recommend intervention thresholds. Healthcare professionals should follow local protocols or other national guidelines for advice on intervention thresholds.\n\n An intervention threshold is the level of risk at which an intervention is recommended. It is out of the scope of this guideline to recommend intervention thresholds. Healthcare professionals should follow local protocols or other national guidelines for advice on intervention thresholds.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# Using GP practice lists to identify people at high risk\n\nWhat is the clinical and cost effectiveness of using GP practice lists to identify people at high risk of fracture, leading to formal risk assessment and possible treatment?\n\n## Why this is important\n\nFracture risk is currently assessed opportunistically. GP records are now universally computerised and contain information that may be useful in identifying patients at high risk of fracture (for example, age, record of prescriptions, major diagnoses and previous fracture). A study is needed to assess whether people at higher risk can be identified by using risk assessment tools to obtain an estimate of risk based on pre-existing information and inviting people at highest risk for a clinical assessment and risk-factor estimation. This could result in a more effective and efficient use of staff time and health service resources than an opportunistic approach.\n\n# FRAX and QFracture in adults receiving bone protective therapy\n\nWhat is the utility of FRAX and QFracture in adults receiving bone protective therapy?\n\n## Why this is important\n\nBecause of concerns about rare but serious side-effects of long-term anti-resorptive therapy, many physicians prescribe these drugs for a finite period of time, usually 3–5\xa0years. Reassessment of fracture risk at the end of this treatment period is important, since some people remain at high risk of fracture and require continued treatment whereas others may benefit from a 'drug holiday' for 1 or more years. Neither FRAX nor QFracture has been examined in treated patients, and it is not known whether the ability of clinical risk factors with or without measurement of BMD to predict fracture risk is similar in untreated and treated patients. There is therefore a need for prospective studies to investigate the predictive power of these tools to assess fracture risk in patients after a period of bone protective therapy.\n\n# FRAX and QFracture in adults with secondary causes of osteoporosis\n\nWhat is the utility of FRAX and QFracture in detecting risk of fragility fracture in adults with secondary causes of osteoporosis?\n\n## Why this is important\n\nIf secondary osteoporosis is entered as a risk factor in FRAX, the algorithm assumes that the effect is mediated solely through effects on BMD. Input of BMD into the questionnaire in such patients will therefore generate the same fracture risk whether or not secondary osteoporosis is entered. However, it is likely that at least some causes of secondary osteoporosis (for example, inflammatory bowel disease) affect fracture risk by mechanisms that are partially independent of BMD and fracture risk may therefore be underestimated in such patients. There is therefore a need to investigate the accuracy of FRAX in predicting fracture risk in patients with causes of secondary osteoporosis other than rheumatoid arthritis and to establish whether their effect on fracture risk is mediated solely through effects on BMD.\n\n# BMD with FRAX\n\nWhat is the added prognostic value of BMD in the assessment of fracture risk with FRAX?\n\n## Why this is important\n\nThe 10-year fracture risk as estimated by FRAX is calculated using clinical risk factors with or without BMD. The clinical risk factors are routinely available, making calculation of fracture risk possible at the time of consultation. However, refinement of a patient's 10-year fracture risk using BMD requires assessment using DXA scanning equipment.\n\nCurrently, there are no definitive studies in primary or secondary care evaluating whether the addition of BMD to FRAX improves the accuracy of the predicted fracture risk. There is a need for studies to examine whether adding BMD to FRAX results in the correct reclassification of patients from low risk to high risk (and vice-versa). Furthermore, studies are also needed to evaluate the clinical usefulness (net benefit) of adding BMD to FRAX; that is, how many more patients are correctly classified as high risk (true positives) and low risk (true negatives).\n\n# FRAX and QFracture in adults living in residential care\n\nWhat is the utility of FRAX and QFracture in detecting risk of fragility fracture in adults living in residential care?\n\n## Why this is important\n\nCare home residents are at high risk of fragility fracture. This is probably related to increased age and frailty with multiple comorbidities, which increase fracture risk. There is also evidence that care home residents have lower BMD, with 70% assessed as having osteoporosis using densitometry criteria alone. However, tools such as FRAX and QFracture, which only estimate fracture risk up to the 9th\xa0decade and use 10-year fracture risk, may underestimate short-term risk in care home residents, who have a mean age of approximately 85\xa0years and a life expectancy of less than 5\xa0years.\n\nA study is required to assess whether care home residents should have targeted fracture risk assessment and whether residents at higher risk of fracture can be identified, using FRAX or QFracture. This could result in a more effective and efficient strategy for fracture prevention, targeting health service resources on those at the very highest fracture risk.", 'Finding more information and resources': 'To find out what NICE has said on topics related to this guideline, see our web page on musculoskeletal conditions.'}	https://www.nice.org.uk/guidance/cg146	This guideline covers assessing the risk of fragility fracture in people aged 18 and over with osteoporosis. It aims to provide guidance on the selection and use of risk assessment tools in the care of adults at risk of fragility fractures in all NHS settings.
890ec0384a8d14181a932a78ab3cf4cb2fee95b5	nice	Cerebral palsy in under 25s: assessment and management	Cerebral palsy in under 25s: assessment and management This guideline covers diagnosing, assessing and managing cerebral palsy in children and young people from birth up to their 25th birthday. It aims to make sure they get the care and treatment they need for the developmental and clinical comorbidities associated with cerebral palsy, so that they can be as active and independent as possible. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Risk factors Recognise the following as independent risk factors for cerebral palsy: antenatal factors: preterm birth (with risk increasing with decreasing gestational age; see the NICE guideline on developmental follow-up of children and young people born preterm for more information on risk factors specific to preterm birth, and the NICE guideline on preterm labour and birth, which covers preventing or delaying preterm birth, steroid treatment for maturation of fetal lungs and neuroprotection for the baby) chorioamnionitis maternal respiratory tract or genito-urinary infection treated in hospital perinatal factors: low birth weight chorioamnionitis neonatal encephalopathy neonatal sepsis (particularly with a birth weight below 1.5 kg) maternal respiratory tract or genito-urinary infection treated in hospital postnatal factors: meningitis. Provide an enhanced clinical and developmental follow‑up programme (see the section on looking for signs of cerebral palsy) for children who have any of the risk factors listed in recommendation 1.1.1. # Causes of cerebral palsy When assessing the likely cause of cerebral palsy in a child, recognise that a number of MRI-identified brain abnormalities have been reported at the following approximate prevalences in children with cerebral palsy: white matter damage: 45% basal ganglia or deep grey matter damage: 13% congenital malformation: 10% focal infarcts: 7%. When assessing the likely cause of cerebral palsy, recognise that white matter damage, including periventricular leukomalacia shown on neuroimaging: is more common in children born preterm than in those born at term may occur in children with any functional level or motor subtype, but is more common in spastic than in dyskinetic cerebral palsy. When assessing the likely cause of cerebral palsy, recognise that basal ganglia or deep grey matter damage is mostly associated with dyskinetic cerebral palsy. When assessing the likely cause of cerebral palsy, recognise that congenital malformations as a cause of cerebral palsy: are more common in children born at term than in those born preterm may occur in children with any functional level or motor subtype are associated with higher levels of functional impairment than other causes. Recognise that the clinical syndrome of neonatal encephalopathy can result from various pathological events, such as a hypoxic–ischaemic brain injury or sepsis, and if there has been more than 1 such event they may interact to damage the developing brain. When assessing the likely cause of cerebral palsy, recognise that neonatal encephalopathy has been reported at the following approximate prevalences in children with cerebral palsy born after 35 weeks: attributed to a perinatal hypoxic–ischaemic injury: 20% not attributed to a perinatal hypoxic–ischaemic injury: 12%. Recognise that for cerebral palsy associated with a perinatal hypoxic–ischaemic injury: the extent of long-term functional impairment is often related to the severity of the initial encephalopathy the dyskinetic motor subtype is more common than other subtypes. Recognise that for cerebral palsy acquired after the neonatal period, the following causes and approximate prevalences have been reported: meningitis: 20% -ther infections: 30% head injury: 12%. When assessing the likely cause of cerebral palsy, recognise that independent risk factors: can have a cumulative impact, adversely affecting the developing brain and resulting in cerebral palsy may have an impact at any stage of development, including the antenatal, perinatal and postnatal periods. ## Using MRI to assess cause Offer MRI to investigate aetiology in a child or young person with suspected or known cerebral palsy if this is not clear from: antenatal, perinatal and postnatal history their developmental progress findings on clinical examination results of cranial ultrasound examinations. Recognise that MRI will not accurately establish the timing of a hypoxic–ischaemic brain injury in a child with cerebral palsy. When deciding the best age to perform an MRI scan for a child with cerebral palsy, take account of the following: Subtle neuro-anatomical changes that could explain the aetiology of cerebral palsy may not be apparent until 2 years of age. The presence of any red flags for a progressive neurological disorder (see the section on red flags for other neurological disorders). That general anaesthesia or sedation is usually needed for young children having MRI. The views of the child or young person and their parents or carers. Explain to parents or carers and the child or young person with cerebral palsy that it is not always possible to identify a cause for cerebral palsy. Consider repeating the MRI scan if: there is a change in the expected clinical and developmental profile or any red flags for a progressive neurological disorder (see the section on red flags for other neurological disorders). Discuss with the child or young person and their parents or carers the reasons for performing MRI in each individual circumstance. # Looking for signs of cerebral palsy Provide an enhanced clinical and developmental follow‑up programme by a multidisciplinary team for children up to 2 years (corrected for gestational age) who are at increased risk of developing cerebral palsy (see the section on risk factors). Consider using the General Movement Assessment (GMA) during routine neonatal follow‑up assessments for children between 0 and 3 months who are at increased risk of developing cerebral palsy. Recognise the following as possible early motor features in the presentation of cerebral palsy: unusual fidgety movements or other abnormalities of movement, including asymmetry or paucity of movement abnormalities of tone, including hypotonia (floppiness), spasticity (stiffness) or dystonia (fluctuating tone) abnormal motor development, including late head control, rolling and crawling feeding difficulties. Refer children who are at increased risk of developing cerebral palsy and who have any of the abnormal features listed in recommendation 1.3.3 to a child development service for an urgent assessment. Recognise that the most common delayed motor milestones in children with cerebral palsy are: not sitting by 8 months (corrected for gestational age) not walking by 18 months (corrected for gestational age) early asymmetry of hand function (hand preference) before 1 year (corrected for gestational age). Refer all children with delayed motor milestones to a child development service for further assessment. Refer children who have persistent toe walking to a child development service for further assessment. If there are concerns that a child may have cerebral palsy but a definitive diagnosis cannot be made, discuss this with their parents or carers and explain that an enhanced clinical and developmental follow‑up programme will be necessary to try to reach a definite conclusion. # Red flags for other neurological disorders Review a diagnosis of cerebral palsy if clinical signs or the child's development do not follow the patterns expected for cerebral palsy, taking into account that the functional and neurological manifestations of cerebral palsy change over time. Recognise the following as red flags for neurological disorders other than cerebral palsy, and refer the child or young person to a specialist in paediatric neurology if any of these are observed: absence of known risk factors (see the section on risk factors) family history of a progressive neurological disorder loss of already attained cognitive or developmental abilities development of unexpected focal neurological signs MRI findings suggestive of a progressive neurological disorder MRI findings not in keeping with clinical signs of cerebral palsy. # Multidisciplinary care Refer all children with suspected cerebral palsy to a child development service for an urgent multidisciplinary assessment, in order to facilitate early diagnosis and intervention. Recognise that children and young people with cerebral palsy and their parents or carers have a central role in decision making and care planning. Ensure that the child or young person with cerebral palsy has access to a local integrated core multidisciplinary team that: is able to meet their individual needs within agreed care pathways can provide the following expertise, as appropriate, through a local network of care: paediatric or adult medicine nursing care physiotherapy -ccupational therapy speech and language therapy dietetics psychology can enable access to other services within their local or regional network as appropriate, including: paediatric or adult neurodisability, neurology, neurorehabilitation, respiratory, gastroenterology and surgical specialist care -rthopaedics -rthotics and rehabilitation services social care visual and hearing specialist services teaching support for preschool and school-age children, including portage (home teaching services for preschool children). Ensure that routes for accessing specialist teams involved in managing comorbidities associated with cerebral palsy are clearly defined on a regional basis. Recognise that ongoing communication between all levels of service provision in the care of children and young people with cerebral palsy is crucial, particularly involvement of primary care from diagnosis onwards. ## Medicines optimisation For guidance on the safe and effective use of medicines, see the NICE guideline on medicines optimisation. ## Movement and posture For guidance on managing problems with movement and posture in children and young people with cerebral palsy, see the NICE guideline on spasticity in under 19s. # Information and support Ensure that information and support focuses as much on the functional abilities of the child or young person with cerebral palsy as on any functional impairment. Provide clear, timely and up‑to‑date information to parents or carers on the following topics: diagnosis (see the section on looking for signs of cerebral palsy) aetiology (see the section on causes of cerebral palsy) prognosis (see the section on information about prognosis) expected developmental progress comorbidities availability of specialist equipment resources available and access to financial, respite, social care and other support for children and young people and their parents, carers and siblings (see also recommendations 1.18.3 and 1.18.8 in the section on care needs) educational placement (including specialist preschool and early years settings) transition (see the section on transition to adults' services). Ensure that clear information about the 'patient pathway' is shared with the child or young person and their parents or carers (for example, by providing them with copies of correspondence). Follow the principles in the recommendations about communication, information and shared decision making in the NICE guideline on patient experience in adult NHS services. Provide information to the child or young person with cerebral palsy, and their parents or carers, on an ongoing basis. Adapt the communication methods and information resources to take account of the needs and understanding of the child or young person and their parents or carers. For example, think about using 1 or more of the following: -ral explanations written information and leaflets mobile technology, including apps augmentative and alternative communication systems (see recommendations 1.9.7 to 1.9.10 in the section on interventions). Work with the child or young person and their parents or carers to develop and maintain a personal 'folder' in their preferred format (electronic or otherwise) containing relevant information that can be shared with their extended family and friends and used in health, social care, educational and transition settings. Information could include: early history motor subtype and limb involvement functional abilities interventions medication comorbidities preferred methods of communication any specialist equipment that is used or needed care plans emergency contact details. Ensure that the child or young person and their parents or carers are provided with information, by a professional with appropriate expertise, about the following topics relevant to them that is tailored to their individual needs: menstruation fertility and contraception sex and sexuality parenting. Provide information to the child or young person and their parents or carers, and to all relevant teams around them, about the local and regional services available (for example, sporting clubs, respite care and specialist schools) for children and young people with cerebral palsy, and how to access them. Provide information about local support and advocacy groups to the child or young person and their parents or carers. # Information about prognosis Provide the following information to parents or carers about the prognosis for walking for a child with cerebral palsy: The more severe the child's physical, functional or cognitive impairment, the greater the possibility of difficulties with walking. If a child can sit at 2 years of age it is likely, but not certain, that they will be able to walk unaided by age 6. If a child cannot sit but can roll at 2 years of age, there is a possibility that they may be able to walk unaided by age 6. If a child cannot sit or roll at 2 years of age, they are unlikely to be able to walk unaided. Recognise the following in relation to prognosis for speech development in a child with cerebral palsy, and discuss this with parents or carers as appropriate: Around 1 in 2 children with cerebral palsy have some difficulty with elements of communication (see the section on communication difficulties). Around 1 in 3 children have specific difficulties with speech and language. The more severe the child's physical, functional or cognitive impairment, the greater the likelihood of difficulties with speech and language. Uncontrolled epilepsy may be associated with difficulties with all forms of communication, including speech. A child with bilateral spastic, dyskinetic or ataxic cerebral palsy is more likely to have difficulties with speech and language than a child with unilateral spastic cerebral palsy. Provide the following information to parents or carers, as appropriate, about prognosis for life expectancy for a child with cerebral palsy: The more severe the child's physical, functional or cognitive impairment, the greater the likelihood of reduced life expectancy. There is an association between reduced life expectancy and the need for enteral tube feeding, but this reflects the severity of swallowing difficulties and is not because of the intervention. ## Using MRI to assess prognosis Do not rely on MRI alone for predicting prognosis in children with cerebral palsy. Take account of the likely cause of cerebral palsy and the findings from MRI (if performed) when discussing prognosis with the child or young person and their parents or carers. # Eating, drinking and swallowing difficulties ## Assessment If eating, drinking and swallowing difficulties are suspected in a child or young person with cerebral palsy, carry out a clinical assessment as first-line investigation to determine the safety, efficiency and enjoyment of eating and drinking. This should include: taking a relevant clinical history, including asking about any previous chest infections -bservation of eating and drinking in a normal mealtime environment by a speech and language therapist with training in assessing and treating dysphagia. Refer the child or young person to a local specialist multidisciplinary team with training in assessing and treating dysphagia if there are clinical concerns about eating, drinking and swallowing, such as: coughing, choking, gagging, altered breathing pattern or change in colour while eating or drinking recurrent chest infection mealtimes regularly being stressful or distressing for the child or young person or their parents or carers prolonged meal duration. Do not use videofluoroscopy or fibroscopic endoscopy for the initial assessment of eating, drinking and swallowing difficulties in children and young people with cerebral palsy. The specialist multidisciplinary team should consider videofluoroscopy if any of the following apply: There is uncertainty about the safety of eating, drinking and swallowing after specialist clinical assessment. The child or young person has recurrent chest infection without overt clinical signs of aspiration. There is deterioration in eating, drinking and swallowing ability with increasing age (particularly after adolescence). There is uncertainty about the impact of modifying food textures (for example, use of thickeners or pureeing). Parents or carers need support to understand eating, drinking and swallowing difficulties, to help with decision making. Videofluoroscopy should only be performed in a centre with a specialist multidisciplinary team who have experience and competence in using it with children and young people with cerebral palsy. Do not routinely perform videofluoroscopy when considering starting enteral tube feeding in children and young people with cerebral palsy. Ensure that children and young people with ongoing eating, drinking and swallowing difficulties have access to tertiary specialist assessment, including advice from other services (such as paediatric surgery and respiratory paediatrics). ## Management Develop strategies and goals in partnership with the child or young person with cerebral palsy and their parents, carers and other family members for interventions to improve eating, drinking and swallowing. Create an individualised plan for managing eating, drinking and swallowing difficulties in children and young people with cerebral palsy, taking into account the understanding, knowledge and skills of parents, carers and any other people involved in feeding the child or young person. Assess the role of the following: postural management and positioning when eating modifying fluid and food textures and flavours feeding techniques, such as pacing and spoon placement equipment, such as specialised feeding utensils -ptimising the mealtime environment strategies for managing behavioural difficulties associated with eating and drinking strategies for developing oral motor skills communication strategies modifications to accommodate visual or other sensory impairments that affect eating, drinking and swallowing the training needs of the people who care for the child or young person, particularly outside the home. Advise parents or carers that intra-oral devices have not been shown to improve eating, drinking and swallowing in children and young people with cerebral palsy. Use outcome measures important to the child or young person and their parents or carers to review: whether individualised goals have been achieved the clinical and functional impact of interventions to improve eating, drinking and swallowing. # Speech, language and communication ## Communication difficulties Talk to children and young people and their parents or carers about communication difficulties that can be associated with cerebral palsy. Information that may be useful to discuss includes the following: communication difficulties occur in around 1 in 2 children and young people with cerebral palsy at least 1 in 10 need augmentative and alternative communication (signs, symbols and speech generating devices) around 1 in 10 cannot use formal methods of augmentative and alternative communication because of cognitive and sensory impairments and communication difficulties communication difficulties may occur with any functional level or motor subtype, but are more common in children and young people with dyskinetic or severe bilateral spastic cerebral palsy communication difficulties do not necessarily correlate with learning disability (intellectual disability). ## Assessment and referral Regularly assess children and young people with cerebral palsy during routine reviews to identify concerns about speech, language and communication, including speech intelligibility. Refer children and young people with cerebral palsy for specialist assessment if there are concerns about speech, language and communication, including speech intelligibility. Specialist assessment of the communication skills, including speech intelligibility, of children and young people with cerebral palsy should be conducted by a multidisciplinary team that includes a speech and language therapist. ## Interventions Recognise the importance of early intervention to improve the communication skills of children and young people with cerebral palsy. Offer interventions to improve speech intelligibility, for example targeting posture, breath control, voice production and rate of speech, to children and young people with cerebral palsy: who have a motor speech disorder and some intelligible speech and for whom speech is the primary means of communication and who can engage with the intervention. Consider augmentative and alternative communication systems for children and young people with cerebral palsy who need support in understanding and producing speech. These may include pictures, objects, symbols and signs, and speech generating devices. If there are ongoing problems with using augmentative and alternative communication systems, refer the child or young person to a specialist service in order to tailor interventions to their individual needs, taking account of their cognitive, linguistic, motor, hearing and visual abilities. Regularly review children and young people who are using augmentative and alternative communication systems, to monitor their progress and ensure that interventions continue to be appropriate for their needs. Provide individualised training in communication techniques for families, carers, preschool and school staff and other people involved in the care of a child or young person with cerebral palsy. # Optimising nutritional status Regularly review the nutritional status of children and young people with cerebral palsy, including measuring their height and weight (or consider alternative anthropometric measurements, particularly if height and weight cannot be measured). Provide timely access to assessment and nutritional interventional support from a dietitian if there are concerns about oral intake, growth or nutritional status. If oral intake is still insufficient to provide adequate nutrition after assessment and nutritional interventions, refer the child or young person to be assessed for enteral tube feeding by a multidisciplinary team with relevant expertise. For guidance on nutritional interventions and enteral tube feeding in over 18s, see the NICE guideline on nutrition support for adults. # Managing saliva control At the time of publication (January 2017), for the indication in recommendation 1.11.2, glycopyrronium bromide (oral solution) did not have a UK marketing authorisation for use in children under 3, and transdermal hyoscine hydrobromide (scopolamine hydrobromide) and trihexyphenidyl hydrochloride did not have UK marketing authorisations for use in children and young people under 18. For recommendations 1.11.5 and 1.11.6, as of September 2019, Xeomin is the only preparation of botulinum toxin A to have marketing authorisation for treating chronic sialorrhoea caused by neurological conditions in adults. No other preparation of botulinum toxin type A has a UK marketing authorisation for this indication. Therefore, no botulinum toxin products are licensed for drooling in children (under 18s). The use of Xeomin for this indication in under 18s is still off-label. See NICE's information on prescribing medicines. Assess factors that may affect drooling in children and young people with cerebral palsy, such as positioning, medication history, reflux and dental issues, before starting drug therapy. To reduce the severity and frequency of drooling in children and young people with cerebral palsy, consider the use of anticholinergic medication: glycopyrronium bromide (oral or by enteral tube) or transdermal hyoscine hydrobromide or trihexyphenidyl hydrochloride for children with dyskinetic cerebral palsy, but only with input from specialist services.When choosing which medicine to use, take into account the preferences of the child or young person and their parents or carers, and the age range and indication covered by the marketing authorisations. Regularly review the effectiveness, tolerability and side effects of all drug treatments used for saliva control. Refer the child or young person to a specialist service if the anticholinergic drug treatments outlined in recommendations 1.11.2 and 1.11.3 are contraindicated, not tolerated or not effective, to consider other treatments for saliva control. Consider specialist assessment and use of botulinum toxin A injections to the salivary glands with ultrasound guidance to reduce the severity and frequency of drooling in children and young people with cerebral palsy if anticholinergic drugs provide insufficient benefit or are not tolerated. Advise children and young people and their parents or carers that high-dose botulinum toxin A injection to the salivary glands can rarely cause swallowing difficulties, and so they should return to hospital immediately if breathing or swallowing difficulties occur. Consider referring young people for a surgical opinion, after an assessment confirming clinically safe swallow, if there is: a potential need for lifelong drug treatment or insufficient benefit or non-tolerance of anticholinergic drugs and botulinum toxin A injections. # Low bone mineral density ## Risk factors Recognise that in children and young people with cerebral palsy the following are independent risk factors for low bone mineral density: non-ambulant (GMFCS level IV or V) vitamin D deficiency presence of eating, drinking and swallowing difficulties or concerns about nutritional status low weight for age (below the 2nd centile) history of low-impact fracture use of anticonvulsant medication. Recognise that there is an increased risk of low-impact fractures in children and young people with cerebral palsy who are non-ambulant or have low bone mineral density. Inform children and young people with cerebral palsy and their parents or carers if they are at an increased risk of low-impact fractures. ## Management If a child and young person with cerebral palsy has 1 or more risk factors for low bone mineral density (see recommendation 1.12.1): assess their dietary intake of calcium and vitamin D and consider the following laboratory investigations of calcium and vitamin D status: serum calcium, phosphate and alkaline phosphatase serum vitamin D urinary calcium/creatinine ratio. Create an individualised care plan for children and young people with cerebral palsy who have 1 or more risk factors for low bone mineral density (see recommendation 1.12.1). Consider the following as possible interventions to reduce the risk of reduced bone mineral density and low-impact fractures: an active movement programme active weight bearing dietetic interventions as appropriate, including nutritional support and calcium and vitamin D supplementation minimising risks associated with movement and handling. Consider a DEXA scan under specialist guidance for children and young people with cerebral palsy who have had a low-impact fracture. Refer children and young people with cerebral palsy with reduced bone density and a history of low-impact fracture to a specialist centre for consideration of bisphosphonate therapy. Do not offer standing frames solely to prevent low bone mineral density in children and young people with cerebral palsy. Do not offer vibration therapy solely to prevent low bone mineral density in children and young people with cerebral palsy. # Pain, discomfort and distress ## Causes Explain to children and young people with cerebral palsy and their parents or carers that pain is common in people with cerebral palsy, especially those with more severe motor impairment, and this should be recognised and addressed. Recognise that common condition-specific causes of pain, discomfort and distress in children and young people with cerebral palsy include: musculoskeletal problems (for example, scoliosis, hip subluxation and dislocation) increased muscle tone (including dystonia and spasticity) muscle fatigue and immobility constipation vomiting gastro-oesophageal reflux disease. Recognise that usual causes of pain, discomfort and distress that affect children and young people generally also occur in those with cerebral palsy, and that difficulties with communication and perception may make identifying the cause more challenging. Common types of pain in children and young people include: non-specific back pain headache non-specific abdominal pain dental pain dysmenorrhea. ## Assessment Take into account that parents and familiar carers have a key role in recognising and assessing pain, discomfort and distress in children and young people with cerebral palsy. When assessing pain in children and young people with cerebral palsy: recognise that assessing the presence and degree of pain can be challenging, especially if: there are communication difficulties or learning disability (intellectual disability) there are difficulties with registering or processing sensory information (see the section on registering and processing sensory information) ask about signs of pain, discomfort, distress and sleep disturbances (see the section on sleep disturbances) at every contact recognise that pain-related behaviour can present differently compared with that in the wider population. Assess for other possible causes of distress in the absence of identifiable physical causes of pain and discomfort, such as: psychological and emotional distress increased sensitivity to environmental triggers thirst or hunger. Consider using tools to identify pain or assess severity of pain in children and young people with cerebral palsy, for example: For children and young people with communication difficulties: Paediatric Pain Profile Non-communicating Children's Pain Checklist – postoperative version. For children and young people without communication difficulties: Numeric pain rating scale. Refer the child or young person for a specialist multidisciplinary team assessment of pain, discomfort, distress and sleep if the cause of these is not clear after routine assessment. ## Management For reversible causes of pain, discomfort and distress identified in children and young people with cerebral palsy, treat the cause as appropriate using targeted interventions in line with the following NICE guidelines: spasticity in under 19s constipation in children and young people gastro-oesophageal reflux disease in children and young people gastro-oesophageal reflux disease and dyspepsia in adults headaches in over 12s low back pain and sciatica in over 16s urinary incontinence in neurological disease urinary tract infection in under 16s. For common interventions used in the management of cerebral palsy (such as physical therapies, botulinum toxin A injections and surgery) that can cause acute pain: advise the child or young person and their parents or carers that these interventions may reduce discomfort in the long term minimise discomfort during these procedures. In the absence of an identifiable cause of pain, discomfort or distress in a child or young person with cerebral palsy: take into account the impact of anxiety, depression or other possible mental health problems consider a 'stepped approach' trial of simple analgesia (such as paracetamol and/or ibuprofen) for mild to moderate pain monitor the duration, pattern and severity of symptoms. If a trial of analgesia is unsuccessful, refer the child or young person to a specialist pain multidisciplinary team, which may be a palliative care service, for a more detailed assessment. # Sleep disturbances ## Causes Explain to parents or carers that, in children and young people with cerebral palsy, sleep disturbances (for example, difficulties with falling asleep, staying asleep or daytime sleepiness): are common may be caused by factors such as environment, hunger and thirst. Recognise that the most common condition-specific causes of sleep disturbances in children and young people with cerebral palsy include: sleep-induced breathing disorders, such as obstructive sleep apnoea seizures pain and discomfort need for repositioning because of immobility poor sleep hygiene (poor night-time routine and environment) night-time interventions, including overnight tube feeding or the use of orthoses comorbidities, including adverse effects of medication. ## Assessment When identifying and assessing sleep disturbances in children and young people with cerebral palsy: recognise that parents and familiar carers have the primary role in this consider using sleep questionnaires or diaries. Always ask about pain, sleep and distress as part of any clinical consultation. ## Management Optimise sleep hygiene for children and young people with cerebral palsy. Manage treatable causes of sleep disturbances that are identified in children and young people with cerebral palsy. If no treatable cause is found, consider a trial of melatonin to manage sleep disturbances for children and young people with cerebral palsy, particularly for problems with falling asleep.At the time of publication (January 2017), melatonin did not have a UK marketing authorisation for use in children and young people under 18 for this indication. See NICE's information on prescribing medicines. Do not offer regular sedative medication to manage primary sleep disorders in children with cerebral palsy without seeking specialist advice. Do not offer sleep positioning systems solely to manage primary sleep disorders in children and young people with cerebral palsy. Refer the child or young person to specialist sleep services for multidisciplinary team assessment and management if there are ongoing sleep disturbances. # Mental health problems Follow the relevant NICE guidelines when identifying and managing mental health problems and psychological and neurodevelopmental disorders in children and young people with cerebral palsy: depression in children and young people depression in adults depression in adults with a chronic physical health problem generalised anxiety disorder and panic disorder in adults challenging behaviour and learning disabilities antisocial behaviour and conduct disorders in children and young people mental health problems in people with learning disabilities autism spectrum disorder in under 19s: recognition, referral and diagnosis autism spectrum disorder in under 19s: support and management autism spectrum disorder in adults attention deficit hyperactivity disorder. ## Identification Take into account that parents and familiar carers have a central role in recognising and assessing emotional difficulties and mental health problems in children and young people with cerebral palsy. Recognise that children and young people with cerebral palsy have an increased prevalence of: mental health and psychological problems, including depression, anxiety and conduct disorders behaviours that challenge, which may be triggered by pain, discomfort or sleep disturbances neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Recognise that emotional and behavioural difficulties (for example, low self-esteem) are reported in up to 1 in 4 children and young people with cerebral palsy. Any multidisciplinary team should: recognise that mental health problems and emotional difficulties can be as important as physical health problems for children and young people with cerebral palsy explore such difficulties during consultations recognise that assessing psychological problems can be challenging in children and young people with communication difficulties or learning disability (intellectual disability). Think about and address the following contributory factors if a change in emotional state occurs in a child or young person with cerebral palsy: pain or discomfort (see the section on pain, discomfort and distress) frustration associated with communication difficulties social factors, such as a change in home circumstances or care provision. Use validated tools, such as the Child Health Questionnaire and the Strengths and Difficulties Questionnaire, to assess mental health problems in children and young people with cerebral palsy. ## Management Refer the child or young person with cerebral palsy for specialist psychological assessment and ongoing management if emotional and behavioural difficulties persist or there are concerns about their mental health. Work in partnership with the child or young person with cerebral palsy, and their parents and primary carers, when assessing and managing mental health problems and setting goals. When making an individual management plan to address the mental health needs of a child or young person with cerebral palsy, take into account ways of providing support to parents or carers. Recognise that there are specific challenges in managing and minimising the impact of mental health problems in children and young people with cerebral palsy. These include: communication difficulties comorbidities, particularly epilepsy and pain side effects and drug interactions of multiple medicines (polypharmacy) adverse effects of medicines used for managing mental health problems on motor function adverse effects of medicines used for managing motor function on mental health specific social care needs. # Registering and processing sensory information Explain to children and young people with cerebral palsy and their parents or carers that difficulties with learning and movement may be exacerbated by difficulties with registering or processing sensory information, which can affect function and participation. Sensory difficulties may include: primary sensory disorders in any of the sensory systems, such as processing of visual or auditory information (for example, difficulties with depth perception may affect the ability to walk on stairs; see recommendations 1.17.3 to 1.17.8 in the section on information on other comorbidities) disorders of sensory processing and perception, such as planning movements or being able to concentrate and pay attention. For children and young people with cerebral palsy who have difficulties with registering and processing sensory information: agree a functional, goal-orientated, individualised programme in partnership with parents or carers explain to parents or carers that there is a lack of evidence to support specific interventions. # Information on other comorbidities Assess children and young people with cerebral palsy regularly for developmental and clinical comorbidities, and recognise that these can have an important impact on wellbeing, function and participation. Manage comorbidities, and refer the child or young person for further specialist care if necessary (for example, if a management programme is unsuccessful). ## Visual impairment Refer all children with cerebral palsy for an initial baseline ophthalmological and orthoptic assessment at the time of diagnosis. Talk to children and young people and their parents or carers about visual impairment that can be associated with cerebral palsy. Information that may be useful to discuss includes the following: around 1 in 2 children and young people with cerebral palsy will have some form of visual impairment visual impairment may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment. Talk to children and young people and their parents or carers about the different types of visual impairment that can be associated with cerebral palsy. Explain that these could include 1 or more of the following: problems with controlling eye movements strabismus (squint) refractive errors (short or long sighted or distorted image) problems of eye function, including retinopathy of prematurity impaired cerebral visual information processing (problems with seeing objects caused by damage to the parts of the brain that control vision) visual field defects (loss of the part of usual field of vision). If concerns about visual impairment are raised by parents, carers or members of the care team, consider referring the child or young person with cerebral palsy to a specialist team for evaluation of the whole visual system (including eye health, eye movements, refraction, squint and visual acuity), especially if there are communication difficulties. Regularly assess children and young people with cerebral palsy for signs of cerebral visual impairment, bearing in mind that this: -ccurs in around 1 in 5 children and young people with cerebral palsy may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment may be difficult to recognise in the early stages. ## Hearing impairment Talk to children and young people and their parents or carers about hearing impairment that can be associated with cerebral palsy. Information that may be useful to discuss includes the following: hearing impairment occurs in around 1 in 10 children and young people with cerebral palsy it may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment it is more common in people with dyskinetic or ataxic cerebral palsy than in those with spastic cerebral palsy regular ongoing hearing assessment is necessary. ## Learning disability (intellectual disability) Talk to children and young people and their parents or carers about learning disability (intellectual disability) that can be associated with cerebral palsy (for example, problems with knowledge acquisition, memory, and understanding and use of language). Information that may be useful to discuss includes the following: learning disability (IQ below 70) occurs in around 1 in 2 children and young people with cerebral palsy severe learning disability (IQ below 50) occurs in around 1 in 4 children and young people with cerebral palsy learning disability can be associated with any functional level, but prevalence increases with increasing severity of motor impairment: GMFCS level I or II: around 1 in 3 have an IQ below 70 GMFCS level III, IV or V: around 2 in 3 have an IQ below 70. ## Behavioural difficulties Talk to children and young people and their parents or carers about behavioural difficulties that can be associated with cerebral palsy. Information that may be useful to discuss includes that around 2 to 3 in 10 children and young people with cerebral palsy have 1 or more of the following: emotional and behavioural difficulties that have an effect on the child or young person's function and participation problems with peer relationships difficulties with attention, concentration and hyperactivity conduct behavioural difficulties. Recognise that difficulties with registering or processing sensory information (see the section on registering and processing sensory information) may present as behavioural difficulties. Support children and young people with cerebral palsy and their families and carers to recognise behavioural difficulties. Manage routine behavioural difficulties within the multidisciplinary team, and refer the child or young person to specialist services if difficulties persist. ## Vomiting, regurgitation and reflux Advise parents or carers that vomiting, regurgitation and gastro-oesophageal reflux are common in children and young people with cerebral palsy. If there is a marked change in the pattern of vomiting, assess for a clinical cause. For guidance on identifying and managing gastro-oesophageal reflux disease, see the NICE guidelines on gastro-oesophageal reflux disease in children and young people and gastro-oesophageal reflux disease and dyspepsia in adults. ## Constipation Recognise that around 3 in 5 children and young people with cerebral palsy have chronic constipation, and: discuss this with children and young people and their parents or carers carry out regular clinical assessments for constipation. For guidance on identifying and managing constipation in under 18s, see the NICE guideline on constipation in children and young people. ## Epilepsy Advise children and their parents or carers that epilepsy may be associated with cerebral palsy. Information that may be useful to discuss includes the following: epilepsy occurs in around 1 in 3 children with cerebral palsy it may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment it is reported in around 1 in 2 children with dyskinetic cerebral palsy. Ensure that dyskinetic movements are not misinterpreted as epilepsy in children with cerebral palsy. For guidance on identifying and managing epilepsy, see the NICE guideline on epilepsies in children, young people and adults. # Care needs Assess the care needs of every child with cerebral palsy, and of their parents or carers, at diagnosis, and reassess regularly. Recognise the importance of social care needs in facilitating participation and independent living for children and young people with cerebral palsy. Provide information on the following topics, and direct families to where they can find further information, at diagnosis of cerebral palsy and as appropriate thereafter: social care services financial support, welfare rights and voluntary organisations support groups (including psychological and emotional support for the child or young person and their parents or carers and siblings) respite and hospice services. Address and review the specific needs of the child or young person with cerebral palsy in relation to accessing their physical environment (for example, home, school, healthcare, workplace, community), in order to optimise their functional participation. Think about the following aspects: mobility equipment, particularly wheelchairs and hoists transport toileting and changing facilities. Ensure effective communication and integrated team working between health and social care providers. When assessing care needs, take into account the role of any social, cultural, spiritual or religious networks that support the child or young person with cerebral palsy and their family. Take into account that English may not be the first language of children and young people with cerebral palsy or their parents or carers. Provide an interpreter if necessary. Follow the principles in the NICE guideline on patient experience in adult NHS services. Explore with the child or young person and their parents or carers the value of respite services, such as carer support either at home or in another setting. Ensure that individual, tailored care pathways (including pain management, rehabilitation and equipment) are in place after any major surgical intervention for children and young people with cerebral palsy (see also the NICE guideline on spasticity in under 19s). # Transition to adults' services Follow the NICE guideline on transition from children's to adults' services for young people using health or social care services. ## Overarching principles Recognise that challenges for young people with cerebral palsy continue into adulthood, and ensure that their individual developmental, social and health needs, particularly those relating to learning and communication, are addressed when planning and delivering transition. Recognise that for young people with cerebral palsy, there may be more than 1 transition period in health and social care settings; for example, college, resident educational and adult home settings. ## Transition planning Develop clear pathways for transition that involve: the young person's GP and named paediatricians and named clinicians in adults' services, both locally and regionally, who have an interest in the management of cerebral palsy. Ensure that professionals involved in providing future care for young people with cerebral palsy have sufficient training in order to address all their health and social care needs. As a minimum standard of care, ensure that the young person has access to adults' services both locally and regionally that include healthcare professionals with an understanding of managing cerebral palsy. Ensure that all relevant information is communicated at each point of transition; for example, using a personal 'folder' containing relevant information as described in recommendation 1.6.5 in the section on information and support (see also recommendations about support before transfer in the NICE guideline on transition from children's to adults' services). Recognise that functional challenges (including those involving eating, drinking and swallowing, communication and mobility) and physical problems (including pain and discomfort) may change over time for people with cerebral palsy, and take this into account in transition planning. Provide a named worker to facilitate timely and effective transition, and recognise the importance of continuity of care (see also recommendations about transition planning in the NICE guideline on transition from children's to adults' services and about continuity of care and relationships in the NICE guideline on patient experience in adult NHS services). # Terms used in this guideline ## Anthropometric measurements Body measurements that include weight, height, knee height, mid-upper arm circumference, waist circumference, head circumference and skinfold thickness measurements. ## Child A person aged 11 years or younger. ## Walk unaided The ability to walk independently in the community without the need for supportive devices such as a walking frame, tripod sticks or crutches. ## Young person A person aged between 12 and 24 years of age.# Context Cerebral palsy is the most common cause of physical disability in children and young people in the developed world, with a prevalence of around 2 to 2.5 per 1,000. The term describes a group of permanent, non-progressive abnormalities of the developing fetal or neonatal brain that lead primarily to disorders of movement and posture, causing 'activity limitation' and 'functional impact'. The interaction of primary neurological and secondary physiological factors leads to challenges in terms of both early recognition of cerebral palsy and lifelong management for the person and their families. Children with cerebral palsy generally present to services in 1 of 2 ways: either by identification of atypical motor patterns in those considered at high risk because of antenatal or perinatal complications, or because of atypical motor development picked up during background population assessment. Recognition of clinical risk and management for people with cerebral palsy change throughout their lives. Understanding the aetiology of the condition, and so minimising the risk and early impact on the brain, may directly affect lifelong outcomes. The management of cerebral palsy is a two-pronged approach, and is provided by a variety of multidisciplinary services with a focus on maximising individual function, choice and independence. The first of these is optimising movement and posture while minimising potential secondary musculoskeletal deformity. This is dealt with by NICE guideline on spasticity in under 19s, which concentrates on the motor disorder of cerebral palsy. The second aspect of management is recognising and intervening to address the many developmental and clinical comorbidities that are associated with cerebral palsy. This is the subject of this guideline, with particular focus on where there may be variation in practice and in patient and family experience across England and Wales. It looks at practical areas of management that are important to children and young people with cerebral palsy, their families and carers, and a wide variety of healthcare and other professionals. These include causation and recognition of cerebral palsy, prognosis and the associated developmental and clinical comorbidities.# Recommendations for research The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline. # Optimising nutritional status in children with cerebral palsy What is the clinical and cost effectiveness of early interventions for optimising protein, energy and micronutrient nutritional status in children with cerebral palsy? ## Why this is important Most children with cerebral palsy have clinically significant oral motor dysfunction, and around 20% of children with cerebral palsy are undernourished. Provision of high-calorie and high-protein diets, either orally or via tube feeding, is well established to improve weight gain. Supplementation with micronutrients (such as vitamin D) is also necessary to ensure nutritional adequacy and prevent deficiencies. There is a lack of evidence about whether a more proactive approach to nutrition support in young children with cerebral palsy would improve growth and other aspects of clinical and developmental function. There is also insufficient evidence to determine whether higher intake of individual nutrients may have additional benefits; for example, there is emerging evidence that increased protein intake improves muscle strength, albeit in a different population (healthy older adults). A multicentre randomised controlled trial is needed that assesses the clinical and cost effectiveness of early interventions to optimise protein, energy and micronutrient nutritional status in this population. # Managing communication difficulties in children with cerebral palsy What is the clinical and cost effectiveness of interventions for managing communication difficulties in children with cerebral palsy? ## Why this is important Communication is an essential life skill that is recognised as a human right. Some children with cerebral palsy find communication difficult because they have little or no clear speech, resulting in social isolation. Alternative and augmentative communication (including signing, symbols, communication charts and computer-based speech generating devices) is now an established part of clinical practice, but the evidence base to inform good practice is very limited. Research evidence in this area is largely limited to single case studies, with a focus on acquisition of skills (for example, recognising symbols or making requests). A multicentre randomised controlled trial is needed to look at the effectiveness of interventions that include alternative and augmentative communication methods and carer training in improving the participation of children at different stages of communication development. # Recognition and early management of pain in children and young people with cerebral palsy Does use of pain assessment tools by parents or carers improve the recognition and early management of pain in children and young people with cerebral palsy in a community setting? ## Why this is important Pain and discomfort are increasingly recognised as having a major impact on quality of life for children and young people with cerebral palsy and their parents or carers. A variety of assessment tools have been developed to quantify qualitative pain behaviours in children and young people with cerebral palsy who cannot communicate. The use of these tools in hospital to help identify signs and symptoms of pain and discomfort associated with specific interventions has become widespread. These tools may also help parents or carers recognise pain and discomfort in children and young people with cerebral palsy in community settings. Reducing pain and discomfort outside hospital is of clear importance to help with all aspects of quality of life, including learning, development and clinical wellbeing. A prospective cohort study is needed that looks at whether use of pain assessment tools by parents or carers improves the recognition and early management of pain. # Association between treating infections in pregnancy and rates of cerebral palsy What is the association between different antibiotic regimes to treat genito-urinary and respiratory tract infections in pregnant women and subsequent rates of cerebral palsy in children? ## Why this is important Treating infection in pregnancy is of prime importance for the woman's health. In large population studies of pregnant women, chorioamnionitis, other genito-urinary infections and respiratory tract infections that result in admission to hospital are significant risk factors for the child being diagnosed with cerebral palsy. The mechanisms are uncertain, but include cytokine-induced damage to developing white matter leading to periventricular leukomalacia and sensitisation of the fetal brain to damage from hypoxia. A prospective multicentre study is needed that looks at the effects of different antibiotic regimes for treating genito-urinary infections in pregnant women on subsequent rates of cerebral palsy. # Prevalence of mental health problems in young people (up to the age of 25) with cerebral palsy What is the prevalence of mental health problems in young people (up to the age of 25) with cerebral palsy? ## Why this is important A number of factors predispose young people with cerebral palsy to an increased risk of mental health problems, which will have a marked impact on their quality of life and challenges of care. However, there is a lack of evidence about the prevalence of such problems in this population. Improved guidance would allow greater access to suitable services for young people with cerebral palsy. In addition, given the link between mental and physical health, improvements in mental healthcare could potentially influence physical health and comorbidities. A prospective cohort study or cross-sectional study is needed that looks at the prevalence of mental health problems in this population.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Risk factors\n\nRecognise the following as independent risk factors for cerebral palsy:\n\nantenatal factors:\n\n\n\npreterm birth (with risk increasing with decreasing gestational age; see the NICE guideline on developmental follow-up of children and young people born preterm for more information on risk factors specific to preterm birth, and the NICE guideline on preterm labour and birth, which covers preventing or delaying preterm birth, steroid treatment for maturation of fetal lungs and neuroprotection for the baby)\n\nchorioamnionitis\n\nmaternal respiratory tract or genito-urinary infection treated in hospital\n\n\n\nperinatal factors:\n\n\n\nlow birth weight\n\nchorioamnionitis\n\nneonatal encephalopathy\n\nneonatal sepsis (particularly with a birth weight below 1.5\xa0kg)\n\nmaternal respiratory tract or genito-urinary infection treated in hospital\n\n\n\npostnatal factors:\n\n\n\nmeningitis.\n\n\n\nProvide an enhanced clinical and developmental follow‑up programme (see the section on looking for signs of cerebral palsy) for children who have any of the risk factors listed in recommendation\xa01.1.1.\n\n# Causes of cerebral palsy\n\nWhen assessing the likely cause of cerebral palsy in a child, recognise that a number of MRI-identified brain abnormalities have been reported at the following approximate prevalences in children with cerebral palsy:\n\nwhite matter damage:\xa045%\n\nbasal ganglia or deep grey matter damage:\xa013%\n\ncongenital malformation:\xa010%\n\nfocal infarcts:\xa07%.\n\nWhen assessing the likely cause of cerebral palsy, recognise that white matter damage, including periventricular leukomalacia shown on neuroimaging:\n\nis more common in children born preterm than in those born at term\n\nmay occur in children with any functional level or motor subtype, but is more common in spastic than in dyskinetic cerebral palsy.\n\nWhen assessing the likely cause of cerebral palsy, recognise that basal ganglia or deep grey matter damage is mostly associated with dyskinetic cerebral palsy.\n\nWhen assessing the likely cause of cerebral palsy, recognise that congenital malformations as a cause of cerebral palsy:\n\nare more common in children born at term than in those born preterm\n\nmay occur in children with any functional level or motor subtype\n\nare associated with higher levels of functional impairment than other causes.\n\nRecognise that the clinical syndrome of neonatal encephalopathy can result from various pathological events, such as a hypoxic–ischaemic brain injury or sepsis, and if there has been more than 1\xa0such event they may interact to damage the developing brain.\n\nWhen assessing the likely cause of cerebral palsy, recognise that neonatal encephalopathy has been reported at the following approximate prevalences in children with cerebral palsy born after 35\xa0weeks:\n\nattributed to a perinatal hypoxic–ischaemic injury:\xa020%\n\nnot attributed to a perinatal hypoxic–ischaemic injury:\xa012%.\n\nRecognise that for cerebral palsy associated with a perinatal hypoxic–ischaemic injury:\n\nthe extent of long-term functional impairment is often related to the severity of the initial encephalopathy\n\nthe dyskinetic motor subtype is more common than other subtypes.\n\nRecognise that for cerebral palsy acquired after the neonatal period, the following causes and approximate prevalences have been reported:\n\nmeningitis:\xa020%\n\nother infections:\xa030%\n\nhead injury:\xa012%.\n\nWhen assessing the likely cause of cerebral palsy, recognise that independent risk factors:\n\ncan have a cumulative impact, adversely affecting the developing brain and resulting in cerebral palsy\n\nmay have an impact at any stage of development, including the antenatal, perinatal and postnatal periods.\n\n## Using MRI to assess cause\n\nOffer MRI to investigate aetiology in a child or young person with suspected or known cerebral palsy if this is not clear from:\n\nantenatal, perinatal and postnatal history\n\ntheir developmental progress\n\nfindings on clinical examination\n\nresults of cranial ultrasound examinations.\n\nRecognise that MRI will not accurately establish the timing of a hypoxic–ischaemic brain injury in a child with cerebral palsy.\n\nWhen deciding the best age to perform an MRI scan for a child with cerebral palsy, take account of the following:\n\nSubtle neuro-anatomical changes that could explain the aetiology of cerebral palsy may not be apparent until 2\xa0years of age.\n\nThe presence of any red flags for a progressive neurological disorder (see the section on red flags for other neurological disorders).\n\nThat general anaesthesia or sedation is usually needed for young children having MRI.\n\nThe views of the child or young person and their parents or carers.\n\nExplain to parents or carers and the child or young person with cerebral palsy that it is not always possible to identify a cause for cerebral palsy.\n\nConsider repeating the MRI scan if:\n\nthere is a change in the expected clinical and developmental profile or\n\nany red flags for a progressive neurological disorder (see the section on red flags for other neurological disorders).\n\nDiscuss with the child or young person and their parents or carers the reasons for performing MRI in each individual circumstance.\n\n# Looking for signs of cerebral palsy\n\nProvide an enhanced clinical and developmental follow‑up programme by a multidisciplinary team for children up to 2\xa0years (corrected for gestational age) who are at increased risk of developing cerebral palsy (see the section on risk factors).\n\nConsider using the General Movement Assessment (GMA) during routine neonatal follow‑up assessments for children between 0\xa0and 3\xa0months who are at increased risk of developing cerebral palsy.\n\nRecognise the following as possible early motor features in the presentation of cerebral palsy:\n\nunusual fidgety movements or other abnormalities of movement, including asymmetry or paucity of movement\n\nabnormalities of tone, including hypotonia (floppiness), spasticity (stiffness) or dystonia (fluctuating tone)\n\nabnormal motor development, including late head control, rolling and crawling\n\nfeeding difficulties.\n\nRefer children who are at increased risk of developing cerebral palsy and who have any of the abnormal features listed in recommendation\xa01.3.3 to a child development service for an urgent assessment.\n\nRecognise that the most common delayed motor milestones in children with cerebral palsy are:\n\nnot sitting by 8\xa0months (corrected for gestational age)\n\nnot walking by 18\xa0months (corrected for gestational age)\n\nearly asymmetry of hand function (hand preference) before 1\xa0year (corrected for gestational age).\n\nRefer all children with delayed motor milestones to a child development service for further assessment.\n\nRefer children who have persistent toe walking to a child development service for further assessment.\n\nIf there are concerns that a child may have cerebral palsy but a definitive diagnosis cannot be made, discuss this with their parents or carers and explain that an enhanced clinical and developmental follow‑up programme will be necessary to try to reach a definite conclusion.\n\n# Red flags for other neurological disorders\n\nReview a diagnosis of cerebral palsy if clinical signs or the child's development do not follow the patterns expected for cerebral palsy, taking into account that the functional and neurological manifestations of cerebral palsy change over time.\n\nRecognise the following as red flags for neurological disorders other than cerebral palsy, and refer the child or young person to a specialist in paediatric neurology if any of these are observed:\n\nabsence of known risk factors (see the section on risk factors)\n\nfamily history of a progressive neurological disorder\n\nloss of already attained cognitive or developmental abilities\n\ndevelopment of unexpected focal neurological signs\n\nMRI findings suggestive of a progressive neurological disorder\n\nMRI findings not in keeping with clinical signs of cerebral palsy.\n\n# Multidisciplinary care\n\nRefer all children with suspected cerebral palsy to a child development service for an urgent multidisciplinary assessment, in order to facilitate early diagnosis and intervention.\n\nRecognise that children and young people with cerebral palsy and their parents or carers have a central role in decision making and care planning.\n\nEnsure that the child or young person with cerebral palsy has access to a local integrated core multidisciplinary team that:\n\nis able to meet their individual needs within agreed care pathways\n\ncan provide the following expertise, as appropriate, through a local network of care:\n\n\n\npaediatric or adult medicine\n\nnursing care\n\nphysiotherapy\n\noccupational therapy\n\nspeech and language therapy\n\ndietetics\n\npsychology\n\n\n\ncan enable access to other services within their local or regional network as appropriate, including:\n\n\n\npaediatric or adult neurodisability, neurology, neurorehabilitation, respiratory, gastroenterology and surgical specialist care\n\northopaedics\n\northotics and rehabilitation services\n\nsocial care\n\nvisual and hearing specialist services\n\nteaching support for preschool and school-age children, including portage (home teaching services for preschool children).\n\n\n\nEnsure that routes for accessing specialist teams involved in managing comorbidities associated with cerebral palsy are clearly defined on a regional basis.\n\nRecognise that ongoing communication between all levels of service provision in the care of children and young people with cerebral palsy is crucial, particularly involvement of primary care from diagnosis onwards.\n\n## Medicines optimisation\n\nFor guidance on the safe and effective use of medicines, see the NICE guideline on medicines optimisation.\n\n## Movement and posture\n\nFor guidance on managing problems with movement and posture in children and young people with cerebral palsy, see the NICE guideline on spasticity in under\xa019s.\n\n# Information and support\n\nEnsure that information and support focuses as much on the functional abilities of the child or young person with cerebral palsy as on any functional impairment.\n\nProvide clear, timely and up‑to‑date information to parents or carers on the following topics:\n\ndiagnosis (see the section on looking for signs of cerebral palsy)\n\naetiology (see the section on causes of cerebral palsy)\n\nprognosis (see the section on information about prognosis)\n\nexpected developmental progress\n\ncomorbidities\n\navailability of specialist equipment\n\nresources available and access to financial, respite, social care and other support for children and young people and their parents, carers and siblings (see also recommendations 1.18.3 and 1.18.8 in the section on care needs)\n\neducational placement (including specialist preschool and early years settings)\n\ntransition (see the section on transition to adults' services).\n\nEnsure that clear information about the 'patient pathway' is shared with the child or young person and their parents or carers (for example, by providing them with copies of correspondence). Follow the principles in the recommendations about communication, information and shared decision making in the NICE guideline on patient experience in adult NHS services.\n\nProvide information to the child or young person with cerebral palsy, and their parents or carers, on an ongoing basis. Adapt the communication methods and information resources to take account of the needs and understanding of the child or young person and their parents or carers. For example, think about using 1\xa0or more of the following:\n\noral explanations\n\nwritten information and leaflets\n\nmobile technology, including apps\n\naugmentative and alternative communication systems (see recommendations 1.9.7 to 1.9.10 in the section on interventions).\n\nWork with the child or young person and their parents or carers to develop and maintain a personal 'folder' in their preferred format (electronic or otherwise) containing relevant information that can be shared with their extended family and friends and used in health, social care, educational and transition settings. Information could include:\n\nearly history\n\nmotor subtype and limb involvement\n\nfunctional abilities\n\ninterventions\n\nmedication\n\ncomorbidities\n\npreferred methods of communication\n\nany specialist equipment that is used or needed\n\ncare plans\n\nemergency contact details.\n\nEnsure that the child or young person and their parents or carers are provided with information, by a professional with appropriate expertise, about the following topics relevant to them that is tailored to their individual needs:\n\nmenstruation\n\nfertility and contraception\n\nsex and sexuality\n\nparenting.\n\nProvide information to the child or young person and their parents or carers, and to all relevant teams around them, about the local and regional services available (for example, sporting clubs, respite care and specialist schools) for children and young people with cerebral palsy, and how to access them.\n\nProvide information about local support and advocacy groups to the child or young person and their parents or carers.\n\n# Information about prognosis\n\nProvide the following information to parents or carers about the prognosis for walking for a child with cerebral palsy:\n\nThe more severe the child's physical, functional or cognitive impairment, the greater the possibility of difficulties with walking.\n\nIf a child can sit at 2\xa0years of age it is likely, but not certain, that they will be able to walk unaided by age\xa06.\n\nIf a child cannot sit but can roll at 2\xa0years of age, there is a possibility that they may be able to walk unaided by age\xa06.\n\nIf a child cannot sit or roll at 2\xa0years of age, they are unlikely to be able to walk unaided.\n\nRecognise the following in relation to prognosis for speech development in a child with cerebral palsy, and discuss this with parents or carers as appropriate:\n\nAround 1\xa0in 2\xa0children with cerebral palsy have some difficulty with elements of communication (see the section on communication difficulties).\n\nAround 1\xa0in 3\xa0children have specific difficulties with speech and language.\n\nThe more severe the child's physical, functional or cognitive impairment, the greater the likelihood of difficulties with speech and language.\n\nUncontrolled epilepsy may be associated with difficulties with all forms of communication, including speech.\n\nA child with bilateral spastic, dyskinetic or ataxic cerebral palsy is more likely to have difficulties with speech and language than a child with unilateral spastic cerebral palsy.\n\nProvide the following information to parents or carers, as appropriate, about prognosis for life expectancy for a child with cerebral palsy:\n\nThe more severe the child's physical, functional or cognitive impairment, the greater the likelihood of reduced life expectancy.\n\nThere is an association between reduced life expectancy and the need for enteral tube feeding, but this reflects the severity of swallowing difficulties and is not because of the intervention.\n\n## Using MRI to assess prognosis\n\nDo not rely on MRI alone for predicting prognosis in children with cerebral palsy.\n\nTake account of the likely cause of cerebral palsy and the findings from MRI (if performed) when discussing prognosis with the child or young person and their parents or carers.\n\n# Eating, drinking and swallowing difficulties\n\n## Assessment\n\nIf eating, drinking and swallowing difficulties are suspected in a child or young person with cerebral palsy, carry out a clinical assessment as first-line investigation to determine the safety, efficiency and enjoyment of eating and drinking. This should include:\n\ntaking a relevant clinical history, including asking about any previous chest infections\n\nobservation of eating and drinking in a normal mealtime environment by a speech and language therapist with training in assessing and treating dysphagia.\n\nRefer the child or young person to a local specialist multidisciplinary team with training in assessing and treating dysphagia if there are clinical concerns about eating, drinking and swallowing, such as:\n\ncoughing, choking, gagging, altered breathing pattern or change in colour while eating or drinking\n\nrecurrent chest infection\n\nmealtimes regularly being stressful or distressing for the child or young person or their parents or carers\n\nprolonged meal duration.\n\nDo not use videofluoroscopy or fibroscopic endoscopy for the initial assessment of eating, drinking and swallowing difficulties in children and young people with cerebral palsy.\n\nThe specialist multidisciplinary team should consider videofluoroscopy if any of the following apply:\n\nThere is uncertainty about the safety of eating, drinking and swallowing after specialist clinical assessment.\n\nThe child or young person has recurrent chest infection without overt clinical signs of aspiration.\n\nThere is deterioration in eating, drinking and swallowing ability with increasing age (particularly after adolescence).\n\nThere is uncertainty about the impact of modifying food textures (for example, use of thickeners or pureeing).\n\nParents or carers need support to understand eating, drinking and swallowing difficulties, to help with decision making.\n\nVideofluoroscopy should only be performed in a centre with a specialist multidisciplinary team who have experience and competence in using it with children and young people with cerebral palsy.\n\nDo not routinely perform videofluoroscopy when considering starting enteral tube feeding in children and young people with cerebral palsy.\n\nEnsure that children and young people with ongoing eating, drinking and swallowing difficulties have access to tertiary specialist assessment, including advice from other services (such as paediatric surgery and respiratory paediatrics).\n\n## Management\n\nDevelop strategies and goals in partnership with the child or young person with cerebral palsy and their parents, carers and other family members for interventions to improve eating, drinking and swallowing.\n\nCreate an individualised plan for managing eating, drinking and swallowing difficulties in children and young people with cerebral palsy, taking into account the understanding, knowledge and skills of parents, carers and any other people involved in feeding the child or young person. Assess the role of the following:\n\npostural management and positioning when eating\n\nmodifying fluid and food textures and flavours\n\nfeeding techniques, such as pacing and spoon placement\n\nequipment, such as specialised feeding utensils\n\noptimising the mealtime environment\n\nstrategies for managing behavioural difficulties associated with eating and drinking\n\nstrategies for developing oral motor skills\n\ncommunication strategies\n\nmodifications to accommodate visual or other sensory impairments that affect eating, drinking and swallowing\n\nthe training needs of the people who care for the child or young person, particularly outside the home.\n\nAdvise parents or carers that intra-oral devices have not been shown to improve eating, drinking and swallowing in children and young people with cerebral palsy.\n\nUse outcome measures important to the child or young person and their parents or carers to review:\n\nwhether individualised goals have been achieved\n\nthe clinical and functional impact of interventions to improve eating, drinking and swallowing.\n\n# Speech, language and communication\n\n## Communication difficulties\n\nTalk to children and young people and their parents or carers about communication difficulties that can be associated with cerebral palsy. Information that may be useful to discuss includes the following:\n\ncommunication difficulties occur in around 1\xa0in 2\xa0children and young people with cerebral palsy\n\nat least 1\xa0in\xa010 need augmentative and alternative communication (signs, symbols and speech generating devices)\n\naround 1\xa0in\xa010 cannot use formal methods of augmentative and alternative communication because of cognitive and sensory impairments and communication difficulties\n\ncommunication difficulties may occur with any functional level or motor subtype, but are more common in children and young people with dyskinetic or severe bilateral spastic cerebral palsy\n\ncommunication difficulties do not necessarily correlate with learning disability (intellectual disability).\n\n## Assessment and referral\n\nRegularly assess children and young people with cerebral palsy during routine reviews to identify concerns about speech, language and communication, including speech intelligibility.\n\nRefer children and young people with cerebral palsy for specialist assessment if there are concerns about speech, language and communication, including speech intelligibility.\n\nSpecialist assessment of the communication skills, including speech intelligibility, of children and young people with cerebral palsy should be conducted by a multidisciplinary team that includes a speech and language therapist.\n\n## Interventions\n\nRecognise the importance of early intervention to improve the communication skills of children and young people with cerebral palsy.\n\nOffer interventions to improve speech intelligibility, for example targeting posture, breath control, voice production and rate of speech, to children and young people with cerebral palsy:\n\nwho have a motor speech disorder and some intelligible speech and\n\nfor whom speech is the primary means of communication and\n\nwho can engage with the intervention.\n\nConsider augmentative and alternative communication systems for children and young people with cerebral palsy who need support in understanding and producing speech. These may include pictures, objects, symbols and signs, and speech generating devices.\n\nIf there are ongoing problems with using augmentative and alternative communication systems, refer the child or young person to a specialist service in order to tailor interventions to their individual needs, taking account of their cognitive, linguistic, motor, hearing and visual abilities.\n\nRegularly review children and young people who are using augmentative and alternative communication systems, to monitor their progress and ensure that interventions continue to be appropriate for their needs.\n\nProvide individualised training in communication techniques for families, carers, preschool and school staff and other people involved in the care of a child or young person with cerebral palsy.\n\n# Optimising nutritional status\n\nRegularly review the nutritional status of children and young people with cerebral palsy, including measuring their height and weight (or consider alternative anthropometric measurements, particularly if height and weight cannot be measured).\n\nProvide timely access to assessment and nutritional interventional support from a dietitian if there are concerns about oral intake, growth or nutritional status.\n\nIf oral intake is still insufficient to provide adequate nutrition after assessment and nutritional interventions, refer the child or young person to be assessed for enteral tube feeding by a multidisciplinary team with relevant expertise.\n\nFor guidance on nutritional interventions and enteral tube feeding in over\xa018s, see the NICE guideline on nutrition support for adults.\n\n# Managing saliva control\n\nAt the time of publication (January 2017), for the indication in recommendation 1.11.2, glycopyrronium bromide (oral solution) did not have a UK marketing authorisation for use in children under\xa03, and transdermal hyoscine hydrobromide (scopolamine hydrobromide) and trihexyphenidyl hydrochloride did not have UK marketing authorisations for use in children and young people under\xa018.\n\nFor recommendations 1.11.5 and 1.11.6, as of September 2019, Xeomin is the only preparation of botulinum toxin\xa0A to have marketing authorisation for treating chronic sialorrhoea caused by neurological conditions in adults. No other preparation of botulinum toxin type\xa0A has a UK marketing authorisation for this indication. Therefore, no botulinum toxin products are licensed for drooling in children (under\xa018s). The use of Xeomin for this indication in under\xa018s is still off-label. See NICE's information on prescribing medicines.\n\nAssess factors that may affect drooling in children and young people with cerebral palsy, such as positioning, medication history, reflux and dental issues, before starting drug therapy.\n\nTo reduce the severity and frequency of drooling in children and young people with cerebral palsy, consider the use of anticholinergic medication:\n\nglycopyrronium bromide (oral or by enteral tube) or\n\ntransdermal hyoscine hydrobromide or\n\ntrihexyphenidyl hydrochloride for children with dyskinetic cerebral palsy, but only with input from specialist services.When choosing which medicine to use, take into account the preferences of the child or young person and their parents or carers, and the age range and indication covered by the marketing authorisations.\n\nRegularly review the effectiveness, tolerability and side effects of all drug treatments used for saliva control.\n\nRefer the child or young person to a specialist service if the anticholinergic drug treatments outlined in recommendations\xa01.11.2 and\xa01.11.3 are contraindicated, not tolerated or not effective, to consider other treatments for saliva control.\n\nConsider specialist assessment and use of botulinum toxin\xa0A injections to the salivary glands with ultrasound guidance to reduce the severity and frequency of drooling in children and young people with cerebral palsy if anticholinergic drugs provide insufficient benefit or are not tolerated.\n\nAdvise children and young people and their parents or carers that high-dose botulinum toxin\xa0A injection to the salivary glands can rarely cause swallowing difficulties, and so they should return to hospital immediately if breathing or swallowing difficulties occur.\n\nConsider referring young people for a surgical opinion, after an assessment confirming clinically safe swallow, if there is:\n\na potential need for lifelong drug treatment or\n\ninsufficient benefit or non-tolerance of anticholinergic drugs and botulinum toxin\xa0A injections.\n\n# Low bone mineral density\n\n## Risk factors\n\nRecognise that in children and young people with cerebral palsy the following are independent risk factors for low bone mineral density:\n\nnon-ambulant (GMFCS level IV\xa0or\xa0V)\n\nvitamin\xa0D deficiency\n\npresence of eating, drinking and swallowing difficulties or concerns about nutritional status\n\nlow weight for age (below the 2nd centile)\n\nhistory of low-impact fracture\n\nuse of anticonvulsant medication.\n\nRecognise that there is an increased risk of low-impact fractures in children and young people with cerebral palsy who are non-ambulant or have low bone mineral density.\n\nInform children and young people with cerebral palsy and their parents or carers if they are at an increased risk of low-impact fractures.\n\n## Management\n\nIf a child and young person with cerebral palsy has 1\xa0or more risk factors for low bone mineral density (see recommendation\xa01.12.1):\n\nassess their dietary intake of calcium and vitamin\xa0D and\n\nconsider the following laboratory investigations of calcium and vitamin\xa0D status:\n\n\n\nserum calcium, phosphate and alkaline phosphatase\n\nserum vitamin\xa0D\n\nurinary calcium/creatinine ratio.\n\n\n\nCreate an individualised care plan for children and young people with cerebral palsy who have 1\xa0or more risk factors for low bone mineral density (see recommendation\xa01.12.1).\n\nConsider the following as possible interventions to reduce the risk of reduced bone mineral density and low-impact fractures:\n\nan active movement programme\n\nactive weight bearing\n\ndietetic interventions as appropriate, including nutritional support and calcium and vitamin\xa0D supplementation\n\nminimising risks associated with movement and handling.\n\nConsider a DEXA scan under specialist guidance for children and young people with cerebral palsy who have had a low-impact fracture.\n\nRefer children and young people with cerebral palsy with reduced bone density and a history of low-impact fracture to a specialist centre for consideration of bisphosphonate therapy.\n\nDo not offer standing frames solely to prevent low bone mineral density in children and young people with cerebral palsy.\n\nDo not offer vibration therapy solely to prevent low bone mineral density in children and young people with cerebral palsy.\n\n# Pain, discomfort and distress\n\n## Causes\n\nExplain to children and young people with cerebral palsy and their parents or carers that pain is common in people with cerebral palsy, especially those with more severe motor impairment, and this should be recognised and addressed.\n\nRecognise that common condition-specific causes of pain, discomfort and distress in children and young people with cerebral palsy include:\n\nmusculoskeletal problems (for example, scoliosis, hip subluxation and dislocation)\n\nincreased muscle tone (including dystonia and spasticity)\n\nmuscle fatigue and immobility\n\nconstipation\n\nvomiting\n\ngastro-oesophageal reflux disease.\n\nRecognise that usual causes of pain, discomfort and distress that affect children and young people generally also occur in those with cerebral palsy, and that difficulties with communication and perception may make identifying the cause more challenging. Common types of pain in children and young people include:\n\nnon-specific back pain\n\nheadache\n\nnon-specific abdominal pain\n\ndental pain\n\ndysmenorrhea.\n\n## Assessment\n\nTake into account that parents and familiar carers have a key role in recognising and assessing pain, discomfort and distress in children and young people with cerebral palsy.\n\nWhen assessing pain in children and young people with cerebral palsy:\n\nrecognise that assessing the presence and degree of pain can be challenging, especially if:\n\n\n\nthere are communication difficulties or learning disability (intellectual disability)\n\nthere are difficulties with registering or processing sensory information (see the section on registering and processing sensory information)\n\n\n\nask about signs of pain, discomfort, distress and sleep disturbances (see the section on sleep disturbances) at every contact\n\nrecognise that pain-related behaviour can present differently compared with that in the wider population.\n\nAssess for other possible causes of distress in the absence of identifiable physical causes of pain and discomfort, such as:\n\npsychological and emotional distress\n\nincreased sensitivity to environmental triggers\n\nthirst or hunger.\n\nConsider using tools to identify pain or assess severity of pain in children and young people with cerebral palsy, for example:\n\nFor children and young people with communication difficulties:\n\n\n\nPaediatric Pain Profile\n\nNon-communicating Children's Pain Checklist – postoperative version.\n\n\n\nFor children and young people without communication difficulties:\n\n\n\nNumeric pain rating scale.\n\n\n\nRefer the child or young person for a specialist multidisciplinary team assessment of pain, discomfort, distress and sleep if the cause of these is not clear after routine assessment.\n\n## Management\n\nFor reversible causes of pain, discomfort and distress identified in children and young people with cerebral palsy, treat the cause as appropriate using targeted interventions in line with the following NICE guidelines:\n\nspasticity in under\xa019s\n\nconstipation in children and young people\n\ngastro-oesophageal reflux disease in children and young people\n\ngastro-oesophageal reflux disease and dyspepsia in adults\n\nheadaches in over\xa012s\n\nlow back pain and sciatica in over\xa016s\n\nurinary incontinence in neurological disease\n\nurinary tract infection in under\xa016s.\n\nFor common interventions used in the management of cerebral palsy (such as physical therapies, botulinum toxin\xa0A injections and surgery) that can cause acute pain:\n\nadvise the child or young person and their parents or carers that these interventions may reduce discomfort in the long term\n\nminimise discomfort during these procedures.\n\nIn the absence of an identifiable cause of pain, discomfort or distress in a child or young person with cerebral palsy:\n\ntake into account the impact of anxiety, depression or other possible mental health problems\n\nconsider a 'stepped approach' trial of simple analgesia (such as paracetamol and/or ibuprofen) for mild to moderate pain\n\nmonitor the duration, pattern and severity of symptoms.\n\nIf a trial of analgesia is unsuccessful, refer the child or young person to a specialist pain multidisciplinary team, which may be a palliative care service, for a more detailed assessment.\n\n# Sleep disturbances\n\n## Causes\n\nExplain to parents or carers that, in children and young people with cerebral palsy, sleep disturbances (for example, difficulties with falling asleep, staying asleep or daytime sleepiness):\n\nare common\n\nmay be caused by factors such as environment, hunger and thirst.\n\nRecognise that the most common condition-specific causes of sleep disturbances in children and young people with cerebral palsy include:\n\nsleep-induced breathing disorders, such as obstructive sleep apnoea\n\nseizures\n\npain and discomfort\n\nneed for repositioning because of immobility\n\npoor sleep hygiene (poor night-time routine and environment)\n\nnight-time interventions, including overnight tube feeding or the use of orthoses\n\ncomorbidities, including adverse effects of medication.\n\n## Assessment\n\nWhen identifying and assessing sleep disturbances in children and young people with cerebral palsy:\n\nrecognise that parents and familiar carers have the primary role in this\n\nconsider using sleep questionnaires or diaries.\n\nAlways ask about pain, sleep and distress as part of any clinical consultation.\n\n## Management\n\nOptimise sleep hygiene for children and young people with cerebral palsy.\n\nManage treatable causes of sleep disturbances that are identified in children and young people with cerebral palsy.\n\nIf no treatable cause is found, consider a trial of melatonin to manage sleep disturbances for children and young people with cerebral palsy, particularly for problems with falling asleep.At the time of publication (January 2017), melatonin did not have a UK marketing authorisation for use in children and young people under 18 for this indication. See\xa0NICE's information on prescribing medicines.\n\nDo not offer regular sedative medication to manage primary sleep disorders in children with cerebral palsy without seeking specialist advice.\n\nDo not offer sleep positioning systems solely to manage primary sleep disorders in children and young people with cerebral palsy.\n\nRefer the child or young person to specialist sleep services for multidisciplinary team assessment and management if there are ongoing sleep disturbances.\n\n# Mental health problems\n\nFollow the relevant NICE guidelines when identifying and managing mental health problems and psychological and neurodevelopmental disorders in children and young people with cerebral palsy:\n\ndepression in children and young people\n\ndepression in adults\n\ndepression in adults with a chronic physical health problem\n\ngeneralised anxiety disorder and panic disorder in adults\n\nchallenging behaviour and learning disabilities\n\nantisocial behaviour and conduct disorders in children and young people\n\nmental health problems in people with learning disabilities\n\nautism spectrum disorder in under\xa019s: recognition, referral and diagnosis\n\nautism spectrum disorder in under\xa019s: support and management\n\nautism spectrum disorder in adults\n\nattention deficit hyperactivity disorder.\n\n## Identification\n\nTake into account that parents and familiar carers have a central role in recognising and assessing emotional difficulties and mental health problems in children and young people with cerebral palsy.\n\nRecognise that children and young people with cerebral palsy have an increased prevalence of:\n\nmental health and psychological problems, including depression, anxiety and conduct disorders\n\nbehaviours that challenge, which may be triggered by pain, discomfort or sleep disturbances\n\nneurodevelopmental disorders, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).\n\nRecognise that emotional and behavioural difficulties (for example, low self-esteem) are reported in up to 1\xa0in 4\xa0children and young people with cerebral palsy.\n\nAny multidisciplinary team should:\n\nrecognise that mental health problems and emotional difficulties can be as important as physical health problems for children and young people with cerebral palsy\n\nexplore such difficulties during consultations\n\nrecognise that assessing psychological problems can be challenging in children and young people with communication difficulties or learning disability (intellectual disability).\n\nThink about and address the following contributory factors if a change in emotional state occurs in a child or young person with cerebral palsy:\n\npain or discomfort (see the section on pain, discomfort and distress)\n\nfrustration associated with communication difficulties\n\nsocial factors, such as a change in home circumstances or care provision.\n\nUse validated tools, such as the Child Health Questionnaire and the Strengths and Difficulties Questionnaire, to assess mental health problems in children and young people with cerebral palsy.\n\n## Management\n\nRefer the child or young person with cerebral palsy for specialist psychological assessment and ongoing management if emotional and behavioural difficulties persist or there are concerns about their mental health.\n\nWork in partnership with the child or young person with cerebral palsy, and their parents and primary carers, when assessing and managing mental health problems and setting goals.\n\nWhen making an individual management plan to address the mental health needs of a child or young person with cerebral palsy, take into account ways of providing support to parents or carers.\n\nRecognise that there are specific challenges in managing and minimising the impact of mental health problems in children and young people with cerebral palsy. These include:\n\ncommunication difficulties\n\ncomorbidities, particularly epilepsy and pain\n\nside effects and drug interactions of multiple medicines (polypharmacy)\n\nadverse effects of medicines used for managing mental health problems on motor function\n\nadverse effects of medicines used for managing motor function on mental health\n\nspecific social care needs.\n\n# Registering and processing sensory information\n\nExplain to children and young people with cerebral palsy and their parents or carers that difficulties with learning and movement may be exacerbated by difficulties with registering or processing sensory information, which can affect function and participation. Sensory difficulties may include:\n\nprimary sensory disorders in any of the sensory systems, such as processing of visual or auditory information (for example, difficulties with depth perception may affect the ability to walk on stairs; see recommendations 1.17.3 to 1.17.8 in the section on information on other comorbidities)\n\ndisorders of sensory processing and perception, such as planning movements or being able to concentrate and pay attention.\n\nFor children and young people with cerebral palsy who have difficulties with registering and processing sensory information:\n\nagree a functional, goal-orientated, individualised programme in partnership with parents or carers\n\nexplain to parents or carers that there is a lack of evidence to support specific interventions.\n\n# Information on other comorbidities\n\nAssess children and young people with cerebral palsy regularly for developmental and clinical comorbidities, and recognise that these can have an important impact on wellbeing, function and participation.\n\nManage comorbidities, and refer the child or young person for further specialist care if necessary (for example, if a management programme is unsuccessful).\n\n## Visual impairment\n\nRefer all children with cerebral palsy for an initial baseline ophthalmological and orthoptic assessment at the time of diagnosis.\n\nTalk to children and young people and their parents or carers about visual impairment that can be associated with cerebral palsy. Information that may be useful to discuss includes the following:\n\naround 1\xa0in 2\xa0children and young people with cerebral palsy will have some form of visual impairment\n\nvisual impairment may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment.\n\nTalk to children and young people and their parents or carers about the different types of visual impairment that can be associated with cerebral palsy. Explain that these could include 1\xa0or more of the following:\n\nproblems with controlling eye movements\n\nstrabismus (squint)\n\nrefractive errors (short or long sighted or distorted image)\n\nproblems of eye function, including retinopathy of prematurity\n\nimpaired cerebral visual information processing (problems with seeing objects caused by damage to the parts of the brain that control vision)\n\nvisual field defects (loss of the part of usual field of vision).\n\nIf concerns about visual impairment are raised by parents, carers or members of the care team, consider referring the child or young person with cerebral palsy to a specialist team for evaluation of the whole visual system (including eye health, eye movements, refraction, squint and visual acuity), especially if there are communication difficulties.\n\nRegularly assess children and young people with cerebral palsy for signs of cerebral visual impairment, bearing in mind that this:\n\noccurs in around 1\xa0in 5\xa0children and young people with cerebral palsy\n\nmay occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment\n\nmay be difficult to recognise in the early stages.\n\n## Hearing impairment\n\nTalk to children and young people and their parents or carers about hearing impairment that can be associated with cerebral palsy. Information that may be useful to discuss includes the following:\n\nhearing impairment occurs in around 1\xa0in 10\xa0children and young people with cerebral palsy\n\nit may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment\n\nit is more common in people with dyskinetic or ataxic cerebral palsy than in those with spastic cerebral palsy\n\nregular ongoing hearing assessment is necessary.\n\n## Learning disability (intellectual disability)\n\nTalk to children and young people and their parents or carers about learning disability (intellectual disability) that can be associated with cerebral palsy (for example, problems with knowledge acquisition, memory, and understanding and use of language). Information that may be useful to discuss includes the following:\n\nlearning disability (IQ below\xa070) occurs in around 1\xa0in 2\xa0children and young people with cerebral palsy\n\nsevere learning disability (IQ below\xa050) occurs in around 1\xa0in 4\xa0children and young people with cerebral palsy\n\nlearning disability can be associated with any functional level, but prevalence increases with increasing severity of motor impairment:\n\n\n\nGMFCS level\xa0I or\xa0II: around 1\xa0in\xa03 have an IQ below\xa070\n\nGMFCS level\xa0III,\xa0IV\xa0or\xa0V: around 2\xa0in\xa03 have an IQ below\xa070.\n\n\n\n## Behavioural difficulties\n\nTalk to children and young people and their parents or carers about behavioural difficulties that can be associated with cerebral palsy. Information that may be useful to discuss includes that around 2\xa0to\xa03 in 10\xa0children and young people with cerebral palsy have 1\xa0or more of the following:\n\nemotional and behavioural difficulties that have an effect on the child or young person's function and participation\n\nproblems with peer relationships\n\ndifficulties with attention, concentration and hyperactivity\n\nconduct behavioural difficulties.\n\nRecognise that difficulties with registering or processing sensory information (see the section on registering and processing sensory information) may present as behavioural difficulties.\n\nSupport children and young people with cerebral palsy and their families and carers to recognise behavioural difficulties.\n\nManage routine behavioural difficulties within the multidisciplinary team, and refer the child or young person to specialist services if difficulties persist.\n\n## Vomiting, regurgitation and reflux\n\nAdvise parents or carers that vomiting, regurgitation and gastro-oesophageal reflux are common in children and young people with cerebral palsy. If there is a marked change in the pattern of vomiting, assess for a clinical cause.\n\nFor guidance on identifying and managing gastro-oesophageal reflux disease, see the NICE guidelines on gastro-oesophageal reflux disease in children and young people and gastro-oesophageal reflux disease and dyspepsia in adults.\n\n## Constipation\n\nRecognise that around 3\xa0in 5\xa0children and young people with cerebral palsy have chronic constipation, and:\n\ndiscuss this with children and young people and their parents or carers\n\ncarry out regular clinical assessments for constipation.\n\nFor guidance on identifying and managing constipation in under\xa018s, see the NICE guideline on constipation in children and young people.\n\n## Epilepsy\n\nAdvise children and their parents or carers that epilepsy may be associated with cerebral palsy. Information that may be useful to discuss includes the following:\n\nepilepsy occurs in around 1\xa0in 3\xa0children with cerebral palsy\n\nit may occur in children and young people with any functional level or motor subtype, but prevalence increases with increasing severity of motor impairment\n\nit is reported in around 1\xa0in 2\xa0children with dyskinetic cerebral palsy.\n\nEnsure that dyskinetic movements are not misinterpreted as epilepsy in children with cerebral palsy.\n\nFor guidance on identifying and managing epilepsy, see the NICE guideline on epilepsies in children, young people and adults.\n\n# Care needs\n\nAssess the care needs of every child with cerebral palsy, and of their parents or carers, at diagnosis, and reassess regularly.\n\nRecognise the importance of social care needs in facilitating participation and independent living for children and young people with cerebral palsy.\n\nProvide information on the following topics, and direct families to where they can find further information, at diagnosis of cerebral palsy and as appropriate thereafter:\n\nsocial care services\n\nfinancial support, welfare rights and voluntary organisations\n\nsupport groups (including psychological and emotional support for the child or young person and their parents or carers and siblings)\n\nrespite and hospice services.\n\nAddress and review the specific needs of the child or young person with cerebral palsy in relation to accessing their physical environment (for example, home, school, healthcare, workplace, community), in order to optimise their functional participation. Think about the following aspects:\n\nmobility\n\nequipment, particularly wheelchairs and hoists\n\ntransport\n\ntoileting and changing facilities.\n\nEnsure effective communication and integrated team working between health and social care providers.\n\nWhen assessing care needs, take into account the role of any social, cultural, spiritual or religious networks that support the child or young person with cerebral palsy and their family.\n\nTake into account that English may not be the first language of children and young people with cerebral palsy or their parents or carers. Provide an interpreter if necessary. Follow the principles in the NICE guideline on patient experience in adult NHS services.\n\nExplore with the child or young person and their parents or carers the value of respite services, such as carer support either at home or in another setting.\n\nEnsure that individual, tailored care pathways (including pain management, rehabilitation and equipment) are in place after any major surgical intervention for children and young people with cerebral palsy (see also the NICE guideline on spasticity in under\xa019s).\n\n# Transition to adults' services\n\nFollow the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\n## Overarching principles\n\nRecognise that challenges for young people with cerebral palsy continue into adulthood, and ensure that their individual developmental, social and health needs, particularly those relating to learning and communication, are addressed when planning and delivering transition.\n\nRecognise that for young people with cerebral palsy, there may be more than 1\xa0transition period in health and social care settings; for example, college, resident educational and adult home settings.\n\n## Transition planning\n\nDevelop clear pathways for transition that involve:\n\nthe young person's GP and\n\nnamed paediatricians and named clinicians in adults' services, both locally and regionally, who have an interest in the management of cerebral palsy.\n\nEnsure that professionals involved in providing future care for young people with cerebral palsy have sufficient training in order to address all their health and social care needs.\n\nAs a minimum standard of care, ensure that the young person has access to adults' services both locally and regionally that include healthcare professionals with an understanding of managing cerebral palsy.\n\nEnsure that all relevant information is communicated at each point of transition; for example, using a personal 'folder' containing relevant information as described in recommendation 1.6.5 in the section on information and support (see also recommendations about support before transfer in the NICE guideline on transition from children's to adults' services).\n\nRecognise that functional challenges (including those involving eating, drinking and swallowing, communication and mobility) and physical problems (including pain and discomfort) may change over time for people with cerebral palsy, and take this into account in transition planning.\n\nProvide a named worker to facilitate timely and effective transition, and recognise the importance of continuity of care (see also recommendations about transition planning in the NICE guideline on transition from children's to adults' services and about continuity of care and relationships in the NICE guideline on patient experience in adult NHS services).\n\n# Terms used in this guideline\n\n## Anthropometric measurements\n\nBody measurements that include weight, height, knee height, mid-upper arm circumference, waist circumference, head circumference and skinfold thickness measurements.\n\n## Child\n\nA person aged 11\xa0years or younger.\n\n## Walk unaided\n\nThe ability to walk independently in the community without the need for supportive devices such as a walking frame, tripod sticks or crutches.\n\n## Young person\n\nA person aged between 12\xa0and 24\xa0years of age.", 'Context': "Cerebral palsy is the most common cause of physical disability in children and young people in the developed world, with a prevalence of around 2\xa0to\xa02.5 per\xa01,000. The term describes a group of permanent, non-progressive abnormalities of the developing fetal or neonatal brain that lead primarily to disorders of movement and posture, causing 'activity limitation' and 'functional impact'.\n\nThe interaction of primary neurological and secondary physiological factors leads to challenges in terms of both early recognition of cerebral palsy and lifelong management for the person and their families. Children with cerebral palsy generally present to services in 1\xa0of\xa02\xa0ways: either by identification of atypical motor patterns in those considered at high risk because of antenatal or perinatal complications, or because of atypical motor development picked up during background population assessment.\n\nRecognition of clinical risk and management for people with cerebral palsy change throughout their lives. Understanding the aetiology of the condition, and so minimising the risk and early impact on the brain, may directly affect lifelong outcomes.\n\nThe management of cerebral palsy is a two-pronged approach, and is provided by a variety of multidisciplinary services with a focus on maximising individual function, choice and independence. The first of these is optimising movement and posture while minimising potential secondary musculoskeletal deformity. This is dealt with by NICE guideline on spasticity in under\xa019s, which concentrates on the motor disorder of cerebral palsy.\n\nThe second aspect of management is recognising and intervening to address the many developmental and clinical comorbidities that are associated with cerebral palsy. This is the subject of this guideline, with particular focus on where there may be variation in practice and in patient and family experience across England and Wales. It looks at practical areas of management that are important to children and young people with cerebral palsy, their families and carers, and a wide variety of healthcare and other professionals. These include causation and recognition of cerebral palsy, prognosis and the associated developmental and clinical comorbidities.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Optimising nutritional status in children with cerebral palsy\n\nWhat is the clinical and cost effectiveness of early interventions for optimising protein, energy and micronutrient nutritional status in children with cerebral palsy?\n\n## Why this is important\n\nMost children with cerebral palsy have clinically significant oral motor dysfunction, and around 20% of children with cerebral palsy are undernourished. Provision of high-calorie and high-protein diets, either orally or via tube feeding, is well established to improve weight gain. Supplementation with micronutrients (such as vitamin\xa0D) is also necessary to ensure nutritional adequacy and prevent deficiencies. There is a lack of evidence about whether a more proactive approach to nutrition support in young children with cerebral palsy would improve growth and other aspects of clinical and developmental function. There is also insufficient evidence to determine whether higher intake of individual nutrients may have additional benefits; for example, there is emerging evidence that increased protein intake improves muscle strength, albeit in a different population (healthy older adults). A multicentre randomised controlled trial is needed that assesses the clinical and cost effectiveness of early interventions to optimise protein, energy and micronutrient nutritional status in this population.\n\n# Managing communication difficulties in children with cerebral palsy\n\nWhat is the clinical and cost effectiveness of interventions for managing communication difficulties in children with cerebral palsy?\n\n## Why this is important\n\nCommunication is an essential life skill that is recognised as a human right. Some children with cerebral palsy find communication difficult because they have little or no clear speech, resulting in social isolation. Alternative and augmentative communication (including signing, symbols, communication charts and computer-based speech generating devices) is now an established part of clinical practice, but the evidence base to inform good practice is very limited. Research evidence in this area is largely limited to single case studies, with a focus on acquisition of skills (for example, recognising symbols or making requests). A multicentre randomised controlled trial is needed to look at the effectiveness of interventions that include alternative and augmentative communication methods and carer training in improving the participation of children at different stages of communication development.\n\n# Recognition and early management of pain in children and young people with cerebral palsy\n\nDoes use of pain assessment tools by parents or carers improve the recognition and early management of pain in children and young people with cerebral palsy in a community setting?\n\n## Why this is important\n\nPain and discomfort are increasingly recognised as having a major impact on quality of life for children and young people with cerebral palsy and their parents or carers. A variety of assessment tools have been developed to quantify qualitative pain behaviours in children and young people with cerebral palsy who cannot communicate. The use of these tools in hospital to help identify signs and symptoms of pain and discomfort associated with specific interventions has become widespread. These tools may also help parents or carers recognise pain and discomfort in children and young people with cerebral palsy in community settings. Reducing pain and discomfort outside hospital is of clear importance to help with all aspects of quality of life, including learning, development and clinical wellbeing. A prospective cohort study is needed that looks at whether use of pain assessment tools by parents or carers improves the recognition and early management of pain.\n\n# Association between treating infections in pregnancy and rates of cerebral palsy\n\nWhat is the association between different antibiotic regimes to treat genito-urinary and respiratory tract infections in pregnant women and subsequent rates of cerebral palsy in children?\n\n## Why this is important\n\nTreating infection in pregnancy is of prime importance for the woman's health. In large population studies of pregnant women, chorioamnionitis, other genito-urinary infections and respiratory tract infections that result in admission to hospital are significant risk factors for the child being diagnosed with cerebral palsy. The mechanisms are uncertain, but include cytokine-induced damage to developing white matter leading to periventricular leukomalacia and sensitisation of the fetal brain to damage from hypoxia. A prospective multicentre study is needed that looks at the effects of different antibiotic regimes for treating genito-urinary infections in pregnant women on subsequent rates of cerebral palsy.\n\n# Prevalence of mental health problems in young people (up to the age of\xa025) with cerebral palsy\n\nWhat is the prevalence of mental health problems in young people (up to the age of\xa025) with cerebral palsy?\n\n## Why this is important\n\nA number of factors predispose young people with cerebral palsy to an increased risk of mental health problems, which will have a marked impact on their quality of life and challenges of care. However, there is a lack of evidence about the prevalence of such problems in this population. Improved guidance would allow greater access to suitable services for young people with cerebral palsy. In addition, given the link between mental and physical health, improvements in mental healthcare could potentially influence physical health and comorbidities. A prospective cohort study or cross-sectional study is needed that looks at the prevalence of mental health problems in this population."}	https://www.nice.org.uk/guidance/ng62	This guideline covers diagnosing, assessing and managing cerebral palsy in children and young people from birth up to their 25th birthday. It aims to make sure they get the care and treatment they need for the developmental and clinical comorbidities associated with cerebral palsy, so that they can be as active and independent as possible.
fb20bc2ac47aeb602d386be7379c0ec76ab6d61b	nice	Antimicrobial stewardship: changing risk-related behaviours in the general population	Antimicrobial stewardship: changing risk-related behaviours in the general population This guideline covers making people aware of how to correctly use antimicrobial medicines (including antibiotics) and the dangers associated with their overuse and misuse. It also includes measures to prevent and control infection that can stop people needing antimicrobials or spreading infection to others. It aims to change people’s behaviour to reduce antimicrobial resistance and the spread of resistant microbes. # Recommendations Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read in conjunction with NICE's guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. # Overarching principles The following recommendations are for directors of public health: Work with health and wellbeing boards, commissioners and local authorities to ensure that the following are a priority locally: the public health aspects of local antimicrobial stewardship programmes (see NICE's guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use) local system-wide infection prevention programmes. Ensure that: Local authorities and clinical commissioning groups work collaboratively to provide consistent information and advice to: the public healthcare professionals, including GPs, other prescribers and community pharmacists. Health and social care practitioners and organisations that commission, provide or support the provision of care are: aware of NICE's guideline on antimicrobial stewardship supported to implement it. # Local system-wide approaches to reducing inappropriate antimicrobial demand and use The following recommendations are for clinical commissioning groups. Ensure resources are available for healthcare professionals to use with the public to provide information about self-limiting infections. These resources should be used to encourage people to manage their infection themselves at home if it is safe to do so. The resources should include information on: How someone can recognise whether they, or someone they are caring for, have a self-limiting infection (for example, by checking the NHS website). How to seek further advice if they not sure whether their infection is self-limiting; for example, by: contacting a community pharmacy calling 111 or a local advice line or helpline using other local triaging arrangements such as practice nurses. Where to seek advice on managing self-limiting infections; for example, from: community pharmacists -ther reliable health resources, such as NHS Choices -ther local triaging services. The natural course of self-limiting infections, including the length of time symptoms are likely to last. How people can self-care (for example, by resting, drinking plenty of fluids and taking over-the-counter preparations to relieve their symptoms, if needed). Explicit advice on when to seek medical help, which symptoms should be considered red flags and safety-netting advice. Ensure resources and advice are also available for people who are prescribed or supplied with antimicrobials, to ensure they take them as instructed by their healthcare professional (see NICE's guideline on medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence). This should include taking the correct dose for the time specified and via the correct route. Ensure the resources advise people not to: Use or take prescription-only antimicrobials without a prescription and advice from a suitably qualified healthcare professional. Keep leftover antimicrobials for use another time. Share, or give, prescription-only antimicrobials to anyone other than the person they were prescribed or supplied for. Use or take antimicrobials prescribed for animals. Use or take prescription-only antimicrobials or give them to others if they have been obtained from anywhere other than their healthcare professional or pharmacist (for example, prescription-only antimicrobials bought online without a prescription). Ask for antimicrobials as a preventive measure against becoming ill or as a 'stand-by' measure; for example, when going on holiday (unless the person has a specific condition that makes this necessary or there is a specific risk; for example, if travelling to areas where malaria is endemic , or there is a high risk of travellers' diarrhoea). The following recommendations are for local authority public health teams. Consider linking to awareness-raising initiatives for the public on reducing inappropriate antimicrobial demand and use and antimicrobial resistance (for example, European Antibiotic Awareness Day and Public Health England's Antibiotic Guardian). Use opportunities that may arise through other local authority activities to distribute information about antimicrobial resistance (for example, waste disposal and recycling information could include advice not to flush leftover antimicrobials down sinks or toilets but to return them to a community pharmacy for safe disposal). # Local system-wide approaches to preventing and limiting the spread of infection For recommendations for clinical settings, see NICE's guideline on healthcare-associated infections: prevention and control in primary and community care. The following recommendations are for local authority public health teams. Ensure information and advice directed at the general public aims to prevent and reduce the spread of infections. Resources such as posters, leaflets and digital resources should be made available through multiple routes to provide a coordinated system of information. Ensure information is available in a variety of formats to meet people's literacy and language needs and the needs of people with sensory disabilities. Consider distributing information and advice through facilities and services operated by local authorities, such as leisure centres and libraries. When deciding where to distribute information, prioritise settings in which people are more vulnerable to infection or where there is a high risk of transmitting infection to others, for example: childcare settings residential and day care settings for older people. Give people information on handwashing that emphasises why it is necessary and effective to thoroughly wash and dry hands to reduce the risk of getting an infection, or passing infection on to their family and other people. Include information on: When hands should be washed and dried; for example, after using the toilet, before eating meals or snacks and after being in close contact with people with colds or other infections. How hands should be washed and dried, including the need to use liquid soap and tepid running water (a handrub can be used if soap and water are unavailable). See the section on standard principles in NICE's guideline on infection control. Use resources shown to be effective in helping people develop and use personalised plans to increase handwashing. (See the section on putting this guideline into practice for examples of resources that may be helpful). Give people advice on food hygiene and signpost them to resources. Include information on: Key points at which it is particularly important to thoroughly wash and dry hands (see recommendation 1.3.5); for example: before eating or preparing food after using the toilet or touching the bin before and after handling raw food. Safe food preparation and cooking methods (this includes ensuring food is cooked at the right temperature and properly heated throughout before eating). How to store food safely, including advice on: fridge temperatures 'use by' and 'best before' dates freezing, defrosting and refreezing food. Using food leftovers safely. See the Food Standard Agency's advice on food safety for more advice on food safety and how to prevent infections from spreading. # Childcare and education providers The following recommendations are for preschool settings. Display information or direct parents and carers to resources about managing the symptoms of infection in children, when to seek medical advice and the appropriate use of antimicrobials. Ensure there are always good standards of food hygiene (see the Food Standard Agency's advice on food safety). Provide facilities for thoroughly washing and drying hands for children, staff and visitors. These should include liquid soap and tepid running water, and handrubs when these are not available. Ensure staff talk to children about the importance of thoroughly washing and drying hands, including: explaining when to wash and dry hands (for example, after using the toilet and before eating) showing them how to wash hands with liquid soap and tepid running water (see the standard principles in NICE's guideline on infection control). Refer to Public Health England's guidance on infection control in schools and other childcare settings for details of how long children should be kept away from childcare when they have an infection. The following recommendations are for schools. Teach all children, in an appropriate way for their age and ability, about the need to reduce inappropriate antimicrobial demand and use. Use existing teaching resources if available (see the section on putting this guideline into practice for examples of resources that may be helpful). Promote a 'whole-school' approach to preventing infections from spreading. The school environment and staff should support children to act in a way that prevents or minimises infection. Ensure that there are always good standards of food hygiene (see the Food Standard Agency's advice on food safety). Provide facilities for washing and drying hands. These should include liquid soap and tepid running water, and handrubs if these are not available (see the standard principles in NICE's guideline on infection control). Refer to Public Health England's guidance on infection control in schools and other childcare settings for details of the length of time children should be kept away from school when they have an infection. Teach all children, in an appropriate way for their age and ability, about the importance of washing and drying hands to prevent infections and stop them from spreading. Discuss when and how hands should be washed. Use existing teaching resources if available (see the section on putting this guideline into practice for examples of resources that may be helpful). Consider giving children information to take home about when and how to wash their hands. Share information with parents and carers that can support their children's learning. This could include teaching their children how and when to wash their hands. Give parents and carers advice on other ways to help prevent infections. This should include advice on being up to date with vaccinations (see NICE's guideline on vaccine uptake in the general population) and preventing the spread of airborne infections. The following recommendations are for educational and residential settings for young people. Display information or direct young people to resources that aim to reduce inappropriate antimicrobial demand and use. The information should: Take into account that many young people will be managing infections on their own for the first time. Explain to young people how to recognise the signs and symptoms associated with a self-limiting infection, when they can safely self-care, how to do so and when they need to seek medical help (see recommendation 1.2.1 and information on the NHS website). Promote community pharmacies and minor ailment services, where they are available, as a source of advice and care (see the NHS information on how your pharmacist can help). Introduce a regularly repeated programme to improve young people's infection prevention knowledge and behaviour. Include: Posters promoting handwashing displayed in various locations, such as public areas of the campus, cafeterias, bulletin boards in halls of residence and public toilets. Signposts to online awareness-raising resources, with links to information on infection control (see the section on putting this guideline into practice for examples of resources that may be helpful). One-off events providing free handrubs. Food safety campaigns such as: face-to-face lectures education materials delivered via the web, including digital and social media promotional materials -ther ways to help prevent infections, such as advice on being up to date with vaccinations and preventing the spread of airborne infections. # Prescribers, primary care and community pharmacy teams This section should be read alongside the recommendations on prescribing (recommendations 1.1.24 to 1.1.37) in NICE's guideline on antimicrobial stewardship. See also NICE's guideline on sepsis: recognition, diagnosis and early management. When people ask about managing self-limiting infections: Share advice on self-care for each of the symptoms. Use and share resources that provide written advice to encourage people to change their behaviour (see recommendation 1.2.1). Verbally emphasise the key messages given in the written resources. Display resources that provide or signpost to advice and information about self-care; for example, the NHS website, 111 and local advice or helplines. Signpost them to further information to read at home, such as online advice. Discuss with them whether taking or using an antimicrobial is the most appropriate option (see the recommendation on discussions with patients and family members or carers under 'antimicrobial prescribing' in NICE's guideline on antimicrobial stewardship). Raise awareness of community pharmacists as an easily accessible first point of contact for advice about managing a self-limiting infection. Consider using computer prompts or decision support aids to prompt healthcare professionals to share information with people on the appropriate use of antimicrobials, self-care and safety netting (see NICE's guideline on antimicrobial stewardship). ## If antimicrobials are prescribed or supplied Share verbal advice and written information that people can take away (see recommendation 1.5.1) about how to use antimicrobials correctly, including: not sharing prescription-only antimicrobials with anyone other than the person they were prescribed or supplied for not keeping them for use another time returning unused antimicrobials to the pharmacy for safe disposal and not flushing them down toilets or sinks. If the person has been given a back-up (delayed) prescription, tell them: How to self-care to manage their symptoms. What the antimicrobials would be used for, if needed. How to recognise whether they need to use the antimicrobials, and if so: how to get them when to start taking or using them how to take or use them. ## If antimicrobials are not prescribed or supplied Give people verbal advice and share written information that they can take away about how to manage their infection themselves (see recommendation 1.5.1). ## General advice in primary care and community pharmacies Share safety-netting advice with everyone who has an infection (regardless of whether or not they are prescribed or supplied with antimicrobials). This should include: how long symptoms are likely to last with and without antimicrobials what to do if symptoms get worse what to do if they experience adverse effects from the treatment when they should ask again for medical advice. # Terms used in this guideline ## Antimicrobial resistance Loss of effectiveness of any anti-infective medicine, including antiviral, antifungal, antibacterial and antiparasitic medicines. ## Antimicrobial stewardship An organisational or healthcare system-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness. ## Capability, opportunity and motivation A theory of behaviour change that can guide interventions to change individual behaviour patterns. For any change in behaviour to occur, a person must: be physically and psychologically capable of performing the necessary actions have the physical and social opportunity to make the change be more motivated to adopt the new, rather than the old behaviour, whenever necessary. This is known as the COM-B model (see the behaviour change wheel: a new method for characterising and designing behaviour change interventions Michie et al. 2011). ## Handrub A preparation applied to the hands to reduce the number of viable microorganisms. This guideline refers to handrubs compliant with British standards (BS EN1500; standard for efficacy of hygienic handrubs using a reference of 60% isopropyl alcohol). ## Inappropriate antimicrobial demand and use 'Inappropriate antimicrobial demand' refers to people asking for antimicrobials for conditions against which they are ineffective (for example, antibiotics to treat a viral infection such as a cold) or for self-limiting infections that will resolve on their own, with no long-term harm to the person's health. 'Inappropriate antimicrobial use' refers to the way in which people may misuse antimicrobials that they have been prescribed or supplied with, and which may result in the antimicrobials becoming ineffective in treating infections. This is because the bacteria, virus, fungus or parasite they are designed to treat may become resistant to the antimicrobial. Examples of inappropriate use include not taking or using the antimicrobials as prescribed and sharing them with others. ## Local triaging arrangements Services that can advise people whether they have a self-limiting infection that they can safely manage themselves or whether their infection needs medical attention. Examples include community pharmacies, practice nurses, 111, other locally developed advice and helplines, and emergency and out-of-hours primary care services. ## Red flags Signs and symptoms of a more serious illness or condition. ## Resources Evidence-based materials that have been developed through a research-based approach with the target audience, wherever possible. They may be in a variety of formats, including posters, leaflets, digital and online resources. ## Safety-netting advice Advising people what to do if their condition deteriorates or does not improve within a certain time, or if they develop adverse effects as a result of the treatment. ## Self-care Approaches a person can use to look after themselves in a healthy way; for example, drinking plenty of fluids and getting sufficient rest when you have a cold. ## Self-limiting infection An infection that resolves on its own and has no long-term harmful effect on a person's health (assuming that they are not immunosuppressed). Examples include colds, flu, oral thrush, winter vomiting bug.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Examples of other resources that may be helpful include the University of Southampton's Germ Defence (see recommendation 1.3.5) and UK Health Security Agency's e-Bug website (see recommendations 1.4.6, 1.4.11 and 1.4.16). Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Antimicrobial stewardship refers to an organisational or healthcare-system-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness. Antimicrobial resistance may lead to standard treatments becoming ineffective, causing infections to persist and increasing the risk of them spreading. Although resistance evolves naturally, the use (and misuse) of antimicrobials speeds up this process. Inadequate infection prevention and control practices, poor sanitary conditions and inappropriate food handling encourage the spread of infections that may need the use of antibiotics. Improvements in nutrition, hygiene and sanitation, and reductions in overcrowded housing, have all helped prevent and decrease the transmission of infectious diseases (Davies SC The drugs don't work. A global threat. London: Penguin). The World Health Organization estimates that, along with these broad environmental factors, antimicrobials add on average 20 years to life expectancy (Self-prescription of antibiotics boosts superbugs epidemic in the European region). But antimicrobial resistance is increasing and there is a lack of new antimicrobials to treat resistant diseases. It is important to ensure the antimicrobials that are currently effective remain so for as long as possible. Infectious diseases are a major cause of illness in the UK. In 2013, for example, 21% of all days lost at work (approximately 27 million days) were caused by coughs, colds and flu and other infectious diseases (Office for National Statistics' Sickness absence in the labour market: February 2014). The incidence of infectious disease tends to be higher in groups with lower socioeconomic status and outcomes tend to be poorer. For example, they are more likely to have tuberculosis, transmit it to others and to have a drug-resistant strain (Department of Health's Annual report of the Chief Medical Officer 2011: volume 1). Although viruses (such as HIV), parasites (such as malaria) and fungi (such as Candida) are showing resistance to antivirals, antiparasitics and antifungals respectively, for the general population antibiotic resistance is the main concern. However for some population subgroups, resistance to antivirals and antifungals may be of equal concern. This includes people who are particularly vulnerable to infection due to supressed immune systems; for example, because of HIV, an inherited condition or treatment they may be having for conditions such as cancer or an organ transplant. In the UK, the spread of multidrug-resistant tuberculosis and gonorrhoea is also of public health concern (see the 'Annual report of the Chief Medical Officer 2011: volume 1'). National campaigns to raise public and professional awareness of antibiotic resistance may reduce antibiotic prescribing and demand (Department of Health's European antibiotic awareness day 2013 evaluation report). But a 2013 survey of 2,033 people in the UK by Ipsos MORI (Antibiotics: a cure for the common cold?) showed that: % wrongly believe antibiotics work on colds or flu around 40% think antibiotics can kill viruses around 7% do not complete a course of antibiotics. There is also evidence that most people who ask a healthcare professional for antibiotics to treat a cough are given them (Antibiotic prescribing for acute cough: the effect of perceived patient demand Coenen et al. 2006). For details on UK policy, see the scope for this guideline.# The committee's discussion This section describes the factors and issues the public health advisory committee considered when developing the recommendations. Please note: this section does not contain recommendations (see the recommendations section). # Background The committee recognised that the threat of antimicrobial resistance can only be tackled by a combination of interventions and measures that address: the prescribing decisions of healthcare professionals people's behaviour relating to infection prevention and control, antimicrobial use and antimicrobial resistance surveillance to track antimicrobial use and resistance in microbes the development of new drugs, treatments and diagnostics antimicrobial use in animal husbandry political commitment to prioritise antimicrobial resistance as a major area of concern for the UK and globally. Changing when and how people use antimicrobials and changing their behaviour to prevent infection helps to keep current medicines effective for as long as possible. But action is also needed by prescribers, dispensers and regulators. The committee noted the importance of ensuring sustained action is taken to reduce antimicrobial resistance. It emphasised that antimicrobial resistance is a long-term problem. It noted that at publication of this guideline, the UK will be 3 years into the UK 5-year antimicrobial resistance strategy 2013 to 2018. The committee reflected on NICE's guideline on antimicrobial stewardship, which covers prescribers' knowledge and behaviour. It wanted to ensure the 2 guidelines complement each other and are read together. It also wanted to ensure interventions that target both the public and prescribers are included in this guideline if they are not already covered in the related antimicrobial stewardship guideline. That is because, otherwise, the committee felt that evidence of effectiveness on these interventions may be missed. The committee also noted that NICE's guidelines on behaviour change: individual approaches, medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes and vaccine uptake in the general population are all relevant to changing knowledge about use and misuse of antimicrobials. # The evidence base – limitations The committee made some recommendations for interventions for which the evidence from the reviews is limited. The committee recommended that clinical commissioning groups provide information to encourage people to manage self-limiting infections at home, if it is safe to do so, to reduce inappropriate antimicrobial demand and use. These recommendations are based on: evidence from expert papers committee members' combined expertise and experience comments received during stakeholder consultation. The committee also made recommendations for primary care teams and community pharmacies about reducing inappropriate antimicrobial demand and use. It agreed that it was important to make recommendations in this area to support and complement those in NICE's guideline on antimicrobial stewardship. The evidence for review 1 was weak and inconsistent, so members also drew on expert papers and their own expertise and experience. The recommendations support existing good practice in this area. Members considered that there are some simple and practical steps that can help prevent the spread of infection and reduce the threat of antimicrobial resistance, and cause no anticipated harm. Examples include: ensuring hands are thoroughly washed and dried before eating meals or snacks advice on storing food and using leftovers safely avoiding flushing unused antimicrobials down sinks or toilets. In taking this pragmatic approach they have drawn on good practice, standard advice from respected sources and their collective expertise, in addition to the published evidence. In considering the cost effectiveness of interventions in this area, the committee have drawn on the 'precautionary principle' (see the section on health economics; principle 15 of the United Nations Global Impact's Rio Declaration on Environment and Development). The precautionary principle is a conservative principle. The conservative approach is to assume that the intervention should be used unless it can be shown with sufficiently high probability that it does more harm than good. # Evidence – effectiveness review The committee found little good-quality published evidence about the effectiveness of interventions to change risk-related behaviours in the general population (review 1). Study methods were often not well reported or had potential biases that may have significantly affected results. This is reflected in the quality ratings for studies, with the majority rated as weak, 12 rated as moderate and none as strong. The committee questioned whether the studies were underpowered (had too few participants) to detect any significant differences. It also questioned whether the effect sizes could be pooled for meta-analysis, but this was not possible because of the diversity of the study outcomes. Most studies measured knowledge rather than behaviour, and when behaviour was measured it was often self-reported rather than observed. The committee noted that behaviour change needs to be the goal of any intervention, and that changes in knowledge do not necessarily lead to changes in behaviour. It agreed that more research is needed to evaluate changes in behaviour (see the recommendations for research section). The way people's knowledge was measured differed between studies and the committee questioned the validity of the measures. Some studies only reported an overall 'knowledge score' for a particular topic. Some used different measures to evaluate an outcome. For example, statements to classify as 'true' or 'false' on handwashing ranged from: "you need to wash your hands after playing in the garden" to "you need to wash your hands after coughing". So an overall score described as 'knowledge of hand hygiene' may be a compilation of different knowledge measures and may not be comparable between studies. In some studies, the baseline levels of knowledge were high. This may have left little room for improvement. Other studies report significant changes, but with the overall level of knowledge remaining low. So an 'effective' result may not be 'clinically significant' (it may not demonstrate a meaningful difference). There was also a lack of long-term follow-up of changes in knowledge or behaviour. The focus of the review was on changing risk-related behaviours, so changes in antimicrobial resistance was not a selected outcome measure and the review did not report it. The committee discussed why some studies that measured only prescribing rates as an outcome were excluded. The rationale was that prescribing is under the control of the prescriber, not the patient. Without any direct measure of patients' knowledge or behaviour (for example, changes in consultation rates) it is not possible to determine whether changes in prescribing were caused by changes in patients' or prescribers' behaviour. But the committee felt that if an intervention solely targeted patients or the public, then prescribing rates may be a reasonable outcome measure. This is because changes in patient behaviour may affect doctors' prescribing habits. As a result, supplementary reviews were carried out. # Supplementary evidence reviews NICE carried out another evidence review (review 2) to look at studies that were excluded from the effectiveness review. These studies targeted patients or the general public only and measured antibiotic prescribing rates. Papers previously excluded because they reported only the incidence of infection were also included in the review, because changes in infection incidence after an intervention may be due to changes in behaviour. Ten studies were included in the review, 3 of which were good quality, 5 moderate quality and 2 weak. ## Antibiotic prescribing The review showed that evidence on the effectiveness of parental education interventions for reducing antibiotic prescribing for children's respiratory tract infections in primary care is inconsistent. Three US studies found no effect, and the 1 UK study found a significant decrease in antibiotic prescribing. The interventions all involved written materials but differed in format, content, additional components and mode of delivery. Baseline prescribing levels also differed between studies. The committee noted that the 1 effective study involved training GPs to discuss written materials with parents, and to give them information on prognosis, treatment options and reasons for re-consultation (warning symptoms to look out for). The committee also noted that an educational intervention based in primary care may be effective in reducing antibiotic prescribing for respiratory tract infections in adults under 65. But this was not the case for older adults. It noted that GPs (and older patients) may think that older people face greater health complications, so GPs may be more likely to prescribe antimicrobials. The committee noted the importance of ensuring interventions are designed to address the beliefs of particular groups such as older adults. ## Hand hygiene Five studies (2 good quality, 1 moderate and 2 weak) measured changes in the incidence of infection. These all focused on hand-hygiene interventions. Three of these studies (1 good quality, 1 moderate and 1 weak) were based in childcare settings. The good-quality study reported that changes to hand hygiene did not reduce the incidence of respiratory or gastrointestinal illnesses but could reduce the transmission of a gastrointestinal illness to other family members. Committee members noted that there was 1 good-quality UK study of a bespoke web-based intervention. This reduced the incidence of respiratory illnesses. The committee heard expert testimony that gave further detail about the web-based intervention to promote handwashing. This included motivational messages that explain how infection can be transmitted by hand and how hand hygiene can reduce the risk of infection in oneself and one's family. It also included an interactive tool that aims to translate knowledge into changes in behaviour through a personalised planner to help people to identify situations during the day when they could increase handwashing. The committee also agreed that it is important to give people the opportunity to change (for example, by providing handwashing facilities). ## Multi-targeted interventions NICE's public health team carried out a rapid review of systematic reviews (review 3) that: evaluated the effectiveness of educational interventions on the public's knowledge and behaviour in relation to antimicrobial use or antimicrobial resistance targeted both the public and healthcare professionals. The committee noted that these multi-targeted interventions did improve people's knowledge of appropriate antimicrobial use (specifically in relation to antibiotics) and did reduce antibiotic prescribing for respiratory illnesses. However, it was not possible to determine whether it is better to provide support to help change someone's behaviour alone, support for changing healthcare professionals' behaviour alone, or a combination of both. Nor was it possible to determine which components of interventions were more effective than others. As for the main review, the focus of this supplementary review was on changing knowledge and behaviour. Change in antimicrobial resistance was not selected as an outcome measure. Although 4 of the 9 included reviews did report changes in antibiotic resistance as an outcome, the results were mixed. Because this outcome was not actively sought, and there were only a limited number of studies, it would be inappropriate to draw any conclusions about the effect of these interventions on antimicrobial resistance. # Action for both prescribers and the public The committee was conscious that to reduce inappropriate antimicrobial demand and use, changes in the behaviour of both prescribers and the public are necessary. It stressed the importance of this guideline being implemented alongside the recommendations for prescribers in NICE's guideline on antimicrobial stewardship. The committee noted evidence identified by review 3 that multi-component, educational interventions that target both clinicians and patients or the public are effective at reducing antibiotic prescribing for self-limiting infections. This evidence did not allow members to determine whether it is better to target patients' behaviour alone, healthcare professionals' behaviour alone or a combination of both. However, they heard expert testimony that drew on additional studies of public information campaigns to reduce antimicrobial resistance. The findings of these studies of repeated 'through the line' campaigns (those that include using mass media such as television and internet as well as leaflet and poster campaigns) have shown some substantial reductions in antibiotic prescribing. But these were often delivered alongside locally targeted community activities, including those focused on prescribing practice by healthcare professionals. The committee noted from this testimony that improved antimicrobial stewardship was most likely to be achieved through interventions that are: strategically coordinated focused on both reducing inappropriate antimicrobial demand and use and preventing and limiting the spread of infection delivered at national and local level aimed at both the public and health professionals. Members noted that directors of public health have an important role to play in working with health and wellbeing boards, commissioners and local authorities to ensure that the following are a priority: public health aspects of local antimicrobial stewardship programmes local system-wide infection prevention programmes. They made a recommendation to this effect (see recommendation 1.1.1). # Population groups and settings The committee noted that in the evidence reviews, interventions targeted specific age groups and life stages. It felt this was a useful way to frame the recommendations. In addition, educational interventions for school-aged children (such as UK Health Security Agency's e-Bug website) often combine teaching about antibiotic use, antimicrobial resistance, handwashing and food hygiene. It decided that these should also be combined in the recommendations. The committee made recommendations in section 1.4 for: preschool settings schools education and residential settings for young people. Preschool and school settings were considered important by the committee because of the high rate of infection in young children and the transmission of infection between them. Although the committee was unable to make recommendations about environmental cleanliness, because this was outside the scope of the guideline, it noted the importance of keeping the environment, facilities and equipment clean. In making recommendations for schools it was keen to take a whole-school approach in which both the environment and teaching support the desired behaviour. The committee noted that young people aged 16 to 24 are some of the highest users of antibiotics. They also misuse antibiotics more than any other age group, in particular through sharing them with others. The committee noted that young people in this age group who have recently moved away from home may not have previous experience of looking after themselves during a self-limiting illness. It noted that this should be considered when offering them advice. People over 65 are the other group that use the most antibiotics. In addition, they may be more vulnerable to infection due to having chronic conditions. People in day or residential care may also be at greater risk of infection being transferred from others. The committee noted the importance of interventions that target these age groups. But although evidence was identified for interventions in preschool, school and university settings, none was identified in settings focusing on older people, including those in day or residential care. The committee therefore noted the need for further research in older age groups, along with studies focusing on populations whose social and economic circumstances or health put them at greater risk of getting or transmitting infectious diseases and antimicrobial-resistant strains. Most interventions took place in healthcare or education settings. Healthcare interventions mainly took place in primary care, but some were in A&E or pharmacies. Other settings included homes and the wider community; for example, targeting the general public via mass media or web-based interventions. The committee was concerned that there were no interventions in the workplace or social care, other than preschool settings. It discussed whether it was possible to generalise findings from preschool settings to other social care settings. Members agreed that the aim of the intervention would be the same. But there was no evidence on how interventions could be effectively delivered in these alternative settings and to different population groups. The committee also noted that the reviews looked only at educational interventions, but there may be other types of intervention that focus on these populations. # Antimicrobials and antimicrobial resistance – knowledge and behaviour The committee noted that most studies focused on improving knowledge of antibiotics rather than antivirals, antifungals or antiparasitics. Interventions usually focused on reducing unnecessary antibiotic use for self-limiting respiratory illnesses (colds and flu). There is growing concern about the increase in antimicrobial resistance to common treatments, particularly in bacteria that cause urinary tract infections (for example, Escherichia coli resistance to third-generation cephalosporins and fluoroquinolones). The committee noted that educational interventions did not tend to improve knowledge of antimicrobial resistance and its implications. The committee agreed that focusing messages on the effects on the whole population was unlikely to lead to changes in behaviour. But making the messages relevant to individual people could be effective. Messages could include the fact that losing effective treatments could directly affect someone's own health, or the health of those close to them. The committee also felt that it is important to get across the fact that you do not have to feel unwell to carry an antimicrobial-resistant organism (for example, you could be a carrier of multi-drug resistant E. coli without having symptoms). It agreed that the fact that someone can spread an antimicrobial-resistant infection to others is a key message. The committee noted that interventions to prevent infection have been shown to be more effective during epidemics. This is because people are more likely to act in a way to prevent or minimise the spread of infection if they can see it may help them. The committee discussed the importance of creating a cultural shift and changing social norms so that people use antimicrobials responsibly. The committee felt that self-care needs to become the 'easy choice' for people. It noted the importance of raising awareness of where to seek advice on managing a self-limiting infection; for example, community pharmacists and other reliable health resources such as the NHS website. It saw the role of the community pharmacist as very important. However, it noted that there are also cost considerations for people, because prescribed medicines may be cheaper than over‑the‑counter medicines, or free for some. The committee discussed the importance of people knowing the natural course of an illness – with and without using antimicrobials – and that there is often very little difference in recovery times. The committee also discussed other ways to improve motivation, such as increasing people's confidence in the effectiveness of over‑the‑counter preparations to manage the symptoms of self-limiting illnesses, taking into account recommendations for specific populations such as the Medicines and Healthcare products Regulatory Agency's advice on over-the-counter cough and cold medicines for children. The committee noted the importance of consistency in the advice people receive from different sources, such as GPs and community pharmacists. The committee discussed the possible unintended consequences of interventions that aim to reduce inappropriate antimicrobial demand and use. It noted that people need to know the warning signs (or red flags) that indicate they should seek help from a healthcare professional and that they should be given advice about what to do if their condition becomes worse or if, when antimicrobials are prescribed, they experience adverse effects from the treatment (safety-netting advice). It also did not want to deter the prudent and appropriate use of antimicrobials. The practice of back-up (delayed) prescribing was discussed as a strategy that is increasingly used to reduce antimicrobial use. The committee noted the importance of people being aware of the circumstances that indicate they should start to take the antimicrobial and how to do so. The committee noted the potential cost benefits to the NHS of interventions that reduce GP consultation rates. There was also evidence that primary care interventions, such as providing information on antibiotic use, can increase people's knowledge of when and how to use antibiotics. Although leaflets alone led to improvements in knowledge among adults, this was not the case for parents of young children. There was evidence for both population groups that leaflets, in combination with structured discussion either face-to-face or via a video presentation, improved antibiotic knowledge and behaviour. The committee noted that most healthcare interventions took place in general practices. There were only 2 studies in pharmacies and 1 in an A&E setting. The committee discussed the importance of ensuring people receive the right information at the right time and in a format that meets their language and literacy needs. It discussed providing information at the following points: before going to see a GP (getting information online or visiting a pharmacy) while waiting for a GP or hospital consultation during a consultation. Education on antibiotic use and antimicrobial resistance in schools was more likely to be effective if students were given this information directly while they were in class or by taking part in practical activities rather than through computer games, mass media campaigns and videos alone. However, the committee noted that there were no direct comparisons of these different types of school activity. There were also some methodological issues with studies of self-learning that did not show a significant effect. A lack of significant intervention effect could be due to the studies being insufficiently powered, or because the intervention needs to be further developed. For example, UK Health Security Agency's e-Bug computer game was made a tedious rather than 'fun' experience by making children complete all levels of the game in a single sitting (hence the low completion rate). Because of these methodological issues, the committee warned against assuming that such interventions are not effective. Expert paper 1 reports on the public's awareness and understanding of appropriate antibiotic use, prescribing and antibiotic resistance in the UK. The qualitative evidence identified core behaviours that could reduce people's use of antibiotics for a self-limiting infection: self-care or getting advice from a community pharmacist for colds, runny nose or flu and other self-limiting infections not requesting antibiotics at a GP appointment acting on advice given by their GP or other prescriber if antibiotics are not prescribed immediately. This is known as back-up (or delayed) prescribing. The qualitative evidence was categorised in relation to the capability, opportunity and motivation model of behaviour (COM‑B). The model was also used as a theoretical basis for proposing areas that could potentially be effective in changing people's behaviour. The committee noted that this model is recommended in NICE's guideline on behaviour change: individual approaches and is relevant to how interventions for infection prevention and antimicrobial use are designed and delivered. # Points of receptiveness and types of information The committee noted that people may be more receptive to information about reducing inappropriate antimicrobial demand and use and preventing and limiting the spread of infection if: they (or a family member) are ill, or particularly vulnerable to infection, or they perceive that there is a particular risk of illness; for example, during an outbreak of flu. Committee members highlighted that the information and advice given by health professionals at these points differs from 'general public information' about reducing inappropriate antimicrobial demand and use and preventing and limiting the spread of infection. The committee heard expert testimony on the varying roles and remits of different agencies that might be involved in providing such information. Members made recommendations for both clinical commissioning groups (on ensuring information and resources are available for people seeking advice about managing self-limiting infections) and local authorities (on raising awareness of the need to reduce inappropriate antimicrobial demand and use and preventing and limiting the spread of infections). # The role of community pharmacists The committee heard expert testimony on the role of community pharmacists. Members noted that community pharmacists are often under-used by the public and were keen to promote them as an easily accessible first point of contact for people seeking advice on managing self-limiting infections. Members recognised the important stewardship role community pharmacists play in relation to local antimicrobial prescribing policy and noted the close collaboration between community pharmacists and GP practices in this area. The committee noted the potential for similarly close collaboration in promoting self-care for managing self-limiting infections. # Mass-media campaigns The committee noted that although mass-media campaigns could raise the profile of antimicrobial resistance and correct use of antibiotics, they had only a small impact on people's knowledge and behaviour. There was some evidence from the effectiveness review that these campaigns can increase parents' knowledge of antimicrobial resistance and reduce their desire for antibiotics for their child. But only if they are combined with direct communication from healthcare professionals and staff at childcare centres, and with the education of healthcare professionals. The committee discussed expert paper 2. This reported the impact of international and national awareness-raising campaigns on people's knowledge of appropriate antimicrobial use and antimicrobial resistance. It also reported how people, as a result, changed their behaviour in relation to antibiotics. # Educational modules delivered by computers and websites In the effectiveness review, evidence statements about using educational modules delivered through computers and websites were also based on only 1 or 2 studies. The committee therefore decided to look at the antimicrobial use, resistance and infection prevention studies to determine whether education delivered via computer and websites does help change knowledge or behaviour. It concluded that educational modules delivered this way could help reduce inappropriate expectations of antibiotics and improve food safety knowledge and hand hygiene. However, members believed that the key to success was not the format of delivery, but the content and quality of the intervention. The committee noted that interventions need to go beyond raising knowledge and awareness. It discussed the need to give people the motivation to change and the tools to help them to start behaving differently. # Preventing infection The committee noted that the effectiveness review had no studies on interventions designed to improve behaviour when coughing and sneezing (such as using and disposing of tissues). So it could not make any recommendations in this area. Recommendations could be made only on hand hygiene and food hygiene interventions. These are for local authorities and for preschool settings, schools and educational and residential settings for young people. While the evidence for young people was from university settings, the committee felt it was transferrable to other similar educational and residential settings for this age group. Most of the evidence from the reviews considered by the committee was weak or inconsistent. But these recommendations support and signpost people to existing good practice advice issued by other national agencies, such as Public Health England and the NHS website. The committee also noted the importance of infection prevention activities that were outside the scope of the guideline such as vaccination programmes and promoting safer sex. The majority of studies of hand hygiene took place with children and young people in preschools, primary and secondary schools and university settings. They indicated that it is possible to improve young children's handwashing behaviour through interactive education, including instruction and use of handwashing training kits. The committee noted the importance of teachers being role models for preventing the spread of infection. It also noted the importance of providing the right facilities and the opportunity to support children to prevent or minimise the spread of infection (for example, by providing liquid soap and tepid running water or handrubs if these are not available). As with the studies on antibiotic use and antimicrobial resistance, the evidence on the effectiveness of hand-hygiene education (based on use of UK Health Security Agency's e-Bug website) was mixed. The committee noted that a possible reason was the high level of existing knowledge before the start of an intervention in some of the study populations. The committee was concerned that some may misinterpret this finding and wrongly believe that education in schools was not needed. It felt that education in schools was vital, particularly among students who have little or no knowledge of antibiotics. In addition, it agreed that handwashing behaviour is a habitual practice that, if established when young, is more likely to continue throughout life. The committee agreed that the combination of education and provision of handrubs may lead to improvements in handwashing behaviour in some populations. For example, there was weak evidence for the effectiveness of providing handrubs along with information posters to university students, and for educational interventions in which people were given handrubs to use at home. Food hygiene interventions were more likely to be targeted at high-risk groups. The studies found were mostly in the US and were community based. Many focused on improving people's knowledge and behaviour about chilling, cooking and washing food. They targeted adults and young people, including: young people in inner cities parents with low incomes women who were pregnant or caregivers -lder people with a high school education or less -lder women Latino communities (people of Latin American origin or descent living in North America). There were very few studies of educational interventions for schoolchildren on food safety knowledge or practice and the findings were inconsistent. The committee noted that some food safety interventions appeared to improve food safety knowledge and practices in the short term. These were: food safety campaigns delivered to university students mass-media campaigns targeting adults or parents campaigns delivered through traditional or social media. # Using resources effectively The committee heard expert testimony about the broad and diverse range of national evidence-based resources that are available. These focus both on reducing inappropriate antimicrobial demand and use and on preventing and limiting the spread of infection. The committee noted some resources provide information directly to the public in a variety of formats such as videos, posters, leaflets and websites. There are also resources specifically designed to support discussions between people seeking advice on managing self-limiting infections and prescribers and other professionals (such as community pharmacists) who may talk to people about using antimicrobials. The committee noted the importance of using or directing people to resources that have been developed through a research-based approach with the target group wherever possible. This ensures consistent, evidence-based messages and an effective use of resources. Members also noted the importance of ensuring resources are used effectively. Expert testimony distinguished between using resources passively (for example, displaying posters or leaving leaflets in GP waiting rooms or community pharmacies) and actively referring to them in discussions with people. The committee noted the importance of actively sharing resources to support shared decision-making about whether antimicrobials are prescribed. It also noted the potential for using such resources as a tool to convert knowledge into intention to change behaviour and to actual change in behaviour. This is reflected in the recommendations that stress the importance of verbally emphasising key messages in written materials and directing people to further information they can read at home. # Health economics Infections and infectious diseases in England cost the NHS an estimated £30 billion per year. Many of these costs are caused by respiratory or gastrointestinal infections (Department of Health's Annual report of the Chief Medical Officer 2011: volume 2). The economic costs of antimicrobial resistance are largely unknown (World Health Organization's Antimicrobial resistance: global report on surveillance 2014). The loss of many of the advances in medical care that antimicrobials have supported will be the main economic burden of antimicrobial resistance. Extremely large economic losses would almost certainly occur if all antimicrobials were rendered ineffectual in the future, even without taking into account the impact on health. So finding ways to delay this will almost certainly be cost effective. However, this cannot be confirmed by modelling because a model would need to be based on assumptions that are not evidence-based. The committee agreed that the 'precautionary principle' could be applied. This is about avoiding or delaying catastrophes by ensuring effective measures are in place. In such circumstances, the burden of proof in relation to effectiveness is on those who do not wish to put precautionary measures in place. In the case of antimicrobial resistance, interventions to reduce the spread of resistance could be assumed to be effective unless there was sufficient proof that such interventions are not needed. Given that it is most unlikely that the effectiveness of such interventions can be disproved, we also need to determine whether a package of such measures is cost effective compared with no intervention. The rules of decision theory for cost effectiveness no longer apply when analysing antimicrobial stewardship. The effects of antimicrobial resistance are so pervasive that it can be assumed the public sector will no longer act as if they were risk-neutral in assessing an intervention but will be risk averse. The scale of the risk of antimicrobial resistance and the complexity of the issue implies that a package of interventions will be needed. The composition of the most cost effective package cannot be determined because of the limitations in the evidence base, but educational components that are cheap and have a potentially large reach are likely to be highly cost effective. # Evidence reviews Details of the evidence discussed are in the evidence reviews. The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. Evidence statement (ES) number 1.1(1) indicates that the linked statement is numbered 1 in review 1 and relates to key question 1. ES1.1(2) indicates that the linked statement is numbered 1 in review 1 and relates to key question 2. ES2.1(1) indicates that the linked statement is numbered 1 in review 2 and relates to key question 1. EP1 indicates that expert paper 1 'Behaviour change and antibiotic prescribing in healthcare settings: Findings from a literature review and behavioural analysis' is linked to a recommendation. EP2 indicates that expert paper 2 'The effectiveness of local and national campaigns in changing the public's behaviour to ensure they only ask for antimicrobials when appropriate and use them correctly' is linked to a recommendation. If a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1.1.1: ES3.2(1); EP3, EP7; IDE Recommendation 1.1.2: ES3.2(1); EP3, EP7; IDE Recommendation 1.2.1: EP1, EP3; IDE Recommendation 1.2.2: EP3; IDE Recommendation 1.2.3: EP1, EP2; IDE Recommendation 1.2.4: EP2, EP3, EP7; IDE Recommendation 1.2.5: EP3; IDE Recommendation 1.3.1: IDE Recommendation 1.3.2: IDE Recommendation 1.3.3: EP3; IDE Recommendation 1.3.4: IDE Recommendation 1.3.5: ES1.8(2), ES1.9(2), ES1.10(2), ES1.11(2), ES2.3(2); EP6; IDE Recommendation 1.3.6: ES1.1(3), ES1.4(3); IDE Recommendation 1.4.1: ES1.10(1); IDE Recommendation 1.4.2: IDE Recommendation 1.4.3: IDE Recommendation 1.4.4: ES1.4(2), ES2.1(2) Recommendation 1.4.5: IDE Recommendation 1.4.6: ES1.9(1); IDE Recommendation 1.4.7: IDE Recommendation 1.4.8: IDE Recommendation 1.4.9: IDE Recommendation 1.4.10: IDE Recommendation 1.4.11: ES1.6(2), ES1.7(2), ES2.2(2); IDE Recommendation 1.4.12: IDE Recommendation 1.4.13: IDE Recommendation 1.4.14: IDE Recommendation 1.4.15: EP1, EP4; IDE Recommendation 1.4.16: ES1.4(3), ES1.8(2), ES1.9(2); IDE Recommendation 1.5.1: ES1.1(1), ES1.2(1), ES1.4(1); EP1, EP4, EP5 Recommendation 1.5.2: IDE Recommendation 1.5.3: ES1.3(1), ES1.7(1); EP1, EP5; IDE Recommendation 1.5.4: ES1.5(1); IDE Recommendation 1.5.5: ES1.3(1), ES1.5(1); EP1, EP5; IDE Recommendation 1.5.6: IDE # Gaps in the evidence The committee's assessment of the evidence and stakeholder and expert comment on antimicrobial stewardship identified a number of gaps. These gaps are set out below. . A lack of studies on the feasibility and effectiveness of interventions to change people's behaviour in relation to using antimicrobials for conditions other than respiratory illnesses. (Source: evidence reviews 1, 2 and 3) . A lack of studies looking at people in diverse social, cultural and economic circumstances. (Source: evidence review 1) . A lack of studies evaluating the effectiveness of interventions to change people's behaviour relating to antimicrobial use, antimicrobial resistance or infection prevention in workplace settings. (Source: evidence review 1) . A lack of studies evaluating the effectiveness of interventions to change people's behaviour relating to antimicrobial use, antimicrobial resistance or infection prevention in day and residential care settings for older people. (Source: evidence review 1) . A lack of studies with robust measures of cost effectiveness. (Source: evidence review 1)# Recommendations for research The guideline committee has made the following recommendations for research to reduce antimicrobial resistance. # Cost effectiveness What is the cost effectiveness of interventions to prevent infection and promote the appropriate use of antimicrobials? ## Why this is important Lack of studies reporting the costs associated with interventions for either infection prevention or antimicrobial use may act as a barrier to their implementation. Studies with high quality research designs and appropriate cost effectiveness measures are needed to assess this. If research funding bodies ensure cost effectiveness measures are included in research, this will provide the data needed to support the analysis of cost effectiveness. # Behavioural strategies and programmes What is the feasibility and effectiveness of specific behavioural strategies and programmes to reduce inappropriate antimicrobial demand and use and to prevent infections occurring and spreading? ## Why this is important Although the committee has based its recommendations on the best available evidence, little good-quality published evidence was found about the effectiveness of interventions to reduce antimicrobial resistance and prevent the spread of infection. Better quality studies are needed in this area. # High-risk groups What interventions to prevent infection and reduce antimicrobial resistance are effective for groups of people at high risk of infection? This includes people who: have suppressed immune systems (for example, because of HIV, an inherited condition or treatment they may be having for conditions such as cancer or an organ transplant) have a chronic disease live in crowded conditions (see Shelter's definition) are homeless have been in prison have migrated from countries with a high prevalence of infectious diseases such as tuberculosis (examples include South Asia and sub-Saharan Africa). ## Why this is important Most interventions have not been designed for people at high risk of acquiring or transmitting infectious diseases and antimicrobial-resistant strains. Interventions for these groups have focused on reducing the use of antibiotics for respiratory illnesses. More interventions are needed to address antimicrobial use for other high-risk conditions. Interventions that effectively improve handwashing and food safety practices and reduce antimicrobial use in low-risk populations cannot be assumed to be effective for high-risk groups. In addition, the lessons learnt from interventions that lead to appropriate use of antimicrobials in low-risk populations cannot necessarily be transferred to high-risk groups. # Workplace How effective are interventions in the workplace that aim to prevent infection and reduce antimicrobial resistance? ## Why this is important The workplace is an important setting for helping to prevent the spread of infection among large numbers of people. Information on what works will have a positive impact on the economy by reducing the potential rise in sickness absence caused by the spread of infectious diseases. More UK randomised control trials are needed in a range of workplace settings. # Older people in day and residential care How effective are interventions in day and residential care for older people that aim to prevent infection and to reduce antimicrobial resistance? ## Why this is important Day and residential care settings for older people are 2 settings where preventing the spread of infection and reducing the risk of antimicrobial resistance are particularly important. This is because many older people are vulnerable to infection as a result of chronic conditions, and there is the risk of infection spreading among large numbers of people. In addition, antimicrobial resistance is increasing in older people, particularly in relation to E. coli infections of the urinary tract.	{'Recommendations': "Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read in conjunction with NICE's guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use.\n\n# Overarching principles\n\nThe following recommendations are for directors of public health:\n\nWork with health and wellbeing boards, commissioners and local authorities to ensure that the following are a priority locally:\n\nthe public health aspects of local antimicrobial stewardship programmes (see NICE's guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use)\n\nlocal system-wide infection prevention programmes.\n\nEnsure that:\n\nLocal authorities and clinical commissioning groups work collaboratively to provide consistent information and advice to:\n\n\n\nthe public\n\nhealthcare professionals, including GPs, other prescribers and community pharmacists.\n\n\n\nHealth and social care practitioners and organisations that commission, provide or support the provision of care are:\n\n\n\naware of NICE's guideline on antimicrobial stewardship\n\nsupported to implement it.\n\n\n\n# Local system-wide approaches to reducing inappropriate antimicrobial demand and use\n\nThe following recommendations are for clinical commissioning groups.\n\nEnsure resources are available for healthcare professionals to use with the public to provide information about self-limiting infections. These resources should be used to encourage people to manage their infection themselves at home if it is safe to do so. The resources should include information on:\n\nHow someone can recognise whether they, or someone they are caring for, have a self-limiting infection (for example, by checking the NHS website).\n\nHow to seek further advice if they not sure whether their infection is self-limiting; for example, by:\n\n\n\ncontacting a community pharmacy\n\ncalling 111 or a local advice line or helpline\n\nusing other local triaging arrangements such as practice nurses.\n\n\n\nWhere to seek advice on managing self-limiting infections; for example, from:\n\n\n\ncommunity pharmacists\n\nother reliable health resources, such as NHS Choices\n\nother local triaging services.\n\n\n\nThe natural course of self-limiting infections, including the length of time symptoms are likely to last.\n\nHow people can self-care (for example, by resting, drinking plenty of fluids and taking over-the-counter preparations to relieve their symptoms, if needed).\n\nExplicit advice on when to seek medical help, which symptoms should be considered red flags and safety-netting advice.\n\nEnsure resources and advice are also available for people who are prescribed or supplied with antimicrobials, to ensure they take them as instructed by their healthcare professional (see NICE's guideline on medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence). This should include taking the correct dose for the time specified and via the correct route.\n\nEnsure the resources advise people not to:\n\nUse or take prescription-only antimicrobials without a prescription and advice from a suitably qualified healthcare professional.\n\nKeep leftover antimicrobials for use another time.\n\nShare, or give, prescription-only antimicrobials to anyone other than the person they were prescribed or supplied for.\n\nUse or take antimicrobials prescribed for animals.\n\nUse or take prescription-only antimicrobials or give them to others if they have been obtained from anywhere other than their healthcare professional or pharmacist (for example, prescription-only antimicrobials bought online without a prescription).\n\nAsk for antimicrobials as a preventive measure against becoming ill or as a 'stand-by' measure; for example, when going on holiday (unless the person has a specific condition that makes this necessary or there is a specific risk; for example, if travelling to areas where malaria is endemic [see the NHS information on how to avoid malaria and antimalarial medication], or there is a high risk of travellers' diarrhoea).\n\nThe following recommendations are for local authority public health teams.\n\nConsider linking to awareness-raising initiatives for the public on reducing inappropriate antimicrobial demand and use and antimicrobial resistance (for example, European Antibiotic Awareness Day and Public Health England's Antibiotic Guardian).\n\nUse opportunities that may arise through other local authority activities to distribute information about antimicrobial resistance (for example, waste disposal and recycling information could include advice not to flush leftover antimicrobials down sinks or toilets but to return them to a community pharmacy for safe disposal).\n\n# Local system-wide approaches to preventing and limiting the spread of infection\n\nFor recommendations for clinical settings, see NICE's guideline on healthcare-associated infections: prevention and control in primary and community care.\n\nThe following recommendations are for local authority public health teams.\n\nEnsure information and advice directed at the general public aims to prevent and reduce the spread of infections. Resources such as posters, leaflets and digital resources should be made available through multiple routes to provide a coordinated system of information.\n\nEnsure information is available in a variety of formats to meet people's literacy and language needs and the needs of people with sensory disabilities.\n\nConsider distributing information and advice through facilities and services operated by local authorities, such as leisure centres and libraries.\n\nWhen deciding where to distribute information, prioritise settings in which people are more vulnerable to infection or where there is a high risk of transmitting infection to others, for example:\n\nchildcare settings\n\nresidential and day care settings for older people.\n\nGive people information on handwashing that emphasises why it is necessary and effective to thoroughly wash and dry hands to reduce the risk of getting an infection, or passing infection on to their family and other people. Include information on:\n\nWhen hands should be washed and dried; for example, after using the toilet, before eating meals or snacks and after being in close contact with people with colds or other infections.\n\nHow hands should be washed and dried, including the need to use liquid soap and tepid running water (a handrub can be used if soap and water are unavailable). See the section on standard principles in NICE's guideline on infection control. Use resources shown to be effective in helping people develop and use personalised plans to increase handwashing. (See the section on putting this guideline into practice for examples of resources that may be helpful).\n\nGive people advice on food hygiene and signpost them to resources. Include information on:\n\nKey points at which it is particularly important to thoroughly wash and dry hands (see recommendation 1.3.5); for example:\n\n\n\nbefore eating or preparing food\n\nafter using the toilet or touching the bin\n\nbefore and after handling raw food.\n\n\n\nSafe food preparation and cooking methods (this includes ensuring food is cooked at the right temperature and properly heated throughout before eating).\n\nHow to store food safely, including advice on:\n\n\n\nfridge temperatures\n\n'use by' and 'best before' dates\n\nfreezing, defrosting and refreezing food.\n\n\n\nUsing food leftovers safely. See the Food Standard Agency's advice on food safety for more advice on food safety and how to prevent infections from spreading.\n\n# Childcare and education providers\n\nThe following recommendations are for preschool settings.\n\nDisplay information or direct parents and carers to resources about managing the symptoms of infection in children, when to seek medical advice and the appropriate use of antimicrobials.\n\nEnsure there are always good standards of food hygiene (see the Food Standard Agency's advice on food safety).\n\nProvide facilities for thoroughly washing and drying hands for children, staff and visitors. These should include liquid soap and tepid running water, and handrubs when these are not available.\n\nEnsure staff talk to children about the importance of thoroughly washing and drying hands, including:\n\nexplaining when to wash and dry hands (for example, after using the toilet and before eating)\n\nshowing them how to wash hands with liquid soap and tepid running water (see the standard principles in NICE's guideline on infection control).\n\nRefer to Public Health England's guidance on infection control in schools and other childcare settings for details of how long children should be kept away from childcare when they have an infection.\n\nThe following recommendations are for schools.\n\nTeach all children, in an appropriate way for their age and ability, about the need to reduce inappropriate antimicrobial demand and use. Use existing teaching resources if available (see the section on putting this guideline into practice for examples of resources that may be helpful).\n\nPromote a 'whole-school' approach to preventing infections from spreading. The school environment and staff should support children to act in a way that prevents or minimises infection.\n\nEnsure that there are always good standards of food hygiene (see the Food Standard Agency's advice on food safety).\n\nProvide facilities for washing and drying hands. These should include liquid soap and tepid running water, and handrubs if these are not available (see the standard principles in NICE's guideline on infection control).\n\nRefer to Public Health England's guidance on infection control in schools and other childcare settings for details of the length of time children should be kept away from school when they have an infection.\n\nTeach all children, in an appropriate way for their age and ability, about the importance of washing and drying hands to prevent infections and stop them from spreading. Discuss when and how hands should be washed. Use existing teaching resources if available (see the section on putting this guideline into practice for examples of resources that may be helpful).\n\nConsider giving children information to take home about when and how to wash their hands.\n\nShare information with parents and carers that can support their children's learning. This could include teaching their children how and when to wash their hands.\n\nGive parents and carers advice on other ways to help prevent infections. This should include advice on being up to date with vaccinations (see NICE's guideline on vaccine uptake in the general population) and preventing the spread of airborne infections.\n\nThe following recommendations are for educational and residential settings for young people.\n\nDisplay information or direct young people to resources that aim to reduce inappropriate antimicrobial demand and use. The information should:\n\nTake into account that many young people will be managing infections on their own for the first time.\n\nExplain to young people how to recognise the signs and symptoms associated with a self-limiting infection, when they can safely self-care, how to do so and when they need to seek medical help (see recommendation 1.2.1 and information on the NHS website).\n\nPromote community pharmacies and minor ailment services, where they are available, as a source of advice and care (see the NHS information on how your pharmacist can help).\n\nIntroduce a regularly repeated programme to improve young people's infection prevention knowledge and behaviour. Include:\n\nPosters promoting handwashing displayed in various locations, such as public areas of the campus, cafeterias, bulletin boards in halls of residence and public toilets.\n\nSignposts to online awareness-raising resources, with links to information on infection control (see the section on putting this guideline into practice for examples of resources that may be helpful).\n\nOne-off events providing free handrubs.\n\nFood safety campaigns such as:\n\n\n\nface-to-face lectures\n\neducation materials delivered via the web, including digital and social media\n\npromotional materials\n\nother ways to help prevent infections, such as advice on being up to date with vaccinations and preventing the spread of airborne infections.\n\n\n\n# Prescribers, primary care and community pharmacy teams\n\nThis section should be read alongside the recommendations on prescribing (recommendations 1.1.24 to 1.1.37) in NICE's guideline on antimicrobial stewardship. See also NICE's guideline on sepsis: recognition, diagnosis and early management.\n\nWhen people ask about managing self-limiting infections:\n\nShare advice on self-care for each of the symptoms.\n\nUse and share resources that provide written advice to encourage people to change their behaviour (see recommendation 1.2.1).\n\nVerbally emphasise the key messages given in the written resources.\n\nDisplay resources that provide or signpost to advice and information about self-care; for example, the NHS website, 111 and local advice or helplines.\n\nSignpost them to further information to read at home, such as online advice.\n\nDiscuss with them whether taking or using an antimicrobial is the most appropriate option (see the recommendation on discussions with patients and family members or carers under 'antimicrobial prescribing' in NICE's guideline on antimicrobial stewardship).\n\nRaise awareness of community pharmacists as an easily accessible first point of contact for advice about managing a self-limiting infection.\n\nConsider using computer prompts or decision support aids to prompt healthcare professionals to share information with people on the appropriate use of antimicrobials, self-care and safety netting (see NICE's guideline on antimicrobial stewardship).\n\n## If antimicrobials are prescribed or supplied\n\nShare verbal advice and written information that people can take away (see recommendation 1.5.1) about how to use antimicrobials correctly, including:\n\nnot sharing prescription-only antimicrobials with anyone other than the person they were prescribed or supplied for\n\nnot keeping them for use another time\n\nreturning unused antimicrobials to the pharmacy for safe disposal and not flushing them down toilets or sinks.\n\nIf the person has been given a back-up (delayed) prescription, tell them:\n\nHow to self-care to manage their symptoms.\n\nWhat the antimicrobials would be used for, if needed.\n\nHow to recognise whether they need to use the antimicrobials, and if so:\n\n\n\nhow to get them\n\nwhen to start taking or using them\n\nhow to take or use them.\n\n\n\n## If antimicrobials are not prescribed or supplied\n\nGive people verbal advice and share written information that they can take away about how to manage their infection themselves (see recommendation 1.5.1).\n\n## General advice in primary care and community pharmacies\n\nShare safety-netting advice with everyone who has an infection (regardless of whether or not they are prescribed or supplied with antimicrobials). This should include:\n\nhow long symptoms are likely to last with and without antimicrobials\n\nwhat to do if symptoms get worse\n\nwhat to do if they experience adverse effects from the treatment\n\nwhen they should ask again for medical advice.\n\n# Terms used in this guideline\n\n## Antimicrobial resistance\n\nLoss of effectiveness of any anti-infective medicine, including antiviral, antifungal, antibacterial and antiparasitic medicines.\n\n## Antimicrobial stewardship\n\nAn organisational or healthcare system-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness.\n\n## Capability, opportunity and motivation\n\nA theory of behaviour change that can guide interventions to change individual behaviour patterns. For any change in behaviour to occur, a person must:\n\nbe physically and psychologically capable of performing the necessary actions\n\nhave the physical and social opportunity to make the change\n\nbe more motivated to adopt the new, rather than the old behaviour, whenever necessary.\n\nThis is known as the COM-B model (see the behaviour change wheel: a new method for characterising and designing behaviour change interventions Michie et al. 2011).\n\n## Handrub\n\nA preparation applied to the hands to reduce the number of viable microorganisms. This guideline refers to handrubs compliant with British standards (BS EN1500; standard for efficacy of hygienic handrubs using a reference of 60% isopropyl alcohol).\n\n## Inappropriate antimicrobial demand and use\n\n'Inappropriate antimicrobial demand' refers to people asking for antimicrobials for conditions against which they are ineffective (for example, antibiotics to treat a viral infection such as a cold) or for self-limiting infections that will resolve on their own, with no long-term harm to the person's health.\n\n'Inappropriate antimicrobial use' refers to the way in which people may misuse antimicrobials that they have been prescribed or supplied with, and which may result in the antimicrobials becoming ineffective in treating infections. This is because the bacteria, virus, fungus or parasite they are designed to treat may become resistant to the antimicrobial. Examples of inappropriate use include not taking or using the antimicrobials as prescribed and sharing them with others.\n\n## Local triaging arrangements\n\nServices that can advise people whether they have a self-limiting infection that they can safely manage themselves or whether their infection needs medical attention. Examples include community pharmacies, practice nurses, 111, other locally developed advice and helplines, and emergency and out-of-hours primary care services.\n\n## Red flags\n\nSigns and symptoms of a more serious illness or condition.\n\n## Resources\n\nEvidence-based materials that have been developed through a research-based approach with the target audience, wherever possible. They may be in a variety of formats, including posters, leaflets, digital and online resources.\n\n## Safety-netting advice\n\nAdvising people what to do if their condition deteriorates or does not improve within a certain time, or if they develop adverse effects as a result of the treatment.\n\n## Self-care\n\nApproaches a person can use to look after themselves in a healthy way; for example, drinking plenty of fluids and getting sufficient rest when you have a cold.\n\n## Self-limiting infection\n\nAn infection that resolves on its own and has no long-term harmful effect on a person's health (assuming that they are not immunosuppressed). Examples include colds, flu, oral thrush, winter vomiting bug.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice. Examples of other resources that may be helpful include the University of Southampton's Germ Defence (see recommendation 1.3.5) and UK Health Security Agency's e-Bug website (see recommendations 1.4.6, 1.4.11 and 1.4.16).\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': "Antimicrobial stewardship refers to an organisational or healthcare-system-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness.\n\nAntimicrobial resistance may lead to standard treatments becoming ineffective, causing infections to persist and increasing the risk of them spreading. Although resistance evolves naturally, the use (and misuse) of antimicrobials speeds up this process. Inadequate infection prevention and control practices, poor sanitary conditions and inappropriate food handling encourage the spread of infections that may need the use of antibiotics.\n\nImprovements in nutrition, hygiene and sanitation, and reductions in overcrowded housing, have all helped prevent and decrease the transmission of infectious diseases (Davies SC The drugs don't work. A global threat. London: Penguin). The World Health Organization estimates that, along with these broad environmental factors, antimicrobials add on average 20\xa0years to life expectancy (Self-prescription of antibiotics boosts superbugs epidemic in the European region).\n\nBut antimicrobial resistance is increasing and there is a lack of new antimicrobials to treat resistant diseases. It is important to ensure the antimicrobials that are currently effective remain so for as long as possible.\n\nInfectious diseases are a major cause of illness in the UK. In 2013, for example, 21% of all days lost at work (approximately 27\xa0million days) were caused by coughs, colds and flu and other infectious diseases (Office for National Statistics' Sickness absence in the labour market: February 2014).\n\nThe incidence of infectious disease tends to be higher in groups with lower socioeconomic status and outcomes tend to be poorer. For example, they are more likely to have tuberculosis, transmit it to others and to have a drug-resistant strain (Department of Health's Annual report of the Chief Medical Officer 2011: volume\xa01).\n\nAlthough viruses (such as HIV), parasites (such as malaria) and fungi (such as Candida) are showing resistance to antivirals, antiparasitics and antifungals respectively, for the general population antibiotic resistance is the main concern. However for some population subgroups, resistance to antivirals and antifungals may be of equal concern. This includes people who are particularly vulnerable to infection due to supressed immune systems; for example, because of HIV, an inherited condition or treatment they may be having for conditions such as cancer or an organ transplant.\n\nIn the UK, the spread of multidrug-resistant tuberculosis and gonorrhoea is also of public health concern (see the 'Annual report of the Chief Medical Officer 2011: volume\xa01').\n\nNational campaigns to raise public and professional awareness of antibiotic resistance may reduce antibiotic prescribing and demand (Department of Health's European antibiotic awareness day 2013 evaluation report). But a 2013 survey of 2,033\xa0people in the UK by Ipsos MORI (Antibiotics: a cure for the common cold?) showed that:\n\n% wrongly believe antibiotics work on colds or flu\n\naround 40% think antibiotics can kill viruses\n\naround 7% do not complete a course of antibiotics.\n\nThere is also evidence that most people who ask a healthcare professional for antibiotics to treat a cough are given them (Antibiotic prescribing for acute cough: the effect of perceived patient demand Coenen et al. 2006).\n\nFor details on UK policy, see the scope for this guideline.", "The committee's discussion": 'This section describes the factors and issues the public health advisory committee considered when developing the recommendations. Please note: this section does not contain recommendations (see the recommendations section).\n\n# Background\n\nThe committee recognised that the threat of antimicrobial resistance can only be tackled by a combination of interventions and measures that address:\n\nthe prescribing decisions of healthcare professionals\n\npeople\'s behaviour relating to infection prevention and control, antimicrobial use and antimicrobial resistance\n\nsurveillance to track antimicrobial use and resistance in microbes\n\nthe development of new drugs, treatments and diagnostics\n\nantimicrobial use in animal husbandry\n\npolitical commitment to prioritise antimicrobial resistance as a major area of concern for the UK and globally.\n\nChanging when and how people use antimicrobials and changing their behaviour to prevent infection helps to keep current medicines effective for as long as possible. But action is also needed by prescribers, dispensers and regulators.\n\nThe committee noted the importance of ensuring sustained action is taken to reduce antimicrobial resistance. It emphasised that antimicrobial resistance is a long-term problem. It noted that at publication of this guideline, the UK will be 3\xa0years into the UK 5-year antimicrobial resistance strategy 2013 to 2018.\n\nThe committee reflected on NICE\'s guideline on antimicrobial stewardship, which covers prescribers\' knowledge and behaviour. It wanted to ensure the 2\xa0guidelines complement each other and are read together. It also wanted to ensure interventions that target both the public and prescribers are included in this guideline if they are not already covered in the related antimicrobial stewardship guideline. That is because, otherwise, the committee felt that evidence of effectiveness on these interventions may be missed.\n\nThe committee also noted that NICE\'s guidelines on behaviour change: individual approaches, medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes and vaccine uptake in the general population are all relevant to changing knowledge about use and misuse of antimicrobials.\n\n# The evidence base – limitations\n\nThe committee made some recommendations for interventions for which the evidence from the reviews is limited.\n\nThe committee recommended that clinical commissioning groups provide information to encourage people to manage self-limiting infections at home, if it is safe to do so, to reduce inappropriate antimicrobial demand and use. These recommendations are based on:\n\nevidence from expert papers\n\ncommittee members\' combined expertise and experience\n\ncomments received during stakeholder consultation.\n\nThe committee also made recommendations for primary care teams and community pharmacies about reducing inappropriate antimicrobial demand and use.\n\nIt agreed that it was important to make recommendations in this area to support and complement those in NICE\'s guideline on antimicrobial stewardship. The evidence for review\xa01 was weak and inconsistent, so members also drew on expert papers and their own expertise and experience. The recommendations support existing good practice in this area.\n\nMembers considered that there are some simple and practical steps that can help prevent the spread of infection and reduce the threat of antimicrobial resistance, and cause no anticipated harm.\n\nExamples include:\n\nensuring hands are thoroughly washed and dried before eating meals or snacks\n\nadvice on storing food and using leftovers safely\n\navoiding flushing unused antimicrobials down sinks or toilets.\n\nIn taking this pragmatic approach they have drawn on good practice, standard advice from respected sources and their collective expertise, in addition to the published evidence.\n\nIn considering the cost effectiveness of interventions in this area, the committee have drawn on the \'precautionary principle\' (see the section on health economics; principle 15 of the United Nations Global Impact\'s Rio Declaration on Environment and Development). The precautionary principle is a conservative principle. The conservative approach is to assume that the intervention should be used unless it can be shown with sufficiently high probability that it does more harm than good.\n\n# Evidence – effectiveness review\n\nThe committee found little good-quality published evidence about the effectiveness of interventions to change risk-related behaviours in the general population (review\xa01). Study methods were often not well reported or had potential biases that may have significantly affected results. This is reflected in the quality ratings for studies, with the majority rated as weak, 12\xa0rated as moderate and none as strong.\n\nThe committee questioned whether the studies were underpowered (had too few participants) to detect any significant differences. It also questioned whether the effect sizes could be pooled for meta-analysis, but this was not possible because of the diversity of the study outcomes.\n\nMost studies measured knowledge rather than behaviour, and when behaviour was measured it was often self-reported rather than observed. The committee noted that behaviour change needs to be the goal of any intervention, and that changes in knowledge do not necessarily lead to changes in behaviour. It agreed that more research is needed to evaluate changes in behaviour (see the recommendations for research section).\n\nThe way people\'s knowledge was measured differed between studies and the committee questioned the validity of the measures. Some studies only reported an overall \'knowledge score\' for a particular topic.\n\nSome used different measures to evaluate an outcome. For example, statements to classify as \'true\' or \'false\' on handwashing ranged from: "you need to wash your hands after playing in the garden" to "you need to wash your hands after coughing". So an overall score described as \'knowledge of hand hygiene\' may be a compilation of different knowledge measures and may not be comparable between studies.\n\nIn some studies, the baseline levels of knowledge were high. This may have left little room for improvement. Other studies report significant changes, but with the overall level of knowledge remaining low. So an \'effective\' result may not be \'clinically significant\' (it may not demonstrate a meaningful difference).\n\nThere was also a lack of long-term follow-up of changes in knowledge or behaviour.\n\nThe focus of the review was on changing risk-related behaviours, so changes in antimicrobial resistance was not a selected outcome measure and the review did not report it. The committee discussed why some studies that measured only prescribing rates as an outcome were excluded. The rationale was that prescribing is under the control of the prescriber, not the patient. Without any direct measure of patients\' knowledge or behaviour (for example, changes in consultation rates) it is not possible to determine whether changes in prescribing were caused by changes in patients\' or prescribers\' behaviour.\n\nBut the committee felt that if an intervention solely targeted patients or the public, then prescribing rates may be a reasonable outcome measure. This is because changes in patient behaviour may affect doctors\' prescribing habits. As a result, supplementary reviews were carried out.\n\n# Supplementary evidence reviews\n\nNICE carried out another evidence review (review 2) to look at studies that were excluded from the effectiveness review. These studies targeted patients or the general public only and measured antibiotic prescribing rates.\n\nPapers previously excluded because they reported only the incidence of infection were also included in the review, because changes in infection incidence after an intervention may be due to changes in behaviour.\n\nTen studies were included in the review, 3\xa0of which were good quality, 5\xa0moderate quality and 2\xa0weak.\n\n## Antibiotic prescribing\n\nThe review showed that evidence on the effectiveness of parental education interventions for reducing antibiotic prescribing for children\'s respiratory tract infections in primary care is inconsistent. Three US studies found no effect, and the 1\xa0UK study found a significant decrease in antibiotic prescribing.\n\nThe interventions all involved written materials but differed in format, content, additional components and mode of delivery. Baseline prescribing levels also differed between studies. The committee noted that the 1\xa0effective study involved training GPs to discuss written materials with parents, and to give them information on prognosis, treatment options and reasons for re-consultation (warning symptoms to look out for).\n\nThe committee also noted that an educational intervention based in primary care may be effective in reducing antibiotic prescribing for respiratory tract infections in adults under\xa065. But this was not the case for older adults. It noted that GPs (and older patients) may think that older people face greater health complications, so GPs may be more likely to prescribe antimicrobials. The committee noted the importance of ensuring interventions are designed to address the beliefs of particular groups such as older adults.\n\n## Hand hygiene\n\nFive studies (2\xa0good quality, 1\xa0moderate and 2\xa0weak) measured changes in the incidence of infection. These all focused on hand-hygiene interventions. Three of these studies (1\xa0good quality, 1\xa0moderate and 1\xa0weak) were based in childcare settings. The good-quality study reported that changes to hand hygiene did not reduce the incidence of respiratory or gastrointestinal illnesses but could reduce the transmission of a gastrointestinal illness to other family members.\n\nCommittee members noted that there was 1\xa0good-quality UK study of a bespoke web-based intervention. This reduced the incidence of respiratory illnesses. The committee heard expert testimony that gave further detail about the web-based intervention to promote handwashing. This included motivational messages that explain how infection can be transmitted by hand and how hand hygiene can reduce the risk of infection in oneself and one\'s family. It also included an interactive tool that aims to translate knowledge into changes in behaviour through a personalised planner to help people to identify situations during the day when they could increase handwashing.\n\nThe committee also agreed that it is important to give people the opportunity to change (for example, by providing handwashing facilities).\n\n## Multi-targeted interventions\n\nNICE\'s public health team carried out a rapid review of systematic reviews (review 3) that:\n\nevaluated the effectiveness of educational interventions on the public\'s knowledge and behaviour in relation to antimicrobial use or antimicrobial resistance\n\ntargeted both the public and healthcare professionals.\n\nThe committee noted that these multi-targeted interventions did improve people\'s knowledge of appropriate antimicrobial use (specifically in relation to antibiotics) and did reduce antibiotic prescribing for respiratory illnesses.\n\nHowever, it was not possible to determine whether it is better to provide support to help change someone\'s behaviour alone, support for changing healthcare professionals\' behaviour alone, or a combination of both. Nor was it possible to determine which components of interventions were more effective than others.\n\nAs for the main review, the focus of this supplementary review was on changing knowledge and behaviour. Change in antimicrobial resistance was not selected as an outcome measure. Although 4\xa0of the 9\xa0included reviews did report changes in antibiotic resistance as an outcome, the results were mixed. Because this outcome was not actively sought, and there were only a limited number of studies, it would be inappropriate to draw any conclusions about the effect of these interventions on antimicrobial resistance.\n\n# Action for both prescribers and the public\n\nThe committee was conscious that to reduce inappropriate antimicrobial demand and use, changes in the behaviour of both prescribers and the public are necessary. It stressed the importance of this guideline being implemented alongside the recommendations for prescribers in NICE\'s guideline on antimicrobial stewardship.\n\nThe committee noted evidence identified by review\xa03 that multi-component, educational interventions that target both clinicians and patients or the public are effective at reducing antibiotic prescribing for self-limiting infections. This evidence did not allow members to determine whether it is better to target patients\' behaviour alone, healthcare professionals\' behaviour alone or a combination of both. However, they heard expert testimony that drew on additional studies of public information campaigns to reduce antimicrobial resistance.\n\nThe findings of these studies of repeated \'through the line\' campaigns (those that include using mass media such as television and internet as well as leaflet and poster campaigns) have shown some substantial reductions in antibiotic prescribing. But these were often delivered alongside locally targeted community activities, including those focused on prescribing practice by healthcare professionals.\n\nThe committee noted from this testimony that improved antimicrobial stewardship was most likely to be achieved through interventions that are:\n\nstrategically coordinated\n\nfocused on both reducing inappropriate antimicrobial demand and use and preventing and limiting the spread of infection\n\ndelivered at national and local level\n\naimed at both the public and health professionals.\n\nMembers noted that directors of public health have an important role to play in working with health and wellbeing boards, commissioners and local authorities to ensure that the following are a priority:\n\npublic health aspects of local antimicrobial stewardship programmes\n\nlocal system-wide infection prevention programmes.\n\nThey made a recommendation to this effect (see recommendation 1.1.1).\n\n# Population groups and settings\n\nThe committee noted that in the evidence reviews, interventions targeted specific age groups and life stages. It felt this was a useful way to frame the recommendations. In addition, educational interventions for school-aged children (such as UK Health Security Agency\'s e-Bug website) often combine teaching about antibiotic use, antimicrobial resistance, handwashing and food hygiene. It decided that these should also be combined in the recommendations.\n\nThe committee made recommendations in section 1.4 for:\n\npreschool settings\n\nschools\n\neducation and residential settings for young people.\n\nPreschool and school settings were considered important by the committee because of the high rate of infection in young children and the transmission of infection between them. Although the committee was unable to make recommendations about environmental cleanliness, because this was outside the scope of the guideline, it noted the importance of keeping the environment, facilities and equipment clean. In making recommendations for schools it was keen to take a whole-school approach in which both the environment and teaching support the desired behaviour.\n\nThe committee noted that young people aged 16\xa0to\xa024 are some of the highest users of antibiotics. They also misuse antibiotics more than any other age group, in particular through sharing them with others. The committee noted that young people in this age group who have recently moved away from home may not have previous experience of looking after themselves during a self-limiting illness. It noted that this should be considered when offering them advice.\n\nPeople over\xa065 are the other group that use the most antibiotics. In addition, they may be more vulnerable to infection due to having chronic conditions. People in day or residential care may also be at greater risk of infection being transferred from others.\n\nThe committee noted the importance of interventions that target these age groups. But although evidence was identified for interventions in preschool, school and university settings, none was identified in settings focusing on older people, including those in day or residential care.\n\nThe committee therefore noted the need for further research in older age groups, along with studies focusing on populations whose social and economic circumstances or health put them at greater risk of getting or transmitting infectious diseases and antimicrobial-resistant strains.\n\nMost interventions took place in healthcare or education settings. Healthcare interventions mainly took place in primary care, but some were in A&E or pharmacies. Other settings included homes and the wider community; for example, targeting the general public via mass media or web-based interventions.\n\nThe committee was concerned that there were no interventions in the workplace or social care, other than preschool settings. It discussed whether it was possible to generalise findings from preschool settings to other social care settings. Members agreed that the aim of the intervention would be the same. But there was no evidence on how interventions could be effectively delivered in these alternative settings and to different population groups.\n\nThe committee also noted that the reviews looked only at educational interventions, but there may be other types of intervention that focus on these populations.\n\n# Antimicrobials and antimicrobial resistance – knowledge and behaviour\n\nThe committee noted that most studies focused on improving knowledge of antibiotics rather than antivirals, antifungals or antiparasitics. Interventions usually focused on reducing unnecessary antibiotic use for self-limiting respiratory illnesses (colds and flu).\n\nThere is growing concern about the increase in antimicrobial resistance to common treatments, particularly in bacteria that cause urinary tract infections (for example, Escherichia coli resistance to third-generation cephalosporins and fluoroquinolones).\n\nThe committee noted that educational interventions did not tend to improve knowledge of antimicrobial resistance and its implications. The committee agreed that focusing messages on the effects on the whole population was unlikely to lead to changes in behaviour. But making the messages relevant to individual people could be effective. Messages could include the fact that losing effective treatments could directly affect someone\'s own health, or the health of those close to them.\n\nThe committee also felt that it is important to get across the fact that you do not have to feel unwell to carry an antimicrobial-resistant organism (for example, you could be a carrier of multi-drug resistant E.\xa0coli without having symptoms).\n\nIt agreed that the fact that someone can spread an antimicrobial-resistant infection to others is a key message. The committee noted that interventions to prevent infection have been shown to be more effective during epidemics. This is because people are more likely to act in a way to prevent or minimise the spread of infection if they can see it may help them.\n\nThe committee discussed the importance of creating a cultural shift and changing social norms so that people use antimicrobials responsibly.\n\nThe committee felt that self-care needs to become the \'easy choice\' for people. It noted the importance of raising awareness of where to seek advice on managing a self-limiting infection; for example, community pharmacists and other reliable health resources such as the NHS website. It saw the role of the community pharmacist as very important. However, it noted that there are also cost considerations for people, because prescribed medicines may be cheaper than over‑the‑counter medicines, or free for some.\n\nThe committee discussed the importance of people knowing the natural course of an illness – with and without using antimicrobials – and that there is often very little difference in recovery times. The committee also discussed other ways to improve motivation, such as increasing people\'s confidence in the effectiveness of over‑the‑counter preparations to manage the symptoms of self-limiting illnesses, taking into account recommendations for specific populations such as the Medicines and Healthcare products Regulatory Agency\'s advice on over-the-counter cough and cold medicines for children.\n\nThe committee noted the importance of consistency in the advice people receive from different sources, such as GPs and community pharmacists.\n\nThe committee discussed the possible unintended consequences of interventions that aim to reduce inappropriate antimicrobial demand and use. It noted that people need to know the warning signs (or red flags) that indicate they should seek help from a healthcare professional and that they should be given advice about what to do if their condition becomes worse or if, when antimicrobials are prescribed, they experience adverse effects from the treatment (safety-netting advice).\n\nIt also did not want to deter the prudent and appropriate use of antimicrobials. The practice of back-up (delayed) prescribing was discussed as a strategy that is increasingly used to reduce antimicrobial use. The committee noted the importance of people being aware of the circumstances that indicate they should start to take the antimicrobial and how to do so.\n\nThe committee noted the potential cost benefits to the NHS of interventions that reduce GP consultation rates. There was also evidence that primary care interventions, such as providing information on antibiotic use, can increase people\'s knowledge of when and how to use antibiotics.\n\nAlthough leaflets alone led to improvements in knowledge among adults, this was not the case for parents of young children. There was evidence for both population groups that leaflets, in combination with structured discussion either face-to-face or via a video presentation, improved antibiotic knowledge and behaviour.\n\nThe committee noted that most healthcare interventions took place in general practices. There were only 2\xa0studies in pharmacies and 1\xa0in an A&E setting. The committee discussed the importance of ensuring people receive the right information at the right time and in a format that meets their language and literacy needs. It discussed providing information at the following points:\n\nbefore going to see a GP (getting information online or visiting a pharmacy)\n\nwhile waiting for a GP or hospital consultation\n\nduring a consultation.\n\nEducation on antibiotic use and antimicrobial resistance in schools was more likely to be effective if students were given this information directly while they were in class or by taking part in practical activities rather than through computer games, mass media campaigns and videos alone. However, the committee noted that there were no direct comparisons of these different types of school activity.\n\nThere were also some methodological issues with studies of self-learning that did not show a significant effect. A lack of significant intervention effect could be due to the studies being insufficiently powered, or because the intervention needs to be further developed. For example, UK Health Security Agency\'s e-Bug computer game was made a tedious rather than \'fun\' experience by making children complete all levels of the game in a single sitting (hence the low completion rate). Because of these methodological issues, the committee warned against assuming that such interventions are not effective.\n\nExpert paper 1 reports on the public\'s awareness and understanding of appropriate antibiotic use, prescribing and antibiotic resistance in the UK. The qualitative evidence identified core behaviours that could reduce people\'s use of antibiotics for a self-limiting infection:\n\nself-care or getting advice from a community pharmacist for colds, runny nose or flu and other self-limiting infections\n\nnot requesting antibiotics at a GP appointment\n\nacting on advice given by their GP or other prescriber if antibiotics are not prescribed immediately. This is known as back-up (or delayed) prescribing.\n\nThe qualitative evidence was categorised in relation to the capability, opportunity and motivation model of behaviour (COM‑B). The model was also used as a theoretical basis for proposing areas that could potentially be effective in changing people\'s behaviour.\n\nThe committee noted that this model is recommended in NICE\'s guideline on behaviour change: individual approaches and is relevant to how interventions for infection prevention and antimicrobial use are designed and delivered.\n\n# Points of receptiveness and types of information\n\nThe committee noted that people may be more receptive to information about reducing inappropriate antimicrobial demand and use and preventing and limiting the spread of infection if:\n\nthey (or a family member) are ill, or particularly vulnerable to infection, or\n\nthey perceive that there is a particular risk of illness; for example, during an outbreak of flu.\n\nCommittee members highlighted that the information and advice given by health professionals at these points differs from \'general public information\' about reducing inappropriate antimicrobial demand and use and preventing and limiting the spread of infection.\n\nThe committee heard expert testimony on the varying roles and remits of different agencies that might be involved in providing such information. Members made recommendations for both clinical commissioning groups (on ensuring information and resources are available for people seeking advice about managing self-limiting infections) and local authorities (on raising awareness of the need to reduce inappropriate antimicrobial demand and use and preventing and limiting the spread of infections).\n\n# The role of community pharmacists\n\nThe committee heard expert testimony on the role of community pharmacists. Members noted that community pharmacists are often under-used by the public and were keen to promote them as an easily accessible first point of contact for people seeking advice on managing self-limiting infections.\n\nMembers recognised the important stewardship role community pharmacists play in relation to local antimicrobial prescribing policy and noted the close collaboration between community pharmacists and GP practices in this area. The committee noted the potential for similarly close collaboration in promoting self-care for managing self-limiting infections.\n\n# Mass-media campaigns\n\nThe committee noted that although mass-media campaigns could raise the profile of antimicrobial resistance and correct use of antibiotics, they had only a small impact on people\'s knowledge and behaviour.\n\nThere was some evidence from the effectiveness review that these campaigns can increase parents\' knowledge of antimicrobial resistance and reduce their desire for antibiotics for their child. But only if they are combined with direct communication from healthcare professionals and staff at childcare centres, and with the education of healthcare professionals.\n\nThe committee discussed expert paper 2. This reported the impact of international and national awareness-raising campaigns on people\'s knowledge of appropriate antimicrobial use and antimicrobial resistance. It also reported how people, as a result, changed their behaviour in relation to antibiotics.\n\n# Educational modules delivered by computers and websites\n\nIn the effectiveness review, evidence statements about using educational modules delivered through computers and websites were also based on only 1\xa0or 2\xa0studies.\n\nThe committee therefore decided to look at the antimicrobial use, resistance and infection prevention studies to determine whether education delivered via computer and websites does help change knowledge or behaviour. It concluded that educational modules delivered this way could help reduce inappropriate expectations of antibiotics and improve food safety knowledge and hand hygiene. However, members believed that the key to success was not the format of delivery, but the content and quality of the intervention.\n\nThe committee noted that interventions need to go beyond raising knowledge and awareness. It discussed the need to give people the motivation to change and the tools to help them to start behaving differently.\n\n# Preventing infection\n\nThe committee noted that the effectiveness review had no studies on interventions designed to improve behaviour when coughing and sneezing (such as using and disposing of tissues). So it could not make any recommendations in this area.\n\nRecommendations could be made only on hand hygiene and food hygiene interventions. These are for local authorities and for preschool settings, schools and educational and residential settings for young people. While the evidence for young people was from university settings, the committee felt it was transferrable to other similar educational and residential settings for this age group.\n\nMost of the evidence from the reviews considered by the committee was weak or inconsistent. But these recommendations support and signpost people to existing good practice advice issued by other national agencies, such as Public Health England and the NHS website.\n\nThe committee also noted the importance of infection prevention activities that were outside the scope of the guideline such as vaccination programmes and promoting safer sex.\n\nThe majority of studies of hand hygiene took place with children and young people in preschools, primary and secondary schools and university settings. They indicated that it is possible to improve young children\'s handwashing behaviour through interactive education, including instruction and use of handwashing training kits.\n\nThe committee noted the importance of teachers being role models for preventing the spread of infection. It also noted the importance of providing the right facilities and the opportunity to support children to prevent or minimise the spread of infection (for example, by providing liquid soap and tepid running water or handrubs if these are not available). As with the studies on antibiotic use and antimicrobial resistance, the evidence on the effectiveness of hand-hygiene education (based on use of UK Health Security Agency\'s e-Bug website) was mixed. The committee noted that a possible reason was the high level of existing knowledge before the start of an intervention in some of the study populations.\n\nThe committee was concerned that some may misinterpret this finding and wrongly believe that education in schools was not needed. It felt that education in schools was vital, particularly among students who have little or no knowledge of antibiotics. In addition, it agreed that handwashing behaviour is a habitual practice that, if established when young, is more likely to continue throughout life.\n\nThe committee agreed that the combination of education and provision of handrubs may lead to improvements in handwashing behaviour in some populations. For example, there was weak evidence for the effectiveness of providing handrubs along with information posters to university students, and for educational interventions in which people were given handrubs to use at home.\n\nFood hygiene interventions were more likely to be targeted at high-risk groups. The studies found were mostly in the US and were community based. Many focused on improving people\'s knowledge and behaviour about chilling, cooking and washing food. They targeted adults and young people, including:\n\nyoung people in inner cities\n\nparents with low incomes\n\nwomen who were pregnant or caregivers\n\nolder people with a high school education or less\n\nolder women\n\nLatino communities (people of Latin American origin or descent living in North America).\n\nThere were very few studies of educational interventions for schoolchildren on food safety knowledge or practice and the findings were inconsistent.\n\nThe committee noted that some food safety interventions appeared to improve food safety knowledge and practices in the short term. These were:\n\nfood safety campaigns delivered to university students\n\nmass-media campaigns targeting adults or parents\n\ncampaigns delivered through traditional or social media.\n\n# Using resources effectively\n\nThe committee heard expert testimony about the broad and diverse range of national evidence-based resources that are available. These focus both on reducing inappropriate antimicrobial demand and use and on preventing and limiting the spread of infection.\n\nThe committee noted some resources provide information directly to the public in a variety of formats such as videos, posters, leaflets and websites. There are also resources specifically designed to support discussions between people seeking advice on managing self-limiting infections and prescribers and other professionals (such as community pharmacists) who may talk to people about using antimicrobials.\n\nThe committee noted the importance of using or directing people to resources that have been developed through a research-based approach with the target group wherever possible. This ensures consistent, evidence-based messages and an effective use of resources.\n\nMembers also noted the importance of ensuring resources are used effectively. Expert testimony distinguished between using resources passively (for example, displaying posters or leaving leaflets in GP waiting rooms or community pharmacies) and actively referring to them in discussions with people.\n\nThe committee noted the importance of actively sharing resources to support shared decision-making about whether antimicrobials are prescribed. It also noted the potential for using such resources as a tool to convert knowledge into intention to change behaviour and to actual change in behaviour. This is reflected in the recommendations that stress the importance of verbally emphasising key messages in written materials and directing people to further information they can read at home.\n\n# Health economics\n\nInfections and infectious diseases in England cost the NHS an estimated £30\xa0billion per year. Many of these costs are caused by respiratory or gastrointestinal infections (Department of Health\'s Annual report of the Chief Medical Officer 2011: volume\xa02).\n\nThe economic costs of antimicrobial resistance are largely unknown (World Health Organization\'s Antimicrobial resistance: global report on surveillance 2014). The loss of many of the advances in medical care that antimicrobials have supported will be the main economic burden of antimicrobial resistance.\n\nExtremely large economic losses would almost certainly occur if all antimicrobials were rendered ineffectual in the future, even without taking into account the impact on health. So finding ways to delay this will almost certainly be cost effective. However, this cannot be confirmed by modelling because a model would need to be based on assumptions that are not evidence-based.\n\nThe committee agreed that the \'precautionary principle\' could be applied. This is about avoiding or delaying catastrophes by ensuring effective measures are in place. In such circumstances, the burden of proof in relation to effectiveness is on those who do not wish to put precautionary measures in place.\n\nIn the case of antimicrobial resistance, interventions to reduce the spread of resistance could be assumed to be effective unless there was sufficient proof that such interventions are not needed.\n\nGiven that it is most unlikely that the effectiveness of such interventions can be disproved, we also need to determine whether a package of such measures is cost effective compared with no intervention. The rules of decision theory for cost effectiveness no longer apply when analysing antimicrobial stewardship. The effects of antimicrobial resistance are so pervasive that it can be assumed the public sector will no longer act as if they were risk-neutral in assessing an intervention but will be risk averse.\n\nThe scale of the risk of antimicrobial resistance and the complexity of the issue implies that a package of interventions will be needed. The composition of the most cost effective package cannot be determined because of the limitations in the evidence base, but educational components that are cheap and have a potentially large reach are likely to be highly cost effective.\n\n# Evidence reviews\n\nDetails of the evidence discussed are in the evidence reviews.\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement (ES) number 1.1(1) indicates that the linked statement is numbered 1 in review 1 and relates to key question 1. ES1.1(2) indicates that the linked statement is numbered 1 in review 1 and relates to key question 2. ES2.1(1) indicates that the linked statement is numbered 1 in review 2 and relates to key question 1. EP1 indicates that expert paper 1 \'Behaviour change and antibiotic prescribing in healthcare settings: Findings from a literature review and behavioural analysis\' is linked to a recommendation. EP2 indicates that expert paper 2 \'The effectiveness of local and national campaigns in changing the public\'s behaviour to ensure they only ask for antimicrobials when appropriate and use them correctly\' is linked to a recommendation.\n\nIf a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1.1.1: ES3.2(1); EP3, EP7; IDE\n\nRecommendation 1.1.2: ES3.2(1); EP3, EP7; IDE\n\nRecommendation 1.2.1: EP1, EP3; IDE\n\nRecommendation 1.2.2: EP3; IDE\n\nRecommendation 1.2.3: EP1, EP2; IDE\n\nRecommendation 1.2.4: EP2, EP3, EP7; IDE\n\nRecommendation 1.2.5: EP3; IDE\n\nRecommendation 1.3.1: IDE\n\nRecommendation 1.3.2: IDE\n\nRecommendation 1.3.3: EP3; IDE\n\nRecommendation 1.3.4: IDE\n\nRecommendation 1.3.5: ES1.8(2), ES1.9(2), ES1.10(2), ES1.11(2), ES2.3(2); EP6; IDE\n\nRecommendation 1.3.6: ES1.1(3), ES1.4(3); IDE\n\nRecommendation 1.4.1: ES1.10(1); IDE\n\nRecommendation 1.4.2: IDE\n\nRecommendation 1.4.3: IDE\n\nRecommendation 1.4.4: ES1.4(2), ES2.1(2)\n\nRecommendation 1.4.5: IDE\n\nRecommendation 1.4.6: ES1.9(1); IDE\n\nRecommendation 1.4.7: IDE\n\nRecommendation 1.4.8: IDE\n\nRecommendation 1.4.9: IDE\n\nRecommendation 1.4.10: IDE\n\nRecommendation 1.4.11: ES1.6(2), ES1.7(2), ES2.2(2); IDE\n\nRecommendation 1.4.12: IDE\n\nRecommendation 1.4.13: IDE\n\nRecommendation 1.4.14: IDE\n\nRecommendation 1.4.15: EP1, EP4; IDE\n\nRecommendation 1.4.16: ES1.4(3), ES1.8(2), ES1.9(2); IDE\n\nRecommendation 1.5.1: ES1.1(1), ES1.2(1), ES1.4(1); EP1, EP4, EP5\n\nRecommendation 1.5.2: IDE\n\nRecommendation 1.5.3: ES1.3(1), ES1.7(1); EP1, EP5; IDE\n\nRecommendation 1.5.4: ES1.5(1); IDE\n\nRecommendation 1.5.5: ES1.3(1), ES1.5(1); EP1, EP5; IDE\n\nRecommendation 1.5.6: IDE\n\n# Gaps in the evidence\n\nThe committee\'s assessment of the evidence and stakeholder and expert comment on antimicrobial stewardship identified a number of gaps. These gaps are set out below.\n\n. A lack of studies on the feasibility and effectiveness of interventions to change people\'s behaviour in relation to using antimicrobials for conditions other than respiratory illnesses.\n\n(Source: evidence reviews\xa01, 2\xa0and\xa03)\n\n. A lack of studies looking at people in diverse social, cultural and economic circumstances.\n\n(Source: evidence review\xa01)\n\n. A lack of studies evaluating the effectiveness of interventions to change people\'s behaviour relating to antimicrobial use, antimicrobial resistance or infection prevention in workplace settings.\n\n(Source: evidence review\xa01)\n\n. A lack of studies evaluating the effectiveness of interventions to change people\'s behaviour relating to antimicrobial use, antimicrobial resistance or infection prevention in day and residential care settings for older people.\n\n(Source: evidence review\xa01)\n\n. A lack of studies with robust measures of cost effectiveness.\n\n(Source: evidence review\xa01)', 'Recommendations for research': "The guideline committee has made the following recommendations for research to reduce antimicrobial resistance.\n\n# Cost effectiveness\n\nWhat is the cost effectiveness of interventions to prevent infection and promote the appropriate use of antimicrobials?\n\n## Why this is important\n\nLack of studies reporting the costs associated with interventions for either infection prevention or antimicrobial use may act as a barrier to their implementation. Studies with high quality research designs and appropriate cost effectiveness measures are needed to assess this. If research funding bodies ensure cost effectiveness measures are included in research, this will provide the data needed to support the analysis of cost effectiveness.\n\n# Behavioural strategies and programmes\n\nWhat is the feasibility and effectiveness of specific behavioural strategies and programmes to reduce inappropriate antimicrobial demand and use and to prevent infections occurring and spreading?\n\n## Why this is important\n\nAlthough the committee has based its recommendations on the best available evidence, little good-quality published evidence was found about the effectiveness of interventions to reduce antimicrobial resistance and prevent the spread of infection. Better quality studies are needed in this area.\n\n# High-risk groups\n\nWhat interventions to prevent infection and reduce antimicrobial resistance are effective for groups of people at high risk of infection? This includes people who:\n\nhave suppressed immune systems (for example, because of HIV, an inherited condition or treatment they may be having for conditions such as cancer or an organ transplant)\n\nhave a chronic disease\n\nlive in crowded conditions (see Shelter's definition)\n\nare homeless\n\nhave been in prison\n\nhave migrated from countries with a high prevalence of infectious diseases such as tuberculosis (examples include South Asia and sub-Saharan Africa).\n\n## Why this is important\n\nMost interventions have not been designed for people at high risk of acquiring or transmitting infectious diseases and antimicrobial-resistant strains. Interventions for these groups have focused on reducing the use of antibiotics for respiratory illnesses. More interventions are needed to address antimicrobial use for other high-risk conditions.\n\nInterventions that effectively improve handwashing and food safety practices and reduce antimicrobial use in low-risk populations cannot be assumed to be effective for high-risk groups. In addition, the lessons learnt from interventions that lead to appropriate use of antimicrobials in low-risk populations cannot necessarily be transferred to high-risk groups.\n\n# Workplace\n\nHow effective are interventions in the workplace that aim to prevent infection and reduce antimicrobial resistance?\n\n## Why this is important\n\nThe workplace is an important setting for helping to prevent the spread of infection among large numbers of people. Information on what works will have a positive impact on the economy by reducing the potential rise in sickness absence caused by the spread of infectious diseases.\n\nMore UK randomised control trials are needed in a range of workplace settings.\n\n# Older people in day and residential care\n\nHow effective are interventions in day and residential care for older people that aim to prevent infection and to reduce antimicrobial resistance?\n\n## Why this is important\n\nDay and residential care settings for older people are 2\xa0settings where preventing the spread of infection and reducing the risk of antimicrobial resistance are particularly important. This is because many older people are vulnerable to infection as a result of chronic conditions, and there is the risk of infection spreading among large numbers of people. In addition, antimicrobial resistance is increasing in older people, particularly in relation to E.\xa0coli infections of the urinary tract."}	https://www.nice.org.uk/guidance/ng63	This guideline covers making people aware of how to correctly use antimicrobial medicines (including antibiotics) and the dangers associated with their overuse and misuse. It also includes measures to prevent and control infection that can stop people needing antimicrobials or spreading infection to others. It aims to change people’s behaviour to reduce antimicrobial resistance and the spread of resistant microbes.
70772de22537a5d3622e86a52e9631f49b32becf	nice	Ibrutinib for previously treated chronic lymphocytic leukaemia and untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation	Ibrutinib for previously treated chronic lymphocytic leukaemia and untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation Evidence-based recommendations on ibrutinib (Imbruvica) for treating chronic lymphocytic leukaemia in adults. # Recommendations Ibrutinib alone is recommended within its marketing authorisation as an option for treating chronic lymphocytic leukaemia in adults: who have had at least 1 prior therapy or who have a 17p deletion or TP53 mutation, and in whom chemo-immunotherapy is unsuitable and -nly when the company provides ibrutinib with the discount agreed in the patient access scheme.# The technology Description of the technology Ibrutinib (Imbruvica, Janssen) is a covalent inhibitor of Bruton's tyrosine kinase. Marketing authorisation Ibrutinib 'as a single agent is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL)' and 'as a single agent or in combination with bendamustine and rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy'. This appraisal was started before ibrutinib received a license extension to include all 'adult patients with previously untreated chronic lymphocytic leukaemia'. It therefore only includes consideration of the second-line use of ibrutinib in adults with CLL and the first-line use of ibrutinib in patients with a 17p deletion or TP53 mutation when chemo-immunotherapy is unsuitable. Adverse reactions The most common adverse reactions included diarrhoea, neutropenia, haemorrhage (for example, bruising), musculoskeletal pain, nausea, rash and pyrexia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Ibrutinib is administered orally at a daily dose of 420 mg (3 tablets) until disease progression or intolerance. Price The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding VAT; 'British national formulary' online, accessed October 2016). The cost of a year's course of ibrutinib treatment is £55,954.50 (excluding VAT). The company has agreed a patient access scheme with the Department of Health. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Janssen and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of ibrutinib, having considered evidence on the nature of chronic lymphocytic leukaemia (CLL) and the value placed on the benefits of ibrutinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness ## Symptoms and management of chronic lymphocytic leukaemia The committee considered the impact of CLL on patients and their families and carers. The committee heard from patient experts that the uncertainty associated with living with CLL greatly affected their quality of life. The committee understood that people with CLL risk infection, and that recurrent infections are common. The patient experts described how people become isolated from family and friends to protect themselves from infection, which stops people from living a normal life, reduces their contribution to society and can shorten life expectancy. The committee heard from clinical and patient experts that current treatment options are associated with significant adverse effects that are often life threatening, which means that not all people can have these treatments. The clinical experts also stated that, once treatment is stopped because of disease progression, if no other treatment is available, survival is poor and so additional treatment options are very valuable. A patient expert described the fatigue and illness she had experienced with chemotherapy, and said that repeat chemotherapy had resulted in only a short period of remission. The committee understood the importance of having different treatment options available for treating CLL. ## Generalisability of clinical trial results The committee discussed the generalisability of the clinical trial results to the 2 populations in the appraisal: patients with relapsed or refractory CLL who have had at least 1 previous treatment and patients with untreated CLL who have a 17p deletion or TP53 mutation. The committee considered the population who have had at least 1 therapy. It was aware that the key trial (RESONATE, n=391, open label) only included patients who were not eligible for treatment with a purine analogue-based therapy, but that the marketing authorisation does not include this restriction. The committee heard from clinical experts that they would wish to offer ibrutinib to patients who had had at least 1 round of fludarabine-containing chemo-immunotherapy or who otherwise reflected the population in RESONATE. The committee concluded that RESONATE was generalisable to patients who had previously had treatment in clinical practice. The committee considered the untreated population with a 17p deletion or TP53 mutation. It noted that RESONATE had not included patients who had not had previous treatment. The company stated that the treatment effect in patients with a 17p deletion in the RESONATE trial who had previously had treatment (33% of patients) could be generalised to patients who had not had treatment. The committee agreed that, without any evidence, it was unclear how generalisable this was. It noted comments from clinical experts that treating CLL in patients with a 17p deletion with fludarabine plus cyclophosphamide and rituximab may worsen their disease and prognosis. The committee also noted that the single-arm Farooqui et al. (2014) study of ibrutinib presented by the company included a few patients with untreated CLL with a 17p deletion, but that the company did not use this to estimate clinical efficacy. The committee agreed that, in the absence of any evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty. The committee noted that there were no data available specifically for people with a TP53 mutation. It discussed whether the results from the previously treated 17p deletion population from RESONATE could be generalised to people with a TP53 mutation. The clinical experts stated that, while 17p deletion was routinely tested for in the NHS, TP53 mutation was not, but that both were on the same gene locus and tended to occur together in the same people. The committee heard that the clinical experts expected the untreated natural history would be similar in both populations, as would the response from ibrutinib. The committee concluded that it was reasonable to extrapolate data from people with a 17p deletion to people with a TP53 mutation. ## Cancer Drugs Fund proposal to address the uncertainty in the untreated 17p deletion or TP53 mutation population To improve evidence related to people with the 17p deletion or TP53 mutation, the committee had invited the company to submit a proposal for its use in the Cancer Drugs Fund (CDF). The committee understood that the company chose not to apply to the CDF. The company stated that there were already observational data available for this group, and collecting further data through the CDF would not address the uncertainty in this population. In support of this, the company submitted data that showed both median progression-free survival and overall survival were not met at 30‑month follow-up, from a study of 243 patients with 17p deletion (both those who had not had previous treatment and those whose disease had relapsed or was refractory). The committee agreed with the company that data collection through the CDF would not resolve this uncertainty. ## Comparators for the previously treated population The committee discussed the relevant comparators, in the context of current clinical practice in the UK. It noted that NICE's technology appraisal on idelalisib for treating chronic lymphocytic leukaemia recommends idelalisib plus rituximab for CLL in adults with treated disease that has relapsed within 24 months. The clinical experts stated that both ibrutinib and idelalisib have been available on the CDF and, wherever possible, treatment with ibrutinib is preferred because of its effectiveness and because of the adverse effects associated with idelalisib. However, the experts agreed that, in the absence of ibrutinib, clinicians would offer idelalisib plus rituximab. The committee agreed that idelalisib plus rituximab is a comparator. The committee discussed the other comparators included in the scope and the company submission: Bendamustine: the committee heard from the clinical experts that bendamustine is no longer available through the CDF and noted comments during the course of the appraisal that it is not available in NHS practice. The committee noted that the company's marketing data indicated that bendamustine is still being used in practice, but agreed that these estimates were based on small numbers and could reflect exceptional individual funding requests. The committee, at its third meeting, was satisfied that bendamustine is not routinely available and is therefore not an appropriate comparator. Fludarabine plus cyclophosphamide and rituximab: the clinical experts stated that retreating with fludarabine plus cyclophosphamide and rituximab would be an option only after a very long remission, and the committee had agreed that the population relevant for this appraisal was unlikely to be eligible for fludarabine (see section 4.3). Chlorambucil (with or without rituximab) and rituximab monotherapy: the committee heard that these were rarely used in clinical practice and concluded they were not comparators. Corticosteroids (with or without rituximab): the committee heard that corticosteroids were considered a palliative option, and did not consider them a comparator. Ofatumumab: the committee was aware that ofatumumab was the treatment in the control arm of the main ibrutinib trial and that the company included ofatumumab in the decision problem. However, NICE had previously not recommended ofatumumab because ofatumumab was not proven to be clinically or cost effective. Additionally, ofatumumab is no longer available on the CDF. The clinical experts confirmed that, since the availability of idelalisib and ibrutinib, clinicians no longer offer ofatumumab monotherapy to patients. The committee heard from consultees that ibrutinib replaced ofatumumab in the CDF and ofatumumab should therefore be considered an appropriate comparator in this appraisal. However, the committee was clear that, in line with NICE's guide to the methods of technology appraisal 2013, ofatumumab was not an appropriate comparator because it was not considered a clinically effective or a cost-effective use of NHS resources in NICE's technology appraisal guidance on ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. 'Physician's choice': the committee was aware the company had presented a comparison with physician's choice, which is a blended comparator. The committee appreciated that the components of the blended comparator included treatments within the NICE scope. The committee recognised comments from the clinical experts and the evidence review group (ERG) that the composition presented by the company did not reflect the treatments offered in the UK. The committee also had concerns about using a blended comparator because this approach averages the cost effectiveness of the treatments included, masking the cost effectiveness of the individual treatments. Therefore, there is a risk of displacing clinically and cost-effective treatment options that are included within the blended comparator. The committee noted comments from the company that, because the data were taken from a single trial (Osterborg et al. 2016) rather than individual datasets, physician's choice was not a blended comparator as such. The committee was aware that the 'blending' referred to the mix of therapies, and not to a mix of trials contributing to the evidence. The ERG highlighted that bendamustine plus rituximab comprises 35% of physician's choice in the company's submission. The committee agreed that this was problematic, because bendamustine plus rituximab was a separate comparator in this appraisal. By contrast, physician's choice included treatments that, although included in the scope, were not considered to be comparators by the committee based on advice from the clinical experts, for example, methylprednisolone plus rituximab (25%), or fludarabine plus cyclophosphamide and rituximab (10%). The committee also considered that where different comparators can be identified for identifiable patient groups, these should be discussed as separate subgroups. The committee concluded that physician's choice was not an appropriate comparator. Best supportive care: before the committee's second meeting of this appraisal, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) published safety concerns for idelalisib. The committee recognised that for some people, idelalisib plus rituximab may not be a treatment option. With no other treatment options available, the committee considered that comparing ibrutinib with best supportive care (which was listed in the scope) would be useful. The company explained that clinicians aim to offer active treatments, and that no standard definition of best supportive care is available.The committee concluded that idelalisib plus rituximab was the most relevant comparator in clinical practice for patients who had relapsed within 2 years, and for those who cannot take idelalisib plus rituximab, best supportive care was the best comparator. ## Comparators for the untreated 17p deletion or TP53 mutation population The committee heard that alemtuzumab was previously offered to people with a 17p deletion or TP53 mutation, but is difficult to obtain because the company for alemtuzumab has limited the marketing authorisation to multiple sclerosis. The committee concluded that this was not an appropriate comparator. The committee noted that NICE's technology appraisal on idelalisib for treating chronic lymphocytic leukaemia recommends idelalisib plus rituximab for untreated CLL in adults with a 17p deletion or TP53 mutation. At its second meeting, the committee was made aware of recent provisional advice by the EMA on idelalisib following a number of serious adverse events in some post-marketing trials. The committee noted that the advice included not starting treatment in people with a 17p deletion or TP53 mutation who had not had previous treatment. At its third meeting, the committee noted that the EMA's Committee for Medicinal Products for Human Use had confirmed that the benefits of idelalisib outweigh the risk of side effects and had now concluded that idelalisib 'can again be initiated in these patients provided they cannot take any alternative treatment and that the measures agreed to prevent infection are followed'. The committee was aware that, in the absence of idelalisib, people with untreated CLL and a 17p deletion or TP53 mutation have no treatment options, and recognised the unmet need in this population. The committee therefore agreed that the relevant comparators for this group were idelalisib plus rituximab or best supportive care. ## Clinical effectiveness of ibrutinib compared with ofatumumab (randomised controlled trial evidence) The committee considered the clinical evidence that came from the randomised controlled RESONATE trial which compared ibrutinib with ofatumumab. The committee noted that after a positive interim analysis the trial terminated early, when the median time in the trial was 9.4 months. The committee acknowledged that the company had re-analysed the data at a median 16‑month follow-up and at a median of 30 months of follow-up. After a median of 16 months, the median progression-free survival had not been reached with ibrutinib; that is, fewer than half of the people randomised to ibrutinib had progressed disease, while for patients randomised to ofatumumab the median progression-free survival was 8.1 months (hazard ratio 0.106, 95% confidence interval 0.073 to 0.153, p<0.0001). At its second meeting, the committee noted that the company presented data from a median 30‑month follow-up that supported the results in its submission. The committee agreed that the results from RESONATE showed that ibrutinib was a very effective therapy, a conclusion that the clinical experts supported. It was clear that the 'immaturity' of the data reflected the effectiveness of ibrutinib and viewed this positively. However, the committee was mindful that it did mean that a greater proportion of the modelled time horizon depended on extrapolations. The committee agreed that the trial showed ibrutinib extended progression-free survival compared with ofatumumab. ## Clinical effectiveness of ibrutinib compared with idelalisib plus ofatumumab (indirect treatment comparison) The committee considered the indirect treatment comparisons conducted by the company, and specifically the comparison of overall survival between ibrutinib with idelalisib plus ofatumumab. The common comparator was ofatumumab. The committee noted that the company adjusted the trial results of RESONATE (which compared ibrutinib with ofatumumab) to account for crossover at disease progression. It agreed that this was appropriate, recognising that the unadjusted hazard ratio for death from the RESONATE trial would underestimate ibrutinib's effectiveness relative to ofatumumab. However, the committee noted that the company did not adjust the hazard ratio from the Jones et al. (2015) trial (also known as the 119 trial, and which compared idelalisib plus ofatumumab with ofatumumab) to account for treatment switching to ibrutinib. The committee heard from the company that it did not adjust for crossover in the 119 trial because this trial did not allow crossover to idelalisib. However, it heard from clinical experts that they considered it very likely that, after progression, patients leaving the trial would go on to receive other life-extending therapies, including ibrutinib, because of a compassionate-use programme for ibrutinib in place at the time. The company stated that this treatment switching was not within the trial period and so it did not believe that adjusting was appropriate. However, distinguishing between crossover to the intervention within a trial and switching treatments, the committee considered that adjusting for treatment switching within the idelalisib trial was appropriate because, based on what it had heard and read in the consultation comments, it was likely that more patients randomised to placebo (compared with idelalisib) in the 119 trial received treatments that both extended life and were not part of standard NHS practice. The committee was aware of the NICE Decision Support Unit document on treatment switching, which supports adjusting for post-study therapies that do not reflect routine care.The committee agreed that the treatment switching to ibrutinib that occurred after the 119 trial was relevant when determining the relative effectiveness of ibrutinib and idelalisib. The committee discussed how to account for the effect of the treatment switching that occurred after the 119 trial on the relative effectiveness of ibrutinib and idelalisib. It recognised that the company did not have access to the data from the 119 trial, so could not adjust this data. The committee considered the options available, which were either to adjust the data from the RESONATE trial only, or to adjust neither trial's data. The committee noted that it had not seen any data to quantify the extent to which switching to ibrutinib occurred after the 119 trial. The committee concluded that the true estimates of the clinical benefit of ibrutinib compared with idelalisib plus rituximab would likely be weaker than, but closer to, the company's estimates of clinical effectiveness when adjusting only the RESONATE data for crossover, compared with estimates based on not adjusting data from either trial. The committee considered the clinical benefits of treatment with ibrutinib compared with idelalisib. The committee noted the promising results associated with ibrutinib. The committee heard from the patient experts about how ibrutinib had changed their lives, and provides long-lasting progression-free survival for many patients. The committee heard from clinical experts that ibrutinib is very well tolerated in most patients. It noted that some adverse reactions can be serious but are manageable, and are less severe than those seen with other treatments for CLL. It heard from clinicians that, because of the risks associated with idelalisib (see section 4.8), their preference would be to offer ibrutinib. The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain. ## Idelalisib plus ofatumumab as a proxy for idelalisib plus rituximab The committee noted that the scope included idelalisib plus rituximab as a comparator, but that the company presented results for idelalisib plus ofatumumab rather than idelalisib plus rituximab. The committee was aware that a double-blind randomised controlled trial comparing rituximab with idelalisib plus rituximab (Sharman et al. 2014, also known as the 116 trial) formed the key evidence for NICE's decision on idelalisib. It questioned why the company had not included this in its network of studies. The company stated that it did not include the 116 trial within a matching-adjusted indirect comparison (MAIC) because the trial had substantial limitations, including differences to RESONATE in trial design, follow-up and crossover and, in its opinion, an indirect comparison of ibrutinib with idelalisib plus ofatumumab provided more robust results. The committee noted that, after consultation, the company presented results from an MAIC including the 116 trial for progression-free survival, but the ERG was unable to verify the results because the analyses lacked statistical details. The committee understood that the company did not include a comparison between ibrutinib and idelalisib plus rituximab because it considered that idelalisib plus ofatumumab was a proxy for idelalisib plus rituximab. The company also stated that, in the appraisal of idelalisib, the committee had accepted that rituximab and ofatumumab were equally effective. However, the committee noted that, in the idelalisib appraisal, it was rituximab and ofatumumab monotherapy that were accepted as being equal, rather than each in combination with idelalisib. The company stated that it was not plausible that the efficacy would differ in combination. The committee heard from the clinical experts that idelalisib plus ofatumumab and idelalisib plus rituximab could be considered equivalent in terms of effectiveness.The committee agreed there were uncertainties around the company's assumptions when comparing ibrutinib with idelalisib plus rituximab. On balance, the committee concluded that the company's assumption that idelalisib plus rituximab is equivalent to idelalisib plus ofatumumab was reasonable. ## Clinical effectiveness of ibrutinib compared with best supportive care (using physician's choice as a proxy for best supportive care) The committee was aware the company had not compared ibrutinib with best supportive care for people who cannot take idelalisib plus rituximab. The committee discussed whether physician's choice could be considered a proxy for best supportive care in people who cannot have idelalisib plus rituximab. However, the committee considered that this was problematic because bendamustine plus rituximab comprises 35% of physician's choice. The committee noted that taking bendamustine out of the mix would lower the cost, but also the effectiveness, of physician's choice. Without formal analyses, it concluded that it could not judge the impact this would have on clinical and cost effectiveness. The committee discussed whether ofatumumab would be a proxy for best supportive care. It noted that, in the Osterborg et al. trial, in the intention-to-treat analyses, patients randomised to ofatumumab lived longer than patients randomised to physician's choice (despite patients crossing over from the physician's choice arm) and therefore ofatumumab was unlikely to reflect best supportive care. The committee concluded that it was not presented with any evidence which compared ibrutinib with best supportive care. However, it concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab. ## Using ibrutinib after idelalisib in the treatment pathway The committee noted that, in clinical practice, ibrutinib could be used after idelalisib. It heard from clinical experts that they would be keen to offer ibrutinib if idelalisib failed, or if patients had stopped idelalisib because of adverse events. The committee, however, was not presented with any data for using ibrutinib after idelalisib. The committee concluded that it could not consider ibrutinib for this setting. # Cost effectiveness The committee considered the assumptions in the company's economic model. The committee noted that a key assumption made by the company was a constant benefit from ibrutinib over the entire course of the model. It heard from clinical experts that the benefits of ibrutinib were likely to decrease over time. The committee noted that a scenario analysis done by the ERG, which reduced the duration of ibrutinib's benefits to 5 years, increased the incremental cost-effectiveness ratio (ICER) for ibrutinib compared with idelalisib plus rituximab. The committee agreed to consider this analysis as part of its decision-making. The committee considered the company's extrapolations of data from RESONATE for progression-free survival and overall survival over the 20‑year time horizon of the model. The committee and the ERG noted that data were immature (see section 4.11) which the committee acknowledged may reflect a successful treatment effect, but which led to uncertainty. The committee considered how overall survival was modelled. It recognised that, during consultation, the company had agreed with the committee that the Weibull function provided the best fit of the options presented. The committee considered how progression-free survival was modelled. The committee noted that the model predicted that some patients live with progressed disease for an improbably long time before dying, recalling that the clinicians observed that patients do not live for long periods with progressed disease. It recognised that the choice of statistical model for extrapolating progression-free survival determined this. The committee noted that the ERG suggested that the exponential function provided a more credible period of time in progressed disease, whereas the company suggested the Weibull function provided a better fit for the data.The committee noted that the choice of model to extrapolate progression-free survival from RESONATE was a key driver of the cost-effectiveness results. The committee agreed that the Weibull function resulted in implausibly long survival after disease progression (estimates marked commercial in confidence by the company). The committee concluded that it preferred the exponential distributions. The committee considered the model inputs for the 17p deletion and TP53 populations. The committee noted that most of the comparator data in the economic model were not specific to this population. This included the hazard ratios for progression-free and overall survival, which were based on the overall population. It was aware of the lack of evidence in these subgroups, and agreed that data from the overall population was the best available and could be used to support decision-making in the untreated 17p deletion and TP53 mutation populations. ## Time horizon The committee considered the time horizon used by the company in its modelling. The committee noted that the company used a 20‑year horizon in its base case, and conducted sensitivity analyses varying this to 10 years and 30 years. The committee noted that the ICERs were sensitive to the time horizon chosen, and the ICER increased with shorter time horizons. The ERG commented that 20 years may be too short a time horizon because, according to the company model, people treated with ibrutinib would still be alive at the end of this time period. By contrast, the committee heard from clinical experts that a time horizon of 20 years might be too long because the population had a mean starting age of 67 years. The committee concluded that, although there was some uncertainty about the most appropriate time horizon, it accepted that the 20‑year time horizon was suitable for decision-making. ## Treatment duration The committee understood that time to progression determines treatment duration, which in turn determines the cost of treatment. Having heard that clinicians in the NHS may continue to offer ibrutinib after disease progression, the committee considered that this could contribute to costs higher than those modelled by the company. The committee considered that it might also contribute to greater benefits than stopping treatment at disease progression, but did not see any evidence to support this. The committee noted that the summary of product characteristic states that treatment should continue only until disease progression or when it is no longer tolerated by the patient. The committee therefore concluded to consider only the costs and benefits of treatment until progression in the modelling. ## Modelling the level of response to treatment The committee noted that for patients in the progression-free health state, costs of routine follow-up were determined by disease response to treatment as measured in RESONATE. The committee heard from clinical experts that patients whose disease has responded to treatment would not be followed up at different intervals depending on the level of response to treatment. After consultation on the first appraisal consultation document, the company maintained that response level should determine routine follow-up and inpatient costs. The ERG agreed with the company that it may be more reasonable to equalise costs at the level of partial response, but stated that the company had not shown that rates of admission to hospital differ by response status. The committee concluded that, after consultation on the first appraisal consultation document, the company had corrected most imbalances in the costs, and that the costs of routine follow-up had a negligible impact on the ICERs. ## Utility values The committee considered the evidence on health-related quality of life presented by the company. The committee noted that the company had collected EQ‑5D data in RESONATE. The committee noted that the quality-of-life values collected at baseline before treatment did not differ much from those collected during either treatment. The clinical experts commented that this did not reflect their clinical experience, stating that symptoms improve immediately with ibrutinib and patients usually have a good quality of life unless they have an adverse event. Having heard the positive experience of patients with ibrutinib, particularly with regard to energy levels and few side effects, the committee was concerned that benefits may not have been appropriately captured, noting that the EQ‑5D does not directly measure fatigue. After consultation on the first appraisal consultation document, the company applied a utility increment for ibrutinib. The committee heard from the ERG that this increment was derived from EQ‑5D data, so did not resolve the committee's concerns about the sensitivity of the EQ‑5D. Also, this increment was based on the quality-of-life difference between idelalisib and rituximab treatment. The ERG noted that it was not appropriate to apply this as an additional increment to the EQ‑5D quality-of-life estimate for ibrutinib. The committee was aware that this had a minor impact on the results. The committee concluded that the EQ‑5D may not have captured the experience of people with CLL, and the base case may have underestimated the quality-of-life benefit with ibrutinib. The committee considered the utility value for post-progression applied in the company's model. The committee heard from the clinical experts that they would not expect utility in the post-progression health state to be as high as assumed by the company. The committee was also aware that the company did not age-adjust the utilities. After consultation on the first appraisal consultation document, the company provided age-adjusted utility values, and chose a lower utility value in the post-progression state (0.60). The committee noted that this had a small impact on the ICERs. The committee agreed with these 2 changes. ## Cost-effectiveness results The committee considered the cost effectiveness of ibrutinib based on the evidence available. The committee reiterated that these ICERs were associated with uncertainty relating to efficacy estimates, utility values and long-term outcomes. The committee noted that the company's results did not reflect all its preferred assumptions, but was aware that exploratory analyses conducted by the ERG addressing many of these assumptions. These included: using the exponential function to extrapolate the overall survival and progression-free Kaplan–Meier survival curves from RESONATE removing the asymmetries in the modelling where the direct drug costs and administration costs associated with ibrutinib were treated differently from other comparators removing the costs of repeated biopsies.The committee was also aware that these ICERs did not include the ERG's exploration of limiting the duration of benefit with ibrutinib to 5 years. The committee recalled that this would increase the committee's preferred ICERs. The committee acknowledged that, after recent advice from the EMA on idelalisib, the costs associated with the adverse effects from idelalisib were likely to increase, which may improve the cost effectiveness of ibrutinib compared with idelalisib. Additionally, the ERG explored the upper bound of the ICER by not adjusting the results of the RESONATE trial for crossover (see section 4.13). The committee considered that the true ICER was likely to fall between the results of the ERG scenarios that did or did not adjust for crossover in the RESONATE trial. The committee considered the ICERs including the updated ibrutinib patient access scheme and the patient access scheme for idelalisib. It noted that the ERG scenario without adjusting for crossover in the RESONATE trial was around £50,000 per quality-adjusted life year (QALY) gained, and the scenario adjusting for crossover was below £50,000 per QALY gained. # Innovation The committee discussed whether it could consider ibrutinib innovative. The committee heard from both the patient and clinical experts that ibrutinib was an important new technology in treating CLL. The committee heard that patients appreciated how well the treatment worked and how easy it was to take, being an oral treatment. The committee heard from the company that ibrutinib is a 'first-in-class' treatment. The committee also heard that some of the benefits of ibrutinib may not have been captured in the modelling, such as the impact on fatigue. The committee concluded that ibrutinib is an innovative treatment. # End of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee considered the short life-expectancy criterion, that is, whether the patient group with CLL included in this appraisal would normally live less than 24 months. The committee was aware that before idelalisib had been recommended as a treatment option, people lived for a shorter length of time. The committee noted that the mean overall survival associated with idelalisib plus rituximab (and on which the NICE decision on idelalisib plus rituximab was based) was estimated to be 21.6 months. The committee noted that no evidence was provided about the life expectancy of people with a 17p deletion or TP53 mutation. However, it was aware that this population probably has a worse prognosis. The committee agreed that the criterion for short life expectancy was met. The committee discussed whether ibrutinib extended life by an average of at least 3 additional months, first considering the previously treated population. The committee acknowledged the uncertainty around the long-term efficacy results from RESONATE (see section 4.11). The committee also noted the estimates for median survival in the overall population from the model (these are commercial in confidence and so are not presented here). The committee recognised the uncertainty in the economic modelling, but concluded that, even with confounding in the indirect comparisons, ibrutinib was likely to extend life more than 3 months compared with idelalisib plus rituximab. The committee noted that there was far greater uncertainty in the degree to which ibrutinib extends life for people with a 17p deletion or TP53 mutation. The committee acknowledged comments from experts that ibrutinib is very effective in this population. On balance, the committee was satisfied that ibrutinib met the extension-to-life criterion. The committee concluded that both end-of-life criteria had been met for the populations in this appraisal. # Conclusions The committee considered all the evidence presented to it. It agreed that ibrutinib represented an important and effective treatment in CLL. The committee was satisfied that, in both populations of this appraisal and with the patient access scheme offered by the company, the ICERs for ibrutinib fell within the range normally considered as a cost-effective use of NHS resources for a treatment that fulfils the end-of-life criteria. # Pharmaceutical Price Regulation Scheme 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA429 Appraisal title: Ibrutinib for previously treated chronic lymphocytic leukaemia and untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation Section Key conclusion Ibrutinib alone is recommended within its marketing authorisation as an option for treating chronic lymphocytic leukaemia (CLL) in adults: who have had at least 1 prior therapy or who have a 17p deletion or TP53 mutation, and in whom chemo-immunotherapy is unsuitable and -nly when the company provides ibrutinib with the discount agreed in the patient access scheme. The committee concluded that idelalisib plus rituximab was the most relevant comparator and, for those who cannot take idelalisib plus rituximab, best supportive care was the best comparator in both populations. The committee was aware that it had not been presented with evidence comparing ibrutinib with best supportive care. The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain. No evidence was presented for ibrutinib compared with best supportive care. However, the committee concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab. The committee agreed that ibrutinib represented an important and effective treatment in CLL. It was satisfied that, in both populations of this appraisal, the incremental cost-effectiveness ratios (ICERs) for ibrutinib fell within the range normally considered as a cost-effective use of NHS resources for a treatment that fulfils the end-of-life criteria, when incorporating the confidential updated patient access scheme for ibrutinib and the existing patient access scheme for idelalisib. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard from clinical and patient experts that current treatment options are associated with significant adverse effects that are often life threatening. The committee understood the importance of the availability of different treatment options for treating CLL. The committee concluded that idelalisib plus rituximab was the most relevant comparator in clinical practice for patients who had relapsed within 2 years and, for those who cannot take idelalisib plus rituximab, best supportive care was the alternative. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain. It also concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab. The committee heard from both the patient and clinical experts that ibrutinib was an important new technology in treating CLL. The committee heard that patients appreciated how well the treatment worked and how easy it was to take, being an oral treatment. The committee heard from the company that ibrutinib is a 'first-in-class' treatment. The committee also heard that some of the benefits of ibrutinib may not have been captured in the modelling, such as the impact on fatigue. The committee concluded that ibrutinib is an innovative treatment. What is the position of the treatment in the pathway of care for the condition? The committee heard from clinical experts that they would wish to offer ibrutinib to patients with CLL who have received at least 1 prior treatment with fludarabine and, as first-line therapy, for people with a 17p deletion or TP53 mutation. The committee also noted that, in clinical practice, ibrutinib could be used after idelalisib, but it was not presented with any data for using ibrutinib after idelalisib. It concluded that ibrutinib could not be considered for this setting. Adverse reactions The committee concluded that ibrutinib was likely to offer a more preferable toxicity profile than the currently available treatment options. Evidence for clinical effectiveness Availability, nature and quality of evidence The key clinical evidence for the previously treated population was the RESONATE trial. The committee noted that, after a positive interim analysis, the RESONATE trial was stopped early, when the median time on-trial was 9.4 months. At its second meeting, the committee noted that the company presented data from a median 30‑month follow-up. The committee understood that, in RESONATE, the comparison was with ofatumumab, which is neither recommended at this position in the treatment pathway by NICE, nor used in UK clinical practice. The committee was aware that no data were available for people with untreated CLL who have a 17p deletion or TP53 mutation. The committee noted comments from clinical experts that treating patients with a 17p deletion with fludarabine plus cyclophosphamide and rituximab worsened their disease and prognosis. The committee agreed that, in the absence of this evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty. The committee noted that there were no data available for people with a TP53 mutation, but concluded that it was reasonable to extrapolate data from people with a 17p deletion to people with a TP53 mutation. The committee noted that, in clinical practice, ibrutinib could be used after idelalisib. The committee was not presented with any data for using ibrutinib after idelalisib. The committee concluded that ibrutinib could not be considered for this setting. Relevance to general clinical practice in the NHS The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain. Uncertainties generated by the evidence The committee noted that data were immature (notably, median progression-free survival and overall survival had not been reached in the ibrutinib arm of RESONATE), which the committee acknowledged may reflect a successful treatment effect, but which led to uncertainty. The committee noted that the scope included idelalisib plus rituximab as a comparator, but that the company presented results for idelalisib plus ofatumumab rather than idelalisib plus rituximab. It was aware that a double-blind randomised controlled trial comparing rituximab with idelalisib plus rituximab (Sharman et al. 2014, also known as the 116 trial) formed the key evidence for NICE's decision on idelalisib. The committee understood that the company considered that idelalisib plus ofatumumab was a proxy for idelalisib plus rituximab. The committee heard from the clinical experts that idelalisib plus ofatumumab and idelalisib plus rituximab could be considered equivalent in terms of efficacy. Therefore, it agreed there were uncertainties around the assumptions when comparing ibrutinib with idelalisib plus rituximab, but concluded that the company's assumption that idelalisib plus rituximab is equivalent to idelalisib plus ofatumumab was reasonable. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee was aware that no data were available for people with untreated CLL who have a 17p deletion or TP53 mutation. The committee agreed that, in the absence of any evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty. The committee also noted that there were no data available specifically for people with a TP53 mutation, but concluded that it was reasonable to extrapolate data from people with a 17p deletion to people with a TP53 mutation. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain. The committee concluded that the true estimates of the clinical benefit of ibrutinib compared with idelalisib and rituximab would likely be weaker than, but closer to, the company's estimates of clinical effectiveness when adjusting only the RESONATE data for crossover compared with estimates based on not adjusting data from either trial. Evidence for cost effectiveness Availability and nature of evidence The committee concluded that idelalisib plus rituximab was the most relevant comparator and these results were presented by the company. The committee considered that, for people who cannot take idelalisib plus rituximab, best supportive care was the best comparator. The committee was aware that it had not been presented with evidence comparing ibrutinib with best supportive care. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee was clear that the 'immaturity' of the data in RESONATE reflected the effectiveness of the drug and viewed this positively. However, the committee was mindful that it did mean that a greater proportion of the modelled time horizon depended on extrapolations. The company assumed constant benefit from ibrutinib over the entire course of the model. It heard from clinical experts that the benefits of ibrutinib were likely to decrease over time. The committee noted a scenario analysis done by the evidence review group (ERG), which reduced the duration of ibrutinib's benefits to 5 years. The committee concluded that there was considerable uncertainty around the extrapolations in the company's model, and it preferred the exponential distributions. The committee considered the model inputs for the 17p deletion and TP53 mutation populations and noted that most of the data in the economic model were based on the overall population. Additionally, the committee remained unsure of whether the results could be extended to people with untreated CLL but, given the lack of evidence, it concluded that data from the overall population was the best available and could be used to support decision-making in the untreated 17p deletion and TP53 mutation populations. The committee concluded that, although there was some uncertainty about the most appropriate time horizon, it accepted that the 20‑year time horizon was suitable for decision-making. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The quality-of-life values collected at baseline before treatment did not differ much from those collected during treatment in both arms of RESONATE. The clinical experts commented that this did not reflect clinical experience, stating that symptoms improve immediately with ibrutinib. Having heard the positive experience of patients with ibrutinib, particularly with regard to energy levels and lack of side effects, the committee was concerned that the quality-of-life benefits may not have been appropriately captured. It also considered the utility increment applied by the company and noted the ERG's concern that it was inappropriate. The committee was aware that this had a minor impact on the results. The committee concluded that the EQ‑5D may not have captured the experience of people with CLL, and the base case may have underestimated the quality-of-life benefit with ibrutinib. Are there specific groups of people for whom the technology is particularly cost effective? No. What are the key drivers of cost effectiveness? The key drivers of cost effectiveness are the choice of Kaplan–Meier parametric curve, time horizon and length of time of benefit with ibrutinib. Most likely cost-effectiveness estimate (given as an ICER) Based on the committee's preferred assumptions, the committee considered that true ICER was likely to fall between the results of the ERG scenarios that did or did not adjust for crossover in the RESONATE trial. The committee considered the ICERs that included the updated ibrutinib patient access scheme and the patient access scheme for idelalisib. It noted that the ERG scenario without an adjustment for crossover was around £50,000 per quality-adjusted life year (QALY) gained and the scenario with this adjustment was below £50,000 per QALY gained. Additional factors taken into account End-of-life considerations The committee concluded that the end-of-life criteria had been met for the populations in this appraisal. Equalities considerations and social value judgements No equality issues were raised during the appraisal.	{'Recommendations': 'Ibrutinib alone is recommended within its marketing authorisation as an option for treating chronic lymphocytic leukaemia in adults:\n\nwho have had at least 1\xa0prior therapy or\n\nwho have a 17p\xa0deletion or TP53\xa0mutation, and in whom chemo-immunotherapy is unsuitable and\n\nonly when the company provides ibrutinib with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nIbrutinib (Imbruvica, Janssen) is a covalent inhibitor of Bruton's tyrosine kinase.\n\nMarketing authorisation\n\nIbrutinib 'as a single agent is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL)' and 'as a single agent or in combination with bendamustine and rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy'.\n\nThis appraisal was started before ibrutinib received a license extension to include all 'adult patients with previously untreated chronic lymphocytic leukaemia'. It therefore only includes consideration of the second-line use of ibrutinib in adults with CLL and the first-line use of ibrutinib in patients with a 17p\xa0deletion or TP53\xa0mutation when chemo-immunotherapy is unsuitable.\n\nAdverse reactions\n\nThe most common adverse reactions included diarrhoea, neutropenia, haemorrhage (for example, bruising), musculoskeletal pain, nausea, rash and pyrexia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nIbrutinib is administered orally at a daily dose of 420\xa0mg (3\xa0tablets) until disease progression or intolerance.\n\nPrice\n\nThe list price for a single tablet of ibrutinib (140\xa0mg) is £51.10 (excluding VAT; 'British national formulary' [BNF] online, accessed October 2016). The cost of a year's course of ibrutinib treatment is £55,954.50 (excluding VAT). The company has agreed a patient access scheme with the Department of Health. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Janssen and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of ibrutinib, having considered evidence on the nature of chronic lymphocytic leukaemia (CLL) and the value placed on the benefits of ibrutinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\n## Symptoms and management of chronic lymphocytic leukaemia\n\nThe committee considered the impact of CLL on patients and their families and carers. The committee heard from patient experts that the uncertainty associated with living with CLL greatly affected their quality of life. The committee understood that people with CLL risk infection, and that recurrent infections are common. The patient experts described how people become isolated from family and friends to protect themselves from infection, which stops people from living a normal life, reduces their contribution to society and can shorten life expectancy. The committee heard from clinical and patient experts that current treatment options are associated with significant adverse effects that are often life threatening, which means that not all people can have these treatments. The clinical experts also stated that, once treatment is stopped because of disease progression, if no other treatment is available, survival is poor and so additional treatment options are very valuable. A patient expert described the fatigue and illness she had experienced with chemotherapy, and said that repeat chemotherapy had resulted in only a short period of remission. The committee understood the importance of having different treatment options available for treating CLL.\n\n## Generalisability of clinical trial results\n\nThe committee discussed the generalisability of the clinical trial results to the 2\xa0populations in the appraisal:\n\npatients with relapsed or refractory CLL who have had at least 1\xa0previous treatment and\n\npatients with untreated CLL who have a 17p\xa0deletion or TP53\xa0mutation.\n\nThe committee considered the population who have had at least 1\xa0therapy. It was aware that the key trial (RESONATE, n=391, open label) only included patients who were not eligible for treatment with a purine analogue-based therapy, but that the marketing authorisation does not include this restriction. The committee heard from clinical experts that they would wish to offer ibrutinib to patients who had had at least 1\xa0round of fludarabine-containing chemo-immunotherapy or who otherwise reflected the population in RESONATE. The committee concluded that RESONATE was generalisable to patients who had previously had treatment in clinical practice.\n\nThe committee considered the untreated population with a 17p\xa0deletion or TP53\xa0mutation. It noted that RESONATE had not included patients who had not had previous treatment. The company stated that the treatment effect in patients with a 17p\xa0deletion in the RESONATE trial who had previously had treatment (33% of patients) could be generalised to patients who had not had treatment. The committee agreed that, without any evidence, it was unclear how generalisable this was. It noted comments from clinical experts that treating CLL in patients with a 17p\xa0deletion with fludarabine plus cyclophosphamide and rituximab may worsen their disease and prognosis. The committee also noted that the single-arm Farooqui et al. (2014) study of ibrutinib presented by the company included a few patients with untreated CLL with a 17p\xa0deletion, but that the company did not use this to estimate clinical efficacy. The committee agreed that, in the absence of any evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty.\n\nThe committee noted that there were no data available specifically for people with a TP53\xa0mutation. It discussed whether the results from the previously treated 17p\xa0deletion population from RESONATE could be generalised to people with a TP53\xa0mutation. The clinical experts stated that, while 17p\xa0deletion was routinely tested for in the NHS, TP53\xa0mutation was not, but that both were on the same gene locus and tended to occur together in the same people. The committee heard that the clinical experts expected the untreated natural history would be similar in both populations, as would the response from ibrutinib. The committee concluded that it was reasonable to extrapolate data from people with a 17p\xa0deletion to people with a TP53\xa0mutation.\n\n## Cancer Drugs Fund proposal to address the uncertainty in the untreated 17p\xa0deletion or TP53\xa0mutation population\n\nTo improve evidence related to people with the 17p\xa0deletion or TP53\xa0mutation, the committee had invited the company to submit a proposal for its use in the Cancer Drugs Fund (CDF). The committee understood that the company chose not to apply to the CDF. The company stated that there were already observational data available for this group, and collecting further data through the CDF would not address the uncertainty in this population. In support of this, the company submitted data that showed both median progression-free survival and overall survival were not met at 30‑month follow-up, from a study of 243\xa0patients with 17p\xa0deletion (both those who had not had previous treatment and those whose disease had relapsed or was refractory). The committee agreed with the company that data collection through the CDF would not resolve this uncertainty.\n\n## Comparators for the previously treated population\n\nThe committee discussed the relevant comparators, in the context of current clinical practice in the UK. It noted that NICE's technology appraisal on idelalisib for treating chronic lymphocytic leukaemia recommends idelalisib plus rituximab for CLL in adults with treated disease that has relapsed within 24\xa0months. The clinical experts stated that both ibrutinib and idelalisib have been available on the CDF and, wherever possible, treatment with ibrutinib is preferred because of its effectiveness and because of the adverse effects associated with idelalisib. However, the experts agreed that, in the absence of ibrutinib, clinicians would offer idelalisib plus rituximab. The committee agreed that idelalisib plus rituximab is a comparator.\n\nThe committee discussed the other comparators included in the scope and the company submission:\n\nBendamustine: the committee heard from the clinical experts that bendamustine is no longer available through the CDF and noted comments during the course of the appraisal that it is not available in NHS practice. The committee noted that the company's marketing data indicated that bendamustine is still being used in practice, but agreed that these estimates were based on small numbers and could reflect exceptional individual funding requests. The committee, at its third meeting, was satisfied that bendamustine is not routinely available and is therefore not an appropriate comparator.\n\nFludarabine plus cyclophosphamide and rituximab: the clinical experts stated that retreating with fludarabine plus cyclophosphamide and rituximab would be an option only after a very long remission, and the committee had agreed that the population relevant for this appraisal was unlikely to be eligible for fludarabine (see section\xa04.3).\n\nChlorambucil (with or without rituximab) and rituximab monotherapy: the committee heard that these were rarely used in clinical practice and concluded they were not comparators.\n\nCorticosteroids (with or without rituximab): the committee heard that corticosteroids were considered a palliative option, and did not consider them a comparator.\n\nOfatumumab: the committee was aware that ofatumumab was the treatment in the control arm of the main ibrutinib trial and that the company included ofatumumab in the decision problem. However, NICE had previously not recommended ofatumumab because ofatumumab was not proven to be clinically or cost effective. Additionally, ofatumumab is no longer available on the CDF. The clinical experts confirmed that, since the availability of idelalisib and ibrutinib, clinicians no longer offer ofatumumab monotherapy to patients. The committee heard from consultees that ibrutinib replaced ofatumumab in the CDF and ofatumumab should therefore be considered an appropriate comparator in this appraisal. However, the committee was clear that, in line with NICE's guide to the methods of technology appraisal 2013, ofatumumab was not an appropriate comparator because it was not considered a clinically effective or a cost-effective use of NHS resources in NICE's technology appraisal guidance on ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab.\n\n'Physician's choice': the committee was aware the company had presented a comparison with physician's choice, which is a blended comparator. The committee appreciated that the components of the blended comparator included treatments within the NICE scope. The committee recognised comments from the clinical experts and the evidence review group (ERG) that the composition presented by the company did not reflect the treatments offered in the UK. The committee also had concerns about using a blended comparator because this approach averages the cost effectiveness of the treatments included, masking the cost effectiveness of the individual treatments. Therefore, there is a risk of displacing clinically and cost-effective treatment options that are included within the blended comparator. The committee noted comments from the company that, because the data were taken from a single trial (Osterborg et al. 2016) rather than individual datasets, physician's choice was not a blended comparator as such. The committee was aware that the 'blending' referred to the mix of therapies, and not to a mix of trials contributing to the evidence. The ERG highlighted that bendamustine plus rituximab comprises 35% of physician's choice in the company's submission. The committee agreed that this was problematic, because bendamustine plus rituximab was a separate comparator in this appraisal. By contrast, physician's choice included treatments that, although included in the scope, were not considered to be comparators by the committee based on advice from the clinical experts, for example, methylprednisolone plus rituximab (25%), or fludarabine plus cyclophosphamide and rituximab (10%). The committee also considered that where different comparators can be identified for identifiable patient groups, these should be discussed as separate subgroups. The committee concluded that physician's choice was not an appropriate comparator.\n\nBest supportive care: before the committee's second meeting of this appraisal, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) published safety concerns for idelalisib. The committee recognised that for some people, idelalisib plus rituximab may not be a treatment option. With no other treatment options available, the committee considered that comparing ibrutinib with best supportive care (which was listed in the scope) would be useful. The company explained that clinicians aim to offer active treatments, and that no standard definition of best supportive care is available.The committee concluded that idelalisib plus rituximab was the most relevant comparator in clinical practice for patients who had relapsed within 2\xa0years, and for those who cannot take idelalisib plus rituximab, best supportive care was the best comparator.\n\n## Comparators for the untreated 17p\xa0deletion or TP53\xa0mutation population\n\nThe committee heard that alemtuzumab was previously offered to people with a 17p\xa0deletion or TP53\xa0mutation, but is difficult to obtain because the company for alemtuzumab has limited the marketing authorisation to multiple sclerosis. The committee concluded that this was not an appropriate comparator.\n\nThe committee noted that NICE's technology appraisal on idelalisib for treating chronic lymphocytic leukaemia recommends idelalisib plus rituximab for untreated CLL in adults with a 17p\xa0deletion or TP53\xa0mutation. At its second meeting, the committee was made aware of recent provisional advice by the EMA on idelalisib following a number of serious adverse events in some post-marketing trials. The committee noted that the advice included not starting treatment in people with a 17p\xa0deletion or TP53\xa0mutation who had not had previous treatment. At its third meeting, the committee noted that the EMA's Committee for Medicinal Products for Human Use had confirmed that the benefits of idelalisib outweigh the risk of side effects and had now concluded that idelalisib 'can again be initiated in these patients provided they cannot take any alternative treatment and that the measures agreed to prevent infection are followed'. The committee was aware that, in the absence of idelalisib, people with untreated CLL and a 17p\xa0deletion or TP53\xa0mutation have no treatment options, and recognised the unmet need in this population. The committee therefore agreed that the relevant comparators for this group were idelalisib plus rituximab or best supportive care.\n\n## Clinical effectiveness of ibrutinib compared with ofatumumab (randomised controlled trial evidence)\n\nThe committee considered the clinical evidence that came from the randomised controlled RESONATE trial which compared ibrutinib with ofatumumab. The committee noted that after a positive interim analysis the trial terminated early, when the median time in the trial was 9.4\xa0months. The committee acknowledged that the company had re-analysed the data at a median 16‑month follow-up and at a median of 30\xa0months of follow-up. After a median of 16\xa0months, the median progression-free survival had not been reached with ibrutinib; that is, fewer than half of the people randomised to ibrutinib had progressed disease, while for patients randomised to ofatumumab the median progression-free survival was 8.1\xa0months (hazard ratio 0.106, 95%\xa0confidence interval 0.073 to 0.153, p<0.0001). At its second meeting, the committee noted that the company presented data from a median 30‑month follow-up that supported the results in its submission. The committee agreed that the results from RESONATE showed that ibrutinib was a very effective therapy, a conclusion that the clinical experts supported. It was clear that the 'immaturity' of the data reflected the effectiveness of ibrutinib and viewed this positively. However, the committee was mindful that it did mean that a greater proportion of the modelled time horizon depended on extrapolations. The committee agreed that the trial showed ibrutinib extended progression-free survival compared with ofatumumab.\n\n## Clinical effectiveness of ibrutinib compared with idelalisib plus ofatumumab (indirect treatment comparison)\n\nThe committee considered the indirect treatment comparisons conducted by the company, and specifically the comparison of overall survival between ibrutinib with idelalisib plus ofatumumab. The common comparator was ofatumumab. The committee noted that the company adjusted the trial results of RESONATE (which compared ibrutinib with ofatumumab) to account for crossover at disease progression. It agreed that this was appropriate, recognising that the unadjusted hazard ratio for death from the RESONATE trial would underestimate ibrutinib's effectiveness relative to ofatumumab. However, the committee noted that the company did not adjust the hazard ratio from the Jones et al. (2015) trial (also known as the 119\xa0trial, and which compared idelalisib plus ofatumumab with ofatumumab) to account for treatment switching to ibrutinib.\n\nThe committee heard from the company that it did not adjust for crossover in the 119\xa0trial because this trial did not allow crossover to idelalisib. However, it heard from clinical experts that they considered it very likely that, after progression, patients leaving the trial would go on to receive other life-extending therapies, including ibrutinib, because of a compassionate-use programme for ibrutinib in place at the time.\n\nThe company stated that this treatment switching was not within the trial period and so it did not believe that adjusting was appropriate. However, distinguishing between crossover to the intervention within a trial and switching treatments, the committee considered that adjusting for treatment switching within the idelalisib trial was appropriate because, based on what it had heard and read in the consultation comments, it was likely that more patients randomised to placebo (compared with idelalisib) in the 119\xa0trial received treatments that both extended life and were not part of standard NHS practice.\n\nThe committee was aware of the NICE Decision Support Unit document on treatment switching, which supports adjusting for post-study therapies that do not reflect routine care.The committee agreed that the treatment switching to ibrutinib that occurred after the 119\xa0trial was relevant when determining the relative effectiveness of ibrutinib and idelalisib.\n\nThe committee discussed how to account for the effect of the treatment switching that occurred after the 119\xa0trial on the relative effectiveness of ibrutinib and idelalisib. It recognised that the company did not have access to the data from the 119\xa0trial, so could not adjust this data. The committee considered the options available, which were either to adjust the data from the RESONATE trial only, or to adjust neither trial's data. The committee noted that it had not seen any data to quantify the extent to which switching to ibrutinib occurred after the 119\xa0trial. The committee concluded that the true estimates of the clinical benefit of ibrutinib compared with idelalisib plus rituximab would likely be weaker than, but closer to, the company's estimates of clinical effectiveness when adjusting only the RESONATE data for crossover, compared with estimates based on not adjusting data from either trial.\n\nThe committee considered the clinical benefits of treatment with ibrutinib compared with idelalisib. The committee noted the promising results associated with ibrutinib. The committee heard from the patient experts about how ibrutinib had changed their lives, and provides long-lasting progression-free survival for many patients. The committee heard from clinical experts that ibrutinib is very well tolerated in most patients. It noted that some adverse reactions can be serious but are manageable, and are less severe than those seen with other treatments for CLL. It heard from clinicians that, because of the risks associated with idelalisib (see section\xa04.8), their preference would be to offer ibrutinib. The committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain.\n\n## Idelalisib plus ofatumumab as a proxy for idelalisib plus rituximab\n\nThe committee noted that the scope included idelalisib plus rituximab as a comparator, but that the company presented results for idelalisib plus ofatumumab rather than idelalisib plus rituximab.\n\nThe committee was aware that a double-blind randomised controlled trial comparing rituximab with idelalisib plus rituximab (Sharman et al. 2014, also known as the 116\xa0trial) formed the key evidence for NICE's decision on idelalisib. It questioned why the company had not included this in its network of studies. The company stated that it did not include the 116\xa0trial within a matching-adjusted indirect comparison (MAIC) because the trial had substantial limitations, including differences to RESONATE in trial design, follow-up and crossover and, in its opinion, an indirect comparison of ibrutinib with idelalisib plus ofatumumab provided more robust results. The committee noted that, after consultation, the company presented results from an MAIC including the 116\xa0trial for progression-free survival, but the ERG was unable to verify the results because the analyses lacked statistical details.\n\nThe committee understood that the company did not include a comparison between ibrutinib and idelalisib plus rituximab because it considered that idelalisib plus ofatumumab was a proxy for idelalisib plus rituximab. The company also stated that, in the appraisal of idelalisib, the committee had accepted that rituximab and ofatumumab were equally effective. However, the committee noted that, in the idelalisib appraisal, it was rituximab and ofatumumab monotherapy that were accepted as being equal, rather than each in combination with idelalisib. The company stated that it was not plausible that the efficacy would differ in combination. The committee heard from the clinical experts that idelalisib plus ofatumumab and idelalisib plus rituximab could be considered equivalent in terms of effectiveness.The committee agreed there were uncertainties around the company's assumptions when comparing ibrutinib with idelalisib plus rituximab. On balance, the committee concluded that the company's assumption that idelalisib plus rituximab is equivalent to idelalisib plus ofatumumab was reasonable.\n\n## Clinical effectiveness of ibrutinib compared with best supportive care (using physician's choice as a proxy for best supportive care)\n\nThe committee was aware the company had not compared ibrutinib with best supportive care for people who cannot take idelalisib plus rituximab. The committee discussed whether physician's choice could be considered a proxy for best supportive care in people who cannot have idelalisib plus rituximab. However, the committee considered that this was problematic because bendamustine plus rituximab comprises 35% of physician's choice. The committee noted that taking bendamustine out of the mix would lower the cost, but also the effectiveness, of physician's choice. Without formal analyses, it concluded that it could not judge the impact this would have on clinical and cost effectiveness. The committee discussed whether ofatumumab would be a proxy for best supportive care. It noted that, in the Osterborg et al. trial, in the intention-to-treat analyses, patients randomised to ofatumumab lived longer than patients randomised to physician's choice (despite patients crossing over from the physician's choice arm) and therefore ofatumumab was unlikely to reflect best supportive care. The committee concluded that it was not presented with any evidence which compared ibrutinib with best supportive care. However, it concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab.\n\n## Using ibrutinib after idelalisib in the treatment pathway\n\nThe committee noted that, in clinical practice, ibrutinib could be used after idelalisib. It heard from clinical experts that they would be keen to offer ibrutinib if idelalisib failed, or if patients had stopped idelalisib because of adverse events. The committee, however, was not presented with any data for using ibrutinib after idelalisib. The committee concluded that it could not consider ibrutinib for this setting.\n\n# Cost effectiveness\n\nThe committee considered the assumptions in the company's economic model. The committee noted that a key assumption made by the company was a constant benefit from ibrutinib over the entire course of the model. It heard from clinical experts that the benefits of ibrutinib were likely to decrease over time. The committee noted that a scenario analysis done by the ERG, which reduced the duration of ibrutinib's benefits to 5\xa0years, increased the incremental cost-effectiveness ratio (ICER) for ibrutinib compared with idelalisib plus rituximab. The committee agreed to consider this analysis as part of its decision-making.\n\nThe committee considered the company's extrapolations of data from RESONATE for progression-free survival and overall survival over the 20‑year time horizon of the model. The committee and the ERG noted that data were immature (see section\xa04.11) which the committee acknowledged may reflect a successful treatment effect, but which led to uncertainty.\n\nThe committee considered how overall survival was modelled. It recognised that, during consultation, the company had agreed with the committee that the Weibull function provided the best fit of the options presented.\n\nThe committee considered how progression-free survival was modelled. The committee noted that the model predicted that some patients live with progressed disease for an improbably long time before dying, recalling that the clinicians observed that patients do not live for long periods with progressed disease. It recognised that the choice of statistical model for extrapolating progression-free survival determined this. The committee noted that the ERG suggested that the exponential function provided a more credible period of time in progressed disease, whereas the company suggested the Weibull function provided a better fit for the data.The committee noted that the choice of model to extrapolate progression-free survival from RESONATE was a key driver of the cost-effectiveness results. The committee agreed that the Weibull function resulted in implausibly long survival after disease progression (estimates marked commercial in confidence by the company). The committee concluded that it preferred the exponential distributions.\n\nThe committee considered the model inputs for the 17p\xa0deletion and TP53\xa0populations. The committee noted that most of the comparator data in the economic model were not specific to this population. This included the hazard ratios for progression-free and overall survival, which were based on the overall population. It was aware of the lack of evidence in these subgroups, and agreed that data from the overall population was the best available and could be used to support decision-making in the untreated 17p\xa0deletion and TP53\xa0mutation populations.\n\n## Time horizon\n\nThe committee considered the time horizon used by the company in its modelling. The committee noted that the company used a 20‑year horizon in its base case, and conducted sensitivity analyses varying this to 10\xa0years and 30\xa0years. The committee noted that the ICERs were sensitive to the time horizon chosen, and the ICER increased with shorter time horizons. The ERG commented that 20\xa0years may be too short a time horizon because, according to the company model, people treated with ibrutinib would still be alive at the end of this time period. By contrast, the committee heard from clinical experts that a time horizon of 20\xa0years might be too long because the population had a mean starting age of 67\xa0years. The committee concluded that, although there was some uncertainty about the most appropriate time horizon, it accepted that the 20‑year time horizon was suitable for decision-making.\n\n## Treatment duration\n\nThe committee understood that time to progression determines treatment duration, which in turn determines the cost of treatment. Having heard that clinicians in the NHS may continue to offer ibrutinib after disease progression, the committee considered that this could contribute to costs higher than those modelled by the company. The committee considered that it might also contribute to greater benefits than stopping treatment at disease progression, but did not see any evidence to support this. The committee noted that the summary of product characteristic states that treatment should continue only until disease progression or when it is no longer tolerated by the patient. The committee therefore concluded to consider only the costs and benefits of treatment until progression in the modelling.\n\n## Modelling the level of response to treatment\n\nThe committee noted that for patients in the progression-free health state, costs of routine follow-up were determined by disease response to treatment as measured in RESONATE. The committee heard from clinical experts that patients whose disease has responded to treatment would not be followed up at different intervals depending on the level of response to treatment. After consultation on the first appraisal consultation document, the company maintained that response level should determine routine follow-up and inpatient costs. The ERG agreed with the company that it may be more reasonable to equalise costs at the level of partial response, but stated that the company had not shown that rates of admission to hospital differ by response status. The committee concluded that, after consultation on the first appraisal consultation document, the company had corrected most imbalances in the costs, and that the costs of routine follow-up had a negligible impact on the ICERs.\n\n## Utility values\n\nThe committee considered the evidence on health-related quality of life presented by the company. The committee noted that the company had collected EQ‑5D data in RESONATE. The committee noted that the quality-of-life values collected at baseline before treatment did not differ much from those collected during either treatment. The clinical experts commented that this did not reflect their clinical experience, stating that symptoms improve immediately with ibrutinib and patients usually have a good quality of life unless they have an adverse event. Having heard the positive experience of patients with ibrutinib, particularly with regard to energy levels and few side effects, the committee was concerned that benefits may not have been appropriately captured, noting that the EQ‑5D does not directly measure fatigue. After consultation on the first appraisal consultation document, the company applied a utility increment for ibrutinib. The committee heard from the ERG that this increment was derived from EQ‑5D data, so did not resolve the committee's concerns about the sensitivity of the EQ‑5D. Also, this increment was based on the quality-of-life difference between idelalisib and rituximab treatment. The ERG noted that it was not appropriate to apply this as an additional increment to the EQ‑5D quality-of-life estimate for ibrutinib. The committee was aware that this had a minor impact on the results. The committee concluded that the EQ‑5D may not have captured the experience of people with CLL, and the base case may have underestimated the quality-of-life benefit with ibrutinib.\n\nThe committee considered the utility value for post-progression applied in the company's model. The committee heard from the clinical experts that they would not expect utility in the post-progression health state to be as high as assumed by the company. The committee was also aware that the company did not age-adjust the utilities. After consultation on the first appraisal consultation document, the company provided age-adjusted utility values, and chose a lower utility value in the post-progression state (0.60). The committee noted that this had a small impact on the ICERs. The committee agreed with these 2\xa0changes.\n\n## Cost-effectiveness results\n\nThe committee considered the cost effectiveness of ibrutinib based on the evidence available. The committee reiterated that these ICERs were associated with uncertainty relating to efficacy estimates, utility values and long-term outcomes. The committee noted that the company's results did not reflect all its preferred assumptions, but was aware that exploratory analyses conducted by the ERG addressing many of these assumptions. These included:\n\nusing the exponential function to extrapolate the overall survival and progression-free Kaplan–Meier survival curves from RESONATE\n\nremoving the asymmetries in the modelling where the direct drug costs and administration costs associated with ibrutinib were treated differently from other comparators\n\nremoving the costs of repeated biopsies.The committee was also aware that these ICERs did not include the ERG's exploration of limiting the duration of benefit with ibrutinib to 5\xa0years. The committee recalled that this would increase the committee's preferred ICERs. The committee acknowledged that, after recent advice from the EMA on idelalisib, the costs associated with the adverse effects from idelalisib were likely to increase, which may improve the cost effectiveness of ibrutinib compared with idelalisib. Additionally, the ERG explored the upper bound of the ICER by not adjusting the results of the RESONATE trial for crossover (see section\xa04.13). The committee considered that the true ICER was likely to fall between the results of the ERG scenarios that did or did not adjust for crossover in the RESONATE trial.\n\nThe committee considered the ICERs including the updated ibrutinib patient access scheme and the patient access scheme for idelalisib. It noted that the ERG scenario without adjusting for crossover in the RESONATE trial was around £50,000 per quality-adjusted life year (QALY) gained, and the scenario adjusting for crossover was below £50,000 per QALY gained.\n\n# Innovation\n\nThe committee discussed whether it could consider ibrutinib innovative. The committee heard from both the patient and clinical experts that ibrutinib was an important new technology in treating CLL. The committee heard that patients appreciated how well the treatment worked and how easy it was to take, being an oral treatment. The committee heard from the company that ibrutinib is a 'first-in-class' treatment. The committee also heard that some of the benefits of ibrutinib may not have been captured in the modelling, such as the impact on fatigue. The committee concluded that ibrutinib is an innovative treatment.\n\n# End of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee considered the short life-expectancy criterion, that is, whether the patient group with CLL included in this appraisal would normally live less than 24\xa0months. The committee was aware that before idelalisib had been recommended as a treatment option, people lived for a shorter length of time. The committee noted that the mean overall survival associated with idelalisib plus rituximab (and on which the NICE decision on idelalisib plus rituximab was based) was estimated to be 21.6\xa0months. The committee noted that no evidence was provided about the life expectancy of people with a 17p\xa0deletion or TP53\xa0mutation. However, it was aware that this population probably has a worse prognosis. The committee agreed that the criterion for short life expectancy was met.\n\nThe committee discussed whether ibrutinib extended life by an average of at least 3\xa0additional months, first considering the previously treated population. The committee acknowledged the uncertainty around the long-term efficacy results from RESONATE (see section\xa04.11). The committee also noted the estimates for median survival in the overall population from the model (these are commercial in confidence and so are not presented here). The committee recognised the uncertainty in the economic modelling, but concluded that, even with confounding in the indirect comparisons, ibrutinib was likely to extend life more than 3\xa0months compared with idelalisib plus rituximab. The committee noted that there was far greater uncertainty in the degree to which ibrutinib extends life for people with a 17p\xa0deletion or TP53\xa0mutation. The committee acknowledged comments from experts that ibrutinib is very effective in this population. On balance, the committee was satisfied that ibrutinib met the extension-to-life criterion. The committee concluded that both end-of-life criteria had been met for the populations in this appraisal.\n\n# Conclusions\n\nThe committee considered all the evidence presented to it. It agreed that ibrutinib represented an important and effective treatment in CLL. The committee was satisfied that, in both populations of this appraisal and with the patient access scheme offered by the company, the ICERs for ibrutinib fell within the range normally considered as a cost-effective use of NHS resources for a treatment that fulfils the end-of-life criteria.\n\n# Pharmaceutical Price Regulation Scheme 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA429\n\nAppraisal title: Ibrutinib for previously treated chronic lymphocytic leukaemia and untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation\n\nSection\n\nKey conclusion\n\nIbrutinib alone is recommended within its marketing authorisation as an option for treating chronic lymphocytic leukaemia (CLL) in adults:\n\nwho have had at least 1 prior therapy or\n\nwho have a 17p deletion or TP53 mutation, and in whom chemo-immunotherapy is unsuitable and\n\nonly when the company provides ibrutinib with the discount agreed in the patient access scheme.\n\n\n\nThe committee concluded that idelalisib plus rituximab was the most relevant comparator and, for those who cannot take idelalisib plus rituximab, best supportive care was the best comparator in both populations. The committee was aware that it had not been presented with evidence comparing ibrutinib with best supportive care.\n\n, 4.8, 4.10\n\nThe committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain.\n\n\n\nNo evidence was presented for ibrutinib compared with best supportive care. However, the committee concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab.\n\n\n\nThe committee agreed that ibrutinib represented an important and effective treatment in CLL. It was satisfied that, in both populations of this appraisal, the incremental cost-effectiveness ratios (ICERs) for ibrutinib fell within the range normally considered as a cost-effective use of NHS resources for a treatment that fulfils the end-of-life criteria, when incorporating the confidential updated patient access scheme for ibrutinib and the existing patient access scheme for idelalisib.\n\n, 4.31\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from clinical and patient experts that current treatment options are associated with significant adverse effects that are often life threatening. The committee understood the importance of the availability of different treatment options for treating CLL.\n\n\n\nThe committee concluded that idelalisib plus rituximab was the most relevant comparator in clinical practice for patients who had relapsed within 2\xa0years and, for those who cannot take idelalisib plus rituximab, best supportive care was the alternative.\n\n, 4.8, 4.10\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain.\n\n\n\nIt also concluded that it was likely that ibrutinib would be more effective compared with best supportive care than when compared with idelalisib plus rituximab.\n\n\n\nThe committee heard from both the patient and clinical experts that ibrutinib was an important new technology in treating CLL. The committee heard that patients appreciated how well the treatment worked and how easy it was to take, being an oral treatment. The committee heard from the company that ibrutinib is a 'first-in-class' treatment. The committee also heard that some of the benefits of ibrutinib may not have been captured in the modelling, such as the impact on fatigue. The committee concluded that ibrutinib is an innovative treatment.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard from clinical experts that they would wish to offer ibrutinib to patients with CLL who have received at least 1\xa0prior treatment with fludarabine and, as first-line therapy, for people with a 17p\xa0deletion or TP53\xa0mutation.\n\n\n\nThe committee also noted that, in clinical practice, ibrutinib could be used after idelalisib, but it was not presented with any data for using ibrutinib after idelalisib. It concluded that ibrutinib could not be considered for this setting.\n\n\n\nAdverse reactions\n\nThe committee concluded that ibrutinib was likely to offer a more preferable toxicity profile than the currently available treatment options.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe key clinical evidence for the previously treated population was the RESONATE trial. The committee noted that, after a positive interim analysis, the RESONATE trial was stopped early, when the median time on-trial was 9.4\xa0months. At its second meeting, the committee noted that the company presented data from a median 30‑month follow-up. The committee understood that, in RESONATE, the comparison was with ofatumumab, which is neither recommended at this position in the treatment pathway by NICE, nor used in UK clinical practice.\n\n, 4.11\n\nThe committee was aware that no data were available for people with untreated CLL who have a 17p\xa0deletion or TP53\xa0mutation. The committee noted comments from clinical experts that treating patients with a 17p\xa0deletion with fludarabine plus cyclophosphamide and rituximab worsened their disease and prognosis. The committee agreed that, in the absence of this evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty.\n\n\n\nThe committee noted that there were no data available for people with a TP53\xa0mutation, but concluded that it was reasonable to extrapolate data from people with a 17p\xa0deletion to people with a TP53\xa0mutation.\n\n\n\nThe committee noted that, in clinical practice, ibrutinib could be used after idelalisib. The committee was not presented with any data for using ibrutinib after idelalisib. The committee concluded that ibrutinib could not be considered for this setting.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that data were immature (notably, median progression-free survival and overall survival had not been reached in the ibrutinib arm of RESONATE), which the committee acknowledged may reflect a successful treatment effect, but which led to uncertainty.\n\n\n\nThe committee noted that the scope included idelalisib plus rituximab as a comparator, but that the company presented results for idelalisib plus ofatumumab rather than idelalisib plus rituximab. It was aware that a double-blind randomised controlled trial comparing rituximab with idelalisib plus rituximab (Sharman et al. 2014, also known as the 116 trial) formed the key evidence for NICE's decision on idelalisib. The committee understood that the company considered that idelalisib plus ofatumumab was a proxy for idelalisib plus rituximab. The committee heard from the clinical experts that idelalisib plus ofatumumab and idelalisib plus rituximab could be considered equivalent in terms of efficacy. Therefore, it agreed there were uncertainties around the assumptions when comparing ibrutinib with idelalisib plus rituximab, but concluded that the company's assumption that idelalisib plus rituximab is equivalent to idelalisib plus ofatumumab was reasonable.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee was aware that no data were available for people with untreated CLL who have a 17p\xa0deletion or TP53\xa0mutation. The committee agreed that, in the absence of any evidence, the data from the previously treated population could be taken into account, but recognised this was associated with uncertainty.\n\n\n\nThe committee also noted that there were no data available specifically for people with a TP53\xa0mutation, but concluded that it was reasonable to extrapolate data from people with a 17p\xa0deletion to people with a TP53\xa0mutation.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that ibrutinib offered a more preferable toxicity profile, and was likely to offer progression-free and overall survival benefits compared with idelalisib plus rituximab, but was mindful that the extent of this benefit was uncertain.\n\n\n\nThe committee concluded that the true estimates of the clinical benefit of ibrutinib compared with idelalisib and rituximab would likely be weaker than, but closer to, the company's estimates of clinical effectiveness when adjusting only the RESONATE data for crossover compared with estimates based on not adjusting data from either trial.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee concluded that idelalisib plus rituximab was the most relevant comparator and these results were presented by the company. The committee considered that, for people who cannot take idelalisib plus rituximab, best supportive care was the best comparator.\n\n\n\nThe committee was aware that it had not been presented with evidence comparing ibrutinib with best supportive care.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee was clear that the 'immaturity' of the data in RESONATE reflected the effectiveness of the drug and viewed this positively. However, the committee was mindful that it did mean that a greater proportion of the modelled time horizon depended on extrapolations.\n\n\n\nThe company assumed constant benefit from ibrutinib over the entire course of the model. It heard from clinical experts that the benefits of ibrutinib were likely to decrease over time. The committee noted a scenario analysis done by the evidence review group (ERG), which reduced the duration of ibrutinib's benefits to 5\xa0years.\n\n\n\nThe committee concluded that there was considerable uncertainty around the extrapolations in the company's model, and it preferred the exponential distributions.\n\n\n\nThe committee considered the model inputs for the 17p\xa0deletion and TP53\xa0mutation populations and noted that most of the data in the economic model were based on the overall population. Additionally, the committee remained unsure of whether the results could be extended to people with untreated CLL but, given the lack of evidence, it concluded that data from the overall population was the best available and could be used to support decision-making in the untreated 17p\xa0deletion and TP53\xa0mutation populations.\n\n\n\nThe committee concluded that, although there was some uncertainty about the most appropriate time horizon, it accepted that the 20‑year time horizon was suitable for decision-making.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe quality-of-life values collected at baseline before treatment did not differ much from those collected during treatment in both arms of RESONATE. The clinical experts commented that this did not reflect clinical experience, stating that symptoms improve immediately with ibrutinib. Having heard the positive experience of patients with ibrutinib, particularly with regard to energy levels and lack of side effects, the committee was concerned that the quality-of-life benefits may not have been appropriately captured. It also considered the utility increment applied by the company and noted the ERG's concern that it was inappropriate. The committee was aware that this had a minor impact on the results. The committee concluded that the EQ‑5D may not have captured the experience of people with CLL, and the base case may have underestimated the quality-of-life benefit with ibrutinib.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of cost effectiveness are the choice of Kaplan–Meier parametric curve, time horizon and length of time of benefit with ibrutinib.\n\n, 4.21, 4.22\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nBased on the committee's preferred assumptions, the committee considered that true ICER was likely to fall between the results of the ERG scenarios that did or did not adjust for crossover in the RESONATE trial. The committee considered the ICERs that included the updated ibrutinib patient access scheme and the patient access scheme for idelalisib. It noted that the ERG scenario without an adjustment for crossover was around £50,000 per quality-adjusted life year (QALY) gained and the scenario with this adjustment was below £50,000 per QALY gained.\n\n, 4.27\n\nAdditional factors taken into account\n\nEnd-of-life considerations\n\nThe committee concluded that the end-of-life criteria had been met for the populations in this appraisal.\n\n, 4.30\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the appraisal.\n\n–"}	https://www.nice.org.uk/guidance/ta429	Evidence-based recommendations on ibrutinib (Imbruvica) for treating chronic lymphocytic leukaemia in adults.
8a65ea7fc47a6bec2d977dabcd72ec11a911f07d	nice	Sofosbuvir–velpatasvir for treating chronic hepatitis C	Sofosbuvir–velpatasvir for treating chronic hepatitis C Evidence-based recommendations on sofosbuvir–velpatasvir (Epclusa) for treating chronic hepatitis C in adults. # Recommendations Sofosbuvir–velpatasvir is recommended as an option for treating chronic hepatitis C in adults, as specified in table 1, only if the company provides the drug with the discount agreed in the simple discount agreement. Table 1 Sofosbuvir–velpatasvir for treating chronic hepatitis C in adults HCV genotype Liver disease stage Treatment Recommendation according to treatment history Untreated Treated With or without compensated cirrhosis Sofosbuvir–velpatasvir Recommended Without cirrhosis Sofosbuvir–velpatasvir Recommended only for people who cannot tolerate interferon or it is not suitable for them Recommended Compensated cirrhosis Sofosbuvir–velpatasvir Recommended Without cirrhosis Sofosbuvir–velpatasvir Recommended Compensated cirrhosis Sofosbuvir–velpatasvir (with or without ribavirin) Recommended With or without compensated cirrhosis Sofosbuvir–velpatasvir Recommended With or without compensated cirrhosis Sofosbuvir–velpatasvir Recommended With or without compensated cirrhosis Sofosbuvir–velpatasvir Recommended Decompensated cirrhosis Sofosbuvir–velpatasvir (with ribavirin) Recommended Abbreviation: HCV, hepatitis C virus. Treated – the person's hepatitis C has not adequately responded to interferon-based treatment. It is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need. This guidance is not intended to affect the position of patients whose treatment with sofosbuvir–velpatasvir was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Sofosbuvir–velpatasvir (Epclusa, Gilead) is a fixed-dose combination drug. Sofosbuvir inhibits hepatitis C virus (HCV) non‑structural viral protein NS5B ribonucleic acid (RNA)-dependent RNA polymerase. Velpatasvir inhibits HCV non-structural protein NS5A. Marketing authorisation Sofosbuvir–velpatasvir has a marketing authorisation in the UK for treating chronic hepatitis C virus (HCV) infection in adults. This includes genotypes 1–6 HCV in people with or without compensated or decompensated cirrhosis. Adverse reactions The summary of product characteristics states that headache, fatigue and nausea are the most common adverse reactions (incidence of 10% or more). For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Sofosbuvir–velpatasvir is taken orally. The recommended dose is 1 tablet once daily, for 12 weeks. Each tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. The marketing authorisation states that decompensated cirrhosis should be treated with sofosbuvir–velpatasvir in combination with ribavirin, for 12 weeks. Ribavirin plus sofosbuvir–velpatasvir may also be considered for people with genotype 3 HCV who have compensated cirrhosis. Price Sofosbuvir–velpatasvir costs £12,993.33 per 28‑day pack. The total cost of a 12‑week treatment course is £38,980. Ribavirin costs £246.65 per 56-tablet pack. The total cost of a 12‑week treatment course of sofosbuvir–velpatasvir with ribavirin is £40,089.93. The company has a simple discount agreement which provides a discount to the list price of sofosbuvir–velpatasvir at the point of purchase or invoice. The level of the discount is commercial in confidence.# Evidence The appraisal committee (section 6) considered evidence submitted by Gilead and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of sofosbuvir–velpatasvir, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of sofosbuvir–velpatasvir by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical need and practice The committee heard from the clinical and patient experts that having treatment options that are free from peginterferon alfa, with or without ribavirin, is important to people with chronic hepatitis C because of the associated adverse reactions, which can lead to irreversible complications. The patient experts explained that some people refuse treatment with peginterferon alfa, which increases their risk of future complications associated with chronic hepatitis C infection. The committee noted that the use of peginterferon alfa is gradually reducing in clinical practice because of the introduction of newer direct-acting antivirals, particularly for genotypes 1 and 4 hepatitis C virus (HCV). However, it was aware that peginterferon alfa, with or without ribavirin, is still a major component of the treatment regimen for other HCV genotypes. It agreed that there is an unmet need for interferon- and ribavirin-free regimens, particularly for genotype 3 HCV (which accounts for approximately 44% of the population of people with hepatitis C). The clinical experts considered that sofosbuvir–velpatasvir is a breakthrough treatment because of its simple dosing regimen, minimal adverse effects and interactions with other drugs, and effectiveness in decompensated cirrhosis (which may reduce the need for liver transplant). Therefore the committee recognised the importance of having an additional effective and tolerable treatment for people with chronic hepatitis C and concluded that sofosbuvir–velpatasvir could be a valuable option, especially for genotype 3 HCV. ## Comparators for sofosbuvir–velpatasvir The committee noted that the company did not include boceprevir and telaprevir (both taken with peginterferon alfa and ribavirin) as comparators because they are no longer used in clinical practice, although the NICE scope included them. The committee was also aware that the company had modelled some comparators in scenario analyses only (excluding them from its base case) because it considered they are not used in clinical practice. For example, daclatasvir with peginterferon alfa plus ribavirin, and simeprevir with peginterferon alfa plus ribavirin, in people with genotype 4 HCV. The committee heard from the clinical experts that boceprevir and telaprevir are not currently used in clinical practice in the UK, because the toxicity associated with peginterferon alfa plus ribavirin is worsened by adding boceprevir or telaprevir. It heard that peginterferon alfa plus ribavirin and daclatasvir or simeprevir are not used to treat genotype 4 HCV because there are several interferon-free regimens available for this population. The committee concluded that it was appropriate to exclude these comparators from the analyses. The committee was aware that the use of peginterferon alfa plus ribavirin is reducing for some HCV genotypes (see section 4.1), and questioned the clinical experts about its relevance. It heard that peginterferon alfa plus ribavirin is the first choice treatment for people with mild, untreated genotype 2 HCV, and understood that its use for other HCV genotypes has not completely stopped. The committee concluded that peginterferon alfa plus ribavirin is a relevant comparator across all HCV genotypes. The committee was aware that for people with decompensated cirrhosis, the company compared sofosbuvir–velpatasvir plus ribavirin with ledipasvir–sofosbuvir plus ribavirin. The committee understood that ledipasvir–sofosbuvir plus ribavirin has a marketing authorisation in the UK for decompensated cirrhosis, but that it is not recommended by NICE for this subgroup. It heard from the clinical experts that the clinical commissioning policy for chronic hepatitis C permits the use of ledipasvir–sofosbuvir plus ribavirin in this population, and concluded that it is a relevant comparator. # Clinical effectiveness ## Sustained virological response The committee considered the key clinical evidence for sofosbuvir–velpatasvir, which came from 4 randomised controlled phase III clinical trials (ASTRAL-1, -2, -3 and -4). The trials included people who had not had treatment for their hepatitis C, and people whose hepatitis C had not adequately responded to interferon-based treatment. ASTRAL-1, -2 and -3 included people with compensated cirrhosis; ASTRAL-4 included people with decompensated cirrhosis. The committee was aware that the evidence review group (ERG) considered that the trials were generally well conducted, although there was a higher risk of bias in ASTRAL-2 and -3 because they were open-label studies. The committee noted that the trial results showed high sustained virological response at 12 weeks irrespective of HCV genotype, cirrhosis stage or treatment history; the sustained virological response ranged from 89% (for people with previously treated genotype 3 HCV and compensated cirrhosis) to 100% (in several subgroups). The committee concluded that the trials showed that sofosbuvir–velpatasvir is effective for treating chronic hepatitis C across all subgroups in all genotypes. ## Effect of drug-resistant HCV mutations on treatment outcome The committee noted consultation comments that the sustained virological response for sofosbuvir–velpatasvir in ASTRAL-3 was lower in people with drug-resistant HCV mutations. The committee noted the comments from the clinical experts that routine testing for drug-resistant HCV mutations is not part of current clinical practice in the UK. It was aware that the European Association for the Study of the Liver's guideline on treating hepatitis C (2016) does not recommend systematic testing for HCV resistance before treatment. The clinical experts explained that resistance testing is difficult to do and there is no agreement on how to interpret the results. The committee noted that, of the 25 people with drug-resistant mutations who had sofosbuvir–velpatasvir in ASTRAL-3, only 4 did not have a sustained virological response. The committee concluded that there is insufficient evidence to consider the group of people with drug-resistant mutations separately to the overall population, and that it would not reflect current clinical practice. ## Adverse effects The committee was aware that the most commonly reported adverse events are headache, fatigue and nausea. It noted that the results showed that sofosbuvir–velpatasvir has a relatively favourable tolerability profile, especially when compared with the peginterferon alfa plus ribavirin regimen. The committee concluded that the adverse events associated with sofosbuvir–velpatasvir are generally tolerable. # Cost effectiveness ## Model structure The committee noted that the structure of the model and its assumptions about the natural history of the disease are similar to models submitted for other NICE technology appraisals for chronic hepatitis C. It was aware that the company had grouped people with mild and moderate fibrosis into a single health state (non-cirrhotic), and agreed that this was consistent with how people are diagnosed in current practice. The committee concluded that the structure of the model is acceptable for decision-making. ## Reinfection and future transmission of hepatitis C virus The committee was aware that the company's base-case model did not allow for reinfection after a sustained virological response, and that the ERG explored including an annual reinfection probability of 2.4% from a meta-analysis by Aspinall et al. (2013). The committee heard from the ERG that the model was sensitive to assumptions about reinfection. The clinical experts stated that 2.4% is an overestimate of the risk of reinfection, because most people having treatment for chronic hepatitis C are not current drug users and therefore their risk of reinfection is low. The clinical experts considered that the estimate of 2.4% was based on outdated studies that are not generalisable to the UK population. The committee noted that the company did not include risk of future virus transmission in the model. It was aware that excluding reinfection may overestimate the health benefits of more effective treatments, and that excluding transmission may underestimate the benefits, but agreed that these opposing effects might not be equal. The committee agreed that it would have preferred to see a model including both reinfection and transmission, but appreciated that this would have needed a different (and potentially more complex) model structure. The committee, noting the comments from clinical experts, agreed that the ERG's reinfection estimate of 2.4% was too high. It concluded that, without a model that incorporated both reinfection and transmission, cost-effectiveness results excluding reinfection and transmission (as in the company's base case) were acceptable for its decision-making. ## Estimates of sustained virological response in the model The committee noted that the sustained virological response rates for the comparators in the company's model were selected from individual arms of selected randomised controlled trials; the company used 1 source for each treatment in each subgroup. The committee was aware that the company could not perform network meta-analyses for all subgroups in the model and that, for the 2 subgroups in which network meta-analyses were feasible, the results were associated with several limitations. The committee agreed that it was appropriate for the company not to use the results of its network meta-analysis to inform efficacy inputs in the model. The committee heard from the ERG that the company's choice of study for each comparator was often arbitrary; although the ERG considered that the company's justification for each choice was valid, it suggested that equally valid justification could have been provided for alternative sources. The committee was aware that the company's approach of selecting results from a single arm of a study means that the results were open to the risks of bias associated with observational studies. It noted that the company could have calculated a mean sustained virological response for each treatment in each subgroup using all available sources. The committee heard from the company that for 85 of the 118 sustained virological response rates used in the model, only 1 source was available. However the committee agreed with the ERG that, because each result was selected from a single arm of a study, the company should have included other study types such as uncontrolled and non-randomised studies. The committee concluded that the company's method of estimating efficacy in the model introduced some uncertainty in the results. The committee noted that, according to the company's deterministic sensitivity analyses, the cost-effectiveness results were sensitive to the sustained virological response for peginterferon alfa plus ribavirin in people without cirrhosis; estimates for other comparators had less of an effect. The committee questioned the clinical experts on the appropriateness of the company's estimates of sustained virological response for peginterferon alfa plus ribavirin in people without cirrhosis, using the estimate of 71% in untreated genotype 3 HCV as an example. It heard from the company that 71% was a conservative estimate in this population, because the results of its meta-analyses (done in response to clarification questions from NICE) ranged from 59% to 67%. The committee questioned whether people with certain baseline characteristics such as mild disease, younger age and low viral load would have higher sustained virological response rates with peginterferon alfa plus ribavirin. It heard from the clinical experts that it is possible to identify people who are more likely to respond to peginterferon alfa plus ribavirin, but that this is not routine practice in the UK. The clinical experts suggested that the sustained virological response for peginterferon alfa plus ribavirin might be much lower than 71% for some populations, and agreed that the company's estimates were generalisable to current practice when considering everyone with untreated genotype 3 HCV. Having concluded that the company's estimates of sustained virological response introduced some uncertainty in the results, but hearing that the rates for peginterferon alfa plus ribavirin were appropriate, the committee concluded that results based on the company's estimates of sustained virological response were acceptable for its decision-making. ## Genotype-specific transition probabilities for developing compensated cirrhosis The committee was aware that the company had assumed that progression from the non-cirrhotic to the compensated cirrhosis health state is faster in genotype 3 HCV than in other genotypes. The clinical experts agreed with this assumption. The committee understood that this approach is consistent with previous NICE technology appraisals in hepatitis C, but noted that this is the first appraisal in which evidence supporting the calculation of HCV genotype-specific transition probabilities has been submitted. The committee heard from the clinical experts that the study selected by the company to inform these transition probabilities (Kanwal et al. 2014) is generalisable to current practice in the UK. However, the committee was concerned that the company had used unadjusted results from Kanwal et al. rather than the prespecified analyses which adjusted for patients' baseline characteristics. The company could not provide a rationale for using the unadjusted data, and the committee concluded that its decision-making should be based on analyses using the adjusted results from Kanwal et al., which the ERG had included in exploratory analyses for some subgroups. ## Transition probabilities for disease progression in people with cirrhosis The committee noted that the company had used transition probabilities for compensated or decompensated cirrhosis to hepatocellular carcinoma from Cardoso et al. (2010), and had not considered estimates from Fattovich et al. (1997) for these transitions. The committee heard from the company that this is consistent with previous NICE technology appraisals in chronic hepatitis C, and that the Cardoso data are more recent and therefore more appropriate. The committee recalled its conclusion from previous technology appraisals for hepatitis C that these transition probabilities lay somewhere between the estimates from Cardoso and Fattovich. It heard from the clinical experts that data from Fattovich et al. are generalisable to current practice, and was aware that the ERG had done exploratory analyses using transition probabilities from Fattovich et al. in some subgroups. The committee concluded that both sources should be taken into account in its decision-making. ## Utility values The committee was aware that the company used utility data from the literature in line with previous NICE technology appraisals for chronic hepatitis C (health state baseline values from Wright et al. 2006 and a utility increment after sustained virological response of 0.04 from Vera-Llonch et al. 2013). The committee noted the ERG's concerns that trial data are preferable to published utility values. It heard from the company that SF-36 data from the clinical trials of sofosbuvir–velpatasvir had not been formally mapped to produce SF-6D utility values for use in the economic model at the time of the submission. The committee emphasised that when available, it prefers utility values collected from the clinical trials of the intervention under evaluation to those estimated from other sources, but it was prepared to accept the estimates from Wright et al. and Vera-Llonch et al. in the economic analyses. The committee was aware that the company had applied on-treatment utility increments (increased quality of life) and decrements (decreased quality of life), to represent the varying effect of different treatments. The committee understood that the company applied decrements for regimens containing peginterferon alfa or ribavirin to reflect the poor tolerability of these treatments. It understood that the company applied utility increments for direct-acting antivirals to reflect the benefits of rapidly suppressing the hepatitis C virus and the improved tolerability profile. The committee was concerned that including treatment-specific changes in utility could lead to double counting, because the company also included utility increments for achieving sustained virological response and utility decrements for each adverse event, but it noted that the effect of removing them was negligible. The committee concluded that it was acceptable to include treatment-specific utility increments and decrements, but noted that there were uncertainties in the company's approach. ## Pricing arrangements The committee noted that the company has a confidential simple discount agreement for sofosbuvir–velpatasvir, with the discount applied at the point of purchase or invoice. It also noted that confidential reduced contract prices for the comparators, agreed between each company and the Commercial Medicines Unit, were included in the analyses done by the ERG, when known and if important to the committee's decision-making. The committee understood that the contract prices were the prices that the NHS pays for these treatments. The committee noted that NICE's guide to the methods of technology appraisal prefers using nationally available price reductions in the reference-case analysis to reflect the price relevant to the NHS. The committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision. # Most plausible incremental cost-effectiveness ratios The committee was aware that incremental cost-effectiveness ratios (ICERs) incorporating its preferred assumptions about transition probabilities (see sections 4.12 and 4.13) were available for only 2 subgroups: people with untreated genotype 2 HCV without cirrhosis, and people with untreated genotype 3 HCV without cirrhosis. The committee understood that, because of the large number of subgroup analyses in the appraisal, the ERG could not do all of its exploratory analyses in all subgroups. The committee was aware that the ERG chose to focus on the comparison with peginterferon alfa plus ribavirin in untreated genotypes 2 and 3 HCV in people without cirrhosis because these were the comparisons that produced the highest ICERs for sofosbuvir–velpatasvir, in both the company's base case and the ERG's alternative base case. The committee noted that, in these 2 subgroups, using the adjusted data from Kanwal et al. increased the company's base-case ICERs for sofosbuvir–velpatasvir by approximately £700–£2,700 per quality-adjusted life year (QALY) gained compared with peginterferon alfa plus ribavirin. Using transition probabilities from Fattovich et al. instead of Cardoso et al. increased the ICERs for sofosbuvir–velpatasvir by approximately £2,500–£4,500 (see table 2). Recalling its conclusion that the transition probabilities for disease progression lay somewhere between the Cardoso and Fattovich estimates, the committee concluded that the most plausible ICERs for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin lay between: £35,091 and £39,783 per QALY gained for people with untreated genotype 2 HCV and without cirrhosis £15,923 and £18,362 per QALY gained for people with untreated genotype 3 HCV and without cirrhosis. ## Table 2 Incremental cost-effectiveness ratios for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin Source of transition probabilities for disease progression a Cardoso (2010) Fattovich (1997) Untreated genotype 2 HCV without cirrhosis and eligible for interferon Company base case(unadjusted data from Kanwal et al.) ERG exploratory analysis of company base case(adjusted data from Kanwal et al.) Untreated genotype 3 HCV without cirrhosis and eligible for interferon Company base case(unadjusted data from Kanwal et al.) ERG exploratory analysis of company base case(adjusted data from Kanwal et al.) Abbreviation: HCV, hepatitis C virus.a except for the transition probabilities from the non-cirrhotic to compensated cirrhosis health state (taken from Kanwal et al. 2014). The committee discussed the most plausible ICERs for sofosbuvir–velpatasvir compared with relevant comparators in all other subgroups, in which the company's base-case ICERs were considerably lower than the ICERs for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin in genotypes 2 and 3 HCV. The committee considered the likely effect of including its preferred assumptions on the company's base-case ICER. It agreed that the ICERs would likely increase by a similar magnitude as in the 2 subgroups explored by the ERG and concluded that they would remain below £20,000 per QALY gained regardless of HCV genotype, treatment history and cirrhosis stage. Exact ICERs for all comparisons cannot be reported because the contract prices for the comparators in this appraisal are confidential and cannot be disclosed. # Recommendations ## Genotypes 1 and 3–6 HCV The committee agreed that, after accounting for its preferred assumptions about transition probabilities, the ICERs for sofosbuvir–velpatasvir for HCV genotypes 1 and 3–6 were lower than £20,000 per QALY gained compared with all relevant comparators, regardless of genotype, treatment history and cirrhosis stage. The committee concluded that sofosbuvir–velpatasvir was cost effective and could be recommended for treating HCV genotypes 1 and 3–6 in people with: untreated disease with or without compensated cirrhosis treated disease with or without compensated cirrhosis. The committee noted that the marketing authorisation for sofosbuvir–velpatasvir states that ribavirin may be added to sofosbuvir–velpatasvir for people with genotype 3 HCV with compensated cirrhosis (see section 2). However it was not presented with analyses of sofosbuvir–velpatasvir plus ribavirin for this population. It noted that ribavirin has a much lower acquisition cost than sofosbuvir–velpatasvir, and agreed that adding ribavirin to the treatment regimen would likely have minimal effect on the ICERs, which were lower in people with compensated cirrhosis than for people without cirrhosis. The committee agreed that, in practice, adding ribavirin to sofosbuvir–velpatasvir would be a clinical decision based on discussion between the patient and their clinician. The committee concluded that sofosbuvir–velpatasvir plus ribavirin could be recommended as a cost-effective use of NHS resources for treating genotype 3 HCV in people with compensated cirrhosis. ## Genotype 2 HCV The committee discussed the group of people with genotype 2 HCV. It agreed that, given that the ICERs for sofosbuvir–velpatasvir were below £20,000 per QALY gained after accounting for its preferred assumptions about transition probabilities, sofosbuvir–velpatasvir was cost effective compared with all comparators for treated and untreated disease with compensated cirrhosis and for treated disease without cirrhosis. The committee concluded that sofosbuvir–velpatasvir could be recommended for treating genotype 2 HCV in people with: untreated disease with compensated cirrhosis treated disease with or without compensated cirrhosis. The committee discussed the group of people with untreated genotype 2 HCV who do not have cirrhosis. For people who can have interferon treatment, the committee noted that peginterferon alfa plus ribavirin is the only active treatment option because sofosbuvir plus ribavirin is only recommended for people with untreated disease if they cannot tolerate interferon or it is not suitable for them. The committee noted that the ICER for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin was above £30,000 per QALY gained when accounting for its preferred assumptions about transition probabilities. Therefore it concluded that sofosbuvir–velpatasvir could not be recommended as a cost-effective use of NHS resources for untreated genotype 2 HCV in people without cirrhosis who can have interferon. For people who cannot tolerate interferon or it is not suitable for them, the committee noted that the ICERs for sofosbuvir–velpatasvir were below £20,000 per QALY gained after accounting for its preferred assumptions about transition probabilities. It agreed that sofosbuvir–velpatasvir was cost effective compared with sofosbuvir plus ribavirin. Therefore, the committee concluded that sofosbuvir–velpatasvir could be recommended as a cost-effective use of NHS resources for untreated genotype 2 HCV for people without cirrhosis, only if they cannot tolerate interferon or it is not suitable for them. ## Decompensated cirrhosis The committee agreed that, after accounting for its preferred assumptions about transition probabilities, the ICERs for sofosbuvir–velpatasvir plus ribavirin compared with ledipasvir–sofosbuvir plus ribavirin for decompensated cirrhosis were lower than £20,000 per QALY gained. The committee concluded that sofosbuvir–velpatasvir plus ribavirin could be recommended as a cost-effective use of NHS resources for treating decompensated cirrhosis. # Other considerations The committee was aware of NHS England's ongoing planning to put in place the capacity needed to make new oral treatments for hepatitis C available. The committee heard that the capacity to treat hepatitis C in all eligible people in the NHS according to NICE's recommendations is still developing. Given that there is not yet a steady state of implementation of the hepatitis C guidance, it was considered necessary to continue to include recommendations relating to treatment and prescribing decisions included in previous NICE guidance for the oral hepatitis C treatments in the guidance. # Innovation The committee considered whether sofosbuvir–velpatasvir could be considered innovative, and whether the company's economic analysis had captured all changes in health-related quality of life. The committee agreed with the company that there is an unmet need for interferon- and ribavirin-free regimens in people with chronic hepatitis C, particularly for genotype 2 or 3 HCV, but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other benefits for people with chronic hepatitis C (for example, possible regression of fibrosis) and wider benefits to society (for example, reduced transmission of HCV, improved earning capacity) that were not captured in the QALY calculation and that, if taken into account, were likely to decrease the ICERs. However, the committee noted that it had taken these potential benefits into account when considering the cost effectiveness of sofosbuvir–velpatasvir and concluded that its recommendations for each population remained unchanged. # Equality issues The committee noted the potential equality issues raised by the company and a professional organisation that there are proportionately more people from Asian and minority ethnic groups, and more people who inject drugs, who have genotype 3 or genotype 4 HCV than other HCV genotypes. Having decided that sofosbuvir–velpatasvir should be recommended for HCV genotypes 3 and 4, the committee agreed that its recommendations for these groups do not have a different effect on people protected by the equality legislation than on the wider population. The committee noted that its recommendations on sofosbuvir–velpatasvir were irrespective of whether or not the person uses injectable drugs. The committee then discussed the group for whom it could not recommend sofosbuvir–velpatasvir as a cost-effective use of NHS resources: untreated genotype 2 HCV in people without cirrhosis, who can have interferon. The committee was aware, from the evidence discussed during a previous technology appraisal for hepatitis C, that the proportion of people from Asian and minority ethnic groups was not disproportionately higher for genotype 2 HCV than for other genotypes. It also noted that the ICER for sofosbuvir–velpatasvir compared with peginterferon alfa in untreated genotype 2 HCV without cirrhosis ranged from £35,100 to £39,800 per QALY gained. Based on the evidence presented, the committee agreed that its recommendations were fair and concluded that no further consideration of potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment. # Summary of appraisal committee's key conclusions TA430 Appraisal title: Sofosbuvir–velpatasvir for treating chronic hepatitis C Section Key conclusion The committee concluded that the trials showed that sofosbuvir–velpatasvir is effective for treating chronic hepatitis C across all subgroups in all genotypes. Sofosbuvir–velpatasvir is recommended as an option for treating chronic hepatitis C in adults, in the subgroups specified below, only if the company provides the drug with the discount agreed in the simple discount agreement. Genotypes 1 and 3–6 hepatitis C virus (HCV) The committee concluded that sofosbuvir–velpatasvir could be considered a cost-effective use of NHS resources for treating HCV genotype 1 and 3–6 regardless of genotype, treatment history and cirrhosis stage. The committee concluded that sofosbuvir–velpatasvir plus ribavirin could be considered a cost-effective use of NHS resources for treating genotype 3 HCV in people with compensated cirrhosis. Genotype 2 HCV The committee concluded that sofosbuvir–velpatasvir could be considered a cost-effective use of NHS resources for treating genotype 2 HCV in people with: untreated disease with compensated cirrhosis treated disease with or without compensated cirrhosis. For people with untreated genotype 2 HCV who do not have cirrhosis, sofosbuvir–velpatasvir could be recommended as a cost-effective use of NHS resources only if interferon is not tolerated or not suitable. Sofosbuvir–velpatasvir was not recommended in people with untreated genotype 2 HCV who do not have cirrhosis and who can have interferon treatment, because of the high incremental cost-effectiveness ratio (ICER) compared with peginterferon alfa plus ribavirin. The ICER was between £35,100 (based on transition probabilities from Cardoso et al. 2010) and £39,800 (based on transition probabilities from Fattovich et al. 1997) per quality-adjusted life year (QALY) gained. Decompensated cirrhosis The committee concluded that sofosbuvir–velpatasvir plus ribavirin could be considered a cost-effective use of NHS resources for treating decompensated cirrhosis. Current practice Clinical need of patients, including the availability of alternative treatments Some of the newer treatments for chronic hepatitis C are given with peginterferon alfa or ribavirin. Having treatment options that are free from peginterferon alfa with or without ribavirin is important to people with chronic hepatitis C, particularly for people with genotype 3 HCV, because of the associated adverse reactions. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Sofosbuvir–velpatasvir has a simple dosing regimen and minimal adverse effects and interactions with other drugs. It is also effective in decompensated cirrhosis, which may reduce the need for liver transplant. What is the position of the treatment in the pathway of care for the condition? Sofosbuvir–velpatasvir provides another alternative to the existing oral treatment combinations for people with chronic hepatitis C, regardless of HCV genotype, treatment history and cirrhosis stage. Adverse reactions The adverse events associated with sofosbuvir–velpatasvir are generally tolerable. Evidence for clinical effectiveness Availability, nature and quality of evidence The key clinical evidence for sofosbuvir–velpatasvir came from 4 randomised controlled phase III clinical trials (ASTRAL-1, -2, -3 and -4). The evidence review group (ERG) considered that the trials were generally well conducted, although there was a higher risk of bias in ASTRAL-2 and -3 because they were open-label studies. The company could not perform network meta-analyses for all subgroups. Uncertainties generated by the evidence The company's estimates of sustained virological response for all comparators were open to the risks of bias associated with observational studies, because the company selected them from individual arms of selected randomised controlled trials. The company should have included other study types and, although the company's justification for choosing each study was valid, equally valid justifications could have been provided for alternative sources. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Sofosbuvir–velpatasvir is effective for treating chronic hepatitis C across all subgroups in all genotypes. There was insufficient evidence to consider the subgroup of people with drug-resistant mutations separately to the overall population. Considering this subgroup separately would not reflect current clinical practice. Estimate of the size of the clinical effectiveness including strength of supporting evidence Having noted the high sustained virological response rates as well as the ERG's comments that the trials were generally well conducted, the committee concluded that the trials showed that sofosbuvir–velpatasvir was effective for treating chronic hepatitis C. Evidence for cost effectiveness Availability and nature of evidence The structure of the model was similar to models submitted for other NICE technology appraisals for chronic hepatitis C. The committee considered that grouping people with mild and moderate fibrosis into a single health state (non-cirrhotic) was consistent with how people are diagnosed in current practice. Although the marketing authorisation for sofosbuvir–velpatasvir states that ribavirin may be added to sofosbuvir–velpatasvir for people with genotype 3 HCV with compensated cirrhosis, the company did not present analyses of sofosbuvir–velpatasvir plus ribavirin for this population. The company excluded several comparators from its base-case cost-effectiveness analyses: boceprevir, telaprevir and (for genotype 4 HCV) peginterferon alfa plus ribavirin and daclatasvir or simeprevir. The committee concluded that it was appropriate to exclude these comparators because they are not currently used in clinical practice in the UK. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee agreed that not capturing the effect of reinfection and future transmission introduces uncertainty in the cost-effectiveness estimates, but concluded that the structure of the company's model was acceptable for decision-making. The company's method of estimating sustained virological response rates in the model introduced some uncertainty in the results. The company's inclusion of treatment-specific changes in utility might have led to double counting, but the impact of removing them was negligible. The company used unadjusted results from Kanwal et al. to estimate genotype-specific transition probabilities for developing compensated cirrhosis. Cost-effectiveness analyses using the prespecified adjusted results from Kanwal (done by the ERG) were only presented for 2 subgroups. The company used transition probabilities for compensated or decompensated cirrhosis to hepatocellular carcinoma from Cardoso et al. (2010), and did not consider estimates from Fattovich et al. (1997). The committee agreed that these transition probabilities lay somewhere between the estimates from Cardoso and Fattovich. Cost-effectiveness analyses using the transition probabilities from Fattovich (done by the ERG) were only presented for 2 subgroups. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee emphasised that when available, it prefers utility values collected from the clinical trials of the intervention under evaluation to those estimated from other sources, but it was prepared to accept the estimates from Wright et al. and Vera‑Llonch et al. in the economic analyses. The committee recognised the additional value of sofosbuvir–velpatasvir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV), but noted that it had taken these potential benefits into account when considering the cost effectiveness of sofosbuvir–velpatasvir. Are there specific groups of people for whom the technology is particularly cost effective? Sofosbuvir–velpatasvir was cost effective for all subgroups in all genotypes except for people with untreated genotype 2 HCV who do not have cirrhosis and who can have interferon treatment. What are the key drivers of cost effectiveness? The cost-effectiveness results were sensitive to the sustained virological response for peginterferon alfa plus ribavirin in people without cirrhosis (estimates for other comparators had less of an effect). They were also sensitive to the rate of reinfection. Based on analyses in only 2 subgroups, the committee noted that the ICERs increased when the ERG used transition probabilities from Fattovich et al. (1997) and adjusted data from Kanwal et al. (2014). Most likely cost-effectiveness estimate (given as an ICER) The committee concluded that the most plausible ICERs included adjusted data from Kanwal; did not include reinfection or transmission risk; and lay between the estimates based on transition probabilities from Cardoso and those that used transition probabilities from Fattovich. The committee was aware that ICERs incorporating these preferred assumptions were available for only 2 subgroups (presented by the ERG). The committee agreed that including its preferred assumptions in the analyses of the other subgroups would likely increase the ICERs by a similar magnitude as in the 2 subgroups explored by the ERG. After accounting for the committee's preferred assumptions, the ICERs for sofosbuvir–velpatasvir (plus ribavirin for treating decompensated cirrhosis) were below £20,000 per QALY gained compared with all relevant comparators in all subgroups, except for people with untreated genotype 2 HCV who do not have cirrhosis and who can have interferon treatment (for whom the ICER lay between £35,100 and £39,800 per QALY gained). Exact ICERs for all comparisons cannot be reported because the contract prices for the comparators in this appraisal are confidential and cannot be disclosed. Additional factors taken into account Pricing arrangements The company has a simple discount agreement which provides a discount to the list price of sofosbuvir–velpatasvir at the point of purchase or invoice. The level of the discount is commercial in confidence. Confidential reduced contract prices for the comparators were included in the analyses done by the ERG, when known and if important to the committee's decision-making. End-of-life considerations Not applicable. Equalities considerations and social value judgements The company and professional groups raised the potential equalities issue that there are proportionately more people from Asian and minority ethnic groups who have genotype 3 and genotype 4 HCV than other HCV genotypes. Having decided that sofosbuvir–velpatasvir should be recommended for HCV genotypes 3 and 4, the committee agreed that its recommendations for these subgroups do not have a different impact on people protected by the equality legislation than on the wider population. The committee also considered the population for whom it could not recommend sofosbuvir–velpatasvir (untreated genotype 2 HCV in people without cirrhosis). It was aware that the proportion of people from Asian and minority ethnic groups was not disproportionately higher in this genotype compared with other genotypes. Based on the evidence presented, the committee agreed that its recommendations were fair and concluded that no further consideration of potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment.	{'Recommendations': "Sofosbuvir–velpatasvir is recommended as an option for treating chronic hepatitis\xa0C in adults, as specified in table\xa01, only if the company provides the drug with the discount agreed in the simple discount agreement.\n\nTable 1 Sofosbuvir–velpatasvir for treating chronic hepatitis\xa0C in adults\n\nHCV genotype\n\nLiver disease stage\n\nTreatment\n\nRecommendation according to treatment history\n\nUntreated\n\nTreated\n\n\n\nWith or without compensated cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended\n\n\n\nWithout cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended only for people who cannot tolerate interferon or it is not suitable for them\n\nRecommended\n\nCompensated cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended\n\n\n\nWithout cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended\n\nCompensated cirrhosis\n\nSofosbuvir–velpatasvir (with or without ribavirin)\n\nRecommended\n\n\n\nWith or without compensated cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended\n\n\n\nWith or without compensated cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended\n\n\n\nWith or without compensated cirrhosis\n\nSofosbuvir–velpatasvir\n\nRecommended\n\n–6\n\nDecompensated cirrhosis\n\nSofosbuvir–velpatasvir (with ribavirin)\n\nRecommended\n\nAbbreviation: HCV, hepatitis\xa0C virus.\n\n\n\nTreated – the person's hepatitis\xa0C has not adequately responded to interferon-based treatment.\n\nIt is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.\n\nThis guidance is not intended to affect the position of patients whose treatment with sofosbuvir–velpatasvir was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.", 'The technology': 'Description of the technology\n\nSofosbuvir–velpatasvir (Epclusa, Gilead) is a fixed-dose combination drug. Sofosbuvir inhibits hepatitis\xa0C virus (HCV) non‑structural viral protein NS5B ribonucleic acid (RNA)-dependent RNA polymerase. Velpatasvir inhibits HCV non-structural protein NS5A.\n\nMarketing authorisation\n\nSofosbuvir–velpatasvir has a marketing authorisation in the UK for treating chronic hepatitis\xa0C virus (HCV) infection in adults. This includes genotypes\xa01–6 HCV in people with or without compensated or decompensated cirrhosis.\n\nAdverse reactions\n\nThe summary of product characteristics states that headache, fatigue and nausea are the most common adverse reactions (incidence of 10% or more). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nSofosbuvir–velpatasvir is taken orally. The recommended dose is 1\xa0tablet once daily, for 12\xa0weeks. Each tablet contains 400\xa0mg sofosbuvir and 100\xa0mg velpatasvir. The marketing authorisation states that decompensated cirrhosis should be treated with sofosbuvir–velpatasvir in combination with ribavirin, for 12\xa0weeks. Ribavirin plus sofosbuvir–velpatasvir may also be considered for people with genotype\xa03 HCV who have compensated cirrhosis.\n\nPrice\n\nSofosbuvir–velpatasvir costs £12,993.33 per 28‑day pack. The total cost of a 12‑week treatment course is £38,980. Ribavirin costs £246.65 per 56-tablet pack. The total cost of a 12‑week treatment course of sofosbuvir–velpatasvir with ribavirin is £40,089.93.\n\nThe company has a simple discount agreement which provides a discount to the list price of sofosbuvir–velpatasvir at the point of purchase or invoice. The level of the discount is commercial in confidence.', 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Gilead and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of sofosbuvir–velpatasvir, having considered evidence on the nature of chronic hepatitis\xa0C and the value placed on the benefits of sofosbuvir–velpatasvir by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and practice\n\nThe committee heard from the clinical and patient experts that having treatment options that are free from peginterferon alfa, with or without ribavirin, is important to people with chronic hepatitis\xa0C because of the associated adverse reactions, which can lead to irreversible complications. The patient experts explained that some people refuse treatment with peginterferon alfa, which increases their risk of future complications associated with chronic hepatitis\xa0C infection. The committee noted that the use of peginterferon alfa is gradually reducing in clinical practice because of the introduction of newer direct-acting antivirals, particularly for genotypes\xa01 and\xa04 hepatitis\xa0C virus (HCV). However, it was aware that peginterferon alfa, with or without ribavirin, is still a major component of the treatment regimen for other HCV genotypes. It agreed that there is an unmet need for interferon- and ribavirin-free regimens, particularly for genotype\xa03 HCV (which accounts for approximately 44% of the population of people with hepatitis\xa0C). The clinical experts considered that sofosbuvir–velpatasvir is a breakthrough treatment because of its simple dosing regimen, minimal adverse effects and interactions with other drugs, and effectiveness in decompensated cirrhosis (which may reduce the need for liver transplant). Therefore the committee recognised the importance of having an additional effective and tolerable treatment for people with chronic hepatitis\xa0C and concluded that sofosbuvir–velpatasvir could be a valuable option, especially for genotype\xa03 HCV.\n\n## Comparators for sofosbuvir–velpatasvir\n\nThe committee noted that the company did not include boceprevir and telaprevir (both taken with peginterferon alfa and ribavirin) as comparators because they are no longer used in clinical practice, although the NICE scope included them. The committee was also aware that the company had modelled some comparators in scenario analyses only (excluding them from its base case) because it considered they are not used in clinical practice. For example, daclatasvir with peginterferon alfa plus ribavirin, and simeprevir with peginterferon alfa plus ribavirin, in people with genotype\xa04 HCV. The committee heard from the clinical experts that boceprevir and telaprevir are not currently used in clinical practice in the UK, because the toxicity associated with peginterferon alfa plus ribavirin is worsened by adding boceprevir or telaprevir. It heard that peginterferon alfa plus ribavirin and daclatasvir or simeprevir are not used to treat genotype\xa04 HCV because there are several interferon-free regimens available for this population. The committee concluded that it was appropriate to exclude these comparators from the analyses.\n\nThe committee was aware that the use of peginterferon alfa plus ribavirin is reducing for some HCV genotypes (see section\xa04.1), and questioned the clinical experts about its relevance. It heard that peginterferon alfa plus ribavirin is the first choice treatment for people with mild, untreated genotype\xa02 HCV, and understood that its use for other HCV genotypes has not completely stopped. The committee concluded that peginterferon alfa plus ribavirin is a relevant comparator across all HCV genotypes.\n\nThe committee was aware that for people with decompensated cirrhosis, the company compared sofosbuvir–velpatasvir plus ribavirin with ledipasvir–sofosbuvir plus ribavirin. The committee understood that ledipasvir–sofosbuvir plus ribavirin has a marketing authorisation in the UK for decompensated cirrhosis, but that it is not recommended by NICE for this subgroup. It heard from the clinical experts that the clinical commissioning policy for chronic hepatitis\xa0C permits the use of ledipasvir–sofosbuvir plus ribavirin in this population, and concluded that it is a relevant comparator.\n\n# Clinical effectiveness\n\n## Sustained virological response\n\nThe committee considered the key clinical evidence for sofosbuvir–velpatasvir, which came from 4\xa0randomised controlled phase\xa0III clinical trials (ASTRAL-1, -2, -3 and -4). The trials included people who had not had treatment for their hepatitis\xa0C, and people whose hepatitis\xa0C had not adequately responded to interferon-based treatment. ASTRAL-1, -2 and -3 included people with compensated cirrhosis; ASTRAL-4 included people with decompensated cirrhosis. The committee was aware that the evidence review group (ERG) considered that the trials were generally well conducted, although there was a higher risk of bias in ASTRAL-2 and -3 because they were open-label studies. The committee noted that the trial results showed high sustained virological response at 12\xa0weeks irrespective of HCV genotype, cirrhosis stage or treatment history; the sustained virological response ranged from 89% (for people with previously treated genotype\xa03 HCV and compensated cirrhosis) to 100% (in several subgroups). The committee concluded that the trials showed that sofosbuvir–velpatasvir is effective for treating chronic hepatitis\xa0C across all subgroups in all genotypes.\n\n## Effect of drug-resistant HCV mutations on treatment outcome\n\nThe committee noted consultation comments that the sustained virological response for sofosbuvir–velpatasvir in ASTRAL-3 was lower in people with drug-resistant HCV mutations. The committee noted the comments from the clinical experts that routine testing for drug-resistant HCV mutations is not part of current clinical practice in the UK. It was aware that the European Association for the Study of the Liver's guideline on treating hepatitis\xa0C (2016) does not recommend systematic testing for HCV resistance before treatment. The clinical experts explained that resistance testing is difficult to do and there is no agreement on how to interpret the results. The committee noted that, of the 25\xa0people with drug-resistant mutations who had sofosbuvir–velpatasvir in ASTRAL-3, only\xa04 did not have a sustained virological response. The committee concluded that there is insufficient evidence to consider the group of people with drug-resistant mutations separately to the overall population, and that it would not reflect current clinical practice.\n\n## Adverse effects\n\nThe committee was aware that the most commonly reported adverse events are headache, fatigue and nausea. It noted that the results showed that sofosbuvir–velpatasvir has a relatively favourable tolerability profile, especially when compared with the peginterferon alfa plus ribavirin regimen. The committee concluded that the adverse events associated with sofosbuvir–velpatasvir are generally tolerable.\n\n# Cost effectiveness\n\n## Model structure\n\nThe committee noted that the structure of the model and its assumptions about the natural history of the disease are similar to models submitted for other NICE technology appraisals for chronic hepatitis\xa0C. It was aware that the company had grouped people with mild and moderate fibrosis into a single health state (non-cirrhotic), and agreed that this was consistent with how people are diagnosed in current practice. The committee concluded that the structure of the model is acceptable for decision-making.\n\n## Reinfection and future transmission of hepatitis\xa0C virus\n\nThe committee was aware that the company's base-case model did not allow for reinfection after a sustained virological response, and that the ERG explored including an annual reinfection probability of 2.4% from a meta-analysis by Aspinall et al. (2013). The committee heard from the ERG that the model was sensitive to assumptions about reinfection. The clinical experts stated that 2.4% is an overestimate of the risk of reinfection, because most people having treatment for chronic hepatitis\xa0C are not current drug users and therefore their risk of reinfection is low. The clinical experts considered that the estimate of 2.4% was based on outdated studies that are not generalisable to the UK population. The committee noted that the company did not include risk of future virus transmission in the model. It was aware that excluding reinfection may overestimate the health benefits of more effective treatments, and that excluding transmission may underestimate the benefits, but agreed that these opposing effects might not be equal. The committee agreed that it would have preferred to see a model including both reinfection and transmission, but appreciated that this would have needed a different (and potentially more complex) model structure. The committee, noting the comments from clinical experts, agreed that the ERG's reinfection estimate of 2.4% was too high. It concluded that, without a model that incorporated both reinfection and transmission, cost-effectiveness results excluding reinfection and transmission (as in the company's base case) were acceptable for its decision-making.\n\n## Estimates of sustained virological response in the model\n\nThe committee noted that the sustained virological response rates for the comparators in the company's model were selected from individual arms of selected randomised controlled trials; the company used 1\xa0source for each treatment in each subgroup. The committee was aware that the company could not perform network meta-analyses for all subgroups in the model and that, for the 2\xa0subgroups in which network meta-analyses were feasible, the results were associated with several limitations. The committee agreed that it was appropriate for the company not to use the results of its network meta-analysis to inform efficacy inputs in the model. The committee heard from the ERG that the company's choice of study for each comparator was often arbitrary; although the ERG considered that the company's justification for each choice was valid, it suggested that equally valid justification could have been provided for alternative sources. The committee was aware that the company's approach of selecting results from a single arm of a study means that the results were open to the risks of bias associated with observational studies. It noted that the company could have calculated a mean sustained virological response for each treatment in each subgroup using all available sources. The committee heard from the company that for 85\xa0of the 118\xa0sustained virological response rates used in the model, only 1\xa0source was available. However the committee agreed with the ERG that, because each result was selected from a single arm of a study, the company should have included other study types such as uncontrolled and non-randomised studies. The committee concluded that the company's method of estimating efficacy in the model introduced some uncertainty in the results.\n\nThe committee noted that, according to the company's deterministic sensitivity analyses, the cost-effectiveness results were sensitive to the sustained virological response for peginterferon alfa plus ribavirin in people without cirrhosis; estimates for other comparators had less of an effect. The committee questioned the clinical experts on the appropriateness of the company's estimates of sustained virological response for peginterferon alfa plus ribavirin in people without cirrhosis, using the estimate of 71% in untreated genotype\xa03 HCV as an example. It heard from the company that 71% was a conservative estimate in this population, because the results of its meta-analyses (done in response to clarification questions from NICE) ranged from 59% to 67%. The committee questioned whether people with certain baseline characteristics such as mild disease, younger age and low viral load would have higher sustained virological response rates with peginterferon alfa plus ribavirin. It heard from the clinical experts that it is possible to identify people who are more likely to respond to peginterferon alfa plus ribavirin, but that this is not routine practice in the UK. The clinical experts suggested that the sustained virological response for peginterferon alfa plus ribavirin might be much lower than 71% for some populations, and agreed that the company's estimates were generalisable to current practice when considering everyone with untreated genotype\xa03 HCV. Having concluded that the company's estimates of sustained virological response introduced some uncertainty in the results, but hearing that the rates for peginterferon alfa plus ribavirin were appropriate, the committee concluded that results based on the company's estimates of sustained virological response were acceptable for its decision-making.\n\n## Genotype-specific transition probabilities for developing compensated cirrhosis\n\nThe committee was aware that the company had assumed that progression from the non-cirrhotic to the compensated cirrhosis health state is faster in genotype\xa03 HCV than in other genotypes. The clinical experts agreed with this assumption. The committee understood that this approach is consistent with previous NICE technology appraisals in hepatitis\xa0C, but noted that this is the first appraisal in which evidence supporting the calculation of HCV genotype-specific transition probabilities has been submitted. The committee heard from the clinical experts that the study selected by the company to inform these transition probabilities (Kanwal et al. 2014) is generalisable to current practice in the UK. However, the committee was concerned that the company had used unadjusted results from Kanwal et al. rather than the prespecified analyses which adjusted for patients' baseline characteristics. The company could not provide a rationale for using the unadjusted data, and the committee concluded that its decision-making should be based on analyses using the adjusted results from Kanwal et al., which the ERG had included in exploratory analyses for some subgroups.\n\n## Transition probabilities for disease progression in people with cirrhosis\n\nThe committee noted that the company had used transition probabilities for compensated or decompensated cirrhosis to hepatocellular carcinoma from Cardoso et al. (2010), and had not considered estimates from Fattovich et al. (1997) for these transitions. The committee heard from the company that this is consistent with previous NICE technology appraisals in chronic hepatitis\xa0C, and that the Cardoso data are more recent and therefore more appropriate. The committee recalled its conclusion from previous technology appraisals for hepatitis\xa0C that these transition probabilities lay somewhere between the estimates from Cardoso and Fattovich. It heard from the clinical experts that data from Fattovich et al. are generalisable to current practice, and was aware that the ERG had done exploratory analyses using transition probabilities from Fattovich et al. in some subgroups. The committee concluded that both sources should be taken into account in its decision-making.\n\n## Utility values\n\nThe committee was aware that the company used utility data from the literature in line with previous NICE technology appraisals for chronic hepatitis\xa0C (health state baseline values from Wright et al. 2006 and a utility increment after sustained virological response of 0.04 from Vera-Llonch et al. 2013). The committee noted the ERG's concerns that trial data are preferable to published utility values. It heard from the company that SF-36 data from the clinical trials of sofosbuvir–velpatasvir had not been formally mapped to produce SF-6D utility values for use in the economic model at the time of the submission. The committee emphasised that when available, it prefers utility values collected from the clinical trials of the intervention under evaluation to those estimated from other sources, but it was prepared to accept the estimates from Wright et al. and Vera-Llonch et al. in the economic analyses.\n\nThe committee was aware that the company had applied on-treatment utility increments (increased quality of life) and decrements (decreased quality of life), to represent the varying effect of different treatments. The committee understood that the company applied decrements for regimens containing peginterferon alfa or ribavirin to reflect the poor tolerability of these treatments. It understood that the company applied utility increments for direct-acting antivirals to reflect the benefits of rapidly suppressing the hepatitis\xa0C virus and the improved tolerability profile. The committee was concerned that including treatment-specific changes in utility could lead to double counting, because the company also included utility increments for achieving sustained virological response and utility decrements for each adverse event, but it noted that the effect of removing them was negligible. The committee concluded that it was acceptable to include treatment-specific utility increments and decrements, but noted that there were uncertainties in the company's approach.\n\n## Pricing arrangements\n\nThe committee noted that the company has a confidential simple discount agreement for sofosbuvir–velpatasvir, with the discount applied at the point of purchase or invoice. It also noted that confidential reduced contract prices for the comparators, agreed between each company and the Commercial Medicines Unit, were included in the analyses done by the ERG, when known and if important to the committee's decision-making. The committee understood that the contract prices were the prices that the NHS pays for these treatments. The committee noted that NICE's guide to the methods of technology appraisal prefers using nationally available price reductions in the reference-case analysis to reflect the price relevant to the NHS. The committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision.\n\n# Most plausible incremental cost-effectiveness ratios\n\nThe committee was aware that incremental cost-effectiveness ratios (ICERs) incorporating its preferred assumptions about transition probabilities (see sections\xa04.12 and 4.13) were available for only 2\xa0subgroups: people with untreated genotype\xa02 HCV without cirrhosis, and people with untreated genotype\xa03 HCV without cirrhosis. The committee understood that, because of the large number of subgroup analyses in the appraisal, the ERG could not do all of its exploratory analyses in all subgroups. The committee was aware that the ERG chose to focus on the comparison with peginterferon alfa plus ribavirin in untreated genotypes\xa02 and\xa03 HCV in people without cirrhosis because these were the comparisons that produced the highest ICERs for sofosbuvir–velpatasvir, in both the company's base case and the ERG's alternative base case. The committee noted that, in these 2\xa0subgroups, using the adjusted data from Kanwal et al. increased the company's base-case ICERs for sofosbuvir–velpatasvir by approximately £700–£2,700 per quality-adjusted life year (QALY) gained compared with peginterferon alfa plus ribavirin. Using transition probabilities from Fattovich et al. instead of Cardoso et al. increased the ICERs for sofosbuvir–velpatasvir by approximately £2,500–£4,500 (see table\xa02). Recalling its conclusion that the transition probabilities for disease progression lay somewhere between the Cardoso and Fattovich estimates, the committee concluded that the most plausible ICERs for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin lay between:\n\n£35,091 and £39,783 per QALY gained for people with untreated genotype\xa02 HCV and without cirrhosis\n\n£15,923 and £18,362 per QALY gained for people with untreated genotype\xa03 HCV and without cirrhosis.\n\n## Table 2 Incremental cost-effectiveness ratios for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin\n\n\n\nSource of transition probabilities for disease progression\n \n a\n\nCardoso (2010)\n\nFattovich (1997)\n\nUntreated genotype\xa02 HCV without cirrhosis and eligible for interferon\n\nCompany base case(unadjusted data from Kanwal et al.)\n\n£32,595\n\n£37,125\n\nERG exploratory analysis of company base case(adjusted data from Kanwal et al.)\n\n£35,091\n\n£39,783\n\nUntreated genotype\xa03 HCV without cirrhosis and eligible for interferon\n\nCompany base case(unadjusted data from Kanwal et al.)\n\n£15,199\n\n£17,540\n\nERG exploratory analysis of company base case(adjusted data from Kanwal et al.)\n\n£15,923\n\n£18,362\n\nAbbreviation: HCV, hepatitis\xa0C virus.a except for the transition probabilities from the non-cirrhotic to compensated cirrhosis health state (taken from Kanwal et al. 2014).\n\nThe committee discussed the most plausible ICERs for sofosbuvir–velpatasvir compared with relevant comparators in all other subgroups, in which the company's base-case ICERs were considerably lower than the ICERs for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin in genotypes\xa02 and\xa03 HCV. The committee considered the likely effect of including its preferred assumptions on the company's base-case ICER. It agreed that the ICERs would likely increase by a similar magnitude as in the 2\xa0subgroups explored by the ERG and concluded that they would remain below £20,000 per QALY gained regardless of HCV genotype, treatment history and cirrhosis stage. Exact ICERs for all comparisons cannot be reported because the contract prices for the comparators in this appraisal are confidential and cannot be disclosed.\n\n# Recommendations\n\n## Genotypes 1 and 3–6\xa0HCV\n\nThe committee agreed that, after accounting for its preferred assumptions about transition probabilities, the ICERs for sofosbuvir–velpatasvir for HCV genotypes\xa01 and\xa03–6 were lower than £20,000 per QALY gained compared with all relevant comparators, regardless of genotype, treatment history and cirrhosis stage. The committee concluded that sofosbuvir–velpatasvir was cost effective and could be recommended for treating HCV genotypes\xa01 and\xa03–6 in people with:\n\nuntreated disease with or without compensated cirrhosis\n\ntreated disease with or without compensated cirrhosis.\n\nThe committee noted that the marketing authorisation for sofosbuvir–velpatasvir states that ribavirin may be added to sofosbuvir–velpatasvir for people with genotype\xa03 HCV with compensated cirrhosis (see section\xa02). However it was not presented with analyses of sofosbuvir–velpatasvir plus ribavirin for this population. It noted that ribavirin has a much lower acquisition cost than sofosbuvir–velpatasvir, and agreed that adding ribavirin to the treatment regimen would likely have minimal effect on the ICERs, which were lower in people with compensated cirrhosis than for people without cirrhosis. The committee agreed that, in practice, adding ribavirin to sofosbuvir–velpatasvir would be a clinical decision based on discussion between the patient and their clinician. The committee concluded that sofosbuvir–velpatasvir plus ribavirin could be recommended as a cost-effective use of NHS resources for treating genotype\xa03 HCV in people with compensated cirrhosis.\n\n## Genotype\xa02 HCV\n\nThe committee discussed the group of people with genotype\xa02 HCV. It agreed that, given that the ICERs for sofosbuvir–velpatasvir were below £20,000 per QALY gained after accounting for its preferred assumptions about transition probabilities, sofosbuvir–velpatasvir was cost effective compared with all comparators for treated and untreated disease with compensated cirrhosis and for treated disease without cirrhosis. The committee concluded that sofosbuvir–velpatasvir could be recommended for treating genotype\xa02 HCV in people with:\n\nuntreated disease with compensated cirrhosis\n\ntreated disease with or without compensated cirrhosis.\n\nThe committee discussed the group of people with untreated genotype\xa02 HCV who do not have cirrhosis. For people who can have interferon treatment, the committee noted that peginterferon alfa plus ribavirin is the only active treatment option because sofosbuvir plus ribavirin is only recommended for people with untreated disease if they cannot tolerate interferon or it is not suitable for them. The committee noted that the ICER for sofosbuvir–velpatasvir compared with peginterferon alfa plus ribavirin was above £30,000 per QALY gained when accounting for its preferred assumptions about transition probabilities. Therefore it concluded that sofosbuvir–velpatasvir could not be recommended as a cost-effective use of NHS resources for untreated genotype\xa02 HCV in people without cirrhosis who can have interferon. For people who cannot tolerate interferon or it is not suitable for them, the committee noted that the ICERs for sofosbuvir–velpatasvir were below £20,000 per QALY gained after accounting for its preferred assumptions about transition probabilities. It agreed that sofosbuvir–velpatasvir was cost effective compared with sofosbuvir plus ribavirin. Therefore, the committee concluded that sofosbuvir–velpatasvir could be recommended as a cost-effective use of NHS resources for untreated genotype\xa02 HCV for people without cirrhosis, only if they cannot tolerate interferon or it is not suitable for them.\n\n## Decompensated cirrhosis\n\nThe committee agreed that, after accounting for its preferred assumptions about transition probabilities, the ICERs for sofosbuvir–velpatasvir plus ribavirin compared with ledipasvir–sofosbuvir plus ribavirin for decompensated cirrhosis were lower than £20,000 per QALY gained. The committee concluded that sofosbuvir–velpatasvir plus ribavirin could be recommended as a cost-effective use of NHS resources for treating decompensated cirrhosis.\n\n# Other considerations\n\nThe committee was aware of NHS England's ongoing planning to put in place the capacity needed to make new oral treatments for hepatitis\xa0C available. The committee heard that the capacity to treat hepatitis\xa0C in all eligible people in the NHS according to NICE's recommendations is still developing. Given that there is not yet a steady state of implementation of the hepatitis\xa0C guidance, it was considered necessary to continue to include recommendations relating to treatment and prescribing decisions included in previous NICE guidance for the oral hepatitis\xa0C treatments in the guidance.\n\n# Innovation\n\nThe committee considered whether sofosbuvir–velpatasvir could be considered innovative, and whether the company's economic analysis had captured all changes in health-related quality of life. The committee agreed with the company that there is an unmet need for interferon- and ribavirin-free regimens in people with chronic hepatitis\xa0C, particularly for genotype\xa02 or\xa03 HCV, but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other benefits for people with chronic hepatitis\xa0C (for example, possible regression of fibrosis) and wider benefits to society (for example, reduced transmission of HCV, improved earning capacity) that were not captured in the QALY calculation and that, if taken into account, were likely to decrease the ICERs. However, the committee noted that it had taken these potential benefits into account when considering the cost effectiveness of sofosbuvir–velpatasvir and concluded that its recommendations for each population remained unchanged.\n\n# Equality issues\n\nThe committee noted the potential equality issues raised by the company and a professional organisation that there are proportionately more people from Asian and minority ethnic groups, and more people who inject drugs, who have genotype\xa03 or genotype\xa04 HCV than other HCV genotypes. Having decided that sofosbuvir–velpatasvir should be recommended for HCV genotypes\xa03 and\xa04, the committee agreed that its recommendations for these groups do not have a different effect on people protected by the equality legislation than on the wider population. The committee noted that its recommendations on sofosbuvir–velpatasvir were irrespective of whether or not the person uses injectable drugs. The committee then discussed the group for whom it could not recommend sofosbuvir–velpatasvir as a cost-effective use of NHS resources: untreated genotype\xa02 HCV in people without cirrhosis, who can have interferon. The committee was aware, from the evidence discussed during a previous technology appraisal for hepatitis\xa0C, that the proportion of people from Asian and minority ethnic groups was not disproportionately higher for genotype\xa02 HCV than for other genotypes. It also noted that the ICER for sofosbuvir–velpatasvir compared with peginterferon alfa in untreated genotype\xa02 HCV without cirrhosis ranged from £35,100 to £39,800 per QALY gained. Based on the evidence presented, the committee agreed that its recommendations were fair and concluded that no further consideration of potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment.\n\n# Summary of appraisal committee's key conclusions\n\nTA430\n\nAppraisal title: Sofosbuvir–velpatasvir for treating chronic hepatitis\xa0C\n\nSection\n\nKey conclusion\n\nThe committee concluded that the trials showed that sofosbuvir–velpatasvir is effective for treating chronic hepatitis\xa0C across all subgroups in all genotypes.\n\nSofosbuvir–velpatasvir is recommended as an option for treating chronic hepatitis\xa0C in adults, in the subgroups specified below, only if the company provides the drug with the discount agreed in the simple discount agreement.\n\nGenotypes\xa01 and 3–6\xa0hepatitis\xa0C virus (HCV)\n\nThe committee concluded that sofosbuvir–velpatasvir could be considered a cost-effective use of NHS resources for treating HCV genotype\xa01 and\xa03–6 regardless of genotype, treatment history and cirrhosis stage.\n\nThe committee concluded that sofosbuvir–velpatasvir plus ribavirin could be considered a cost-effective use of NHS resources for treating genotype\xa03 HCV in people with compensated cirrhosis.\n\nGenotype\xa02 HCV\n\nThe committee concluded that sofosbuvir–velpatasvir could be considered a cost-effective use of NHS resources for treating genotype\xa02 HCV in people with:\n\nuntreated disease with compensated cirrhosis\n\ntreated disease with or without compensated cirrhosis.\n\nFor people with untreated genotype\xa02 HCV who do not have cirrhosis, sofosbuvir–velpatasvir could be recommended as a cost-effective use of NHS resources only if interferon is not tolerated or not suitable. Sofosbuvir–velpatasvir was not recommended in people with untreated genotype\xa02 HCV who do not have cirrhosis and who can have interferon treatment, because of the high incremental cost-effectiveness ratio (ICER) compared with peginterferon alfa plus ribavirin. The ICER was between £35,100 (based on transition probabilities from Cardoso et al. 2010) and £39,800 (based on transition probabilities from Fattovich et al. 1997) per quality-adjusted life year (QALY) gained.\n\nDecompensated cirrhosis\n\nThe committee concluded that sofosbuvir–velpatasvir plus ribavirin could be considered a cost-effective use of NHS resources for treating decompensated cirrhosis.\n\n, 4.5, 4.17–4.23\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nSome of the newer treatments for chronic hepatitis\xa0C are given with peginterferon alfa or ribavirin. Having treatment options that are free from peginterferon alfa with or without ribavirin is important to people with chronic hepatitis\xa0C, particularly for people with genotype\xa03 HCV, because of the associated adverse reactions.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nSofosbuvir–velpatasvir has a simple dosing regimen and minimal adverse effects and interactions with other drugs. It is also effective in decompensated cirrhosis, which may reduce the need for liver transplant.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nSofosbuvir–velpatasvir provides another alternative to the existing oral treatment combinations for people with chronic hepatitis\xa0C, regardless of HCV genotype, treatment history and cirrhosis stage.\n\n\n\nAdverse reactions\n\nThe adverse events associated with sofosbuvir–velpatasvir are generally tolerable.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe key clinical evidence for sofosbuvir–velpatasvir came from 4\xa0randomised controlled phase\xa0III clinical trials (ASTRAL-1, -2, -3 and -4). The evidence review group (ERG) considered that the trials were generally well conducted, although there was a higher risk of bias in ASTRAL-2 and -3 because they were open-label studies.\n\nThe company could not perform network meta-analyses for all subgroups.\n\n, 4.10\n\nUncertainties generated by the evidence\n\nThe company's estimates of sustained virological response for all comparators were open to the risks of bias associated with observational studies, because the company selected them from individual arms of selected randomised controlled trials. The company should have included other study types and, although the company's justification for choosing each study was valid, equally valid justifications could have been provided for alternative sources.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nSofosbuvir–velpatasvir is effective for treating chronic hepatitis\xa0C across all subgroups in all genotypes.\n\nThere was insufficient evidence to consider the subgroup of people with drug-resistant mutations separately to the overall population. Considering this subgroup separately would not reflect current clinical practice.\n\n, 4.6\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nHaving noted the high sustained virological response rates as well as the ERG's comments that the trials were generally well conducted, the committee concluded that the trials showed that sofosbuvir–velpatasvir was effective for treating chronic hepatitis\xa0C.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe structure of the model was similar to models submitted for other NICE technology appraisals for chronic hepatitis\xa0C. The committee considered that grouping people with mild and moderate fibrosis into a single health state (non-cirrhotic) was consistent with how people are diagnosed in current practice.\n\nAlthough the marketing authorisation for sofosbuvir–velpatasvir states that ribavirin may be added to sofosbuvir–velpatasvir for people with genotype 3\xa0HCV with compensated cirrhosis, the company did not present analyses of sofosbuvir–velpatasvir plus ribavirin for this population.\n\nThe company excluded several comparators from its base-case cost-effectiveness analyses: boceprevir, telaprevir and (for genotype\xa04 HCV) peginterferon alfa plus ribavirin and daclatasvir or simeprevir. The committee concluded that it was appropriate to exclude these comparators because they are not currently used in clinical practice in the UK.\n\n, 4.8, 4.20\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee agreed that not capturing the effect of reinfection and future transmission introduces uncertainty in the cost-effectiveness estimates, but concluded that the structure of the company's model was acceptable for decision-making.\n\nThe company's method of estimating sustained virological response rates in the model introduced some uncertainty in the results.\n\nThe company's inclusion of treatment-specific changes in utility might have led to double counting, but the impact of removing them was negligible.\n\nThe company used unadjusted results from Kanwal et al. to estimate genotype-specific transition probabilities for developing compensated cirrhosis. Cost-effectiveness analyses using the prespecified adjusted results from Kanwal (done by the ERG) were only presented for 2\xa0subgroups.\n\nThe company used transition probabilities for compensated or decompensated cirrhosis to hepatocellular carcinoma from Cardoso et al. (2010), and did not consider estimates from Fattovich et al. (1997). The committee agreed that these transition probabilities lay somewhere between the estimates from Cardoso and Fattovich. Cost-effectiveness analyses using the transition probabilities from Fattovich (done by the ERG) were only presented for 2\xa0subgroups.\n\n–4.13, 4.15, 4.17\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee emphasised that when available, it prefers utility values collected from the clinical trials of the intervention under evaluation to those estimated from other sources, but it was prepared to accept the estimates from Wright et al. and Vera‑Llonch et al. in the economic analyses.\n\nThe committee recognised the additional value of sofosbuvir–velpatasvir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV), but noted that it had taken these potential benefits into account when considering the cost effectiveness of sofosbuvir–velpatasvir.\n\n, 4.25\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nSofosbuvir–velpatasvir was cost effective for all subgroups in all genotypes except for people with untreated genotype\xa02 HCV who do not have cirrhosis and who can have interferon treatment.\n\n–4.23\n\nWhat are the key drivers of cost effectiveness?\n\nThe cost-effectiveness results were sensitive to the sustained virological response for peginterferon alfa plus ribavirin in people without cirrhosis (estimates for other comparators had less of an effect). They were also sensitive to the rate of reinfection.\n\nBased on analyses in only 2\xa0subgroups, the committee noted that the ICERs increased when the ERG used transition probabilities from Fattovich et al. (1997) and adjusted data from Kanwal et al. (2014).\n\n, 4.11, 4.17\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that the most plausible ICERs included adjusted data from Kanwal; did not include reinfection or transmission risk; and lay between the estimates based on transition probabilities from Cardoso and those that used transition probabilities from Fattovich. The committee was aware that ICERs incorporating these preferred assumptions were available for only 2\xa0subgroups (presented by the ERG). The committee agreed that including its preferred assumptions in the analyses of the other subgroups would likely increase the ICERs by a similar magnitude as in the 2\xa0subgroups explored by the ERG.\n\nAfter accounting for the committee's preferred assumptions, the ICERs for sofosbuvir–velpatasvir (plus ribavirin for treating decompensated cirrhosis) were below £20,000 per QALY gained compared with all relevant comparators in all subgroups, except for people with untreated genotype\xa02 HCV who do not have cirrhosis and who can have interferon treatment (for whom the ICER lay between £35,100 and £39,800 per QALY gained). Exact ICERs for all comparisons cannot be reported because the contract prices for the comparators in this appraisal are confidential and cannot be disclosed.\n\n, 4.18\n\nAdditional factors taken into account\n\nPricing arrangements\n\nThe company has a simple discount agreement which provides a discount to the list price of sofosbuvir–velpatasvir at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\nConfidential reduced contract prices for the comparators were included in the analyses done by the ERG, when known and if important to the committee's decision-making.\n\n, 4.16\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe company and professional groups raised the potential equalities issue that there are proportionately more people from Asian and minority ethnic groups who have genotype\xa03 and genotype\xa04 HCV than other HCV genotypes. Having decided that sofosbuvir–velpatasvir should be recommended for HCV genotypes\xa03 and 4, the committee agreed that its recommendations for these subgroups do not have a different impact on people protected by the equality legislation than on the wider population. The committee also considered the population for whom it could not recommend sofosbuvir–velpatasvir (untreated genotype\xa02 HCV in people without cirrhosis). It was aware that the proportion of people from Asian and minority ethnic groups was not disproportionately higher in this genotype compared with other genotypes. Based on the evidence presented, the committee agreed that its recommendations were fair and concluded that no further consideration of potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment.\n\n"}	https://www.nice.org.uk/guidance/ta430	Evidence-based recommendations on sofosbuvir–velpatasvir (Epclusa) for treating chronic hepatitis C in adults.
96b16ee2b570b2052b169ba9dd03d06b9b478804	nice	Pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib	Pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib Evidence-based recommendations on pomalidomide (Imnovid) for multiple myeloma previously treated with lenalidomide and bortezomib in adults. # Recommendations Pomalidomide, in combination with low‑dose dexamethasone, is recommended as an option for treating multiple myeloma in adults at third or subsequent relapse; that is, after 3 previous treatments including both lenalidomide and bortezomib, only when the company provides pomalidomide with the discount agreed in the patient access scheme. This guidance is not intended to affect the position of patients whose treatment with pomalidomide was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Pomalidomide (Imnovid, Celgene) is an immunomodulating agent that has shown an anti‑cancer effect in relapsed and refractory multiple myeloma, particularly in patients who have disease that is resistant, or refractory, to previously used anti‑myeloma therapies. It is given orally. Marketing authorisation Pomalidomide 'in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least 2 prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy'. Adverse reactions The most common treatment‑related adverse events associated with pomalidomide include anaemia, pneumonia, neutropenia, fatigue, pyrexia and thrombocytopenia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended starting dosage of pomalidomide is 4 mg once daily taken orally on days 1 to 21 of repeated 28‑day cycles. The recommended dosage of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of each 28‑day treatment cycle. Price £8,884 per 21‑tablet pack (excluding VAT; MIMS online and company submission): 1 mg, 2 mg, 3 mg and 4 mg. The average cost of a course of treatment is £44,420. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pomalidomide, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Celgene and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of pomalidomide, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of pomalidomide by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Nature of the condition Multiple myeloma is a chronic and ultimately fatal condition that seriously affects quality of life, and treatments that improve both survival and quality of life are important to patients. The clinical experts pointed out that multiple myeloma is a heterogeneous disease; when deciding which treatments to use, response to previous treatments and toxicity are important so having a range of treatment options is valuable. The experts highlighted that there is a clear unmet need in the current treatment pathway, because very few options are available after using existing NICE‑recommended treatments (thalidomide, bortezomib and lenalidomide). Moreover, quality of life is an especially important consideration at this stage of the pathway because of the accumulation of toxicities over multiple lines of therapy. The experts highlighted that patients place particular value on therapies that can be taken orally. The committee recognised the need for an effective, well‑tolerated treatment option for people with multiple myeloma at third or subsequent relapse who have had at least 3 previous treatments, including both lenalidomide and bortezomib. # Treatment pathway The committee considered the likely position of pomalidomide with dexamethasone in the treatment pathway for relapsed and refractory multiple myeloma, noting that its marketing authorisation specified that it should only be used after at least 2 previous treatment regimens, including both lenalidomide and bortezomib. The committee was aware that NICE currently recommends lenalidomide as third‑line treatment, and it asked the experts if this reflects clinical practice. The clinical experts confirmed that for most patients, lenalidomide is offered at third line, after thalidomide then bortezomib (they clarified that a small proportion of people had received lenalidomide at second line through the Cancer Drugs Fund). The experts agreed that the evidence for pomalidomide with dexamethasone in this indication was largely for patients whose disease was heavily pre‑treated, which was consistent with using it after 3 or more previous therapies. The committee concluded that the appropriate positioning of pomalidomide, in line with clinical practice and the evidence base was after third or subsequent relapse (that is, after 3 previous treatments including both lenalidomide and bortezomib) and that this positioning would be the focus of its considerations. # Comparators The committee considered the options available for treating multiple myeloma after third or subsequent relapse. The committee queried whether the comparators included in the scope reflected clinical practice: Panobinostat with bortezomib and dexamethasone – The clinical experts stated that panobinostat is used primarily after third relapse and so is an appropriate comparator for pomalidomide. However, they noted that panobinostat is associated with an adverse toxicity profile which is particularly problematic in patients who have already had multiple therapies. The patient expert noted that panobinostat is associated with severe gastrointestinal problems that can severely affect daily activities. The clinical experts also highlighted that for some patients bortezomib may no longer work by this later stage in the pathway. The clinical experts did however acknowledge that if pomalidomide were not available, panobinostat with bortezomib and dexamethasone would likely be the most commonly prescribed treatment regimen. Bendamustine with thalidomide and dexamethasone – The clinical experts stated that bendamustine is available on the Cancer Drugs Fund but only when no other treatment alternatives are available. Conventional chemotherapy – The experts noted that conventional chemotherapy would be an option for treating multiple myeloma after third or subsequent relapse, but its use is reliant on the patients' fitness and manageable drug toxicity. Ideally, conventional chemotherapy would be used even later in the treatment pathway after all active agents had been tried. The experts highlighted that in choosing a treatment, healthcare professionals and patients together consider comorbidities, route of administration, and the response to and toxicity of previous treatments. As such, all of the treatments noted above are used in clinical practice and are appropriate comparators. However, the experts reiterated that none of these treatments is used very often because of the current availability of pomalidomide through the Cancer Drugs Fund. The committee understood the concerns around the comparators and that the clinical experts valued pomalidomide because it was a clinically effective, oral, well‑tolerated treatment. The committee concluded that the comparators in the scope were appropriate. # Clinical effectiveness The committee considered the comparator in MM‑003, the main phase III, open‑label trial presented by the company. The committee noted that it compared pomalidomide plus low‑dose dexamethasone with high‑dose dexamethasone alone. It heard from the clinical experts that although high‑dose dexamethasone was appropriate when MM‑003 was started, it no longer represents an option for active treatment in England. The committee noted that no direct comparative evidence was available for any of the comparators, and recalled its discussions during the previous appraisal about the challenges in obtaining evidence for pomalidomide compared with current therapies. The company presented a case for the clinical effectiveness of high‑dose dexamethasone to be used as a proxy for the clinical effectiveness of conventional chemotherapy. The experts noted that despite different toxicity levels, conventional chemotherapy and high‑dose dexamethasone have similar delivery mechanisms, and agreed that this was a reasonable assumption. The committee concluded that high‑dose dexamethasone was a reasonable proxy for conventional chemotherapy. The committee discussed the clinical‑effectiveness data from MM‑003 and its generalisability to clinical practice in England. The committee heard that patients in the trial were younger than typically seen in clinical practice, but the clinical experts' experience in practice suggests that older patients experience similar outcomes with pomalidomide. Moreover, in a subgroup analysis in MM‑003, pomalidomide worked as well in older patients as it did in the younger age group. The results, based on the assessment of outcomes by the independent response adjudication committee (median follow‑up 10 months), suggested that pomalidomide and low‑dose dexamethasone resulted in a statistically significant median progression‑free survival gain of 1.8 months compared with high‑dose dexamethasone alone (and therefore, by proxy, compared with conventional chemotherapy). The median overall survival gain with pomalidomide and low‑dose dexamethasone was between 4.6 months and 7.0 months depending on whether the results were based on the intention‑to‑treat population or adjusted for crossover (56% of patients crossed over to the pomalidomide arm). The committee concluded that pomalidomide and low‑dose dexamethasone is clinically more effective than high‑dose dexamethasone alone (and, by proxy, conventional chemotherapy). ## Indirect clinical‑effectiveness evidence The committee understood that there was no direct evidence for the comparators other than conventional chemotherapy, and that there was no evidence to support making comparisons using a conventional mixed treatment comparison. The company therefore selected individual treatment arms from available studies and ran separate analyses comparing pomalidomide and low‑dose dexamethasone with each of the comparators: Bendamustine with thalidomide and dexamethasone – The company included individual patient data from MM‑002 for pomalidomide (because it was most comparable to the studies available for bendamustine) and from the MUK‑1 trial for bendamustine, supplemented by data on 21 patients from the Gooding and Tarant studies. Panobinostat with bortezomib and dexamethasone – No patient level data were available for panobinostat; so the company conducted a matched adjusted indirect comparison including pooled data from the MM‑002, MM‑003 and MM‑010 trials for pomalidomide, and data from the PANORAMA‑2 trial for panobinostat.The company also adjusted the comparisons to reflect differences in the characteristics of patients within the datasets available (covariate adjustment). The committee discussed the main limitations around these analyses raised by the evidence review group (ERG): Only 55 patients had panobinostat so the data are limited. Patients in PANORAMA‑2 (panobinostat) had on average 1 less line of therapy compared with patients in the MM studies (pomalidomide). For the comparison of pomalidomide with bendamustine, the ERG disagreed with the exclusion of the MM‑003 and MM‑010 trials. The ERG noted that the company had excluded these trials because the assessment of comparability between studies was based mainly on how many people had disease that was refractory to lenalidomide in each study. However, the ERG stated that MM‑002 included 3‑ to 4‑times more lenalidomide‑refractory patients than the bendamustine studies. Therefore, the ERG was not clear that this justified the exclusion of MM‑003 and MM‑010, but acknowledged that this did not substantially affect the results. The MUK‑1 trial included more patients with untreated disease than MM‑002 which favoured bendamustine and was not reflective of the population being appraised.The committee acknowledged that these indirect comparisons were associated with considerable uncertainty but recognised that the company had presented the best evidence available. The committee concluded that the results based on the company's indirect comparisons were acceptable for its decision‑making. The committee considered the clinical effectiveness of pomalidomide compared with bendamustine. Pomalidomide with low‑dose dexamethasone resulted in a median of 16.5‑month extension of overall survival (95% confidence interval 12.6 to 19.8) compared with a median of 8.1 months (95% CI 5.3 to 13.5) for bendamustine with thalidomide and dexamethasone, with a statistically significant covariate‑adjusted hazard ratio of 0.58. Pomalidomide with low‑dose dexamethasone was associated with a median progression‑free survival benefit of 4.2 months compared with 3.3 months for bendamustine with thalidomide and dexamethasone, with a statistically significant covariate‑adjusted hazard ratio of 0.79.The committee noted that the results were associated with very wide confidence intervals, and also noted the disparity in overall survival results between the pre‑ and post‑progression states. However, on balance, the committee concluded that pomalidomide with low‑dose dexamethasone is associated with greater clinical efficacy than bendamustine with thalidomide and dexamethasone. The committee considered the clinical effectiveness of pomalidomide compared with panobinostat. Pomalidomide with low‑dose dexamethasone was associated with a median overall survival benefit of 12.4 months (95% CI 11.1 to 13.4) compared with 17.5 months (95% CI 10.8 to 22.22) for panobinostat with bortezomib and dexamethasone. Pomalidomide with low‑dose dexamethasone was associated with a smaller median progression‑free survival benefit of 4.1 months compared with 5.3 months for panobinostat with bortezomib and dexamethasone.The committee recalled comments from clinical and patient experts that panobinostat was associated with toxicity, which has a severe effect on quality of life at this stage of the disease. Although panobinostat with bortezomib and dexamethasone appeared to be more effective, the committee recognised that pomalidomide is an oral treatment and concluded that pomalidomide with low‑dose dexamethasone is a valuable treatment option at third and subsequent relapse. # Cost effectiveness The committee considered the cost‑effectiveness evidence submitted by the company, noting that the model structure was in line with that used in the previous appraisal. The committee noted that the comments from the ERG around model structure related mainly to identifying and correcting programming errors. The committee agreed that the model structure was appropriate and concluded that it would consider results based on the ERG's correction of errors in the company's base case. The committee noted that the main change for this review was the inclusion of data from the updated indirect comparisons (see sections 4.7 to 4.10). For the comparison with conventional chemotherapy including data from the MM‑030 trial, the company included the data adjusted for crossover using the 2‑stage method, and the ERG agreed that this method was most appropriate. The company also included covariate‑adjusted comparisons within the model for comparisons with bendamustine and panobinostat, conducted using the corrected group prognosis (CGP) method in the base‑case analysis, and the mean of covariates method in a scenario analysis. The ERG included the CGP method in its preferred analysis but did not state that this was a better approach; the committee was aware that it had a small effect on the incremental cost‑effectiveness ratios (ICERs). The ERG's main concern with the company's analyses was that because the company used different datasets for pomalidomide in each comparison, a fully incremental analysis was not possible. The ERG preferred to use the pooled dataset for pomalidomide (based on MM‑030, MM‑002 and MM‑010) for all comparisons because it would include a larger dataset and allow for a full incremental analysis. However, the committee noted that this would mean losing the head‑to‑head trial data compared with conventional chemotherapy, and some of the trial arm comparability for pomalidomide compared with bendamustine. The committee understood the ERG's approach but did not consider that it was more appropriate than the company's approach. The committee concluded that it would base its decisions on the company's base‑case ICERs, corrected by the ERG for errors. Compared with conventional chemotherapy, the company's base‑case ICER (corrected by the ERG) for pomalidomide with low‑dose dexamethasone was £48,673 per quality‑adjusted life year (QALY) gained. The committee was aware this was based on data directly from the MM‑003 trial and was therefore less uncertain than the other comparisons. It concluded that this was the most plausible ICER for pomalidomide with low‑dose dexamethasone compared with conventional chemotherapy. Compared with bendamustine, the company's base‑case ICER (corrected by the ERG) for pomalidomide with low‑dose dexamethasone was £45,082 per QALY gained. The committee considered that this comparison was likely to be biased in favour of bendamustine, so adjusting for this would lower the ICER. The committee also noted that bendamustine is now available for a lower price (£27 per vial compared with £276 per vial). The ERG stated that accounting for this would increase the ICER. The committee concluded that the ICER for pomalidomide with low‑dose dexamethasone compared with bendamustine was associated with uncertainty, but was likely to be less than £50,000 per QALY gained. The precise ICERs for pomalidomide compared with panobinostat cannot be reported because of a confidential patient access scheme for panobinostat. Based on the company's base case (corrected by the ERG), pomalidomide plus low‑dose dexamethasone resulted in cost savings and also a QALY loss, producing ICERs that reflected 'savings per QALY lost'. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So the higher the ICER, the more cost effective a treatment becomes. The committee recalled the uncertainties underpinning the indirect comparison with panobinostat but was satisfied that the ICER was in the 'southwest' quadrant of the cost‑effectiveness plane. Also noting the toxicity associated with panobinostat, the advantages of oral treatment and therefore the improved quality of life associated with pomalidomide, the committee concluded that an additional treatment option would be of value to patients. It further concluded that pomalidomide plus low‑dose dexamethasone was recommended as a cost‑effective use of NHS resources. # End-of-life considerations The committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The company discussed whether life expectancy without pomalidomide would be less than 24 months. The committee noted that median overall survival estimated from the model was 13.10 months for panobinostat, 8.90 months for bendamustine and 6.21 months for conventional chemotherapy. The committee considered that this was also consistent with means below 24 months, and concluded that this criterion was met for all comparisons. It noted, however, that the model was based on trial populations of patients whose disease had been heavily pre‑treated. This end‑of‑life criterion could not, therefore, be assumed to have been met if pomalidomide was positioned any earlier than at third and subsequent relapse in the treatment sequence. The committee discussed whether a survival benefit of over 3 months can be expected for pomalidomide compared with the comparators. The committee was aware that pomalidomide was less effective than panobinostat (see section 4.10) and therefore did not meet this criterion. The committee noted that pomalidomide was associated with a median overall survival gain of 13.1 months compared with about 6.0 months for conventional chemotherapy and 9.0 months for bendamustine. The committee noted that results were associated with uncertainty, but was satisfied that a survival gain of 3.0 months was plausible. The committee concluded that this end‑of‑life criterion was met for 2 of the 3 comparisons (that is, compared with bendamustine and conventional chemotherapy). Having established that pomalidomide meets the end‑of‑life criteria compared with bendamustine and conventional chemotherapy, the committee recalled that the most plausible ICERs were below £50,000 per QALY gained in both cases. The committee was mindful of the uncertainties underpinning these ICERs, and noted that they were at the upper end of the range normally considered to be cost effective if end‑of‑life criteria were met. However, the committee acknowledged that the ICERs were based on best available evidence. It recalled testimonies from clinical and patient experts about the significant value of pomalidomide at this point in the pathway. The committee noted its conclusion in section 4.15 that the savings per QALY lost for pomalidomide compared with panobinostat were high enough for it to be considered a cost‑effective use of NHS resources without applying the end‑of‑life criteria. The committee concluded that it could recommend pomalidomide with low‑dose dexamethasone for treating relapsed and refractory multiple myeloma at third or subsequent relapse; that is, after 3 previous treatments including lenalidomide and bortezomib, as a cost‑effective use of NHS resources, only when the company provides pomalidomide with the discount agreed in the patient access scheme. # Summary of appraisal committee's key conclusions TA427 Appraisal title: Pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib Section Key conclusion Pomalidomide, in combination with low‑dose dexamethasone, is recommended as an option for treating multiple myeloma in adults at third or subsequent relapse; that is, after 3 previous treatments including both lenalidomide and bortezomib, only when the company provides pomalidomide with the discount agreed in the patient access scheme. The committee concluded that the appropriate positioning of pomalidomide, in line with clinical practice and the evidence base was after third or subsequent relapse (that is, after 3 previous treatments including both lenalidomide and bortezomib) and that this positioning would be the focus of its considerations. The committee acknowledged that the indirect comparisons were associated with considerable uncertainty but recognised that the company had presented the best evidence available. The most plausible ICERs for pomalidomide with low‑dose dexamethasone compared with conventional chemotherapy and bendamustine with thalidomide and dexamethasone were below £50,000 per QALY gained, and the committee concluded that pomalidomide meets the end‑of‑life criteria compared with bendamustine and conventional chemotherapy. The end‑of‑life criterion for an additional 3 months survival gain was not met for the comparison with panobinostat with bortezomib and dexamethasone and the ICERs reflected 'savings per QALY lost'; that is, pomalidomide was less effective but less costly. The committee noted its conclusion in section 4.15 that the savings per QALY lost for pomalidomide compared with panobinostat were high enough for it to be considered a cost‑effective use of NHS resources without applying the end‑of‑life criteria. The committee concluded that it could recommend pomalidomide with low‑dose dexamethasone for treating relapsed and refractory multiple myeloma at third or subsequent relapse; that is: after 3 previous treatments including both lenalidomide and bortezomib, as a cost‑effective use of NHS resources, only when the company provides pomalidomide with the discount agreed in the patient access scheme. Current practice Clinical need of patients, including the availability of alternative treatments There is a clear unmet need in the current treatment pathway, because very few options are available after using existing NICE‑recommended treatments (thalidomide, bortezomib and lenalidomide). The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The committee understood that the clinical experts valued pomalidomide because it was a clinically effective, oral, well‑tolerated treatment. What is the position of the treatment in the pathway of care for the condition? The committee concluded that, based on clinical practice and the evidence available, the appropriate positioning of pomalidomide was after third or subsequent relapse; that is, after 3 previous treatments including both lenalidomide and bortezomib. Adverse reactions The committee heard that quality of life is an especially important consideration at this stage of the pathway because of the accumulation of toxicities over multiple lines of therapy. The clinical experts stated that pomalidomide provided a well‑tolerated treatment option. Evidence for clinical effectiveness Availability, nature and quality of evidence The company presented evidence from MM‑003, a phase III, open‑label trial that compared pomalidomide plus low‑dose dexamethasone with high‑dose dexamethasone alone. The committee agreed that high‑dose dexamethasone was a reasonable proxy for the clinical effectiveness of conventional chemotherapy. Because there was no direct evidence other than for conventional chemotherapy, the company selected individual treatment arms from available studies and ran separate analyses comparing pomalidomide and low‑dose dexamethasone with each of the comparators. Relevance to general clinical practice in the NHS The committee heard that patients in the trial were younger than typically seen in clinical practice, but the clinical experts' experience in practice suggests that older patients experience similar outcomes with pomalidomide. Uncertainties generated by the evidence The committee heard from the clinical experts that although high‑dose dexamethasone was appropriate when MM‑003 was started, it no longer represents an option for active treatment in England. The indirect comparisons were associated with considerable uncertainty and the committee recognised that the company had presented the best evidence available. The committee concluded that the results based on the company's indirect comparisons were acceptable for its decision‑making. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No subgroups were identified. Estimate of the size of the clinical effectiveness including strength of supporting evidence Pomalidomide and low‑dose dexamethasone compared with high‑dose dexamethasone: Progression‑free survival gain of 1.8 months in favour of pomalidomide. Overall survival gain between 4.6 months and 7.0 months in favour of pomalidomide. Pomalidomide and low‑dose dexamethasone compared with bendamustine: Progression‑free survival benefit of 4.2 months compared with 3.3 months in favour of pomalidomide. Overall survival gain of 16.5‑month compared with 8.1 months in favour of pomalidomide. Pomalidomide and low‑dose dexamethasone compared with panobinostat: Progression‑free survival benefit of 4.1 months compared with 5.3 months for panobinostat. Overall survival benefit of 12.4 months compared with 17.5 months for panobinostat. How has the new clinical evidence that has emerged since the original appraisal (TA338) influenced the current recommendations? The key clinical trial evidence from MM‑003 was used in this review. However, the indirect comparisons were updated to include the most up to date data. Evidence for cost effectiveness Availability and nature of evidence The company presented an economic model comparing pomalidomide and low‑dose dexamethasone with: conventional chemotherapy; bendamustine with thalidomide and dexamethasone; and panobinostat with bortezomib and dexamethasone. Uncertainties around and plausibility of assumptions and inputs in the economic model The company submitted an economic model that was in line with that used in the previous appraisal (TA338). The committee agreed that the model structure was appropriate. The committee noted that the comments from the ERG around model structure related mainly to identifying and correcting programming errors. The committee agreed that it would consider results based on the ERG's correction of errors in the company's base case. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? Quality of life benefits and utility values were incorporated as in the original appraisal. No additional issues were identified. Are there specific groups of people for whom the technology is particularly cost effective? No subgroups were identified. What are the key drivers of cost effectiveness? The ICERs varied based on the clinical datasets included, and using crossover adjustment and covariate adjustment methods. The committee concluded that it would base its decisions on the company's base‑case ICERs, corrected by the ERG for errors. Most likely cost‑effectiveness estimate (given as an ICER) Pomalidomide compared with conventional chemotherapy: ICER of £48,673 per QALY gained. Pomalidomide compared with bendamustine: the ICER was associated with uncertainty but was likely to be less than £50,000 per QALY gained. Pomalidomide compared with panobinostat: the precise ICERs cannot be reported but pomalidomide resulted in cost savings but also a QALY loss, producing ICERs that reflected 'savings per QALY lost'. How has the new cost‑effectiveness evidence that has emerged since the original appraisal (TA338) influenced the current recommendations? The committee noted that the main change since the original appraisal was the inclusion of data from the updated indirect comparisons and this influenced the current recommendations. Additional factors taken into account Patient access schemes (PPRS) The manufacturer of pomalidomide has agreed a patient access scheme with the Department of Health. This is a simple discount scheme, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. End‑of‑life considerations All comparisons met the criterion of 'life expectancy less than 24 months'. Two of the 3 comparisons met the criterion of 'survival benefit of over 3 months': pomalidomide compared with bendamustine and pomalidomide compared with conventional chemotherapy. The committee concluded that pomalidomide meets the end‑of‑life criteria compared with bendamustine and conventional chemotherapy. Equalities considerations and social value judgements N/A	{'Recommendations': 'Pomalidomide, in combination with low‑dose dexamethasone, is recommended as an option for treating multiple myeloma in adults at third or subsequent relapse; that is, after 3\xa0previous treatments including both lenalidomide and bortezomib, only when the company provides pomalidomide with the discount agreed in the patient access scheme.\n\nThis guidance is not intended to affect the position of patients whose treatment with pomalidomide was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nPomalidomide (Imnovid, Celgene) is an immunomodulating agent that has shown an anti‑cancer effect in relapsed and refractory multiple myeloma, particularly in patients who have disease that is resistant, or refractory, to previously used anti‑myeloma therapies. It is given orally.\n\nMarketing authorisation\n\nPomalidomide 'in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least 2\xa0prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy'.\n\nAdverse reactions\n\nThe most common treatment‑related adverse events associated with pomalidomide include anaemia, pneumonia, neutropenia, fatigue, pyrexia and thrombocytopenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended starting dosage of pomalidomide is 4\xa0mg once daily taken orally on days 1\xa0to 21\xa0of repeated 28‑day cycles.\n\nThe recommended dosage of dexamethasone is 40\xa0mg orally once daily on days 1, 8, 15\xa0and 22\xa0of each 28‑day treatment cycle.\n\nPrice\n\n£8,884\xa0per\xa021‑tablet pack (excluding VAT; MIMS online and company submission): 1\xa0mg, 2\xa0mg, 3\xa0mg and 4\xa0mg. The average cost of a course of treatment is £44,420.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pomalidomide, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Celgene and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of pomalidomide, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of pomalidomide by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Nature of the condition\n\nMultiple myeloma is a chronic and ultimately fatal condition that seriously affects quality of life, and treatments that improve both survival and quality of life are important to patients. The clinical experts pointed out that multiple myeloma is a heterogeneous disease; when deciding which treatments to use, response to previous treatments and toxicity are important so having a range of treatment options is valuable. The experts highlighted that there is a clear unmet need in the current treatment pathway, because very few options are available after using existing NICE‑recommended treatments (thalidomide, bortezomib and lenalidomide). Moreover, quality of life is an especially important consideration at this stage of the pathway because of the accumulation of toxicities over multiple lines of therapy. The experts highlighted that patients place particular value on therapies that can be taken orally. The committee recognised the need for an effective, well‑tolerated treatment option for people with multiple myeloma at third or subsequent relapse who have had at least 3\xa0previous treatments, including both lenalidomide and bortezomib.\n\n# Treatment pathway\n\nThe committee considered the likely position of pomalidomide with dexamethasone in the treatment pathway for relapsed and refractory multiple myeloma, noting that its marketing authorisation specified that it should only be used after at least 2\xa0previous treatment regimens, including both lenalidomide and bortezomib. The committee was aware that NICE currently recommends lenalidomide as third‑line treatment, and it asked the experts if this reflects clinical practice. The clinical experts confirmed that for most patients, lenalidomide is offered at third line, after thalidomide then bortezomib (they clarified that a small proportion of people had received lenalidomide at second line through the Cancer Drugs Fund). The experts agreed that the evidence for pomalidomide with dexamethasone in this indication was largely for patients whose disease was heavily pre‑treated, which was consistent with using it after 3\xa0or more previous therapies. The committee concluded that the appropriate positioning of pomalidomide, in line with clinical practice and the evidence base was after third or subsequent relapse (that is, after 3\xa0previous treatments including both lenalidomide and bortezomib) and that this positioning would be the focus of its considerations.\n\n# Comparators\n\nThe committee considered the options available for treating multiple myeloma after third or subsequent relapse. The committee queried whether the comparators included in the scope reflected clinical practice:\n\nPanobinostat with bortezomib and dexamethasone – The clinical experts stated that panobinostat is used primarily after third relapse and so is an appropriate comparator for pomalidomide. However, they noted that panobinostat is associated with an adverse toxicity profile which is particularly problematic in patients who have already had multiple therapies. The patient expert noted that panobinostat is associated with severe gastrointestinal problems that can severely affect daily activities. The clinical experts also highlighted that for some patients bortezomib may no longer work by this later stage in the pathway. The clinical experts did however acknowledge that if pomalidomide were not available, panobinostat with bortezomib and dexamethasone would likely be the most commonly prescribed treatment regimen.\n\nBendamustine with thalidomide and dexamethasone – The clinical experts stated that bendamustine is available on the Cancer Drugs Fund but only when no other treatment alternatives are available.\n\nConventional chemotherapy – The experts noted that conventional chemotherapy would be an option for treating multiple myeloma after third or subsequent relapse, but its use is reliant on the patients' fitness and manageable drug toxicity. Ideally, conventional chemotherapy would be used even later in the treatment pathway after all active agents had been tried.\n\nThe experts highlighted that in choosing a treatment, healthcare professionals and patients together consider comorbidities, route of administration, and the response to and toxicity of previous treatments. As such, all of the treatments noted above are used in clinical practice and are appropriate comparators. However, the experts reiterated that none of these treatments is used very often because of the current availability of pomalidomide through the Cancer Drugs Fund. The committee understood the concerns around the comparators and that the clinical experts valued pomalidomide because it was a clinically effective, oral, well‑tolerated treatment. The committee concluded that the comparators in the scope were appropriate.\n\n# Clinical effectiveness\n\nThe committee considered the comparator in MM‑003, the main phase III, open‑label trial presented by the company. The committee noted that it compared pomalidomide plus low‑dose dexamethasone with high‑dose dexamethasone alone. It heard from the clinical experts that although high‑dose dexamethasone was appropriate when MM‑003\xa0was started, it no longer represents an option for active treatment in England. The committee noted that no direct comparative evidence was available for any of the comparators, and recalled its discussions during the previous appraisal about the challenges in obtaining evidence for pomalidomide compared with current therapies. The company presented a case for the clinical effectiveness of high‑dose dexamethasone to be used as a proxy for the clinical effectiveness of conventional chemotherapy. The experts noted that despite different toxicity levels, conventional chemotherapy and high‑dose dexamethasone have similar delivery mechanisms, and agreed that this was a reasonable assumption. The committee concluded that high‑dose dexamethasone was a reasonable proxy for conventional chemotherapy.\n\nThe committee discussed the clinical‑effectiveness data from MM‑003\xa0and its generalisability to clinical practice in England. The committee heard that patients in the trial were younger than typically seen in clinical practice, but the clinical experts' experience in practice suggests that older patients experience similar outcomes with pomalidomide. Moreover, in a subgroup analysis in MM‑003, pomalidomide worked as well in older patients as it did in the younger age group. The results, based on the assessment of outcomes by the independent response adjudication committee (median follow‑up 10\xa0months), suggested that pomalidomide and low‑dose dexamethasone resulted in a statistically significant median progression‑free survival gain of 1.8\xa0months compared with high‑dose dexamethasone alone (and therefore, by proxy, compared with conventional chemotherapy). The median overall survival gain with pomalidomide and low‑dose dexamethasone was between 4.6\xa0months and 7.0\xa0months depending on whether the results were based on the intention‑to‑treat population or adjusted for crossover (56% of patients crossed over to the pomalidomide arm). The committee concluded that pomalidomide and low‑dose dexamethasone is clinically more effective than high‑dose dexamethasone alone (and, by proxy, conventional chemotherapy).\n\n## Indirect clinical‑effectiveness evidence\n\nThe committee understood that there was no direct evidence for the comparators other than conventional chemotherapy, and that there was no evidence to support making comparisons using a conventional mixed treatment comparison. The company therefore selected individual treatment arms from available studies and ran separate analyses comparing pomalidomide and low‑dose dexamethasone with each of the comparators:\n\nBendamustine with thalidomide and dexamethasone – The company included individual patient data from MM‑002\xa0for pomalidomide (because it was most comparable to the studies available for bendamustine) and from the MUK‑1\xa0trial for bendamustine, supplemented by data on 21\xa0patients from the Gooding and Tarant studies.\n\nPanobinostat with bortezomib and dexamethasone – No patient level data were available for panobinostat; so the company conducted a matched adjusted indirect comparison including pooled data from the MM‑002, MM‑003\xa0and MM‑010\xa0trials for pomalidomide, and data from the PANORAMA‑2\xa0trial for panobinostat.The company also adjusted the comparisons to reflect differences in the characteristics of patients within the datasets available (covariate adjustment).\n\nThe committee discussed the main limitations around these analyses raised by the evidence review group (ERG):\n\nOnly 55\xa0patients had panobinostat so the data are limited.\n\nPatients in PANORAMA‑2\xa0(panobinostat) had on average 1\xa0less line of therapy compared with patients in the MM studies (pomalidomide).\n\nFor the comparison of pomalidomide with bendamustine, the ERG disagreed with the exclusion of the MM‑003\xa0and MM‑010\xa0trials. The ERG noted that the company had excluded these trials because the assessment of comparability between studies was based mainly on how many people had disease that was refractory to lenalidomide in each study. However, the ERG stated that MM‑002\xa0included 3‑ to 4‑times more lenalidomide‑refractory patients than the bendamustine studies. Therefore, the ERG was not clear that this justified the exclusion of MM‑003\xa0and MM‑010, but acknowledged that this did not substantially affect the results.\n\nThe MUK‑1\xa0trial included more patients with untreated disease than MM‑002\xa0which favoured bendamustine and was not reflective of the population being appraised.The committee acknowledged that these indirect comparisons were associated with considerable uncertainty but recognised that the company had presented the best evidence available. The committee concluded that the results based on the company's indirect comparisons were acceptable for its decision‑making.\n\nThe committee considered the clinical effectiveness of pomalidomide compared with bendamustine.\n\nPomalidomide with low‑dose dexamethasone resulted in a median of 16.5‑month extension of overall survival (95% confidence interval [CI] 12.6\xa0to 19.8) compared with a median of 8.1\xa0months (95% CI 5.3\xa0to 13.5) for bendamustine with thalidomide and dexamethasone, with a statistically significant covariate‑adjusted hazard ratio of 0.58.\n\nPomalidomide with low‑dose dexamethasone was associated with a median progression‑free survival benefit of 4.2\xa0months compared with 3.3\xa0months for bendamustine with thalidomide and dexamethasone, with a statistically significant covariate‑adjusted hazard ratio of 0.79.The committee noted that the results were associated with very wide confidence intervals, and also noted the disparity in overall survival results between the pre‑ and post‑progression states. However, on balance, the committee concluded that pomalidomide with low‑dose dexamethasone is associated with greater clinical efficacy than bendamustine with thalidomide and dexamethasone.\n\nThe committee considered the clinical effectiveness of pomalidomide compared with panobinostat.\n\nPomalidomide with low‑dose dexamethasone was associated with a median overall survival benefit of 12.4\xa0months (95% CI 11.1\xa0to 13.4) compared with 17.5\xa0months (95% CI 10.8\xa0to 22.22) for panobinostat with bortezomib and dexamethasone.\n\nPomalidomide with low‑dose dexamethasone was associated with a smaller median progression‑free survival benefit of 4.1\xa0months compared with 5.3\xa0months for panobinostat with bortezomib and dexamethasone.The committee recalled comments from clinical and patient experts that panobinostat was associated with toxicity, which has a severe effect on quality of life at this stage of the disease. Although panobinostat with bortezomib and dexamethasone appeared to be more effective, the committee recognised that pomalidomide is an oral treatment and concluded that pomalidomide with low‑dose dexamethasone is a valuable treatment option at third and subsequent relapse.\n\n# Cost effectiveness\n\nThe committee considered the cost‑effectiveness evidence submitted by the company, noting that the model structure was in line with that used in the previous appraisal. The committee noted that the comments from the ERG around model structure related mainly to identifying and correcting programming errors. The committee agreed that the model structure was appropriate and concluded that it would consider results based on the ERG's correction of errors in the company's base case.\n\nThe committee noted that the main change for this review was the inclusion of data from the updated indirect comparisons (see sections\xa04.7\xa0to 4.10). For the comparison with conventional chemotherapy including data from the MM‑030\xa0trial, the company included the data adjusted for crossover using the 2‑stage method, and the ERG agreed that this method was most appropriate. The company also included covariate‑adjusted comparisons within the model for comparisons with bendamustine and panobinostat, conducted using the corrected group prognosis (CGP) method in the base‑case analysis, and the mean of covariates method in a scenario analysis. The ERG included the CGP method in its preferred analysis but did not state that this was a better approach; the committee was aware that it had a small effect on the incremental cost‑effectiveness ratios (ICERs). The ERG's main concern with the company's analyses was that because the company used different datasets for pomalidomide in each comparison, a fully incremental analysis was not possible. The ERG preferred to use the pooled dataset for pomalidomide (based on MM‑030, MM‑002\xa0and MM‑010) for all comparisons because it would include a larger dataset and allow for a full incremental analysis. However, the committee noted that this would mean losing the head‑to‑head trial data compared with conventional chemotherapy, and some of the trial arm comparability for pomalidomide compared with bendamustine. The committee understood the ERG's approach but did not consider that it was more appropriate than the company's approach. The committee concluded that it would base its decisions on the company's base‑case ICERs, corrected by the ERG for errors.\n\nCompared with conventional chemotherapy, the company's base‑case ICER (corrected by the ERG) for pomalidomide with low‑dose dexamethasone was £48,673\xa0per\xa0quality‑adjusted life year (QALY) gained. The committee was aware this was based on data directly from the MM‑003\xa0trial and was therefore less uncertain than the other comparisons. It concluded that this was the most plausible ICER for pomalidomide with low‑dose dexamethasone compared with conventional chemotherapy.\n\nCompared with bendamustine, the company's base‑case ICER (corrected by the ERG) for pomalidomide with low‑dose dexamethasone was £45,082\xa0per\xa0QALY gained. The committee considered that this comparison was likely to be biased in favour of bendamustine, so adjusting for this would lower the ICER. The committee also noted that bendamustine is now available for a lower price (£27\xa0per\xa0vial compared with £276\xa0per\xa0vial). The ERG stated that accounting for this would increase the ICER. The committee concluded that the ICER for pomalidomide with low‑dose dexamethasone compared with bendamustine was associated with uncertainty, but was likely to be less than £50,000\xa0per\xa0QALY gained.\n\nThe precise ICERs for pomalidomide compared with panobinostat cannot be reported because of a confidential patient access scheme for panobinostat. Based on the company's base case (corrected by the ERG), pomalidomide plus low‑dose dexamethasone resulted in cost savings and also a QALY loss, producing ICERs that reflected 'savings per\xa0QALY lost'. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So the higher the ICER, the more cost effective a treatment becomes. The committee recalled the uncertainties underpinning the indirect comparison with panobinostat but was satisfied that the ICER was in the 'southwest' quadrant of the cost‑effectiveness plane. Also noting the toxicity associated with panobinostat, the advantages of oral treatment and therefore the improved quality of life associated with pomalidomide, the committee concluded that an additional treatment option would be of value to patients. It further concluded that pomalidomide plus low‑dose dexamethasone was recommended as a cost‑effective use of NHS resources.\n\n# End-of-life considerations\n\nThe committee considered the advice about life‑extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\nThe company discussed whether life expectancy without pomalidomide would be less than 24\xa0months. The committee noted that median overall survival estimated from the model was 13.10\xa0months for panobinostat, 8.90\xa0months for bendamustine and 6.21\xa0months for conventional chemotherapy. The committee considered that this was also consistent with means below 24\xa0months, and concluded that this criterion was met for all comparisons. It noted, however, that the model was based on trial populations of patients whose disease had been heavily pre‑treated. This end‑of‑life criterion could not, therefore, be assumed to have been met if pomalidomide was positioned any earlier than at third and subsequent relapse in the treatment sequence.\n\nThe committee discussed whether a survival benefit of over 3\xa0months can be expected for pomalidomide compared with the comparators. The committee was aware that pomalidomide was less effective than panobinostat (see section\xa04.10) and therefore did not meet this criterion. The committee noted that pomalidomide was associated with a median overall survival gain of 13.1\xa0months compared with about 6.0\xa0months for conventional chemotherapy and 9.0\xa0months for bendamustine. The committee noted that results were associated with uncertainty, but was satisfied that a survival gain of 3.0\xa0months was plausible. The committee concluded that this end‑of‑life criterion was met for 2\xa0of the 3\xa0comparisons (that is, compared with bendamustine and conventional chemotherapy).\n\nHaving established that pomalidomide meets the end‑of‑life criteria compared with bendamustine and conventional chemotherapy, the committee recalled that the most plausible ICERs were below £50,000\xa0per\xa0QALY gained in both cases. The committee was mindful of the uncertainties underpinning these ICERs, and noted that they were at the upper\xa0end of the range normally considered to be cost effective if end‑of‑life criteria were met. However, the committee acknowledged that the ICERs were based on best available evidence. It recalled testimonies from clinical and patient experts about the significant value of pomalidomide at this point in the pathway. The committee noted its conclusion in section\xa04.15\xa0that the savings per\xa0QALY lost for pomalidomide compared with panobinostat were high enough for it to be considered a cost‑effective use of NHS resources without applying the end‑of‑life criteria. The committee concluded that it could recommend pomalidomide with low‑dose dexamethasone for treating relapsed and refractory multiple myeloma at third or subsequent relapse; that is, after 3\xa0previous treatments including lenalidomide and bortezomib, as a cost‑effective use of NHS resources, only when the company provides pomalidomide with the discount agreed in the patient access scheme.\n\n# Summary of appraisal committee's key conclusions\n\nTA427\n\nAppraisal title: Pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib\n\nSection\n\nKey conclusion\n\nPomalidomide, in combination with low‑dose dexamethasone, is recommended as an option for treating multiple myeloma in adults at third or subsequent relapse; that is, after 3\xa0previous treatments including both lenalidomide and bortezomib, only when the company provides pomalidomide with the discount agreed in the patient access scheme.\n\nThe committee concluded that the appropriate positioning of pomalidomide, in line with clinical practice and the evidence base was after third or subsequent relapse (that is, after 3\xa0previous treatments including both lenalidomide and bortezomib) and that this positioning would be the focus of its considerations.\n\nThe committee acknowledged that the indirect comparisons were associated with considerable uncertainty but recognised that the company had presented the best evidence available.\n\nThe most plausible ICERs for pomalidomide with low‑dose dexamethasone compared with conventional chemotherapy and bendamustine with thalidomide and dexamethasone were below £50,000\xa0per\xa0QALY gained, and the committee concluded that pomalidomide meets the end‑of‑life criteria compared with bendamustine and conventional chemotherapy.\n\nThe end‑of‑life criterion for an additional 3\xa0months survival gain was not met for the comparison with panobinostat with bortezomib and dexamethasone and the ICERs reflected 'savings per\xa0QALY lost'; that is, pomalidomide was less effective but less costly. The committee noted its conclusion in section\xa04.15\xa0that the savings per\xa0QALY lost for pomalidomide compared with panobinostat were high enough for it to be considered a cost‑effective use of NHS resources without applying the end‑of‑life criteria. The committee concluded that it could recommend pomalidomide with low‑dose dexamethasone for treating relapsed and refractory multiple myeloma at third or subsequent relapse; that is: after 3\xa0previous treatments including both lenalidomide and bortezomib, as a cost‑effective use of NHS resources, only when the company provides pomalidomide with the discount agreed in the patient access scheme.\n\n, 4.3, 4.8, 4.15, 4.19\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThere is a clear unmet need in the current treatment pathway, because very few options are available after using existing NICE‑recommended treatments (thalidomide, bortezomib and lenalidomide).\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe committee understood that the clinical experts valued pomalidomide because it was a clinically effective, oral, well‑tolerated treatment.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that, based on clinical practice and the evidence available, the appropriate positioning of pomalidomide was after third or subsequent relapse; that is, after 3\xa0previous treatments including both lenalidomide and bortezomib.\n\n\n\n\n\nAdverse reactions\n\nThe committee heard that quality of life is an especially important consideration at this stage of the pathway because of the accumulation of toxicities over multiple lines of therapy. The clinical experts stated that pomalidomide provided a well‑tolerated treatment option.\n\n, 4.4, 4.11\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe company presented evidence from MM‑003, a phase III, open‑label trial that compared pomalidomide plus low‑dose dexamethasone with high‑dose dexamethasone alone. The committee agreed that high‑dose dexamethasone was a reasonable proxy for the clinical effectiveness of conventional chemotherapy.\n\nBecause there was no direct evidence other than for conventional chemotherapy, the company selected individual treatment arms from available studies and ran separate analyses comparing pomalidomide and low‑dose dexamethasone with each of the comparators.\n\n, 4.7\n\nRelevance to general clinical practice in the NHS\n\nThe committee heard that patients in the trial were younger than typically seen in clinical practice, but the clinical experts' experience in practice suggests that older patients experience similar outcomes with pomalidomide.\n\n\n\nUncertainties generated by the evidence\n\nThe committee heard from the clinical experts that although high‑dose dexamethasone was appropriate when MM‑003\xa0was started, it no longer represents an option for active treatment in England.\n\nThe indirect comparisons were associated with considerable uncertainty and the committee recognised that the company had presented the best evidence available. The committee concluded that the results based on the company's indirect comparisons were acceptable for its decision‑making.\n\n, 4.8\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups were identified.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nPomalidomide and low‑dose dexamethasone compared with high‑dose dexamethasone:\n\nProgression‑free survival gain of 1.8\xa0months in favour of pomalidomide.\n\nOverall survival gain between 4.6\xa0months and 7.0\xa0months in favour of pomalidomide.\n\n\n\nPomalidomide and low‑dose dexamethasone compared with bendamustine:\n\nProgression‑free survival benefit of 4.2\xa0months compared with 3.3\xa0months in favour of pomalidomide.\n\nOverall survival gain of 16.5‑month compared with 8.1\xa0months in favour of pomalidomide.\n\n\n\nPomalidomide and low‑dose dexamethasone compared with panobinostat:\n\nProgression‑free survival benefit of 4.1\xa0months compared with 5.3\xa0months for panobinostat.\n\nOverall survival benefit of 12.4\xa0months compared with 17.5\xa0months for panobinostat.\n\n, 4.9, 4.10\n\n\n\nHow has the new clinical evidence that has emerged since the original appraisal (TA338) influenced the current recommendations?\n\nThe key clinical trial evidence from MM‑003\xa0was used in this review. However, the indirect comparisons were updated to include the most up to date data.\n\n–\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented an economic model comparing pomalidomide and low‑dose dexamethasone with: conventional chemotherapy; bendamustine with thalidomide and dexamethasone; and panobinostat with bortezomib and dexamethasone.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe company submitted an economic model that was in line with that used in the previous appraisal (TA338). The committee agreed that the model structure was appropriate.\n\nThe committee noted that the comments from the ERG around model structure related mainly to identifying and correcting programming errors. The committee agreed that it would consider results based on the ERG's correction of errors in the company's base case.\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nQuality of life benefits and utility values were incorporated as in the original appraisal. No additional issues were identified.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were identified.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe ICERs varied based on the clinical datasets included, and using crossover adjustment and covariate adjustment methods. The committee concluded that it would base its decisions on the company's base‑case ICERs, corrected by the ERG for errors.\n\n\n\n\n\n\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nPomalidomide compared with conventional chemotherapy: ICER of £48,673\xa0per\xa0QALY gained.\n\nPomalidomide compared with bendamustine: the ICER was associated with uncertainty but was likely to be less than £50,000\xa0per\xa0QALY gained.\n\nPomalidomide compared with panobinostat: the precise ICERs cannot be reported but pomalidomide resulted in cost savings but also a QALY loss, producing ICERs that reflected 'savings per\xa0QALY lost'.\n\n–4.15\n\nHow has the new cost‑effectiveness evidence that has emerged since the original appraisal (TA338) influenced the current recommendations?\n\nThe committee noted that the main change since the original appraisal was the inclusion of data from the updated indirect comparisons and this influenced the current recommendations.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of pomalidomide has agreed a patient access scheme with the Department of Health. This is a simple discount scheme, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\n–\n\nEnd‑of‑life considerations\n\nAll comparisons met the criterion of 'life expectancy less than 24\xa0months'.\n\nTwo of the 3\xa0comparisons met the criterion of 'survival benefit of over 3\xa0months': pomalidomide compared with bendamustine and pomalidomide compared with conventional chemotherapy.\n\nThe committee concluded that pomalidomide meets the end‑of‑life criteria compared with bendamustine and conventional chemotherapy.\n\n, 4.18\n\nEqualities considerations and social value judgements\n\nN/A\n\n–"}	https://www.nice.org.uk/guidance/ta427	Evidence-based recommendations on pomalidomide (Imnovid) for multiple myeloma previously treated with lenalidomide and bortezomib in adults.
739490cbb82248a99ed3d071b3f3bd8f458643d0	nice	Pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer	Pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer Evidence-based recommendations on pertuzumab (Perjeta) for treating HER2-positive breast cancer that is locally advanced, inflammatory, or early-stage with a high risk of recurrence, in adults. # Recommendations Pertuzumab, in combination with trastuzumab and chemotherapy, is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of adults with human epidermal growth factor receptor 2 (HER2)‑positive breast cancer; that is, in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence. It is recommended only if the company provides pertuzumab with the discount agreed in the patient access scheme.# The technology Description of the technology Pertuzumab (Perjeta, Roche) is a recombinant monoclonal antibody which targets human epidermal growth factor receptor 2 (HER2)-positive breast tumours. It interrupts the activation of the HER2 intracellular signalling pathway, leading to cell growth arrest and apoptosis. It is administered by intravenous infusion. Marketing authorisation Pertuzumab has a marketing authorisation in the UK 'in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer at high risk of recurrence'. Adverse reactions The summary of product characteristics includes the following adverse reactions for pertuzumab: decreased appetite, headache, cough, diarrhoea, vomiting, nausea, constipation, rash, pain, oedema, fatigue, asthaenia and left ventricular dysfunction. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended dosage of pertuzumab is an initial loading dose of 840 mg, followed by a maintenance dose of 420 mg every 3 weeks for 3 to 6 cycles. Price Pertuzumab costs £2,395 per 420‑mg vial (excluding VAT). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pertuzumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of pertuzumab, having considered evidence on the nature of HER2-positive breast cancer and the value placed on the benefits of pertuzumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Patient experience for people with HER2-positive breast cancer The committee heard from the patient expert that after having pertuzumab, she had experienced a complete response that her clinician described as 'spectacular'. She felt that taking pertuzumab not only had the benefit of removing the physical signs of cancer, but also had a major effect on her psychological wellbeing. When a person's tumour responds to treatment it can improve quality of life, and reassure them that the treatment is working. The clinical experts agreed that outcomes such as pathological complete response can have a strong psychological benefit for patients. They explained that pathological complete response is an indication that not only are tumour cells in the breast responding to treatment (and, in the case of total pathological response, that tumour cells in the lymph nodes are also responding to treatment), but that that any tumour cells which may have already spread beyond the breast and nodes but that are undetectable (micro-metastases) would also have been treated. In addition, a reduction in size or the disappearance of tumour in the breast potentially allows for less radical surgery in patients who would otherwise be advised to have mastectomy. The committee agreed that neoadjuvant treatment outcomes such as pathological complete response seemed beneficial from a clinical perspective, and could provide important psychological benefits for patients. However, given the limitations of the evidence, it considered that there was uncertainty about whether a pathological complete response after neoadjuvant therapy was the sole and most reliable indicator of, or translated directly into, treatment-related long-term event-free and overall survival benefit (section 4.5). The committee also noted comments from Breast Cancer Now which indicated that although it considered pertuzumab to be a potentially promising treatment, the charity strongly supported the collection of more evidence because many of the cited benefits are hypothetical. The committee concluded that HER2-positive breast cancer can have a substantial negative effect on quality of life, and that patients and clinicians place a strong value on effective early treatments that would be of particular value if they were proven to improve long-term outcomes. # Current clinical management of HER2-positive breast cancer The committee heard from the clinical experts that there is variation across the NHS in the use of neoadjuvant therapy (primary systemic therapy) before surgery in HER2-positive breast cancer, which was demonstrated in an informal survey presented by one of the clinical experts. They stated that this may relate to service configuration issues, such as staffing levels and access to HER2 testing, and that this restricted access to neoadjuvant treatment in some parts of the UK. The clinical experts indicated that despite this variation, there is a trend in the NHS towards increasing use of neoadjuvant treatment for HER2-positive breast cancer, following the demonstrated survival benefits of HER2 agents given later in the disease pathway. In very extensive or inoperable disease, neoadjuvant treatment may shrink the tumour and make it operable. In other cases it may allow for breast-conserving surgery, thereby reducing the need for more complicated procedures (such as mastectomy and breast reconstruction) and their associated risks, lessening the treatment burden for both patients and the NHS. The clinical experts stated that another advantage of neoadjuvant treatment is that outcomes can be more directly linked to treatment (because there is less chance of confounding from other treatments), and that this was useful to inform future treatment decisions. The committee heard from the company and the ERG that around 75% of neoadjuvant treatment regimens for patients with HER2-positive cancers contain trastuzumab. The clinical experts stated there is variation in the chemotherapy given in combination with trastuzumab. The committee was interested in any disadvantages of neoadjuvant therapy, for example the potential for tumour growth before surgery. It heard from the clinical experts that it is extremely unlikely that a tumour would grow in size during neoadjuvant treatment, that patients are typically closely monitored, including with MRI scans, so that any disease progression would be quickly identified. In most patients tumour shrinkage (albeit not necessarily total pathological response) is seen, and this can occur quite rapidly during a course of neoadjuvant treatment. The committee concluded that in current NHS practice there is a trend towards offering more neoadjuvant therapy in HER2-positive breast cancer, and that most neoadjuvant regimens in this patient group include trastuzumab. # Clinical effectiveness ## Strength of clinical trial evidence The company submitted evidence from 2 phase II randomised controlled trials relevant to the population in the scope, NeoSphere and TRYPHAENA. However, the committee considered both of these to have substantial limitations for the purposes of providing comparative effectiveness data for pertuzumab. Both trials were at an early stage of research (phase II) and lacked longer-term efficacy data, had small patient numbers, were open label, and were not powered for key outcomes of interest including progression-free survival and overall survival. The trial data were further limited because only 2 of the 4 arms in NeoSphere included licensed treatment combinations (arm A n=107, trastuzumab and docetaxel, and arm B, n=107, pertuzumab, trastuzumab and docetaxel), and because TRYPHAENA was a cardiac safety trial (so not primarily designed to test efficacy) and had pertuzumab in all 3 treatment arms with no control group. However, the committee agreed that despite these limitations, both trials contained data that helped to demonstrate the clinical effectiveness of pertuzumab. In NeoSphere there was a statistically significant increase in pathological complete response when pertuzumab was added to trastuzumab and docetaxel (both given every 3 weeks for 4 cycles; see section 4.4). TRYPHAENA included pathological complete response as a secondary outcome, and therefore provided additional supportive evidence. The committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA. ## Results of clinical trial evidence The committee noted that of the 3 available definitions of pathological complete response, the primary outcome in NeoSphere, pathological complete response in the breast, was the least stringent measure; it classified patients as responders even if there was residual disease in lymph nodes or ductal carcinoma in situ. Total pathological complete response, a secondary outcome in NeoSphere, is the preferred definition for regulatory purposes, which requires the disappearance of invasive cancer in the breast and lymph nodes (although in situ cancer in the breast may still be present). However, the committee noted that the addition of pertuzumab to trastuzumab plus docetaxel was associated with larger increases in all 3 definitions of pathological complete response than trastuzumab plus docetaxel alone (there was an absolute difference in pathological complete response of 16.8 to 20.6 percentage points between the 2 groups, depending on the definition). In addition, although there was no control arm, the TRYPHAENA trial also showed high rates of pathological complete response in all 3 pertuzumab treatment arms (total pathological complete response rates ranged from 57.3% to 66.2%). The committee also heard from 1 clinical expert who stated that the ability of pertuzumab to remove all cancer including ductal carcinoma in situ was 'remarkable', and it was also aware that the patient expert had a pathological complete response with pertuzumab that her clinician described as 'spectacular' (section 4.1). The committee accepted that the available evidence suggested that pertuzumab was an effective treatment to induce pathological complete response. However, it expressed concerns about the reliability of pathological complete response as a surrogate for longer-term survival outcomes for patients (section 4.5), and it noted that the trial was not powered for long-term outcomes. The committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response when added to trastuzumab and docetaxel, but that there was no reliable trial evidence of event-free or overall survival benefit. ## Association of pathological complete response with survival The committee discussed the value of pathological complete response as a clinically meaningful indicator of longer-term event-free and overall survival. It was aware that a number of studies have been done to investigate this, including the CTNeoBC meta-analysis, which the company had described in its submission and used in its modelling. CTNeoBC evaluated the prognostic value of pathological complete response, and found that at patient-level there was a correlation between pathological complete response and survival outcomes. However, at trial-level, CTNeoBC concluded that the evidence that a treatment-related improvement in pathological complete response translated into a treatment-related improvement in survival outcomes was very weak (correlation coefficients of 0.03 and 0.24 for event-free survival and overall survival respectively). The committee understood that correlation between 2 variables at an individual level does not necessarily imply that one can be used as a surrogate for the other when estimating the effect of a specific treatment. The committee was also aware that the ERG had reviewed the wider evidence in this area, and had stated that the evidence of a positive treatment effect translating into a positive effect on survival was not convincing. The committee agreed that there was considerable uncertainty about whether pathological complete response could be viewed as a surrogate marker of long-term benefit. However, it heard from the clinical experts that if a patient had a pathological complete response, they considered this to be a good indicator of long-term benefit, particularly in oestrogen receptor-negative tumours. The committee accepted that neoadjuvant pertuzumab was an effective treatment for inducing pathological complete response. It agreed that the evidence was limited with regard to long-term outcomes, but considered whether the outcome of pathological complete response may itself only be a marker of drug activity at a cellular or micro-metastatic level, and noted the improved overall survival demonstrated with the addition of pertuzumab in the CLEOPATRA trial in metastatic HER2-positive breast cancer. It was also aware that both the US Food and Drug Administration and the European Medicines Agency had concluded that it was 'reasonably likely' that pathological complete response was associated with improved survival outcomes. The committee was minded to accept that the complete disappearance of cancer in the breast and nodes was more likely to be associated with improved long-term outcomes than completely unrelated. On balance, although there was uncertainty about the exact relationship, the committee accepted that pathological complete response was more likely than not to have an association with longer-term survival. It concluded that despite the uncertainty, and in line with current oncological thinking, earlier HER2-specific treatment would have patient benefit in the long term, as well as the short-term benefit of tumour shrinkage or disappearance. ## Generalisability of NeoSphere trial evidence to clinical practice in England The committee noted that most patients in NeoSphere were described as having 'operable' disease (defined as tumours over 2 cm in diameter with no clinically involved lymph nodes or involved mobile ipsilateral axillary nodes ), and that people in this category would have the best prognosis of the 3 subgroups in the trial (that is, operable, locally advanced and inflammatory). In addition, the low patient numbers in the trial resulted in one of the rare subtypes, inflammatory breast cancer, having only 7 patients in the comparator arm and 10 patients in the intervention arm. The committee considered that there were likely to have been very few UK patients in the trial; only 214 patients had either the intervention or comparator as stated in the scope, across 59 centres, and of these only 2 centres were in the UK. However, the committee agreed that the comparator used reflected current NHS practice, because 75% of neoadjuvant treatment regimens in the UK include trastuzumab. Furthermore, in response to the appraisal consultation document, the company had stated that clinical expert opinion supported the generalisability of the clinical trial evidence, although it did not provide any supporting evidence. The committee concluded that although there was some uncertainty about the generalisability of the NeoSphere trial to current NHS practice, it was appropriate for decision-making. ## Adverse events associate with pertuzumab The committee noted that TRYPHAENA was specifically designed to assess the cardiac safety of pertuzumab. However, the committee considered 1 of the 2 primary outcomes used to measure cardiac safety, left ventricular systolic dysfunction, to be a poor indicator of cardiac safety. The committee noted that adverse events in NeoSphere were similar in both the intervention and comparator arms. The committee also heard from the patient expert who found the effects of pertuzumab to be very manageable, with the only notable effects being diarrhoea and a slower than expected return to normal hair growth. The committee concluded that based on the evidence, pertuzumab had an acceptable adverse event profile. # Cost effectiveness ## Health economic model: structure and parameter assumptions Although the locoregional recurrence health state omitted surgery (which would be the best option for patients at this stage of the treatment pathway), the committee considered the general structure of the model and sequencing of health states to be plausible. However, it had concerns about the parameter assumptions used in the model for effectiveness (section 4.9) and costs (section 4.11). Furthermore, the committee expressed concern that in September 2015 the company had submitted to the Scottish Medicines Consortium (SMC) for consideration of pertuzumab for the same indication. In the SMC submission, the company had derived substantially different incremental costs, utility values and cost-effectiveness results to those submitted to NICE, but had not provided a full and clear explanation of the reasons for the differences. In response to the appraisal consultation document, the company provided a detailed explanation which more clearly demonstrated that the main difference between the 2 submissions was the incorporation of costs of drugs funded by the Cancer Drugs Fund (CDF), which were available in England but not Scotland. Although the committee regretted that this uncertainty had not been resolved earlier, it welcomed this additional transparency from the company, which helped to reassure the committee at its second meeting that none of the variation was a cause for concern. The committee was satisfied it now understood the reasons for the variation between the NICE and SMC incremental cost-effectiveness ratios (ICERs), and concluded that the structure of the model was generally appropriate for decision-making, although it was still subject to uncertainty because of some parameter assumptions. ## Health economic model: clinical-effectiveness assumptions The company assumed that pathological complete response was a surrogate for survival in the model, because the event-free survival data from the trial were not robust enough to be used in the model. The committee was aware that the NICE guide to the methods of technology appraisal contains guidance on the use of surrogate outcomes within health economic models, stating that: 'evidence in support of the surrogate-to-final end point outcome relationship must be provided together with an explanation of how the relationship is quantified for use in modelling'. The committee noted that the company had attempted to provide evidence to support the relationship using the CTNeoBC meta-analysis. This study identified a patient-level relationship between pathological complete response and survival, but could not validate pathological complete response as a valid surrogate for survival. The committee was aware of the authors' conclusions that there were several possible reasons for the lack of proof of surrogacy, including low overall pathological complete response rates, heterogeneous patient populations, and inclusion of only a single study designed to evaluate effects of targeted therapy. The committee also considered that it may be difficult to prove this relationship because pathological complete response was a binary outcome (response or no response), whereas in clinical practice, the outcome may be more nuanced; it is possible that the proportion of individual patient response may affect long-term outcomes without necessarily meeting the threshold to be classified as a response in the trial. The committee noted that the company had attempted to explore uncertainty in this area with a scenario analysis using the less robust survival data from NeoSphere, which improved the cost-effectiveness results for pertuzumab. Overall, in the absence of an alternative source of robust effectiveness data and taking into account that it considered that pathological complete response was more likely than not to be associated with longer-term outcomes (section 4.5), the committee concluded that the company's approach to model clinical effectiveness was acceptable. However, it was subject to high levels of uncertainty, and the committee would need to interpret any survival estimates with caution. ## Health economic model: health-related quality-of-life assumptions The committee discussed differences in the quality-adjusted life year (QALY) gains in the SMC and NICE company submissions (0.31 in the SMC submission, 0.261 in the NICE submission). It also discussed the differences in the utility value for the progressed state used in the model (0.5 in the SMC submission, 0.452 in the NICE submission). The committee heard from the company that some of the difference in QALY gains was because it had added an extra assumption to the model submitted to NICE, specifically that the utility value could not be higher than the age-matched population without disease. The company also explained that it used a lower utility value in the NICE submission because it considered a study by Lloyd et al. (2006) to provide a more appropriate utility measure. The company did not explain why it considered a different utility value from that used in the SMC submission to be appropriate. At the first appraisal committee meeting, the committee could not be sure of the effect of these differences because the company had not provided sufficient explanation. However, in response to the appraisal consultation document, the company supplied a more detailed explanation of the main differences and their effects. The committee accepted this explanation and concluded that the health-related quality of life assumptions used in the NICE model were appropriate for decision-making. ## Health economic model: cost assumptions The committee discussed whether the inclusion of drugs funded by the CDF in the metastatic heath states was a fair reflection of the future costs of treatment for HER2-positive breast cancer in England. The committee noted that by including these drugs, the additional costs of neoadjuvant pertuzumab were being offset in the model by the costs of additional drugs for metastatic disease in the comparator arm funded by the CDF (including pertuzumab and trastuzumab emtansine). The committee was aware that the CDF is a temporary funding vehicle for cancer drugs that cannot yet demonstrate cost effectiveness, and is currently in a transitional period to determine which drugs should be funded. For patients starting neoadjuvant treatment today, the costs of treatment for metastatic disease (if needed) are likely to be incurred several years in the future, by which time there is no guarantee that the CDF will still be operating in the same way. The committee was aware that in modelling the future costs and benefits of treatments, there is always an element of uncertainty. However, given the transitional nature of the CDF, the committee questioned the validity of the large cost offsets assumed by the company. The committee also noted the ERG's comment that the company had incorporated pertuzumab as a second-line metastatic treatment in the model, although its licence is for use in combination with trastuzumab and docetaxel in patients who have not had previous anti-HER2 therapy or chemotherapy for their metastatic disease. Furthermore, the committee raised concerns about the company's precise drug costs. The company used list prices for the CDF-funded treatments, but the NHS may be paying lower prices for these drugs which would increase the ICER. In its response to the appraisal consultation document, the company provided various scenario analyses that changed assumptions for the drugs funded by the CDF, including using actual costs currently paid by the NHS for these drugs, and completely removing CDF-funded treatments. Furthermore, in order to mitigate the risks of any future changes to the CDF, the company submitted a confidential simple discount patient access scheme. The committee appreciated the company's attempt to resolve the uncertainty both with the presentation of additional scenario analyses, and the offer to risk-share against any changes in CDF-funded treatments by reducing the costs of pertuzumab. It concluded that this helped to reduce uncertainty in the cost-effectiveness results. ## Incremental cost-effectiveness results The committee considered the cost-effectiveness results presented by the company and the ERG. It noted that in the original company submission and ERG report, there were a number of different base-case scenarios, but that all were subject to uncertainty. Particular issues of relevance included assumptions about the future costs and availability of CDF-funded treatments, and also effectiveness assumptions. In exploratory analyses, both the company and ERG models were most sensitive to assumptions about clinical effectiveness (that is, assumptions about the rates of pathological complete response, which influenced survival estimates in the model). However, the committee accepted that there was evidence that rates of pathological complete response were statistically significantly higher with the addition of pertuzumab to trastuzumab and docetaxel (section 4.4), and that correspondingly high rates of pathological complete response had also been demonstrated in the TRYPHAENA trial. With respect to costs and availability of CDF drugs in the metastatic setting, the company had attempted to address uncertainty in scenario analyses (section 4.11). The committee agreed that because of the high levels of uncertainty in the cost-effectiveness assumptions, it would be prudent to use the more conservative ICERs from the ERG, and to focus on scenarios which excluded any cost offsets from metastatic treatments funded by the CDF. The committee noted that in these more conservative scenarios, and incorporating the simple discount patient access scheme for pertuzumab, the ICERs fell within the range normally considered to be a cost-effective use of NHS resources. The committee noted that the comparatively early regulatory approval for pertuzumab had limited the clinical trial evidence available such that it was suboptimal for the purposes of long-term modelling and health technology assessment. In these uncertain circumstances, the committee welcomed the company's approach to discount the cost of pertuzumab as it increased the likelihood that pertuzumab would be cost effective with more conservative assumptions than had been used in the model. The committee concluded that pertuzumab could be recommended as a cost-effective use of NHS resources for the neoadjuvant treatment of HER2-positive breast cancer. The committee discussed whether it would be appropriate to specify the number of cycles of pertuzumab that should be used in clinical practice. It was aware that the NeoSphere trial and the model used 4 cycles, but that the licence allowed for 3 to 6 cycles, which was a large variation (effectively meaning that for some patients dosage and costs could be double that of others). It heard from the clinical experts that they would use pertuzumab for 3 to 6 cycles but that this would vary. One clinical expert stated that the clinical effect of 3 cycles was probably the same as the effect after 6 cycles. The committee noted that the ERG had done a sensitivity analysis (without the patient access scheme discount) varying the number of cycles of pertuzumab, which caused the ICER to increase from £23,467 per QALY gained (ERG's base case, based on 4 cycles of pertuzumab) to £42,955 per QALY gained (using 6 cycles of pertuzumab and amending the costs but not the effectiveness of treatment), suggesting that the results were sensitive to this assumption. The committee concluded that patients should normally have no more than 4 cycles of neoadjuvant treatment with pertuzumab. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA424 Appraisal title: Pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer Section Key conclusion Pertuzumab, in combination with trastuzumab and chemotherapy, is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of adults with human epidermal growth factor receptor 2 (HER2) positive breast cancer; that is, in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence. It is recommended only if the company provides pertuzumab with the discount agreed in the patient access scheme. Patients should normally have no more than 4 cycles of neoadjuvant treatment with pertuzumab. The committee agreed that because of the high levels of uncertainty in the cost-effectiveness assumptions, it would be prudent to use the more conservative ICERs from the ERG, and to focus on scenarios which excluded any cost offsets from metastatic treatments funded by the CDF. The committee noted that in these more conservative scenarios, and incorporating the simple discount patient access scheme for pertuzumab, the ICERs fell within the range normally considered to be a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard from the patient expert that that taking pertuzumab not only had the benefit of removing the physical signs of cancer, but also had a major effect on her psychological wellbeing. The committee concluded that HER2-positive breast cancer can have a substantial negative effect on quality of life, and that patients and clinicians place a strong value on effective early treatments. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? After having pertuzumab, the patient expert had a complete response that her clinician described as 'spectacular'. The patient expert felt that taking pertuzumab not only had the benefit of removing the physical signs of cancer, but also had a major effect on her psychological wellbeing. The clinical experts agreed response can have an important psychological benefit. In addition a pathological complete response is an indication that not only are tumour cells responding to treatment, but that any micro-metastases are likely to have also been treated. A reduction or disappearance of tumour in the breast also potentially allows for less radical surgery in patients who would otherwise be advised to have mastectomy. The committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response when added to trastuzumab and docetaxel, but that there was no reliable trial evidence of event-free or overall survival benefit. The committee was minded to accept that the complete disappearance of cancer in the breast and nodes was more likely to be associated with improved long-term outcomes than completely unrelated. On balance, although there was uncertainty about the exact relationship, the committee accepted that pathological complete response was more likely than not to have an association with longer-term survival. What is the position of the treatment in the pathway of care for the condition? The committee heard from the clinical experts that there is variation across the NHS in the use of neoadjuvant therapy before surgery in HER2-positive breast cancer. They stated that this may relate to service configuration issues, such as staffing levels and access to HER2 testing, and that this restricted access to neoadjuvant treatment in some parts of the UK. The clinical experts indicated that despite this variation, there is a trend in the NHS towards increasing use of neoadjuvant treatment for HER2-positive breast cancer, following the demonstrated survival benefits of HER2 agents given later in the disease pathway. A reduction in the size of the tumour may make the disease operable when initially it is very extensive, and in other cases allow breast-conserving surgery, thereby reducing the need for more complicated procedures (such as mastectomy and breast reconstruction) and their associated risks. Adverse reactions The committee noted that adverse events in NeoSphere were similar in both the intervention and comparator arms. The committee also heard from the patient expert who found the effects of pertuzumab to be very manageable. The committee concluded that pertuzumab had an acceptable adverse event profile. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA. Relevance to general clinical practice in the NHS The committee noted that patients in the NeoSphere trial were described as having 'operable' disease (defined as tumours over 2 cm in diameter with no lymph nodes or only 1 lymph node involved), and people in this category would have the best prognosis. The committee considered that there were likely to have been very few UK patients in the trial; there were only 214 patients who had either the intervention or comparator as stated in the scope, across 59 centres, and of these only 2 centres were in the UK. The committee concluded that although there was some uncertainty about the generalisability of the NeoSphere trial to current NHS practice, it was appropriate for decision-making. Uncertainties generated by the evidence The committee discussed the value of pathological complete response as a clinically meaningful indicator of longer-term survival outcomes. It was aware that a number of studies have been done in this area, including the CTNeoBC meta-analysis. At trial-level, CTNeoBC concluded that the evidence that a treatment-related improvement in pathological complete response translated into a treatment-related improvement in survival outcomes was very weak. The committee was also aware that the ERG had reviewed the wider evidence in this area, and had stated that the evidence of a positive treatment effect translating into a positive effect on survival was not convincing. On balance, although there was uncertainty about the exact relationship, the committee accepted that pathological complete response was more likely than not to have an association with longer-term survival. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No specific committee consideration. Estimate of the size of the clinical effectiveness including strength of supporting evidence The company submitted evidence from 2 phase II randomised controlled trials, but were at an early stage of research (phase II) and lacked longer-term efficacy data, had small patient numbers, were open label, and were not powered for key outcomes of interest including progression-free survival and overall survival. The committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA. The committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response when added to trastuzumab and docetaxel, and that that pathological complete response was more likely than not to have an association with longer-term survival. Evidence for cost effectiveness Availability and nature of evidence The company derived a new economic model. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee concluded that the structure of the model was generally appropriate for decision-making, although it was still subject to uncertainty because of some parameter assumptions. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee discussed differences in the quality-adjusted life year (QALY) gains and the utility value for the progressed state used in the models in submissions to the Scottish Medicines Consortium (SMC) and NICE. At the first appraisal committee meeting, the committee could not be sure of the effect of these differences because the company had not provided sufficient explanation. However, in response to the appraisal consultation document, the company supplied a more detailed explanation of the main differences and their effects. The committee accepted this explanation and concluded that the health-related quality of life assumptions used in the NICE model were appropriate for decision-making. Are there specific groups of people for whom the technology is particularly cost effective? No specific committee consideration. What are the key drivers of cost effectiveness? In exploratory analyses, both the company and ERG models were most sensitive to assumptions about clinical effectiveness (that is, assumptions about the rates of pathological complete response, which influenced survival estimates in the model). However, the committee accepted that there was evidence that rates of pathological complete response were statistically significantly higher with the addition of pertuzumab to trastuzumab and docetaxel and that correspondingly high rates of pathological complete response had also been demonstrated in the TRYPHAENA trial. Most likely cost-effectiveness estimate (given as an ICER) The committee agreed that because of the high levels of uncertainty in the cost-effectiveness assumptions, it would be prudent to use the more conservative ICERs from the ERG, and to focus on scenarios that excluded any cost offsets from metastatic treatments funded by the CDF. The committee noted that in these more conservative scenarios, and incorporating the simple discount patient access scheme for pertuzumab, the ICERs fell within the range normally considered to be a cost-effective use of NHS resources. The committee noted that the comparatively early regulatory approval for pertuzumab had limited the clinical trial evidence available such that it was suboptimal for the purposes of long-term modelling and health technology assessment. In these uncertain circumstances, the committee welcomed the company's approach to discount the cost of pertuzumab as it increased the likelihood that pertuzumab would be cost effective with more conservative assumptions than had been used in the model. The committee concluded that pertuzumab could be recommended as a cost-effective use of NHS resources for the neoadjuvant treatment of HER2-positive breast cancer. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End-of-life considerations Not applicable. Equalities considerations and social value judgements Not applicable.	{'Recommendations': 'Pertuzumab, in combination with trastuzumab and chemotherapy, is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of adults with human epidermal growth factor receptor\xa02 (HER2)‑positive breast cancer; that is, in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence. It is recommended only if the company provides pertuzumab with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nPertuzumab (Perjeta, Roche) is a recombinant monoclonal antibody which targets human epidermal growth factor receptor 2 (HER2)-positive breast tumours. It interrupts the activation of the HER2 intracellular signalling pathway, leading to cell growth arrest and apoptosis. It is administered by intravenous infusion.\n\nMarketing authorisation\n\nPertuzumab has a marketing authorisation in the UK 'in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer at high risk of recurrence'.\n\nAdverse reactions\n\nThe summary of product characteristics includes the following adverse reactions for pertuzumab: decreased appetite, headache, cough, diarrhoea, vomiting, nausea, constipation, rash, pain, oedema, fatigue, asthaenia and left ventricular dysfunction. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dosage of pertuzumab is an initial loading dose of 840\xa0mg, followed by a maintenance dose of 420\xa0mg every 3\xa0weeks for 3\xa0to 6\xa0cycles.\n\nPrice\n\nPertuzumab costs £2,395 per 420‑mg vial (excluding VAT).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pertuzumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of pertuzumab, having considered evidence on the nature of HER2-positive breast cancer and the value placed on the benefits of pertuzumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Patient experience for people with HER2-positive breast cancer\n\nThe committee heard from the patient expert that after having pertuzumab, she had experienced a complete response that her clinician described as 'spectacular'. She felt that taking pertuzumab not only had the benefit of removing the physical signs of cancer, but also had a major effect on her psychological wellbeing. When a person's tumour responds to treatment it can improve quality of life, and reassure them that the treatment is working. The clinical experts agreed that outcomes such as pathological complete response can have a strong psychological benefit for patients. They explained that pathological complete response is an indication that not only are tumour cells in the breast responding to treatment (and, in the case of total pathological response, that tumour cells in the lymph nodes are also responding to treatment), but that that any tumour cells which may have already spread beyond the breast and nodes but that are undetectable (micro-metastases) would also have been treated. In addition, a reduction in size or the disappearance of tumour in the breast potentially allows for less radical surgery in patients who would otherwise be advised to have mastectomy. The committee agreed that neoadjuvant treatment outcomes such as pathological complete response seemed beneficial from a clinical perspective, and could provide important psychological benefits for patients. However, given the limitations of the evidence, it considered that there was uncertainty about whether a pathological complete response after neoadjuvant therapy was the sole and most reliable indicator of, or translated directly into, treatment-related long-term event-free and overall survival benefit (section\xa04.5). The committee also noted comments from Breast Cancer Now which indicated that although it considered pertuzumab to be a potentially promising treatment, the charity strongly supported the collection of more evidence because many of the cited benefits are hypothetical. The committee concluded that HER2-positive breast cancer can have a substantial negative effect on quality of life, and that patients and clinicians place a strong value on effective early treatments that would be of particular value if they were proven to improve long-term outcomes.\n\n# Current clinical management of HER2-positive breast cancer\n\nThe committee heard from the clinical experts that there is variation across the NHS in the use of neoadjuvant therapy (primary systemic therapy) before surgery in HER2-positive breast cancer, which was demonstrated in an informal survey presented by one of the clinical experts. They stated that this may relate to service configuration issues, such as staffing levels and access to HER2 testing, and that this restricted access to neoadjuvant treatment in some parts of the UK. The clinical experts indicated that despite this variation, there is a trend in the NHS towards increasing use of neoadjuvant treatment for HER2-positive breast cancer, following the demonstrated survival benefits of HER2 agents given later in the disease pathway. In very extensive or inoperable disease, neoadjuvant treatment may shrink the tumour and make it operable. In other cases it may allow for breast-conserving surgery, thereby reducing the need for more complicated procedures (such as mastectomy and breast reconstruction) and their associated risks, lessening the treatment burden for both patients and the NHS. The clinical experts stated that another advantage of neoadjuvant treatment is that outcomes can be more directly linked to treatment (because there is less chance of confounding from other treatments), and that this was useful to inform future treatment decisions. The committee heard from the company and the ERG that around 75% of neoadjuvant treatment regimens for patients with HER2-positive cancers contain trastuzumab. The clinical experts stated there is variation in the chemotherapy given in combination with trastuzumab. The committee was interested in any disadvantages of neoadjuvant therapy, for example the potential for tumour growth before surgery. It heard from the clinical experts that it is extremely unlikely that a tumour would grow in size during neoadjuvant treatment, that patients are typically closely monitored, including with MRI scans, so that any disease progression would be quickly identified. In most patients tumour shrinkage (albeit not necessarily total pathological response) is seen, and this can occur quite rapidly during a course of neoadjuvant treatment. The committee concluded that in current NHS practice there is a trend towards offering more neoadjuvant therapy in HER2-positive breast cancer, and that most neoadjuvant regimens in this patient group include trastuzumab.\n\n# Clinical effectiveness\n\n## Strength of clinical trial evidence\n\nThe company submitted evidence from 2\xa0phase\xa0II randomised controlled trials relevant to the population in the scope, NeoSphere and TRYPHAENA. However, the committee considered both of these to have substantial limitations for the purposes of providing comparative effectiveness data for pertuzumab. Both trials were at an early stage of research (phase\xa0II) and lacked longer-term efficacy data, had small patient numbers, were open label, and were not powered for key outcomes of interest including progression-free survival and overall survival. The trial data were further limited because only 2 of the 4 arms in NeoSphere included licensed treatment combinations (arm\xa0A n=107, trastuzumab and docetaxel, and arm\xa0B, n=107, pertuzumab, trastuzumab and docetaxel), and because TRYPHAENA was a cardiac safety trial (so not primarily designed to test efficacy) and had pertuzumab in all 3\xa0treatment arms with no control group. However, the committee agreed that despite these limitations, both trials contained data that helped to demonstrate the clinical effectiveness of pertuzumab. In NeoSphere there was a statistically significant increase in pathological complete response when pertuzumab was added to trastuzumab and docetaxel (both given every 3\xa0weeks for 4\xa0cycles; see section\xa04.4). TRYPHAENA included pathological complete response as a secondary outcome, and therefore provided additional supportive evidence. The committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA.\n\n## Results of clinical trial evidence\n\nThe committee noted that of the 3\xa0available definitions of pathological complete response, the primary outcome in NeoSphere, pathological complete response in the breast, was the least stringent measure; it classified patients as responders even if there was residual disease in lymph nodes or ductal carcinoma in\xa0situ. Total pathological complete response, a secondary outcome in NeoSphere, is the preferred definition for regulatory purposes, which requires the disappearance of invasive cancer in the breast and lymph nodes (although in\xa0situ cancer in the breast may still be present). However, the committee noted that the addition of pertuzumab to trastuzumab plus docetaxel was associated with larger increases in all 3\xa0definitions of pathological complete response than trastuzumab plus docetaxel alone (there was an absolute difference in pathological complete response of 16.8 to\xa020.6 percentage points between the 2\xa0groups, depending on the definition). In addition, although there was no control arm, the TRYPHAENA trial also showed high rates of pathological complete response in all 3\xa0pertuzumab treatment arms (total pathological complete response rates ranged from 57.3% to 66.2%). The committee also heard from 1 clinical expert who stated that the ability of pertuzumab to remove all cancer including ductal carcinoma in situ was 'remarkable', and it was also aware that the patient expert had a pathological complete response with pertuzumab that her clinician described as 'spectacular' (section\xa04.1). The committee accepted that the available evidence suggested that pertuzumab was an effective treatment to induce pathological complete response. However, it expressed concerns about the reliability of pathological complete response as a surrogate for longer-term survival outcomes for patients (section\xa04.5), and it noted that the trial was not powered for long-term outcomes. The committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response when added to trastuzumab and docetaxel, but that there was no reliable trial evidence of event-free or overall survival benefit.\n\n## Association of pathological complete response with survival\n\nThe committee discussed the value of pathological complete response as a clinically meaningful indicator of longer-term event-free and overall survival. It was aware that a number of studies have been done to investigate this, including the CTNeoBC meta-analysis, which the company had described in its submission and used in its modelling. CTNeoBC evaluated the prognostic value of pathological complete response, and found that at patient-level there was a correlation between pathological complete response and survival outcomes. However, at trial-level, CTNeoBC concluded that the evidence that a treatment-related improvement in pathological complete response translated into a treatment-related improvement in survival outcomes was very weak (correlation coefficients of 0.03 and 0.24 for event-free survival and overall survival respectively). The committee understood that correlation between 2 variables at an individual level does not necessarily imply that one can be used as a surrogate for the other when estimating the effect of a specific treatment. The committee was also aware that the ERG had reviewed the wider evidence in this area, and had stated that the evidence of a positive treatment effect translating into a positive effect on survival was not convincing. The committee agreed that there was considerable uncertainty about whether pathological complete response could be viewed as a surrogate marker of long-term benefit. However, it heard from the clinical experts that if a patient had a pathological complete response, they considered this to be a good indicator of long-term benefit, particularly in oestrogen receptor-negative tumours. The committee accepted that neoadjuvant pertuzumab was an effective treatment for inducing pathological complete response. It agreed that the evidence was limited with regard to long-term outcomes, but considered whether the outcome of pathological complete response may itself only be a marker of drug activity at a cellular or micro-metastatic level, and noted the improved overall survival demonstrated with the addition of pertuzumab in the CLEOPATRA trial in metastatic HER2-positive breast cancer. It was also aware that both the US Food and Drug Administration and the European Medicines Agency had concluded that it was 'reasonably likely' that pathological complete response was associated with improved survival outcomes. The committee was minded to accept that the complete disappearance of cancer in the breast and nodes was more likely to be associated with improved long-term outcomes than completely unrelated. On balance, although there was uncertainty about the exact relationship, the committee accepted that pathological complete response was more likely than not to have an association with longer-term survival. It concluded that despite the uncertainty, and in line with current oncological thinking, earlier HER2-specific treatment would have patient benefit in the long term, as well as the short-term benefit of tumour shrinkage or disappearance.\n\n## Generalisability of NeoSphere trial evidence to clinical practice in England\n\nThe committee noted that most patients in NeoSphere were described as having 'operable' disease (defined as tumours over 2\xa0cm in diameter [T2 to\xa03] with no clinically involved lymph nodes [N0] or involved mobile ipsilateral axillary nodes [N1]), and that people in this category would have the best prognosis of the 3\xa0subgroups in the trial (that is, operable, locally advanced and inflammatory). In addition, the low patient numbers in the trial resulted in one of the rare subtypes, inflammatory breast cancer, having only 7\xa0patients in the comparator arm and 10\xa0patients in the intervention arm. The committee considered that there were likely to have been very few UK patients in the trial; only 214\xa0patients had either the intervention or comparator as stated in the scope, across 59\xa0centres, and of these only 2\xa0centres were in the UK. However, the committee agreed that the comparator used reflected current NHS practice, because 75% of neoadjuvant treatment regimens in the UK include trastuzumab. Furthermore, in response to the appraisal consultation document, the company had stated that clinical expert opinion supported the generalisability of the clinical trial evidence, although it did not provide any supporting evidence. The committee concluded that although there was some uncertainty about the generalisability of the NeoSphere trial to current NHS practice, it was appropriate for decision-making.\n\n## Adverse events associate with pertuzumab\n\nThe committee noted that TRYPHAENA was specifically designed to assess the cardiac safety of pertuzumab. However, the committee considered 1\xa0of the 2\xa0primary outcomes used to measure cardiac safety, left ventricular systolic dysfunction, to be a poor indicator of cardiac safety. The committee noted that adverse events in NeoSphere were similar in both the intervention and comparator arms. The committee also heard from the patient expert who found the effects of pertuzumab to be very manageable, with the only notable effects being diarrhoea and a slower than expected return to normal hair growth. The committee concluded that based on the evidence, pertuzumab had an acceptable adverse event profile.\n\n# Cost effectiveness\n\n## Health economic model: structure and parameter assumptions\n\nAlthough the locoregional recurrence health state omitted surgery (which would be the best option for patients at this stage of the treatment pathway), the committee considered the general structure of the model and sequencing of health states to be plausible. However, it had concerns about the parameter assumptions used in the model for effectiveness (section\xa04.9) and costs (section\xa04.11). Furthermore, the committee expressed concern that in September 2015 the company had submitted to the Scottish Medicines Consortium (SMC) for consideration of pertuzumab for the same indication. In the SMC submission, the company had derived substantially different incremental costs, utility values and cost-effectiveness results to those submitted to NICE, but had not provided a full and clear explanation of the reasons for the differences. In response to the appraisal consultation document, the company provided a detailed explanation which more clearly demonstrated that the main difference between the 2 submissions was the incorporation of costs of drugs funded by the Cancer Drugs Fund (CDF), which were available in England but not Scotland. Although the committee regretted that this uncertainty had not been resolved earlier, it welcomed this additional transparency from the company, which helped to reassure the committee at its second meeting that none of the variation was a cause for concern. The committee was satisfied it now understood the reasons for the variation between the NICE and SMC incremental cost-effectiveness ratios (ICERs), and concluded that the structure of the model was generally appropriate for decision-making, although it was still subject to uncertainty because of some parameter assumptions.\n\n## Health economic model: clinical-effectiveness assumptions\n\nThe company assumed that pathological complete response was a surrogate for survival in the model, because the event-free survival data from the trial were not robust enough to be used in the model. The committee was aware that the NICE guide to the methods of technology appraisal contains guidance on the use of surrogate outcomes within health economic models, stating that: 'evidence in support of the surrogate-to-final end point outcome relationship must be provided together with an explanation of how the relationship is quantified for use in modelling'. The committee noted that the company had attempted to provide evidence to support the relationship using the CTNeoBC meta-analysis. This study identified a patient-level relationship between pathological complete response and survival, but could not validate pathological complete response as a valid surrogate for survival. The committee was aware of the authors' conclusions that there were several possible reasons for the lack of proof of surrogacy, including low overall pathological complete response rates, heterogeneous patient populations, and inclusion of only a single study designed to evaluate effects of targeted therapy. The committee also considered that it may be difficult to prove this relationship because pathological complete response was a binary outcome (response or no response), whereas in clinical practice, the outcome may be more nuanced; it is possible that the proportion of individual patient response may affect long-term outcomes without necessarily meeting the threshold to be classified as a response in the trial. The committee noted that the company had attempted to explore uncertainty in this area with a scenario analysis using the less robust survival data from NeoSphere, which improved the cost-effectiveness results for pertuzumab. Overall, in the absence of an alternative source of robust effectiveness data and taking into account that it considered that pathological complete response was more likely than not to be associated with longer-term outcomes (section\xa04.5), the committee concluded that the company's approach to model clinical effectiveness was acceptable. However, it was subject to high levels of uncertainty, and the committee would need to interpret any survival estimates with caution.\n\n## Health economic model: health-related quality-of-life assumptions\n\nThe committee discussed differences in the quality-adjusted life year (QALY) gains in the SMC and NICE company submissions (0.31 in the SMC submission, 0.261 in the NICE submission). It also discussed the differences in the utility value for the progressed state used in the model (0.5 in the SMC submission, 0.452 in the NICE submission). The committee heard from the company that some of the difference in QALY gains was because it had added an extra assumption to the model submitted to NICE, specifically that the utility value could not be higher than the age-matched population without disease. The company also explained that it used a lower utility value in the NICE submission because it considered a study by Lloyd et al. (2006) to provide a more appropriate utility measure. The company did not explain why it considered a different utility value from that used in the SMC submission to be appropriate. At the first appraisal committee meeting, the committee could not be sure of the effect of these differences because the company had not provided sufficient explanation. However, in response to the appraisal consultation document, the company supplied a more detailed explanation of the main differences and their effects. The committee accepted this explanation and concluded that the health-related quality of life assumptions used in the NICE model were appropriate for decision-making.\n\n## Health economic model: cost assumptions\n\nThe committee discussed whether the inclusion of drugs funded by the CDF in the metastatic heath states was a fair reflection of the future costs of treatment for HER2-positive breast cancer in England. The committee noted that by including these drugs, the additional costs of neoadjuvant pertuzumab were being offset in the model by the costs of additional drugs for metastatic disease in the comparator arm funded by the CDF (including pertuzumab and trastuzumab emtansine). The committee was aware that the CDF is a temporary funding vehicle for cancer drugs that cannot yet demonstrate cost effectiveness, and is currently in a transitional period to determine which drugs should be funded. For patients starting neoadjuvant treatment today, the costs of treatment for metastatic disease (if needed) are likely to be incurred several years in the future, by which time there is no guarantee that the CDF will still be operating in the same way. The committee was aware that in modelling the future costs and benefits of treatments, there is always an element of uncertainty. However, given the transitional nature of the CDF, the committee questioned the validity of the large cost offsets assumed by the company. The committee also noted the ERG's comment that the company had incorporated pertuzumab as a second-line metastatic treatment in the model, although its licence is for use in combination with trastuzumab and docetaxel in patients who have not had previous anti-HER2 therapy or chemotherapy for their metastatic disease. Furthermore, the committee raised concerns about the company's precise drug costs. The company used list prices for the CDF-funded treatments, but the NHS may be paying lower prices for these drugs which would increase the ICER. In its response to the appraisal consultation document, the company provided various scenario analyses that changed assumptions for the drugs funded by the CDF, including using actual costs currently paid by the NHS for these drugs, and completely removing CDF-funded treatments. Furthermore, in order to mitigate the risks of any future changes to the CDF, the company submitted a confidential simple discount patient access scheme. The committee appreciated the company's attempt to resolve the uncertainty both with the presentation of additional scenario analyses, and the offer to risk-share against any changes in CDF-funded treatments by reducing the costs of pertuzumab. It concluded that this helped to reduce uncertainty in the cost-effectiveness results.\n\n## Incremental cost-effectiveness results\n\nThe committee considered the cost-effectiveness results presented by the company and the ERG. It noted that in the original company submission and ERG report, there were a number of different base-case scenarios, but that all were subject to uncertainty. Particular issues of relevance included assumptions about the future costs and availability of CDF-funded treatments, and also effectiveness assumptions. In exploratory analyses, both the company and ERG models were most sensitive to assumptions about clinical effectiveness (that is, assumptions about the rates of pathological complete response, which influenced survival estimates in the model). However, the committee accepted that there was evidence that rates of pathological complete response were statistically significantly higher with the addition of pertuzumab to trastuzumab and docetaxel (section\xa04.4), and that correspondingly high rates of pathological complete response had also been demonstrated in the TRYPHAENA trial. With respect to costs and availability of CDF drugs in the metastatic setting, the company had attempted to address uncertainty in scenario analyses (section\xa04.11). The committee agreed that because of the high levels of uncertainty in the cost-effectiveness assumptions, it would be prudent to use the more conservative ICERs from the ERG, and to focus on scenarios which excluded any cost offsets from metastatic treatments funded by the CDF. The committee noted that in these more conservative scenarios, and incorporating the simple discount patient access scheme for pertuzumab, the ICERs fell within the range normally considered to be a cost-effective use of NHS resources. The committee noted that the comparatively early regulatory approval for pertuzumab had limited the clinical trial evidence available such that it was suboptimal for the purposes of long-term modelling and health technology assessment. In these uncertain circumstances, the committee welcomed the company's approach to discount the cost of pertuzumab as it increased the likelihood that pertuzumab would be cost effective with more conservative assumptions than had been used in the model. The committee concluded that pertuzumab could be recommended as a cost-effective use of NHS resources for the neoadjuvant treatment of HER2-positive breast cancer.\n\nThe committee discussed whether it would be appropriate to specify the number of cycles of pertuzumab that should be used in clinical practice. It was aware that the NeoSphere trial and the model used 4\xa0cycles, but that the licence allowed for 3\xa0to 6\xa0cycles, which was a large variation (effectively meaning that for some patients dosage and costs could be double that of others). It heard from the clinical experts that they would use pertuzumab for 3\xa0to 6\xa0cycles but that this would vary. One clinical expert stated that the clinical effect of 3\xa0cycles was probably the same as the effect after 6\xa0cycles. The committee noted that the ERG had done a sensitivity analysis (without the patient access scheme discount) varying the number of cycles of pertuzumab, which caused the ICER to increase from £23,467 per QALY gained (ERG's base case, based on 4\xa0cycles of pertuzumab) to £42,955 per QALY gained (using 6\xa0cycles of pertuzumab and amending the costs but not the effectiveness of treatment), suggesting that the results were sensitive to this assumption. The committee concluded that patients should normally have no more than 4\xa0cycles of neoadjuvant treatment with pertuzumab.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA424\n\nAppraisal title: Pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer\n\nSection\n\nKey conclusion\n\nPertuzumab, in combination with trastuzumab and chemotherapy, is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of adults with human epidermal growth factor receptor\xa02 (HER2) positive breast cancer; that is, in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence. It is recommended only if the company provides pertuzumab with the discount agreed in the patient access scheme.\n\nPatients should normally have no more than 4\xa0cycles of neoadjuvant treatment with pertuzumab.\n\nThe committee agreed that because of the high levels of uncertainty in the cost-effectiveness assumptions, it would be prudent to use the more conservative ICERs from the ERG, and to focus on scenarios which excluded any cost offsets from metastatic treatments funded by the CDF. The committee noted that in these more conservative scenarios, and incorporating the simple discount patient access scheme for pertuzumab, the ICERs fell within the range normally considered to be a cost-effective use of NHS resources.\n\n, 4.12, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the patient expert that that taking pertuzumab not only had the benefit of removing the physical signs of cancer, but also had a major effect on her psychological wellbeing. The committee concluded that HER2-positive breast cancer can have a substantial negative effect on quality of life, and that patients and clinicians place a strong value on effective early treatments.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nAfter having pertuzumab, the patient expert had a complete response that her clinician described as 'spectacular'. The patient expert felt that taking pertuzumab not only had the benefit of removing the physical signs of cancer, but also had a major effect on her psychological wellbeing. The clinical experts agreed response can have an important psychological benefit. In addition a pathological complete response is an indication that not only are tumour cells responding to treatment, but that any micro-metastases are likely to have also been treated. A reduction or disappearance of tumour in the breast also potentially allows for less radical surgery in patients who would otherwise be advised to have mastectomy.\n\nThe committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response when added to trastuzumab and docetaxel, but that there was no reliable trial evidence of event-free or overall survival benefit. The committee was minded to accept that the complete disappearance of cancer in the breast and nodes was more likely to be associated with improved long-term outcomes than completely unrelated. On balance, although there was uncertainty about the exact relationship, the committee accepted that pathological complete response was more likely than not to have an association with longer-term survival.\n\n, 4.4, 4.5\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard from the clinical experts that there is variation across the NHS in the use of neoadjuvant therapy before surgery in HER2-positive breast cancer. They stated that this may relate to service configuration issues, such as staffing levels and access to HER2 testing, and that this restricted access to neoadjuvant treatment in some parts of the UK. The clinical experts indicated that despite this variation, there is a trend in the NHS towards increasing use of neoadjuvant treatment for HER2-positive breast cancer, following the demonstrated survival benefits of HER2 agents given later in the disease pathway. A reduction in the size of the tumour may make the disease operable when initially it is very extensive, and in other cases allow breast-conserving surgery, thereby reducing the need for more complicated procedures (such as mastectomy and breast reconstruction) and their associated risks.\n\n\n\nAdverse reactions\n\nThe committee noted that adverse events in NeoSphere were similar in both the intervention and comparator arms. The committee also heard from the patient expert who found the effects of pertuzumab to be very manageable. The committee concluded that pertuzumab had an acceptable adverse event profile.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee noted that patients in the NeoSphere trial were described as having 'operable' disease (defined as tumours over 2 cm in diameter with no lymph nodes or only 1 lymph node involved), and people in this category would have the best prognosis.\n\nThe committee considered that there were likely to have been very few UK patients in the trial; there were only 214 patients who had either the intervention or comparator as stated in the scope, across 59 centres, and of these only 2 centres were in the UK. The committee concluded that although there was some uncertainty about the generalisability of the NeoSphere trial to current NHS practice, it was appropriate for decision-making.\n\n\n\nUncertainties generated by the evidence\n\nThe committee discussed the value of pathological complete response as a clinically meaningful indicator of longer-term survival outcomes. It was aware that a number of studies have been done in this area, including the CTNeoBC meta-analysis. At trial-level, CTNeoBC concluded that the evidence that a treatment-related improvement in pathological complete response translated into a treatment-related improvement in survival outcomes was very weak.\n\nThe committee was also aware that the ERG had reviewed the wider evidence in this area, and had stated that the evidence of a positive treatment effect translating into a positive effect on survival was not convincing.\n\nOn balance, although there was uncertainty about the exact relationship, the committee accepted that pathological complete response was more likely than not to have an association with longer-term survival.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo specific committee consideration.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe company submitted evidence from 2 phase II randomised controlled trials, but were at an early stage of research (phase II) and lacked longer-term efficacy data, had small patient numbers, were open label, and were not powered for key outcomes of interest including progression-free survival and overall survival. The committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA.\n\nThe committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response when added to trastuzumab and docetaxel, and that that pathological complete response was more likely than not to have an association with longer-term survival.\n\n, 4.4, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company derived a new economic model.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee concluded that the structure of the model was generally appropriate for decision-making, although it was still subject to uncertainty because of some parameter assumptions.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee discussed differences in the quality-adjusted life year (QALY) gains and the utility value for the progressed state used in the models in submissions to the Scottish Medicines Consortium (SMC) and NICE. At the first appraisal committee meeting, the committee could not be sure of the effect of these differences because the company had not provided sufficient explanation. However, in response to the appraisal consultation document, the company supplied a more detailed explanation of the main differences and their effects. The committee accepted this explanation and concluded that the health-related quality of life assumptions used in the NICE model were appropriate for decision-making.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific committee consideration.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nIn exploratory analyses, both the company and ERG models were most sensitive to assumptions about clinical effectiveness (that is, assumptions about the rates of pathological complete response, which influenced survival estimates in the model). However, the committee accepted that there was evidence that rates of pathological complete response were statistically significantly higher with the addition of pertuzumab to trastuzumab and docetaxel and that correspondingly high rates of pathological complete response had also been demonstrated in the TRYPHAENA trial.\n\n, 4.5, 4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee agreed that because of the high levels of uncertainty in the cost-effectiveness assumptions, it would be prudent to use the more conservative ICERs from the ERG, and to focus on scenarios that excluded any cost offsets from metastatic treatments funded by the CDF. The committee noted that in these more conservative scenarios, and incorporating the simple discount patient access scheme for pertuzumab, the ICERs fell within the range normally considered to be a cost-effective use of NHS resources. The committee noted that the comparatively early regulatory approval for pertuzumab had limited the clinical trial evidence available such that it was suboptimal for the purposes of long-term modelling and health technology assessment. In these uncertain circumstances, the committee welcomed the company's approach to discount the cost of pertuzumab as it increased the likelihood that pertuzumab would be cost effective with more conservative assumptions than had been used in the model. The committee concluded that pertuzumab could be recommended as a cost-effective use of NHS resources for the neoadjuvant treatment of HER2-positive breast cancer.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNot applicable.\n\n–"}	https://www.nice.org.uk/guidance/ta424	Evidence-based recommendations on pertuzumab (Perjeta) for treating HER2-positive breast cancer that is locally advanced, inflammatory, or early-stage with a high risk of recurrence, in adults.
7a71b2a2d35c6897d08199688fa6506c297fec6a	nice	Dasatinib, nilotinib and high-dose imatinib for treating imatinib-resistant or intolerant chronic myeloid leukaemia	Dasatinib, nilotinib and high-dose imatinib for treating imatinib-resistant or intolerant chronic myeloid leukaemia Evidence-based recommendations on dasatinib (Sprycel), nilotinib (Tasigna) and high-dose imatinib (Glivec) for treating imatinib-resistant or intolerant chronic myeloid leukaemia in adults. # Recommendations Dasatinib and nilotinib are recommended as options for treating only chronic- or accelerated-phase Philadelphia-chromosome-positive chronic myeloid leukaemia in adults, if: they cannot have imatinib, or their disease is imatinib-resistant and the companies provide the drugs with the discounts agreed in the relevant patient access schemes. High-dose imatinib (that is, 600 mg in the chronic phase or 800 mg in the accelerated and blast-crisis phases) is not recommended for treating Philadelphia-chromosome-positive chronic myeloid leukaemia in adults whose disease is imatinib-resistant. This guidance is not intended to affect the position of patients whose treatment with imatinib or dasatinib was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technologies Description of the technologies Dasatinib (Sprycel, Bristol-Myers Squibb), a tyrosine kinase inhibitor, is an orally active inhibitor of Src and the Src family of tyrosine kinases. These are involved in cell growth, differentiation, migration and survival, and many are involved in oncogenesis, tumour metastasis and angiogenesis. Imatinib (Glivec, Novartis Pharmaceuticals) is an orally active tyrosine kinase inhibitor, designed to competitively inhibit Bcr‑Abl tyrosine kinase activity. By blocking specific signals in cells expressing Bcr‑Abl, imatinib reduces the uncontrolled proliferation of white blood cells that is a characteristic feature of chronic myeloid leukaemia (CML). Nilotinib (Tasigna, Novartis Pharmaceuticals), a tyrosine kinase inhibitor (TKI), is an orally active phenylaminopyrimidine derivative of imatinib. Studies suggest that nilotinib inhibits 32 of 33 mutant Bcr‑Abl forms that are resistant to imatinib. Marketing authorisations Dasatinib has a marketing authorisation for the treatment of adult patients with 'newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase' and adult patients with 'chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate'. Imatinib has a marketing authorisation for the treatment of 'adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment' and for 'adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis'. Nilotinib has a marketing authorisation for the treatment of adult patients with 'newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase' and adult patients with 'chronic phase and accelerated-phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib'. Adverse reactions The most common reported side effects with dasatinib are headache, pleural effusion, shortness of breath, cough, diarrhoea, nausea, vomiting, abdominal pain, skin rash, musculoskeletal pain, infections, haemorrhage, superficial oedema, fatigue, fever, neutropenia, thrombocytopenia and anaemia. The summary of product characteristics states: 'Dasatinib should be administered with caution to patients who have or may develop prolongation of the QT interval'. The most common side effects with imatinib are nausea, vomiting, oedema (fluid retention), muscle cramps, skin rash, diarrhoea, abdominal pain, headache and fatigue. The most common side effects with nilotinib are thrombocytopenia, neutropenia, anaemia, headache, nausea, constipation, diarrhoea, rash, pruritus, fatigue and increased blood levels of lipase and bilirubin. Nilotinib prolongs the QT interval and is therefore contraindicated in people with hypokalaemia, hypomagnesaemia or long QT syndrome. For full details of adverse reactions and contraindications, see the summary of product characteristics of the respective technologies. Recommended doses and schedules Dasatinib is administered orally. The recommended starting dosage is 100 mg once daily in the chronic phase or 140 mg once daily in the accelerated and blast-crisis phase and treatment should continue until disease progression or until no longer tolerated by the patient. Dose increase or reduction is recommended based on patient response and tolerability. Imatinib is administered orally. The recommended starting dosage is 400 mg once daily in the chronic phase or 600 mg once daily in the accelerated and blast-crisis phase and treatment should be continued as long as the patient continues to benefit. Dose increase to 600 mg once daily in the chronic phase or 800 mg (400 mg twice daily) in the accelerated and blast-crisis phase may be considered for people who have imatinib resistance. Nilotinib is administered orally. The recommended starting dosage is 400 mg twice daily for imatinib-resistant or intolerant CML in the chronic phase and 400 mg twice daily in the accelerated phase and treatment should be continued as long as the patient continues to benefit. Prices Dasatinib is available at a cost of £2,504.96 for both a pack of 30 100-mg or 140-mg tablets (excluding VAT; 'British national formulary' online, accessed October 2016). The cost of dasatinib treatment is £30,477.00 per year, assuming a treatment regimen of 100 mg once daily or 140 mg once daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of dasatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Imatinib was available at a cost of £1,604.00 for a 400-mg 30‑tablet pack (excluding VAT; BNF edition 61) resulting in an annual cost of imatinib treatment of £39,033.00, assuming a treatment regimen of 400 mg twice daily. The cost of imatinib has increased to £1,836.48 for a 400-mg 30‑tablet pack (excluding VAT; BNF online, accessed October 2016). The cost of imatinib treatment is now £44,718.00 per year assuming a treatment regimen of 400 mg twice daily. Costs may vary in different settings because of negotiated procurement discounts. Nilotinib is available at a cost of £2,432.85 for a pack of 112 200-mg tablets (excluding VAT; BNF online, accessed October 2016). The cost of nilotinib treatment is £31,736.00 per year, assuming a treatment regimen of 400 mg twice daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nilotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance. Sections 4.1 to 4.32 reflect the committee's consideration of the evidence submitted in the original appraisal (NICE technology appraisal guidance 241). Sections 4.33 to 4.40 reflect the committee's consideration of the additional evidence submitted for the Cancer Drugs Fund reconsideration. It focused on a cost-minimisation analysis using a revised patient access scheme, which provides a simple discount to the list price of dasatinib. The level of the discount is commercial in confidence. See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of dasatinib, high-dose imatinib and nilotinib for the treatment of chronic myeloid leukaemia (CML) that is resistant to standard-dose imatinib, and of dasatinib and nilotinib for the treatment of CML in people with imatinib intolerance, having considered evidence on the nature of CML and the value placed on the benefits of the interventions by people with the condition, those who represent them and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness (NICE technology appraisal guidance 241) The committee discussed current clinical practice for treating CML. The committee heard from the clinical experts that standard-dose imatinib is given in line with NICE technology appraisal guidance 70 to people presenting with chronic-phase CML. The clinical experts stated that in approximately 60% of people there is a good response to standard-dose imatinib, and that these people will continue to receive the treatment for life and have a normal life expectancy. The committee recognised the innovative nature and major change in the treatment of CML that imatinib had provided. However, it heard that 40% of people develop intolerance or resistance to standard-dose imatinib. The committee heard that high-dose imatinib, dasatinib and nilotinib are in widespread use and are a major advance over earlier therapies (that is, interferon alfa and hydroxycarbamide). The clinical experts suggested that if dasatinib, high-dose imatinib or nilotinib were not available, people would receive treatment with interferon alfa, hydroxycarbamide or best supportive care, and that for many people hydroxycarbamide or interferon alfa are considered to be little better than best supportive care. The committee also heard from the clinical experts that bone marrow stem cell transplantation could be used, although it carries high risks and is restricted to fit, younger people. The committee concluded that any one of these treatments could be considered a comparator with high-dose imatinib, nilotinib or dasatinib. The committee noted that high-dose imatinib had been recommended only in the context of clinical research in NICE technology appraisal guidance 70. It heard from the clinical experts that high-dose imatinib is being used in clinical practice for people whose CML has previously had a good response to treatment with standard-dose imatinib. The committee acknowledged the clinical experts' view that for CML that is resistant to standard-dose imatinib, high-dose imatinib was unlikely to be as beneficial as dasatinib and nilotinib. The committee heard from the clinical experts that, in clinical practice, treatment with dasatinib, high-dose imatinib and nilotinib is given in accordance with European guidelines, which specify time-dependent targets. If the CML is responding to treatment, the treatment will be continued until progression or until the person dies (from non-CML causes). If CML does not respond to dasatinib or nilotinib within 12 months, treatment may be stopped, or may be changed to hydroxycarbamide and/or, if suitable, stem cell transplantation. The committee heard from the clinical experts that in more than 50% of people with imatinib-resistant CML who have dasatinib or nilotinib, there is a good response to treatment and that this response is usually as good as the initial response to standard-dose imatinib. The clinical experts expected that these people would receive dasatinib or nilotinib treatment for the rest of their lives, and possibly have a nearly normal life expectancy (that is, at least 10 more years). For people receiving interferon alfa or hydroxycarbamide in the chronic phase, the prognosis is poor, with a median life expectancy of around 5 years. It heard from the clinical experts that with modern therapy the accelerated phase is no longer considered to be a distinct disease phase, so in effect the disease progresses from a prolonged chronic-phase to blast-crisis phase. The committee discussed the clinical-effectiveness evidence for dasatinib, high-dose imatinib and nilotinib for the treatment of chronic-phase CML that is resistant to standard-dose imatinib. It was aware of only 1 comparative trial, which compared dasatinib with high-dose imatinib, but noted the restricted comparison (only with high-dose imatinib) and the comments from the assessment groups on the interpretation of this trial. The committee noted that the clinical trials available were non-comparative, of short duration and had used surrogate outcomes to predict overall survival. The committee noted the wide range of results across the interventions, with major cytogenetic response rates ranging from 33.3 to 58.9% with dasatinib, 32.7 to 42.5% with high-dose imatinib (but with 1 outlying result of 63.5%), and 35.3 to 56.1% with nilotinib. The committee discussed the clinical trial evidence in light of the views of the patient and clinical experts. The committee noted the poor quality of the evidence base. However, it heard from the clinical experts and patient experts that clinical benefits, particularly of dasatinib and nilotinib, have been demonstrated. In addition, the clinical experts argued that the people in the clinical trials did not reflect the population seen in clinical practice because the trials included people who had worse disease prognoses than would be seen in current clinical practice. The committee concluded that it is clear that dasatinib, high-dose imatinib and nilotinib provide clinical benefit for people with imatinib-resistant CML. However, the committee agreed that the limited evidence base means that the magnitude of the benefit is uncertain. The committee also agreed that there was no good evidence to distinguish between dasatinib and nilotinib; a conclusion supported by the clinical experts. The committee was aware that continued use of imatinib is not an option for people with imatinib intolerance. It noted that most of the clinical-effectiveness evidence came from trials that included a mixed population of people with imatinib-resistant CML and people with imatinib intolerance. The committee noted that in the trials that reported response rates separately, CML in people with imatinib intolerance generally had a higher response rate to dasatinib and nilotinib than people with imatinib-resistant CML, and that this was reflected in the estimates of overall survival used in the economic analyses. The committee agreed that this was a reasonable assumption given that people with imatinib intolerance generally have had a shorter duration of prior treatment than those whose CML develops resistance to imatinib over time. The committee discussed the side effects of treatment for imatinib-resistant CML and for people with CML who have imatinib intolerance. It noted the adverse effects reported in the trials with dasatinib, high-dose imatinib and nilotinib in imatinib-resistant CML. The committee concluded that dasatinib and nilotinib are better tolerated than imatinib, and that older treatments, particularly interferon alfa, can be poorly tolerated. The committee considered the treatment of the blast-crisis phase of CML in clinical practice. The committee heard from the clinical experts that at the blast-crisis stage of the disease, life expectancy is about 3 to 6 months. The committee also heard from the clinical experts that the treatment strategy in the blast-crisis phase of the disease is different from that in the accelerated or chronic phases, with dasatinib and high-dose imatinib given as adjuvant treatment with intensive chemotherapy for acute leukaemia. The committee was aware that no evidence was presented on the use of dasatinib or high-dose imatinib in this way and that the evidence base for the blast-crisis phase of the disease is very limited. # Cost effectiveness (NICE technology appraisal guidance 241) The committee then considered the economic models provided by the companies and the assessment groups for chronic-phase CML that is resistant to standard-dose imatinib. In each it took particular note of the incremental cost-effectiveness ratio (ICER) for the comparison between the most cost effective of the tyrosine kinase inhibitors (given that dasatinib and nilotinib are considered equal), and the most cost effective of the older treatments (given that none were definitively favoured). In all the comparisons, the committee also took particular note of the relationship between treatment duration and overall survival; because these are the main influences on costs and benefits and the clinical experts stated that these were closely related. From the model developed by Bristol-Myers Squibb, the committee particularly noted the comparison between dasatinib and interferon alfa, which generated an ICER of £38,900 per quality-adjusted life year (QALY) gained. The estimated treatment duration with interferon alfa was 0.65 years (at a total estimated cost of £129,000), resulting in 3.56 years of overall survival, and the estimated treatment duration with dasatinib was 7.46 years (at a cost of £314,000), resulting in 11.76 years of overall survival. The committee considered that the model had a number of limitations, of which the most important were that it estimated the cost for people receiving interferon alfa to be higher than (in some cases double) that of all the other economic models, and it did not include a comparison with hydroxycarbamide. After consultation on the appraisal consultation document, Bristol-Myers Squibb provided an additional economic analysis. The committee noted that the additional analysis included hydroxycarbamide as a comparator and bone marrow stem cell transplantation as a third-line treatment. It noted that Bristol-Myers Squibb calculated the ICER for dasatinib to be £28,000 per QALY gained compared with hydroxycarbamide, and the total QALYs and costs associated with treatment with dasatinib in the additional economic analysis were more favourable to dasatinib than those in the company's original economic analysis. The committee compared these findings with those of the other economic models, and examined the assumptions that had been used in the additional analysis. Bristol-Myers Squibb's estimates for comparator costs were higher than had been used in other economic models. The committee considered that the assumption that 30.8% of people who stopped treatment would receive bone marrow stem cell transplantation was likely to be an overestimate given contraindications to bone marrow stem cell transplantation and the lack of availability of a matched donor for many people. Secondly, the committee considered that the assumed ongoing monthly cost of £2,400 after bone marrow stem cell transplantation (at £80,000) was an unreasonably high estimate, given that only a minority of people who survive transplantation develop complications that incur high ongoing costs. Thirdly, the committee considered the utility value estimate of 0.6 for the health state associated with successful transplantation to be unreasonable, in view of the utility value of 0.85 for successful dasatinib treatment, and the utility value of 0.68 for failed dasatinib treatment. The committee noted that these utility values were not derived from a common source. The committee therefore concluded that the ICER from this analysis was not reliable and could not form a suitable basis for a recommendation. The committee considered the economic model developed by Novartis for chronic-phase CML that is resistant to standard-dose imatinib. It noted that in the base-case analysis, nilotinib dominated (that is, it was less expensive and more effective than) high-dose imatinib and, in an exploratory analysis, nilotinib compared with a combination of hydroxycarbamide and stem cell transplantation resulted in an ICER of £44,000 per QALY gained. The estimated treatment duration with hydroxycarbamide and stem cell transplantation resulting in 4.21 years of overall survival (at a cost of £80,900) was not reported, and the estimated treatment duration with nilotinib was 2 years, resulting in 5.8 years of overall survival (at a cost of £139,000). The committee noted that if the treatment duration and overall survival seen in clinical practice were more accurately modelled and if hydroxycarbamide alone was a comparator, the base-case ICER of £44,000 per QALY gained would be likely to increase. The committee considered the economic model developed by Peninsula Technology Assessment Group (PenTAG) and subsequently updated by Southampton Health Technology Assessments Centre (SHTAC) for chronic-phase CML that is resistant to standard-dose imatinib. The committee noted that the PenTAG model did not link treatment duration with overall survival and that some of the results were not plausible. In particular, it noted that the estimated overall survival for interferon alfa was implausible and the treatment duration for people receiving nilotinib was lower than would be seen in clinical practice, given the estimated overall survival. The committee understood that the model updated by SHTAC attempted to correct PenTAG's overestimate of survival on interferon alfa and the discrepancy between the nilotinib and dasatinib treatment durations, but the SHTAC base-case treatment durations still did not reflect the fact that in clinical practice, people will receive treatment until progression or death (this was confirmed by the clinical experts; see section 4.5). The committee did not consider that a conclusive ICER had been presented in any of the economic models, but agreed that, taking all the models' assumptions into account, the least implausible analysis was the SHTAC scenario in which the treatment durations of dasatinib, high-dose imatinib and nilotinib were set to 10 years with overall survival estimates of 12.4 to 13.4 years. It noted that in this analysis both high-dose imatinib and nilotinib were dominated (that is, more expensive and less effective) by dasatinib, and dasatinib compared with hydroxycarbamide resulted in an ICER of £43,800 per QALY gained. The committee noted its earlier conclusions that more than 50% of people receiving these treatments are likely to do so for more than 10 years, with many people receiving them until death. The committee agreed that if treatment is continued for most of the person's lifetime, then the ICERs would increase. The committee concluded that there was no evidence to distinguish between dasatinib and nilotinib and that the ICERs for these treatments compared with hydroxycarbamide were uncertain and likely to be higher than £43,800 per QALY gained. The committee discussed the cost effectiveness of the technologies for the treatment of chronic-phase CML in people who have imatinib intolerance. It acknowledged the difficulties of undertaking an assessment of cost effectiveness without reasonable comparative evidence, relying on surrogate outcomes and uncertain treatment durations. However, it was aware that the effectiveness of dasatinib and nilotinib was likely to be greater in people with imatinib intolerance than in people with imatinib-resistant CML. Noting the uncertainties in these analyses, particularly about treatment duration, the committee concluded that dasatinib and nilotinib were likely to be at least as cost effective in people with imatinib intolerance as in people with imatinib-resistant CML and, as such, the cost effectiveness of dasatinib and nilotinib for people with imatinib intolerance could be inferred from the cost effectiveness in people with imatinib-resistant CML. The committee noted that Novartis had agreed a patient access scheme with the Department of Health. The company had presented ICERs for the scheme based on an analysis reflecting the scenario considered most plausible by the committee, outlined in section 4.19. The committee noted that the Novartis adjusted analysis based on the SHTAC update of the PenTAG model resulted in an ICER of £30,800 per QALY gained. It also noted that when SHTAC replicated the analysis the ICER increased slightly to £31,300 per QALY gained. It also noted that the company argued that a number of further changes to the SHTAC analysis should be made, namely: a reduction in treatment duration from 10.0 to 6.5 years a lower dose intensity of nilotinib based on clinical trial data an assumption of survival benefit equal to that of dasatinib a lower utility value associated with hydroxycarbamide treatment in the chronic phase, and a lower estimate of overall survival for hydroxycarbamide treatment.The committee noted that when the modifications and the discount were applied, the ICERs for nilotinib compared with hydroxycarbamide decreased to £22,800 per QALY gained when a treatment duration of 6.5 years was assumed, and £25,000 per QALY gained when a treatment duration of 10 years was assumed. The committee agreed that some of these adjustments were plausible, but not all. The treatment duration could be less than 10 years but the estimate of 6.5 years, which was based on treatment being withdrawn in all people who did not have a complete cytogenetic response, was not plausible. Also the committee did not agree with Novartis that the utility value for people treated with hydroxycarbamide should be lower for the same health states achieved by other treatments. It accepted that health state durations were shorter with hydroxycarbamide but thought that this should not be compounded by utility value adjustments. The committee therefore concluded that the Novartis adjusted ICER of £22,800 per QALY gained was too optimistic. However, the committee accepted that with the patient access scheme in place and its earlier conclusion that some of the adjustments to the model were plausible, the ICER for nilotinib is likely to be less than the SHTAC replicated ICER of £31,300 per QALY gained. The committee concluded that the use of nilotinib for the treatment of imatinib-resistant CML could be regarded as a cost-effective use of NHS resources. The committee therefore recommended the use of nilotinib for the treatment of adults with chronic- and accelerated-phase CML that is resistant to standard-dose imatinib or who have imatinib intolerance, if the company makes nilotinib available with the discount agreed as part of the patient access scheme. The committee then reflected on all of the models and results presented for high-dose imatinib for the treatment of CML that is resistant to standard-dose imatinib, together with the clinical and patient experts' views on the use of the technologies. It noted that high-dose imatinib was dominated (that is, more expensive and less effective than another treatment) in all models. Therefore the committee agreed that high-dose imatinib could not be recommended as a cost-effective use of NHS resources for the treatment of CML that is resistant to standard-dose imatinib. The committee then considered the cost effectiveness of dasatinib for the treatment of CML that is resistant to standard-dose imatinib. The committee noted its earlier conclusion that the updated economic analysis provided by Bristol-Myers Squibb could not form a suitable basis for a recommendation given the limitations described in section 4.15. It also noted that all other estimated ICERs were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested. Therefore the committee concluded that dasatinib could not be recommended as a cost-effective use of NHS resources for the treatment of adults with chronic-phase CML that is resistant to standard-dose imatinib, or who have imatinib intolerance. Furthermore, the committee noted that, given the patient access scheme for nilotinib and the assumed equivalence of effectiveness of dasatinib and nilotinib, dasatinib is considerably more expensive but no more effective than nilotinib. The committee then considered the cost-effectiveness evidence for dasatinib, high-dose imatinib and nilotinib for the treatment of the accelerated and blast-crisis phases of CML. The committee noted the clinical experts' view that there is no longer considered to be a distinguishable accelerated phase of CML. However, it acknowledged that this phase continues to be recognisable for some people, and saw no reason not to recommend nilotinib for treatment of CML in the accelerated phase. The committee noted that, as for the chronic phase, high-dose imatinib continued to be dominated (that is, it was more expensive and less effective than another treatment), and dasatinib continued to be as effective but more expensive, and concluded that neither drug could be recommended for the treatment of accelerated-phase CML. The committee noted that nilotinib does not have a marketing authorisation for the treatment of blast-crisis phase CML. It noted that treatment for the blast-crisis phase is different from that used in the other phases, with interventions generally used as adjuvant treatment to intensive chemotherapy for acute leukaemia. The committee was aware that no evidence using the interventions in this way had been submitted. To the extent that dasatinib could be considered a stand-alone treatment, the committee concluded that the evidence was particularly limited. The committee considered that all 3 of the estimates it saw, 1 from PenTAG and 2 from Bristol-Myers Squibb to be highly speculative. The PenTAG model comparing dasatinib with best supportive care included cost estimates of £88,000 and £80,000 for dasatinib and no treatment respectively. The committee considered that the small cost difference from which this was derived was unlikely to reflect reality, as the costs for best supportive care included in the no treatment arm would also be incurred in the dasatinib treatment arm after treatment with dasatinib is stopped. Neither of the Bristol-Myers Squibb models included best supportive care as a comparator and the committee was not convinced that high-dose imatinib and bone marrow stem cell transplantation were sufficient comparators. This compounded the very poor evidence base supporting the calculations and the committee concluded that dasatinib could not be considered a cost-effective use of NHS resources for the treatment of blast-crisis phase CML. The committee recognised the innovative nature and major change in the treatment of CML that imatinib has provided since it has been introduced and recommended for use by NICE, and discussed whether dasatinib and nilotinib should be considered to be innovative treatments. The committee considered that the development of dasatinib and nilotinib was not a step change in the treatment of CML when standard-dose imatinib had failed because of resistance or intolerance and did not identify any potential significant and substantial health-related benefits that had not been included in the economic models. The committee noted the importance of registries in gathering data on CML, particularly when treatment with standard-dose imatinib has failed. It supported collecting information in a suitable registry about treatments, long-term outcomes (particularly overall survival) and treatment-related adverse events in CML that is resistant to standard-dose imatinib. # End-of-life considerations (NICE technology appraisal guidance 241) The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The committee discussed the possibility that the end-of-life criteria defined by NICE in its supplementary advice might be met by dasatinib or high-dose imatinib for people with blast-crisis phase CML. The committee noted that in the blast-crisis phase of CML, life expectancy is short (about 3 to 6 months). The committee also agreed that this is a very small population, because fewer than 10% of all people with CML will present at the blast-crisis stage. However, the committee agreed that the available evidence on life extension in the blast-crisis phase was too weak and was not considered to be robust. In addition, no data were presented for the interventions as used in clinical practice. The committee concluded that dasatinib and high-dose imatinib do not fulfil the end-of-life criteria for people with blast-crisis phase CML. # Equality issues (NICE technology appraisal guidance 241) The committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. It noted that the submission from Bristol-Myers Squibb highlighted that if dasatinib, high-dose imatinib or nilotinib are not recommended for the treatment of imatinib-resistant CML, then allogeneic stem cell transplantation is the only treatment that may deliver clinical efficacy. Because only a small number of people who have imatinib-resistant CML are eligible for allogeneic stem cell transplantation, this could raise equality issues in relation to race, age (older people), and comorbidities. However, the committee concluded that allowing for clinical decisions relating to a range of possible treatments based on individual assessment of risk and benefit does not limit access to the technology for any specific protected group compared with other people. # Cancer Drugs Fund partial reconsideration of NICE technology appraisal guidance 241 This appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance. The committee considered the company's (Bristol-Myers Squibb) submission for the Cancer Drugs Fund reconsideration that included: a revised patient access scheme that provides a simple discount to the list price of dasatinib an updated systematic literature review, which provided a naive comparison of clinical outcomes of dasatinib compared with nilotinib a cost-minimisation analysis of dasatinib compared with nilotinib and high-dose imatinib. ## Clinical and cost effectiveness The committee discussed the appropriateness of the company's cost-minimisation analysis for dasatinib compared with imatinib. The committee noted that high-dose imatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase Philadelphia-chromosome-positive CML that is resistant to standard-dose imatinib (see sections 4.24 and 4.26). Therefore the committee considered that a cost-minimisation analysis of dasatinib compared with high-dose imatinib was uninformative in providing evidence that dasatinib is a cost-effective use of NHS resources. The committee discussed the appropriateness of the company's cost-minimisation analysis for dasatinib compared with nilotinib in chronic- and accelerated-phase CML. The evidence review group (ERG) highlighted that the use of a cost-minimisation analysis assumes that all health outcomes and treatment costs (other than drug acquisition) are equivalent. The committee recalled its judgement that that there was no good evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness (see section 4.9). The committee discussed the clinical evidence the company submitted as part of the reconsideration and concluded that there was no new evidence that would change the conclusions it made during the previous technology appraisal. Therefore, the committee considered that it was plausible that cost-minimisation analysis was appropriate to inform its decision-making because treatment with dasatinib is sufficiently similar to nilotinib. The committee recalled that nilotinib does not have a marketing authorisation for treating blast-crisis phase CML, and that treatment for this phase of the disease is different from that used in the other phases (see section 4.27). Therefore the committee considered that a cost-minimisation analysis of dasatinib compared with nilotinib would not be appropriate to inform a recommendation for dasatinib for blast-crisis phase CML. The committee noted that nilotinib is available with a patient access scheme, which provides a simple discount to the list price of nilotinib. The level of the discount is commercial in confidence. The committee discussed the results of the ERG's cost-minimisation analysis which took into account the patient access schemes of both nilotinib and dasatinib. It concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended for Philadelphia-chromosome-positive CML in the chronic or accelerated phase in adults who cannot have imatinib, or when their disease is imatinib-resistant. ## End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee concluded that applying this advice would not change the conclusion that was made in NICE technology appraisal guidance 241 that dasatinib does not fulfil the end-of-life criteria for people with blast-crisis phase CML (see section 4.31). ## Pharmaceutical Price Regulation Scheme 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA425 Appraisal title: Dasatinib, nilotinib and high-dose imatinib for treating imatinib-resistant or intolerant chronic myeloid leukaemia Section Key conclusion Dasatinib and nilotinib are recommended as options for treating chronic- or accelerated-phase Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in adults, only if: they cannot have imatinib or their disease is imatinib-resistant and the companies provide the drugs with the discounts agreed in the relevant patient access schemes. High-dose imatinib (that is, 600 mg in the chronic phase or 800 mg in the accelerated and blast-crisis phases) is not recommended for treating Philadelphia-chromosome-positive CML in adults whose disease is imatinib-resistant. The committee accepted that, with the patient access scheme in place, the use of nilotinib for the treatment of imatinib-resistant CML could be regarded as a cost-effective use of NHS resources. All other estimated incremental cost-effectiveness ratios (ICERs) were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested. High-dose imatinib was dominated (that is, more expensive and less effective than another treatment) in all models. Cancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard that 40% of people develop intolerance or resistance to standard-dose imatinib. The clinical experts suggested that if dasatinib, high-dose imatinib or nilotinib were not available, people would receive treatment with interferon alfa, hydroxycarbamide or best supportive care, and that for many people hydroxycarbamide or interferon alfa are considered to be little better than best supportive care. It also heard that bone marrow stem cell transplantation could be used, although it carries high risks and is restricted to fit, younger people. The committee heard that fewer than 10% of all people with CML will present with the blast-crisis phase of the disease, and that at this stage life expectancy is about 3–6 months. It also heard from the clinical experts that treatment strategy in the blast-crisis phase of the disease is different from that in the accelerated or chronic phases, with dasatinib and high-dose imatinib given as adjuvant treatment with intensive chemotherapy for acute leukaemia. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee heard that high-dose imatinib, dasatinib and nilotinib are a major advance over earlier therapies, that is, interferon alfa and hydroxycarbamide. The committee heard from the clinical experts that in more than 50% of people with imatinib-resistant CML treated with dasatinib or nilotinib, there is a good response to treatment and that this response is usually as good as the initial response to standard-dose imatinib. The committee acknowledged the clinical experts' view that for CML that is resistant to standard-dose imatinib, high-dose imatinib was unlikely to be as beneficial as dasatinib and nilotinib. The committee was aware that continued use of imatinib is not an option for people with imatinib intolerance. The committee considered that the development of dasatinib and nilotinib was not a step change innovation, and did not identify any potential significant and substantial health-related benefits that had not been included in the economic models. What is the position of the treatment in the pathway of care for the condition? The committee heard from the clinical experts that high-dose imatinib is being used in clinical practice for people whose CML has previously had a good response to treatment with standard-dose imatinib. The committee acknowledged the clinical experts' view that for CML that is resistant to standard-dose imatinib, high-dose imatinib was unlikely to be as beneficial as dasatinib and nilotinib. Adverse effects The committee concluded that dasatinib and nilotinib are better tolerated than imatinib, and that older treatment, particularly interferon alfa, can be poorly tolerated. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee was aware of only 1 comparative trial, which compared dasatinib with high-dose imatinib, but noted the restricted comparison (only with high-dose imatinib) and the comments from the assessment groups on the interpretation problems with this trial. The committee noted that the clinical trials available were non-comparative, of short duration and had used surrogate outcomes to predict overall survival. The committee was aware that no evidence was presented on the use of dasatinib or high-dose imatinib given as adjuvant treatment with intensive chemotherapy for acute leukaemia and that the evidence base in the blast-crisis phase of the disease is very limited. The committee noted that most of the clinical effectiveness evidence came from trials that included a mixed population of people with imatinib-resistant CML and people with imatinib intolerance. Relevance to general clinical practice in the NHS The clinical experts argued that the people in the clinical trials did not reflect the population seen in clinical practice because the trials included people who had worse disease prognoses than would be seen in current clinical practice. Uncertainties generated by the evidence The committee agreed that the limited evidence base means that the magnitude of the benefit (for people with imatinib-resistant CML) is uncertain. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee noted that in the trials that reported response rates separately, CML in people with imatinib intolerance generally had a higher response rate to dasatinib and nilotinib than people with imatinib-resistant CML, and that this was reflected in the estimates of overall survival used in the economic analyses. The committee agreed that this was a reasonable assumption given that people with imatinib intolerance generally have had a shorter duration of prior treatment than those whose CML develops resistance to imatinib over time. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that it is clear that dasatinib, high-dose imatinib and nilotinib provide clinical benefit for people with imatinib-resistant CML, but that the limited evidence base means that the magnitude of the benefit is uncertain. Evidence for cost effectiveness Availability and nature of evidence The committee considered the economic models provided by the companies and the assessment groups. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee considered that the model developed by Bristol-Myers Squibb had a number of limitations, of which the most important were that it estimated the cost for people receiving interferon alfa to be higher than (in some cases double) that of all the other economic models, and it did not include a comparison with hydroxycarbamide. It noted the additional analysis provided by Bristol-Myers Squibb, and considered that the assumption that 30.8% of people who stopped treatment would receive bone marrow stem cell transplantation was likely to be an overestimate. Also, the estimated ongoing monthly cost of bone marrow stem cell transplantation was unreasonably high. Finally, the committee considered the utility value estimate for the health state associated with successful transplantation to be unreasonable. The committee considered the economic model developed by Novartis for chronic-phase CML that is resistant to standard-dose imatinib. The committee noted that if the treatment duration and overall survival seen in clinical practice were more accurately modelled and if hydroxycarbamide alone was a comparator, the base-case ICER of £44,000 per quality-adjusted life year (QALY) gained would be likely to increase. The committee considered the Novartis adjusted analysis and concluded that the treatment duration which was based on treatment being withdrawn in all people who did not have a complete cytogenetic response, or the utility value for people treated with hydroxycarbamide should be lower for the same health states achieved by other treatments, were not plausible. It accepted that health state durations were shorter with hydroxycarbamide but thought that this should not be compounded by utility value adjustments. The committee noted the Peninsula Technology Assessment Group model did not link treatment duration with overall survival and that some of the results were not plausible. It understood that the Southampton Health Technology Assessments Centre base-case treatment durations still did not reflect the fact that in clinical practice, people will receive treatment until progression or death. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee considered the Bristol-Myers Squibb additional analysis, and noted the utility value estimate of 0.6 for the health state associated with successful transplants to be unreasonable, in view of the utility value of 0.85 for successful dasatinib treatment, and the utility value of 0.68 for failed dasatinib treatment. The committee did not agree with the assumption in the Novartis adjusted analysis that the utility value for people treated with hydroxycarbamide should be lower for the same health states achieved by other treatments. The committee did not identify any potential significant and substantial health-related benefits that had not been included in the economic models. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? The committee noted that high-dose imatinib was dominated (that is, more expensive and less effective than another treatment) in all models. The committee concluded that the updated economic analysis provided by Bristol-Myers Squibb could not form a suitable basis for a recommendation, and also noted that all other estimated ICERs were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested. Furthermore, the committee noted that, given the patient access scheme for nilotinib and the assumed equivalence of effectiveness of dasatinib and nilotinib, dasatinib is considerably more expensive but no more effective than nilotinib. The committee noted the clinical experts' view that there is no longer considered to be a distinguishable accelerated phase of CML. It saw no reason not to recommend nilotinib for treatment of CML in the accelerated phase. The committee noted that, as for the chronic phase, high-dose imatinib continued to be dominated (that is, it was more expensive and less effective than another treatment), and dasatinib continued to be as effective but more expensive. The committee noted that nilotinib does not have a marketing authorisation for the treatment of blast-crisis phase CML. It considered that the interventions used to treat blast-crisis phase CML are generally used as adjuvant treatment to intensive chemotherapy for acute leukaemia. It was aware that no evidence using the interventions in this way had been submitted. To the extent that dasatinib could be considered a stand-alone treatment, the committee concluded that the evidence was particularly limited. Most likely cost-effectiveness estimate (given as an ICER) The committee did not consider that a conclusive ICER had been presented in any of the economic models. The committee concluded that dasatinib and nilotinib were likely to be at least as cost effective in people with imatinib intolerance as in people with imatinib-resistant CML. It noted that high-dose imatinib was dominated (more expensive and less effective) in all models. The Novartis' adjusted ICER of £22,800 per QALY gained was too optimistic, however, with the patient access scheme in place, the use of nilotinib for the treatment of imatinib-resistant CML could be regarded as a cost-effective. Given the committee's conclusion that updated economic analysis provided by Bristol-Myers Squibb could not form a suitable basis for a recommendation all other estimated ICERs were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested. Committee noted that treatment for the blast-crisis phase is different from that used in the other phases. To the extent that dasatinib could be considered a stand-alone treatment, the committee concluded that the evidence was particularly limited. The committee considered all 3 estimates of cost effectiveness it saw to be highly speculative with a very poor evidence base supporting the calculations. Cancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources. Additional factors taken into account Patient access schemes (PPRS) The committee noted that the company of nilotinib had agreed a patient access scheme with the Department of Health. Cancer Drugs Fund reconsideration: the committee noted that the company of dasatinib had agreed a patient access scheme with the Department of Health. End-of-life considerations The committee noted that in the blast-crisis phase of CML, life expectancy is short (about 3–6 months). The committee also agreed that this is a very small population, because fewer than 10% of all people with CML will present at this stage. However, the committee agreed that the available evidence on life extension in the blast-crisis phase was too weak and was not considered to be robust. In addition, no data were presented for the interventions as used in clinical practice. The committee concluded that dasatinib and high-dose imatinib do not fulfil the end-of-life criteria for people with blast-crisis phase CML. Equalities considerations and social value judgements The committee noted the argument that if dasatinib, high-dose imatinib or nilotinib are not recommended for the treatment of imatinib-resistant CML and that this could raise issues in relation to race, age (the older people), and comorbidities. However, the committee concluded that allowing for clinical decisions relating to a range of possible treatments based on individual assessment of risk and benefit does not limit access to the technology for any specific protected group compared with other people.	{'Recommendations': 'Dasatinib and nilotinib are recommended as options for treating only chronic- or accelerated-phase Philadelphia-chromosome-positive chronic myeloid leukaemia in adults, if:\n\nthey cannot have imatinib, or their disease is imatinib-resistant and\n\nthe companies provide the drugs with the discounts agreed in the relevant patient access schemes.\n\nHigh-dose imatinib (that is, 600\xa0mg in the chronic phase or 800\xa0mg in the accelerated and blast-crisis phases) is not recommended for treating Philadelphia-chromosome-positive chronic myeloid leukaemia in adults whose disease is imatinib-resistant.\n\nThis guidance is not intended to affect the position of patients whose treatment with imatinib or dasatinib was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technologies': "Description of the technologies\n\nDasatinib (Sprycel, Bristol-Myers Squibb), a tyrosine kinase inhibitor, is an orally active inhibitor of Src and the Src family of tyrosine kinases. These are involved in cell growth, differentiation, migration and survival, and many are involved in oncogenesis, tumour metastasis and angiogenesis.\n\nImatinib (Glivec, Novartis Pharmaceuticals) is an orally active tyrosine kinase inhibitor, designed to competitively inhibit Bcr‑Abl tyrosine kinase activity. By blocking specific signals in cells expressing Bcr‑Abl, imatinib reduces the uncontrolled proliferation of white blood cells that is a characteristic feature of chronic myeloid leukaemia (CML).\n\nNilotinib (Tasigna, Novartis Pharmaceuticals), a tyrosine kinase inhibitor (TKI), is an orally active phenylaminopyrimidine derivative of imatinib. Studies suggest that nilotinib inhibits 32\xa0of 33\xa0mutant Bcr‑Abl forms that are resistant to imatinib.\n\nMarketing authorisations\n\nDasatinib has a marketing authorisation for the treatment of adult patients with 'newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase' and adult patients with 'chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate'.\n\nImatinib has a marketing authorisation for the treatment of 'adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment' and for 'adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis'.\n\nNilotinib has a marketing authorisation for the treatment of adult patients with 'newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase' and adult patients with 'chronic phase and accelerated-phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib'.\n\nAdverse reactions\n\nThe most common reported side effects with dasatinib are headache, pleural effusion, shortness of breath, cough, diarrhoea, nausea, vomiting, abdominal pain, skin rash, musculoskeletal pain, infections, haemorrhage, superficial oedema, fatigue, fever, neutropenia, thrombocytopenia and anaemia. The summary of product characteristics states: 'Dasatinib should be administered with caution to patients who have or may develop prolongation of the QT interval'.\n\nThe most common side effects with imatinib are nausea, vomiting, oedema (fluid retention), muscle cramps, skin rash, diarrhoea, abdominal pain, headache and fatigue.\n\nThe most common side effects with nilotinib are thrombocytopenia, neutropenia, anaemia, headache, nausea, constipation, diarrhoea, rash, pruritus, fatigue and increased blood levels of lipase and bilirubin. Nilotinib prolongs the QT interval and is therefore contraindicated in people with hypokalaemia, hypomagnesaemia or long QT syndrome.\n\nFor full details of adverse reactions and contraindications, see the summary of product characteristics of the respective technologies.\n\nRecommended doses and schedules\n\nDasatinib is administered orally. The recommended starting dosage is 100\xa0mg once daily in the chronic phase or 140\xa0mg once daily in the accelerated and blast-crisis phase and treatment should continue until disease progression or until no longer tolerated by the patient. Dose increase or reduction is recommended based on patient response and tolerability.\n\nImatinib is administered orally. The recommended starting dosage is 400\xa0mg once daily in the chronic phase or 600\xa0mg once daily in the accelerated and blast-crisis phase and treatment should be continued as long as the patient continues to benefit. Dose increase to 600\xa0mg once daily in the chronic phase or 800\xa0mg (400\xa0mg twice daily) in the accelerated and blast-crisis phase may be considered for people who have imatinib resistance.\n\nNilotinib is administered orally. The recommended starting dosage is 400\xa0mg twice daily for imatinib-resistant or intolerant CML in the chronic phase and 400\xa0mg twice daily in the accelerated phase and treatment should be continued as long as the patient continues to benefit.\n\nPrices\n\nDasatinib is available at a cost of £2,504.96 for both a pack of\xa030 100-mg or 140-mg tablets (excluding VAT; 'British national formulary' [BNF] online, accessed October 2016). The cost of dasatinib treatment is £30,477.00 per year, assuming a treatment regimen of 100\xa0mg once daily or 140\xa0mg once daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of dasatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\nImatinib was available at a cost of £1,604.00 for a 400-mg 30‑tablet pack (excluding VAT; BNF edition 61) resulting in an annual cost of imatinib treatment of £39,033.00, assuming a treatment regimen of 400\xa0mg twice daily. The cost of imatinib has increased to £1,836.48 for a 400-mg 30‑tablet pack (excluding VAT; BNF online, accessed October 2016). The cost of imatinib treatment is now £44,718.00 per year assuming a treatment regimen of 400\xa0mg twice daily. Costs may vary in different settings because of negotiated procurement discounts.\n\nNilotinib is available at a cost of £2,432.85 for a pack of 112 200-mg tablets (excluding VAT; BNF online, accessed October 2016). The cost of nilotinib treatment is £31,736.00 per year, assuming a treatment regimen of 400\xa0mg twice daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nilotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance. Sections 4.1 to 4.32 reflect the committee's consideration of the evidence submitted in the original appraisal (NICE technology appraisal guidance\xa0241). Sections 4.33 to 4.40 reflect the committee's consideration of the additional evidence submitted for the Cancer Drugs Fund reconsideration. It focused on a cost-minimisation analysis using a revised patient access scheme, which provides a simple discount to the list price of dasatinib. The level of the discount is commercial in confidence.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of dasatinib, high-dose imatinib and nilotinib for the treatment of chronic myeloid leukaemia (CML) that is resistant to standard-dose imatinib, and of dasatinib and nilotinib for the treatment of CML in people with imatinib intolerance, having considered evidence on the nature of CML and the value placed on the benefits of the interventions by people with the condition, those who represent them and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0241)\n\nThe committee discussed current clinical practice for treating CML. The committee heard from the clinical experts that standard-dose imatinib is given in line with NICE technology appraisal guidance 70 to people presenting with chronic-phase CML. The clinical experts stated that in approximately 60% of people there is a good response to standard-dose imatinib, and that these people will continue to receive the treatment for life and have a normal life expectancy. The committee recognised the innovative nature and major change in the treatment of CML that imatinib had provided. However, it heard that 40% of people develop intolerance or resistance to standard-dose imatinib.\n\nThe committee heard that high-dose imatinib, dasatinib and nilotinib are in widespread use and are a major advance over earlier therapies (that is, interferon alfa and hydroxycarbamide). The clinical experts suggested that if dasatinib, high-dose imatinib or nilotinib were not available, people would receive treatment with interferon alfa, hydroxycarbamide or best supportive care, and that for many people hydroxycarbamide or interferon alfa are considered to be little better than best supportive care. The committee also heard from the clinical experts that bone marrow stem cell transplantation could be used, although it carries high risks and is restricted to fit, younger people. The committee concluded that any one of these treatments could be considered a comparator with high-dose imatinib, nilotinib or dasatinib.\n\nThe committee noted that high-dose imatinib had been recommended only in the context of clinical research in NICE technology appraisal guidance\xa070. It heard from the clinical experts that high-dose imatinib is being used in clinical practice for people whose CML has previously had a good response to treatment with standard-dose imatinib. The committee acknowledged the clinical experts' view that for CML that is resistant to standard-dose imatinib, high-dose imatinib was unlikely to be as beneficial as dasatinib and nilotinib.\n\nThe committee heard from the clinical experts that, in clinical practice, treatment with dasatinib, high-dose imatinib and nilotinib is given in accordance with European guidelines, which specify time-dependent targets. If the CML is responding to treatment, the treatment will be continued until progression or until the person dies (from non-CML causes). If CML does not respond to dasatinib or nilotinib within 12\xa0months, treatment may be stopped, or may be changed to hydroxycarbamide and/or, if suitable, stem cell transplantation.\n\nThe committee heard from the clinical experts that in more than 50% of people with imatinib-resistant CML who have dasatinib or nilotinib, there is a good response to treatment and that this response is usually as good as the initial response to standard-dose imatinib. The clinical experts expected that these people would receive dasatinib or nilotinib treatment for the rest of their lives, and possibly have a nearly normal life expectancy (that is, at least 10\xa0more years). For people receiving interferon alfa or hydroxycarbamide in the chronic phase, the prognosis is poor, with a median life expectancy of around 5\xa0years. It heard from the clinical experts that with modern therapy the accelerated phase is no longer considered to be a distinct disease phase, so in effect the disease progresses from a prolonged chronic-phase to blast-crisis phase.\n\nThe committee discussed the clinical-effectiveness evidence for dasatinib, high-dose imatinib and nilotinib for the treatment of chronic-phase CML that is resistant to standard-dose imatinib. It was aware of only 1\xa0comparative trial, which compared dasatinib with high-dose imatinib, but noted the restricted comparison (only with high-dose imatinib) and the comments from the assessment groups on the interpretation of this trial.\n\nThe committee noted that the clinical trials available were non-comparative, of short duration and had used surrogate outcomes to predict overall survival. The committee noted the wide range of results across the interventions, with major cytogenetic response rates ranging from 33.3 to 58.9% with dasatinib, 32.7 to 42.5% with high-dose imatinib (but with 1\xa0outlying result of 63.5%), and 35.3 to 56.1% with nilotinib. The committee discussed the clinical trial evidence in light of the views of the patient and clinical experts. The committee noted the poor quality of the evidence base. However, it heard from the clinical experts and patient experts that clinical benefits, particularly of dasatinib and nilotinib, have been demonstrated. In addition, the clinical experts argued that the people in the clinical trials did not reflect the population seen in clinical practice because the trials included people who had worse disease prognoses than would be seen in current clinical practice.\n\nThe committee concluded that it is clear that dasatinib, high-dose imatinib and nilotinib provide clinical benefit for people with imatinib-resistant CML. However, the committee agreed that the limited evidence base means that the magnitude of the benefit is uncertain. The committee also agreed that there was no good evidence to distinguish between dasatinib and nilotinib; a conclusion supported by the clinical experts.\n\nThe committee was aware that continued use of imatinib is not an option for people with imatinib intolerance. It noted that most of the clinical-effectiveness evidence came from trials that included a mixed population of people with imatinib-resistant CML and people with imatinib intolerance. The committee noted that in the trials that reported response rates separately, CML in people with imatinib intolerance generally had a higher response rate to dasatinib and nilotinib than people with imatinib-resistant CML, and that this was reflected in the estimates of overall survival used in the economic analyses. The committee agreed that this was a reasonable assumption given that people with imatinib intolerance generally have had a shorter duration of prior treatment than those whose CML develops resistance to imatinib over time.\n\nThe committee discussed the side effects of treatment for imatinib-resistant CML and for people with CML who have imatinib intolerance. It noted the adverse effects reported in the trials with dasatinib, high-dose imatinib and nilotinib in imatinib-resistant CML. The committee concluded that dasatinib and nilotinib are better tolerated than imatinib, and that older treatments, particularly interferon\xa0alfa, can be poorly tolerated.\n\nThe committee considered the treatment of the blast-crisis phase of CML in clinical practice. The committee heard from the clinical experts that at the blast-crisis stage of the disease, life expectancy is about 3\xa0to 6\xa0months. The committee also heard from the clinical experts that the treatment strategy in the blast-crisis phase of the disease is different from that in the accelerated or chronic phases, with dasatinib and high-dose imatinib given as adjuvant treatment with intensive chemotherapy for acute leukaemia. The committee was aware that no evidence was presented on the use of dasatinib or high-dose imatinib in this way and that the evidence base for the blast-crisis phase of the disease is very limited.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0241)\n\nThe committee then considered the economic models provided by the companies and the assessment groups for chronic-phase CML that is resistant to standard-dose imatinib. In each it took particular note of the incremental cost-effectiveness ratio (ICER) for the comparison between the most cost effective of the tyrosine kinase inhibitors (given that dasatinib and nilotinib are considered equal), and the most cost effective of the older treatments (given that none were definitively favoured). In all the comparisons, the committee also took particular note of the relationship between treatment duration and overall survival; because these are the main influences on costs and benefits and the clinical experts stated that these were closely related.\n\nFrom the model developed by Bristol-Myers Squibb, the committee particularly noted the comparison between dasatinib and interferon\xa0alfa, which generated an ICER of £38,900 per quality-adjusted life year (QALY) gained. The estimated treatment duration with interferon\xa0alfa was 0.65\xa0years (at a total estimated cost of £129,000), resulting in 3.56\xa0years of overall survival, and the estimated treatment duration with dasatinib was 7.46\xa0years (at a cost of £314,000), resulting in 11.76\xa0years of overall survival. The committee considered that the model had a number of limitations, of which the most important were that it estimated the cost for people receiving interferon\xa0alfa to be higher than (in some cases double) that of all the other economic models, and it did not include a comparison with hydroxycarbamide. After consultation on the appraisal consultation document, Bristol-Myers Squibb provided an additional economic analysis. The committee noted that the additional analysis included hydroxycarbamide as a comparator and bone marrow stem cell transplantation as a third-line treatment. It noted that Bristol-Myers Squibb calculated the ICER for dasatinib to be £28,000 per QALY gained compared with hydroxycarbamide, and the total QALYs and costs associated with treatment with dasatinib in the additional economic analysis were more favourable to dasatinib than those in the company's original economic analysis.\n\nThe committee compared these findings with those of the other economic models, and examined the assumptions that had been used in the additional analysis. Bristol-Myers Squibb's estimates for comparator costs were higher than had been used in other economic models. The committee considered that the assumption that 30.8% of people who stopped treatment would receive bone marrow stem cell transplantation was likely to be an overestimate given contraindications to bone marrow stem cell transplantation and the lack of availability of a matched donor for many people. Secondly, the committee considered that the assumed ongoing monthly cost of £2,400 after bone marrow stem cell transplantation (at £80,000) was an unreasonably high estimate, given that only a minority of people who survive transplantation develop complications that incur high ongoing costs. Thirdly, the committee considered the utility value estimate of\xa00.6 for the health state associated with successful transplantation to be unreasonable, in view of the utility value of\xa00.85 for successful dasatinib treatment, and the utility value of\xa00.68 for failed dasatinib treatment. The committee noted that these utility values were not derived from a common source. The committee therefore concluded that the ICER from this analysis was not reliable and could not form a suitable basis for a recommendation.\n\nThe committee considered the economic model developed by Novartis for chronic-phase CML that is resistant to standard-dose imatinib. It noted that in the base-case analysis, nilotinib dominated (that is, it was less expensive and more effective than) high-dose imatinib and, in an exploratory analysis, nilotinib compared with a combination of hydroxycarbamide and stem cell transplantation resulted in an ICER of £44,000 per QALY gained. The estimated treatment duration with hydroxycarbamide and stem cell transplantation resulting in 4.21\xa0years of overall survival (at a cost of £80,900) was not reported, and the estimated treatment duration with nilotinib was 2\xa0years, resulting in 5.8\xa0years of overall survival (at a cost of £139,000). The committee noted that if the treatment duration and overall survival seen in clinical practice were more accurately modelled and if hydroxycarbamide alone was a comparator, the base-case ICER of £44,000 per QALY gained would be likely to increase.\n\nThe committee considered the economic model developed by Peninsula Technology Assessment Group (PenTAG) and subsequently updated by Southampton Health Technology Assessments Centre (SHTAC) for chronic-phase CML that is resistant to standard-dose imatinib. The committee noted that the PenTAG model did not link treatment duration with overall survival and that some of the results were not plausible. In particular, it noted that the estimated overall survival for interferon\xa0alfa was implausible and the treatment duration for people receiving nilotinib was lower than would be seen in clinical practice, given the estimated overall survival.\n\nThe committee understood that the model updated by SHTAC attempted to correct PenTAG's overestimate of survival on interferon\xa0alfa and the discrepancy between the nilotinib and dasatinib treatment durations, but the SHTAC base-case treatment durations still did not reflect the fact that in clinical practice, people will receive treatment until progression or death (this was confirmed by the clinical experts; see section\xa04.5).\n\nThe committee did not consider that a conclusive ICER had been presented in any of the economic models, but agreed that, taking all the models' assumptions into account, the least implausible analysis was the SHTAC scenario in which the treatment durations of dasatinib, high-dose imatinib and nilotinib were set to 10\xa0years with overall survival estimates of 12.4\xa0to 13.4\xa0years. It noted that in this analysis both high-dose imatinib and nilotinib were dominated (that is, more expensive and less effective) by dasatinib, and dasatinib compared with hydroxycarbamide resulted in an ICER of £43,800 per QALY gained. The committee noted its earlier conclusions that more than 50% of people receiving these treatments are likely to do so for more than 10\xa0years, with many people receiving them until death. The committee agreed that if treatment is continued for most of the person's lifetime, then the ICERs would increase. The committee concluded that there was no evidence to distinguish between dasatinib and nilotinib and that the ICERs for these treatments compared with hydroxycarbamide were uncertain and likely to be higher than £43,800 per QALY gained.\n\nThe committee discussed the cost effectiveness of the technologies for the treatment of chronic-phase CML in people who have imatinib intolerance. It acknowledged the difficulties of undertaking an assessment of cost effectiveness without reasonable comparative evidence, relying on surrogate outcomes and uncertain treatment durations. However, it was aware that the effectiveness of dasatinib and nilotinib was likely to be greater in people with imatinib intolerance than in people with imatinib-resistant CML. Noting the uncertainties in these analyses, particularly about treatment duration, the committee concluded that dasatinib and nilotinib were likely to be at least as cost effective in people with imatinib intolerance as in people with imatinib-resistant CML and, as such, the cost effectiveness of dasatinib and nilotinib for people with imatinib intolerance could be inferred from the cost effectiveness in people with imatinib-resistant CML.\n\nThe committee noted that Novartis had agreed a patient access scheme with the Department of Health. The company had presented ICERs for the scheme based on an analysis reflecting the scenario considered most plausible by the committee, outlined in section\xa04.19.\n\nThe committee noted that the Novartis adjusted analysis based on the SHTAC update of the PenTAG model resulted in an ICER of £30,800 per QALY gained. It also noted that when SHTAC replicated the analysis the ICER increased slightly to £31,300 per QALY gained. It also noted that the company argued that a number of further changes to the SHTAC analysis should be made, namely:\n\na reduction in treatment duration from 10.0\xa0to 6.5\xa0years\n\na lower dose intensity of nilotinib based on clinical trial data\n\nan assumption of survival benefit equal to that of dasatinib\n\na lower utility value associated with hydroxycarbamide treatment in the chronic phase, and\n\na lower estimate of overall survival for hydroxycarbamide treatment.The committee noted that when the modifications and the discount were applied, the ICERs for nilotinib compared with hydroxycarbamide decreased to £22,800 per QALY gained when a treatment duration of 6.5\xa0years was assumed, and £25,000 per QALY gained when a treatment duration of 10\xa0years was assumed. The committee agreed that some of these adjustments were plausible, but not all. The treatment duration could be less than 10\xa0years but the estimate of 6.5\xa0years, which was based on treatment being withdrawn in all people who did not have a complete cytogenetic response, was not plausible. Also the committee did not agree with Novartis that the utility value for people treated with hydroxycarbamide should be lower for the same health states achieved by other treatments. It accepted that health state durations were shorter with hydroxycarbamide but thought that this should not be compounded by utility value adjustments.\n\nThe committee therefore concluded that the Novartis adjusted ICER of £22,800 per QALY gained was too optimistic. However, the committee accepted that with the patient access scheme in place and its earlier conclusion that some of the adjustments to the model were plausible, the ICER for nilotinib is likely to be less than the SHTAC replicated ICER of £31,300 per QALY gained. The committee concluded that the use of nilotinib for the treatment of imatinib-resistant CML could be regarded as a cost-effective use of NHS resources. The committee therefore recommended the use of nilotinib for the treatment of adults with chronic- and accelerated-phase CML that is resistant to standard-dose imatinib or who have imatinib intolerance, if the company makes nilotinib available with the discount agreed as part of the patient access scheme.\n\nThe committee then reflected on all of the models and results presented for high-dose imatinib for the treatment of CML that is resistant to standard-dose imatinib, together with the clinical and patient experts' views on the use of the technologies. It noted that high-dose imatinib was dominated (that is, more expensive and less effective than another treatment) in all models. Therefore the committee agreed that high-dose imatinib could not be recommended as a cost-effective use of NHS resources for the treatment of CML that is resistant to standard-dose imatinib.\n\nThe committee then considered the cost effectiveness of dasatinib for the treatment of CML that is resistant to standard-dose imatinib. The committee noted its earlier conclusion that the updated economic analysis provided by Bristol-Myers Squibb could not form a suitable basis for a recommendation given the limitations described in section 4.15. It also noted that all other estimated ICERs were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested. Therefore the committee concluded that dasatinib could not be recommended as a cost-effective use of NHS resources for the treatment of adults with chronic-phase CML that is resistant to standard-dose imatinib, or who have imatinib intolerance. Furthermore, the committee noted that, given the patient access scheme for nilotinib and the assumed equivalence of effectiveness of dasatinib and nilotinib, dasatinib is considerably more expensive but no more effective than nilotinib.\n\nThe committee then considered the cost-effectiveness evidence for dasatinib, high-dose imatinib and nilotinib for the treatment of the accelerated and blast-crisis phases of CML. The committee noted the clinical experts' view that there is no longer considered to be a distinguishable accelerated phase of CML. However, it acknowledged that this phase continues to be recognisable for some people, and saw no reason not to recommend nilotinib for treatment of CML in the accelerated phase. The committee noted that, as for the chronic phase, high-dose imatinib continued to be dominated (that is, it was more expensive and less effective than another treatment), and dasatinib continued to be as effective but more expensive, and concluded that neither drug could be recommended for the treatment of accelerated-phase CML.\n\nThe committee noted that nilotinib does not have a marketing authorisation for the treatment of blast-crisis phase CML. It noted that treatment for the blast-crisis phase is different from that used in the other phases, with interventions generally used as adjuvant treatment to intensive chemotherapy for acute leukaemia. The committee was aware that no evidence using the interventions in this way had been submitted. To the extent that dasatinib could be considered a stand-alone treatment, the committee concluded that the evidence was particularly limited. The committee considered that all 3\xa0of the estimates it saw, 1\xa0from PenTAG and 2\xa0from Bristol-Myers Squibb to be highly speculative. The PenTAG model comparing dasatinib with best supportive care included cost estimates of £88,000 and £80,000 for dasatinib and no treatment respectively. The committee considered that the small cost difference from which this was derived was unlikely to reflect reality, as the costs for best supportive care included in the no treatment arm would also be incurred in the dasatinib treatment arm after treatment with dasatinib is stopped. Neither of the Bristol-Myers Squibb models included best supportive care as a comparator and the committee was not convinced that high-dose imatinib and bone marrow stem cell transplantation were sufficient comparators. This compounded the very poor evidence base supporting the calculations and the committee concluded that dasatinib could not be considered a cost-effective use of NHS resources for the treatment of blast-crisis phase CML.\n\nThe committee recognised the innovative nature and major change in the treatment of CML that imatinib has provided since it has been introduced and recommended for use by NICE, and discussed whether dasatinib and nilotinib should be considered to be innovative treatments. The committee considered that the development of dasatinib and nilotinib was not a step change in the treatment of CML when standard-dose imatinib had failed because of resistance or intolerance and did not identify any potential significant and substantial health-related benefits that had not been included in the economic models.\n\nThe committee noted the importance of registries in gathering data on CML, particularly when treatment with standard-dose imatinib has failed. It supported collecting information in a suitable registry about treatments, long-term outcomes (particularly overall survival) and treatment-related adverse events in CML that is resistant to standard-dose imatinib.\n\n# End-of-life considerations (NICE technology appraisal guidance\xa0241)\n\nThe committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe committee discussed the possibility that the end-of-life criteria defined by NICE in its supplementary advice might be met by dasatinib or high-dose imatinib for people with blast-crisis phase CML. The committee noted that in the blast-crisis phase of CML, life expectancy is short (about 3\xa0to 6\xa0months). The committee also agreed that this is a very small population, because fewer than 10% of all people with CML will present at the blast-crisis stage. However, the committee agreed that the available evidence on life extension in the blast-crisis phase was too weak and was not considered to be robust. In addition, no data were presented for the interventions as used in clinical practice. The committee concluded that dasatinib and high-dose imatinib do not fulfil the end-of-life criteria for people with blast-crisis phase CML.\n\n# Equality issues (NICE technology appraisal guidance\xa0241)\n\nThe committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. It noted that the submission from Bristol-Myers Squibb highlighted that if dasatinib, high-dose imatinib or nilotinib are not recommended for the treatment of imatinib-resistant CML, then allogeneic stem cell transplantation is the only treatment that may deliver clinical efficacy. Because only a small number of people who have imatinib-resistant CML are eligible for allogeneic stem cell transplantation, this could raise equality issues in relation to race, age (older people), and comorbidities. However, the committee concluded that allowing for clinical decisions relating to a range of possible treatments based on individual assessment of risk and benefit does not limit access to the technology for any specific protected group compared with other people.\n\n# Cancer Drugs Fund partial reconsideration of NICE technology appraisal guidance\xa0241\n\nThis appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance. The committee considered the company's (Bristol-Myers Squibb) submission for the Cancer Drugs Fund reconsideration that included:\n\na revised patient access scheme that provides a simple discount to the list price of dasatinib\n\nan updated systematic literature review, which provided a naive comparison of clinical outcomes of dasatinib compared with nilotinib\n\na cost-minimisation analysis of dasatinib compared with nilotinib and high-dose imatinib.\n\n## Clinical and cost effectiveness\n\nThe committee discussed the appropriateness of the company's cost-minimisation analysis for dasatinib compared with imatinib. The committee noted that high-dose imatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase Philadelphia-chromosome-positive CML that is resistant to standard-dose imatinib (see sections 4.24 and 4.26). Therefore the committee considered that a cost-minimisation analysis of dasatinib compared with high-dose imatinib was uninformative in providing evidence that dasatinib is a cost-effective use of NHS resources.\n\nThe committee discussed the appropriateness of the company's cost-minimisation analysis for dasatinib compared with nilotinib in chronic- and accelerated-phase CML. The evidence review group (ERG) highlighted that the use of a cost-minimisation analysis assumes that all health outcomes and treatment costs (other than drug acquisition) are equivalent. The committee recalled its judgement that that there was no good evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness (see section 4.9). The committee discussed the clinical evidence the company submitted as part of the reconsideration and concluded that there was no new evidence that would change the conclusions it made during the previous technology appraisal. Therefore, the committee considered that it was plausible that cost-minimisation analysis was appropriate to inform its decision-making because treatment with dasatinib is sufficiently similar to nilotinib.\n\nThe committee recalled that nilotinib does not have a marketing authorisation for treating blast-crisis phase CML, and that treatment for this phase of the disease is different from that used in the other phases (see section\xa04.27). Therefore the committee considered that a cost-minimisation analysis of dasatinib compared with nilotinib would not be appropriate to inform a recommendation for dasatinib for blast-crisis phase CML.\n\nThe committee noted that nilotinib is available with a patient access scheme, which provides a simple discount to the list price of nilotinib. The level of the discount is commercial in confidence. The committee discussed the results of the ERG's cost-minimisation analysis which took into account the patient access schemes of both nilotinib and dasatinib. It concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended for Philadelphia-chromosome-positive CML in the chronic or accelerated phase in adults who cannot have imatinib, or when their disease is imatinib-resistant.\n\n## End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\nThe committee concluded that applying this advice would not change the conclusion that was made in NICE technology appraisal guidance 241 that dasatinib does not fulfil the end-of-life criteria for people with blast-crisis phase CML (see section\xa04.31).\n\n## Pharmaceutical Price Regulation Scheme\xa02014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA425\n\nAppraisal title: Dasatinib, nilotinib and high-dose imatinib for treating imatinib-resistant or intolerant chronic myeloid leukaemia\n\nSection\n\nKey conclusion\n\nDasatinib and nilotinib are recommended as options for treating chronic- or accelerated-phase Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in adults, only if:\n\nthey cannot have imatinib or their disease is imatinib-resistant and\n\nthe companies provide the drugs with the discounts agreed in the relevant patient access schemes.\n\n\n\nHigh-dose imatinib (that is, 600\xa0mg in the chronic phase or 800\xa0mg in the accelerated and blast-crisis phases) is not recommended for treating Philadelphia-chromosome-positive CML in adults whose disease is imatinib-resistant.\n\n\n\nThe committee accepted that, with the patient access scheme in place, the use of nilotinib for the treatment of imatinib-resistant CML could be regarded as a cost-effective use of NHS resources. All other estimated incremental cost-effectiveness ratios (ICERs) were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested.\n\n, 4.24, 4.25\n\nHigh-dose imatinib was dominated (that is, more expensive and less effective than another treatment) in all models.\n\n\n\nCancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard that 40% of people develop intolerance or resistance to standard-dose imatinib.\n\n\n\nThe clinical experts suggested that if dasatinib, high-dose imatinib or nilotinib were not available, people would receive treatment with interferon alfa, hydroxycarbamide or best supportive care, and that for many people hydroxycarbamide or interferon alfa are considered to be little better than best supportive care. It also heard that bone marrow stem cell transplantation could be used, although it carries high risks and is restricted to fit, younger people.\n\n\n\nThe committee heard that fewer than 10% of all people with CML will present with the blast-crisis phase of the disease, and that at this stage life expectancy is about 3–6 months. It also heard from the clinical experts that treatment strategy in the blast-crisis phase of the disease is different from that in the accelerated or chronic phases, with dasatinib and high-dose imatinib given as adjuvant treatment with intensive chemotherapy for acute leukaemia.\n\n, 4.29\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard that high-dose imatinib, dasatinib and nilotinib are a major advance over earlier therapies, that is, interferon alfa and hydroxycarbamide.\n\n\n\nThe committee heard from the clinical experts that in more than 50% of people with imatinib-resistant CML treated with dasatinib or nilotinib, there is a good response to treatment and that this response is usually as good as the initial response to standard-dose imatinib. The committee acknowledged the clinical experts' view that for CML that is resistant to standard-dose imatinib, high-dose imatinib was unlikely to be as beneficial as dasatinib and nilotinib.\n\n\n\nThe committee was aware that continued use of imatinib is not an option for people with imatinib intolerance.\n\n\n\nThe committee considered that the development of dasatinib and nilotinib was not a step change innovation, and did not identify any potential significant and substantial health-related benefits that had not been included in the economic models.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard from the clinical experts that high-dose imatinib is being used in clinical practice for people whose CML has previously had a good response to treatment with standard-dose imatinib. The committee acknowledged the clinical experts' view that for CML that is resistant to standard-dose imatinib, high-dose imatinib was unlikely to be as beneficial as dasatinib and nilotinib.\n\n\n\nAdverse effects\n\nThe committee concluded that dasatinib and nilotinib are better tolerated than imatinib, and that older treatment, particularly interferon\xa0alfa, can be poorly tolerated.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee was aware of only 1 comparative trial, which compared dasatinib with high-dose imatinib, but noted the restricted comparison (only with high-dose imatinib) and the comments from the assessment groups on the interpretation problems with this trial.\n\n\n\nThe committee noted that the clinical trials available were non-comparative, of short duration and had used surrogate outcomes to predict overall survival.\n\n\n\nThe committee was aware that no evidence was presented on the use of dasatinib or high-dose imatinib given as adjuvant treatment with intensive chemotherapy for acute leukaemia and that the evidence base in the blast-crisis phase of the disease is very limited.\n\n\n\nThe committee noted that most of the clinical effectiveness evidence came from trials that included a mixed population of people with imatinib-resistant CML and people with imatinib intolerance.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe clinical experts argued that the people in the clinical trials did not reflect the population seen in clinical practice because the trials included people who had worse disease prognoses than would be seen in current clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee agreed that the limited evidence base means that the magnitude of the benefit (for people with imatinib-resistant CML) is uncertain.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee noted that in the trials that reported response rates separately, CML in people with imatinib intolerance generally had a higher response rate to dasatinib and nilotinib than people with imatinib-resistant CML, and that this was reflected in the estimates of overall survival used in the economic analyses. The committee agreed that this was a reasonable assumption given that people with imatinib intolerance generally have had a shorter duration of prior treatment than those whose CML develops resistance to imatinib over time.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that it is clear that dasatinib, high-dose imatinib and nilotinib provide clinical benefit for people with imatinib-resistant CML, but that the limited evidence base means that the magnitude of the benefit is uncertain.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee considered the economic models provided by the companies and the assessment groups.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee considered that the model developed by Bristol-Myers Squibb had a number of limitations, of which the most important were that it estimated the cost for people receiving interferon\xa0alfa to be higher than (in some cases double) that of all the other economic models, and it did not include a comparison with hydroxycarbamide.\n\n\n\nIt noted the additional analysis provided by Bristol-Myers Squibb, and considered that the assumption that 30.8% of people who stopped treatment would receive bone marrow stem cell transplantation was likely to be an overestimate. Also, the estimated ongoing monthly cost of bone marrow stem cell transplantation was unreasonably high. Finally, the committee considered the utility value estimate for the health state associated with successful transplantation to be unreasonable.\n\n\n\nThe committee considered the economic model developed by Novartis for chronic-phase CML that is resistant to standard-dose imatinib. The committee noted that if the treatment duration and overall survival seen in clinical practice were more accurately modelled and if hydroxycarbamide alone was a comparator, the base-case ICER of £44,000 per quality-adjusted life year (QALY) gained would be likely to increase.\n\n\n\nThe committee considered the Novartis adjusted analysis and concluded that the treatment duration which was based on treatment being withdrawn in all people who did not have a complete cytogenetic response, or the utility value for people treated with hydroxycarbamide should be lower for the same health states achieved by other treatments, were not plausible. It accepted that health state durations were shorter with hydroxycarbamide but thought that this should not be compounded by utility value adjustments.\n\n\n\nThe committee noted the Peninsula Technology Assessment Group model did not link treatment duration with overall survival and that some of the results were not plausible. It understood that the Southampton Health Technology Assessments Centre base-case treatment durations still did not reflect the fact that in clinical practice, people will receive treatment until progression or death.\n\n, 4.18\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee considered the Bristol-Myers Squibb additional analysis, and noted the utility value estimate of 0.6 for the health state associated with successful transplants to be unreasonable, in view of the utility value of 0.85 for successful dasatinib treatment, and the utility value of 0.68 for failed dasatinib treatment.\n\n\n\nThe committee did not agree with the assumption in the Novartis adjusted analysis that the utility value for people treated with hydroxycarbamide should be lower for the same health states achieved by other treatments.\n\n\n\nThe committee did not identify any potential significant and substantial health-related benefits that had not been included in the economic models.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n-\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee noted that high-dose imatinib was dominated (that is, more expensive and less effective than another treatment) in all models.\n\n\n\nThe committee concluded that the updated economic analysis provided by Bristol-Myers Squibb could not form a suitable basis for a recommendation, and also noted that all other estimated ICERs were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested. Furthermore, the committee noted that, given the patient access scheme for nilotinib and the assumed equivalence of effectiveness of dasatinib and nilotinib, dasatinib is considerably more expensive but no more effective than nilotinib.\n\n\n\nThe committee noted the clinical experts' view that there is no longer considered to be a distinguishable accelerated phase of CML. It saw no reason not to recommend nilotinib for treatment of CML in the accelerated phase. The committee noted that, as for the chronic phase, high-dose imatinib continued to be dominated (that is, it was more expensive and less effective than another treatment), and dasatinib continued to be as effective but more expensive.\n\n\n\nThe committee noted that nilotinib does not have a marketing authorisation for the treatment of blast-crisis phase CML. It considered that the interventions used to treat blast-crisis phase CML are generally used as adjuvant treatment to intensive chemotherapy for acute leukaemia. It was aware that no evidence using the interventions in this way had been submitted. To the extent that dasatinib could be considered a stand-alone treatment, the committee concluded that the evidence was particularly limited.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee did not consider that a conclusive ICER had been presented in any of the economic models.\n\n\n\nThe committee concluded that dasatinib and nilotinib were likely to be at least as cost effective in people with imatinib intolerance as in people with imatinib-resistant CML.\n\n\n\nIt noted that high-dose imatinib was dominated (more expensive and less effective) in all models.\n\n\n\nThe Novartis' adjusted ICER of £22,800 per QALY gained was too optimistic, however, with the patient access scheme in place, the use of nilotinib for the treatment of imatinib-resistant CML could be regarded as a cost-effective.\n\n\n\nGiven the committee's conclusion that updated economic analysis provided by Bristol-Myers Squibb could not form a suitable basis for a recommendation all other estimated ICERs were higher than those normally considered acceptable for the NHS, and were highly likely to be above the figures suggested.\n\n\n\nCommittee noted that treatment for the blast-crisis phase is different from that used in the other phases. To the extent that dasatinib could be considered a stand-alone treatment, the committee concluded that the evidence was particularly limited. The committee considered all 3 estimates of cost effectiveness it saw to be highly speculative with a very poor evidence base supporting the calculations.\n\n\n\n\n\nCancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee noted that the company of nilotinib had agreed a patient access scheme with the Department of Health.\n\n\n\nCancer Drugs Fund reconsideration: the committee noted that the company of dasatinib had agreed a patient access scheme with the Department of Health.\n\n\n\nEnd-of-life considerations\n\nThe committee noted that in the blast-crisis phase of CML, life expectancy is short (about 3–6 months). The committee also agreed that this is a very small population, because fewer than 10% of all people with CML will present at this stage. However, the committee agreed that the available evidence on life extension in the blast-crisis phase was too weak and was not considered to be robust. In addition, no data were presented for the interventions as used in clinical practice. The committee concluded that dasatinib and high-dose imatinib do not fulfil the end-of-life criteria for people with blast-crisis phase CML.\n\n\n\nEqualities considerations and social value judgements\n\nThe committee noted the argument that if dasatinib, high-dose imatinib or nilotinib are not recommended for the treatment of imatinib-resistant CML and that this could raise issues in relation to race, age (the older people), and comorbidities. However, the committee concluded that allowing for clinical decisions relating to a range of possible treatments based on individual assessment of risk and benefit does not limit access to the technology for any specific protected group compared with other people.\n\n"}	https://www.nice.org.uk/guidance/ta425	Evidence-based recommendations on dasatinib (Sprycel), nilotinib (Tasigna) and high-dose imatinib (Glivec) for treating imatinib-resistant or intolerant chronic myeloid leukaemia in adults.
390217f3ae65f0768451c00ff34c7d0f887ea360	nice	Dasatinib, nilotinib and imatinib for untreated chronic myeloid leukaemia	Dasatinib, nilotinib and imatinib for untreated chronic myeloid leukaemia Evidence-based recommendations on dasatinib (Sprycel), nilotinib (Tasigna) and imatinib (Glivec) for untreated chronic myeloid leukaemia in adults. # Recommendations Imatinib is recommended as an option for untreated, chronic-phase Philadelphia-chromosome-positive chronic myeloid leukaemia in adults. Dasatinib and nilotinib are recommended, within their marketing authorisations, as options for untreated chronic-phase Philadelphia-chromosome-positive chronic myeloid leukaemia in adults. The drugs are recommended only if the companies provide them with the discounts agreed in the relevant patient access schemes.# The technologies Description of the technologies Dasatinib (Sprycel, Bristol-Myers Squibb), a tyrosine kinase inhibitor, is an orally active inhibitor of Src and the Src family of tyrosine kinases. These are involved in cell growth, differentiation, migration and survival, and many are involved in oncogenesis, tumour metastasis and angiogenesis. Imatinib (Glivec, Novartis Pharmaceuticals) is an orally active tyrosine kinase inhibitor, designed to competitively inhibit Bcr‑Abl tyrosine kinase activity. By blocking specific signals in cells expressing Bcr‑Abl, imatinib reduces the uncontrolled proliferation of white blood cells that is a characteristic feature of chronic myeloid leukaemia (CML). Nilotinib (Tasigna, Novartis Pharmaceuticals), a tyrosine kinase inhibitor, is an orally active phenylaminopyrimidine derivative of imatinib. Studies suggest that nilotinib inhibits 32 of 33 mutant Bcr‑Abl forms that are resistant to imatinib. Marketing authorisations Dasatinib has a marketing authorisation for the treatment of 'adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase' and adult patients with 'chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate'. Imatinib has a marketing authorisation for the treatment of adult and paediatric patients with 'newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment' and for 'adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis'. Nilotinib has a marketing authorisation for the treatment of adult patients with 'newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase' and adult patients with 'chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib'. Adverse reactions The most common reported side effects with dasatinib are headache, pleural effusion, shortness of breath, cough, diarrhoea, nausea, vomiting, abdominal pain, skin rash, musculoskeletal pain, infections, haemorrhage, superficial oedema, fatigue, fever, neutropenia, thrombocytopenia and anaemia. The summary of product characteristics states: 'Dasatinib should be administered with caution to patients who have or may develop prolongation of the QT interval'. The most common side effects with imatinib are nausea, vomiting, oedema (fluid retention), muscle cramps, skin rash, diarrhoea, abdominal pain, headache and fatigue. The most common side effects with nilotinib are thrombocytopenia, neutropenia, anaemia, headache, nausea, constipation, diarrhoea, rash, pruritus, fatigue and increased blood levels of lipase and bilirubin. Nilotinib prolongs the QT interval and is therefore contraindicated in people with hypokalaemia, hypomagnesaemia or long QT syndrome. For full details of adverse reactions and contraindications, see the summary of product characteristics of the respective technologies. Recommended doses and schedules Dasatinib is administered orally. The recommended starting dosage is 100 mg once daily in the chronic phase and treatment should continue until disease progression or until no longer tolerated by the patient. Dose increase or reduction is recommended based on patient response and tolerability. Imatinib is administered orally. The recommended starting dosage is 400 mg once daily in the chronic phase and treatment should be continued as long as the patient continues to benefit. Nilotinib is administered orally. The recommended starting dosage is 300 mg twice daily for newly diagnosed chronic-phase CML and treatment should be continued as long as the patient continues to benefit. Prices Dasatinib is available at a cost of £2,504.96 for a pack of 30 100-mg tablets (excluding VAT; 'British national formulary' online, accessed October 2016). The cost of dasatinib treatment is £30,477.00 per year, assuming a treatment regimen of 100 mg once daily once daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of dasatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Imatinib was available at a cost of £1,604.00 for a 400-mg 30‑tablet pack (excluding VAT; BNF edition 61) resulting in an annual cost of imatinib treatment of £39,033.00, assuming a treatment regimen of 400 mg twice daily. The cost of imatinib has increased to £1,836.48 for a 400-mg 30‑tablet pack (excluding VAT; BNF online, accessed October 2016). The cost of imatinib treatment is now £44,718.00 per year assuming a treatment regimen of 400 mg twice daily. Costs may vary in different settings because of negotiated procurement discounts. Nilotinib is available at a cost of £2,432.85 for a pack of 112 150-mg tablets (excluding VAT; BNF online, accessed October 2016). The cost of nilotinib treatment is £31,715.00 per year, assuming a treatment regimen of 300 mg twice daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nilotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia. Sections 4.1 to 4.28 reflect the committee's consideration of the evidence submitted in the original appraisal (NICE technology appraisal guidance 251). Sections 4.29 to 4.32 reflect the committee's consideration of the additional evidence submitted for the Cancer Drugs Fund reconsideration. It focused on a cost-minimisation analysis using a revised patient access scheme, which provides a simple discount to the list price of dasatinib. The level of the discount is commercial in confidence. See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of dasatinib, having considered evidence on the nature of chronic myeloid leukaemia (CML) and the value placed on the benefits of dasatinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness (NICE technology appraisal guidance 251) The committee discussed current clinical practice for the treatment of CML. The committee heard from the clinical experts that standard-dose imatinib is the usual first-line treatment for chronic-phase CML, in line with the guidance on first-line imatinib for CML (NICE technology appraisal guidance 70), and that clinical experience of dasatinib and nilotinib for chronic-phase CML is largely restricted to the context of clinical trials. To understand the full CML treatment pathway, the committee discussed the possible treatment pathway for chronic-phase CML that has failed to respond to first-line tyrosine kinase inhibitor treatment. It was noted by the committee that nilotinib, but not dasatinib or high-dose imatinib, was recommended in the guidance on dasatinib, high-dose imatinib and nilotinib when standard-dose imatinib has failed because of resistance or intolerance. However, the clinical experts stated that, for a very small proportion of people whose CML is resistant to standard-dose imatinib or who are intolerant of imatinib, there may be clinical reasons for the use of dasatinib, including comorbidities and disease resistance to nilotinib. The committee also heard from the clinical experts that standard-dose imatinib could be a potential second-line treatment if dasatinib or nilotinib were to replace it as the standard first-line treatment. The committee noted the views of the clinical experts that the use of standard-dose imatinib in the second-line setting would preferably be limited to people who were intolerant to first-line dasatinib or nilotinib, and that standard-dose imatinib would be less likely to be offered to people with resistance to first-line dasatinib or nilotinib because the clinical experts believed it is a less effective agent. The clinical experts also commented that hydroxyurea would not be used as a second-line treatment for CML in place of a tyrosine kinase inhibitor because it does not affect the progression of the disease and is used for palliative purposes or as a short-term measure between lines of treatment. The committee discussed the clinical-effectiveness evidence for dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of CML. It was aware of 2 comparative trials, 1 that compared dasatinib with imatinib (DASISION) and 1 that compared nilotinib with imatinib (ENESTnd). It noted that no trials directly comparing dasatinib and nilotinib were available. The committee considered that both trials were good quality international randomised controlled trials and that the demographic characteristics of the participants and the overall trial designs were sufficiently similar to enable indirect comparison of dasatinib and nilotinib. However, it was also noted that both the clinical trials were of short duration and provided only short-term data on progression-free and overall survival and that surrogate outcome measures were used. The committee also noted that the trial populations may not be completely representative of a UK CML population, because of the lower age at diagnosis compared with the general population. However, the committee was reassured by the views of the clinical experts that the age difference was not a major factor, and it concluded that the populations included in the trials were broadly relevant to UK clinical practice. The committee considered the results of the clinical trials, which showed that statistically significantly more people receiving dasatinib and nilotinib had a complete cytogenetic response and a major molecular response than people receiving standard-dose imatinib at 12‑month follow-up. The committee also noted the views of the clinical and patient experts that nilotinib and dasatinib are more effective drugs with a theoretically superior mechanism of action to standard-dose imatinib, although imatinib remains very effective for most patients. The committee concluded that the available evidence suggests that dasatinib and nilotinib provided superior clinical benefit, as measured by surrogate outcome measures, to standard-dose imatinib in the first-line treatment chronic-phase CML. The committee considered the results of the indirect comparison of dasatinib and nilotinib conducted by the assessment group, which showed no statistically significant differences in rates of complete cytogenetic response and major molecular response by 12 months between the 2 treatments. The committee was also aware of another published study, which conducted a matching-adjusted indirect comparison of dasatinib and nilotinib, and showed statistically significantly higher major molecular response rates and overall survival by 12 months for people taking nilotinib compared with dasatinib. The committee noted the comment from the clinical specialist that this study had been sponsored by Novartis. Overall, the committee concluded that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness. The committee considered the assessment group's analysis of short-term surrogate response markers as predictors of longer-term patient-relevant outcomes. The committee noted that the clinical evidence was taken from a mixture of longer-term randomised and observational studies of imatinib only. However, the committee accepted that the results of the analysis, which showed that people with either a complete cytogenetic response or major molecular response after 12 months experienced better long-term survival, could be potentially applied to people receiving dasatinib or nilotinib. The committee discussed the adverse side effects of tyrosine kinase inhibitors for people with CML. It noted from the clinical trials that all 3 drugs were well tolerated and that stopping rates because of adverse events for people taking dasatinib and nilotinib compared with standard-dose imatinib were similar. However, the committee noted that health-related quality of life was not reported in either trial. The committee also heard from the patient experts that, in their experience, side effects associated with tyrosine kinase inhibitors were considered to be easily manageable over time, were not a major concern for people with CML, and that, although dasatinib and nilotinib were associated with different adverse effects, tolerability was similar between both drugs. The committee also noted that QT interval prolongation was listed in the special warnings and precautions for use in the summary of product characteristics for both dasatinib and nilotinib. However, the committee was reassured by the views of the clinical experts that there was no increased cardiovascular risk at the licensed doses. The committee concluded that all 3 drugs appeared to be well tolerated and represented important treatments for people with CML. # Cost effectiveness (NICE technology appraisal guidance 251) The committee discussed the cost effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of CML. The committee noted that the acquisition costs of dasatinib and nilotinib were in excess of £30,000 per person per year, and that the cost of standard-dose imatinib had recently increased to approximately £20,000 per person per year. It also noted that the Department of Health had approved a patient access scheme for nilotinib, the details of which are commercial in confidence. The patient access scheme discount was reflected in the acquisition cost of nilotinib used in both the assessment group's and Novartis' cost-effectiveness analyses. The committee considered the economic models provided by the companies, Bristol-Myers Squibb and Novartis, and also by the assessment group. It noted key differences in the treatment pathways and approaches to modelling overall survival in the 3 economic models. The committee also considered the comments received from both companies on the assessment group's economic model and the responses provided by the assessment group to these comments. The committee noted that the assessment group's economic model included a range of scenarios because of uncertainty about the impact of dasatinib and nilotinib on long-term survival and about subsequent lines of treatment at the time of modelling. It noted that 4 base-case scenarios were modelled, which varied according to the methodology used to estimate overall survival, subsequent second- and third-line treatment options and whether costs and quality-adjusted life years (QALYs) per person progressing beyond the first- and second-line tyrosine kinase inhibitor should be considered equal across treatment arms. The committee was aware that nilotinib was the only tyrosine kinase inhibitor considered as a possible second-line treatment in the assessment group's original economic analyses (in 2 of the 4 base-case scenarios), and that this reflected the guidance on dasatinib, high-dose imatinib and nilotinib when standard-dose imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241). The committee further noted that the assessment group had conducted extensive deterministic sensitivity analyses to explore uncertainty around key structural assumptions in its model. The committee concluded that, although assumptions in the modelling around survival and subsequent lines of treatment were associated with substantial uncertainty, the assessment group, by considering the impact of alternative assumptions, had made considerable effort to address this. The committee considered the original outputs of the economic model developed by the assessment group as part of its assessment report sent for consultation (before revisions were made following the comments received on the assessment report). The committee acknowledged the wide variation in the cost-effectiveness results across the scenarios presented by the assessment group, which reflected the considerable structural uncertainty in the modelling of first-line tyrosine kinase inhibitors for CML. However, it also noted that in the base-case analysis for all scenarios, dasatinib was either dominated by nilotinib or generated incremental cost-effectiveness ratios (ICER) of more than £300,000 per QALY gained compared with imatinib. The committee noted that in the 2 scenarios that did not consider the use of second-line nilotinib following first-line treatment with dasatinib or standard-dose imatinib, the ICERs for nilotinib compared with standard-dose imatinib were £36,000 per QALY gained (scenario 1) and £26,000 per QALY gained (scenario 2). The committee also noted that in the scenarios that did consider second-line nilotinib following first-line treatment with dasatinib or standard-dose imatinib (that is, scenarios 3 and 4), nilotinib generated fewer QALYs but generated substantial cost savings compared with imatinib followed by second-line nilotinib. The committee concluded that the assessment group's original base-case cost-effectiveness results indicated that dasatinib was not cost effective and that nilotinib was on the border of cost effectiveness (the range usually considered a cost-effective use of NHS resources is between £20,000 and £30,000 per QALY gained) in many of the analyses presented when the patient access scheme was applied. The committee carefully considered the comments received from consultees on the assessment group's economic model and the assessment group's response to these comments. The committee noted the key criticisms from Bristol-Myers Squibb about the different modelling approaches used to estimate survival on first- and second-line treatment, which Bristol-Myers Squibb argued were inconsistent with the underlying disease and resulted in incorrect or unreliable treatment durations being modelled. However, the committee agreed that only short-term data were available for survival on first-line dasatinib and nilotinib and that the assessment group had adequately acknowledged and addressed the advantages and disadvantages of different survival modelling approaches by presenting a range of scenarios rather than a single base-case cost-effectiveness analysis. It noted that, by using a cumulative survival approach in its base-case scenario analyses, the assessment group had used a similar approach to modelling survival as Novartis in its economic model and that the surrogate survival approach used in its sensitivity analyses was similar to the approach used by Bristol-Myers Squibb in its model. The committee also noted that many of the weaknesses associated with these alternative approaches to modelling survival that were highlighted by Bristol-Myers Squibb were clearly acknowledged by the assessment group and were also reflected in both companies' models. It agreed with the assessment group that, although probabilistic sensitivity analysis has an important role in exploring parameter uncertainty in NICE appraisals, its usefulness is limited in situations in which there is substantial structural uncertainty: in this case there is extensive uncertainty around the possible treatment sequences following first-line tyrosine kinase inhibitor treatment failure and modelling of short-term survival data. The committee therefore concluded that the assessment group had adequately addressed this structural uncertainty by presenting a range of deterministic scenario analyses. The committee also considered the comments received from Novartis about the assessment group's economic model. The committee noted that the assessment group had accepted Novartis' comments in relation to the costs of medical management in the chronic phase and had subsequently reduced the cost in its model. The committee noted that when these changes were made, the revised base-case ICERs for the scenarios that compared nilotinib with imatinib followed by no second-line nilotinib were £25,000 (scenario 1) and £20,000 per QALY gained (scenario 2). The committee also noted that, in response to additional comments received from Novartis, the assessment group had also explored the effect of adjustments to the mean dose intensity of imatinib (increased from 100% to 106%) and mean survival after stem cell transplantation (reduced from 17.0 years to 7.5 years). The committee agreed that the adjustment to mean survival after stem cell transplantation, which resulted in ICERs of £17,000 and £18,000 per QALY gained in scenarios 1 and 2, was plausible, but that an increased dose of imatinib taken from a single time point in 1 trial could not be assumed to reflect the evidence as a whole or clinical practice. For all scenarios, dasatinib continued to be dominated by nilotinib or to generate ICERs of over £200,000 per QALY gained compared with imatinib. The committee was satisfied that the assessment group had appropriately addressed comments received from the companies on its economic model and that the ICERs generated from the assessment group's revised analysis provided a suitable basis for recommendation. The committee considered which of the scenarios modelled by the assessment group gave the most realistic estimates of cost effectiveness for dasatinib, nilotinib and standard-dose imatinib. At the time of the first appraisal committee meeting, the committee was aware that there was considerable uncertainty about which treatments would be given to people with chronic-phase CML following first-line treatment – this was driven by uncertainty about the final guidance that would be issued by NICE on the second-line treatment of chronic and accelerated phase CML; that is, in adults whose CML is resistant to standard-dose imatinib or who are intolerant of imatinib (published as NICE technology appraisal guidance 241 by the time of the second appraisal committee meeting). The committee was also aware at the first appraisal committee meeting that a scenario of second-line imatinib following first-line treatment with nilotinib or dasatinib had not been modelled by the assessment group despite clinical specialist opinion that this would be a plausible treatment pathway for people with CML that is intolerant to a first-line second-generation tyrosine kinase inhibitor. The committee also considered the comments received from consultees following consultation on the assessment consultation document that scenarios 1 and 2 of the assessment group's model did not reflect clinical practice and should not be used to inform the recommendations. The committee accepted that hydroxyurea and stem cell transplantation would not be routinely used in the second-line setting in place of a tyrosine kinase inhibitor. The committee therefore considered that scenarios 3 and 4 were initially incomplete (at the time of the first appraisal committee meeting) but that scenarios 1 and 2 of the assessment group's model provided only relatively approximate estimates of the cost effectiveness of first-line treatment with tyrosine kinase inhibitors. The committee therefore considered the further additional analyses carried out by the assessment group after consultation on the appraisal consultation document. It noted that the assessment group had modelled 2 additional scenarios – 1 comprising first-line treatment with nilotinib followed by second-line standard-dose imatinib, and the other comprising first-line treatment with dasatinib followed by second-line standard-dose imatinib. In both scenarios, hydroxyurea and stem cell transplantation were only considered as third-line treatments. The committee agreed that these analyses were an important addition to the assessment group's model because they enabled a comparison in scenarios 3 and 4 of all the relevant first- and second-line treatment sequences. The committee thus considered the ICERs from scenarios 3 and 4 of the assessment group's model, including the results from the further additional analyses presented by the assessment group following the first appraisal committee meeting. The committee noted that the ICER for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib was £11,000 per QALY gained for both scenarios and that this was in the range normally considered a cost-effective use of NHS resources. It also noted that treatment with first-line nilotinib followed by imatinib resulted in more QALYs and lower costs than first-line treatment with dasatinib followed either by imatinib or nilotinib (that is, nilotinib dominated dasatinib). The implications of these results were consistent with those from scenarios 1 and 2. The committee concluded that the results of the assessment group's analyses indicated that nilotinib represented a cost-effective first-line treatment for people with chronic-phase CML, and that dasatinib did not. With regard to imatinib, the committee was aware that the ICERs for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib were sensitive to a number of parameters, including assumptions about the dose intensity of nilotinib and the average time spent on second-line nilotinib or imatinib treatment. The committee noted that changes to these input parameters, notably adjusting the modelled dose intensity of first-line nilotinib to levels recommended in the summary of product characteristics, reversed the relative cost effectiveness of nilotinib and imatinib. In addition, the committee recognised that, although more of the sensitivity analyses produced favourable ICERs for nilotinib when compared with standard-dose imatinib, imatinib has a proven longer-term record of safety and efficacy: there were 7 years of survival data for first-line imatinib from the IRIS trial, with positive results for complete cytogenetic response and disease progression, while there were still only short-term survival data for dasatinib and nilotinib. Finally, the committee considered that it was important to have an alternative tyrosine kinase inhibitor treatment available if it is no more expensive than alternatives. The committee therefore concluded that it would be appropriate to recommend both nilotinib and standard-dose imatinib as options for the first-line treatment of people with chronic-phase CML. In addition it recognised that, given that imatinib and nilotinib have comparable cost effectiveness, should one of the drugs become significantly cheaper, it should be preferred (taking into consideration administration costs, required dose and product price per dose). The committee further concluded that the recommendations for first-line tyrosine kinase inhibitors should be considered for review in 2 years' time when the price of standard-dose imatinib may be affected by the entry of new companies. The committee was aware that the additional analyses produced by the assessment group following the first appraisal committee meeting indicated that the ICERs for first-line nilotinib followed by imatinib compared with first-line nilotinib and no subsequent tyrosine kinase inhibitor were £57,000 and £31,000 per QALY gained using the assessment group's non-simplified method and simplified method, respectively. The committee also noted that the original analyses produced by the assessment group indicated that the ICERs for first-line imatinib followed by nilotinib compared with first-line nilotinib and no subsequent tyrosine kinase inhibitor were £213,000 and £50,000 per QALY gained using the non-simplified method and simplified method, respectively. The committee acknowledged that the analyses produced apparently inconsistent results (with NICE technology appraisal guidance 241) about the cost effectiveness of second-line treatment with a tyrosine kinase inhibitor but accepted that consideration of second-line treatments was outside the remit of this appraisal. It also accepted that the evidence on which to reach a definite conclusion was insufficient and conflicting, that there was considerable uncertainty around these ICERs, and that more data were needed to fully assess the cost effectiveness of first and second-line tyrosine kinase inhibitor treatments. Meanwhile it considered the implication of this appraisal, that both imatinib and nilotinib (with the agreed discount under the patient access scheme) should be available first and second line, to be reasonable. The committee gave further consideration to its conclusion on the cost effectiveness of dasatinib compared with imatinib and nilotinib from the assessment group's model in the light of consultation points raised by Bristol-Myers Squibb. The committee noted that the ICERs for first-line treatment with dasatinib followed either by nilotinib or imatinib compared with first-line treatment with standard-dose imatinib followed by nilotinib exceeded £300,000 per QALY gained. The committee further noted that this result was broadly unaltered by changes to all input parameters in the deterministic sensitivity analyses. As described in section 4.18, it was also aware that first-line treatment with dasatinib followed either by imatinib or nilotinib was dominated by first-line nilotinib followed by imatinib. The committee also noted that the conclusions from these estimates were corroborated by the results generated by the Bristol-Myers Squibb model, when corrected by the assessment group. These corrections (which concerned formulae errors and included the patient access scheme discount for nilotinib) resulted in an ICER of £46,000 per QALY gained for dasatinib compared with imatinib, with nilotinib dominating dasatinib. When the model was further adjusted by the assessment group so that dasatinib was not taken as a second- or third-line treatment after imatinib or nilotinib, the committee noted that the ICER for dasatinib compared with imatinib increased to £96,000 per QALY gained, which it agreed could not be considered cost effective. The committee was aware that, as part of its response to the consultation on the appraisal consultation document, Bristol-Myers Squibb had made some adjustments to its model by incorporating changes that the assessment group had made to its own model following feedback from Novartis (see section 4.14). The committee noted from the information submitted from Bristol-Myers Squibb incorporating identical medical management costs to those used in the assessment group's model, correcting formulae errors, and incorporating an estimate of the discount for nilotinib agreed under the patient access scheme, led to an ICER for dasatinib compared with standard-dose imatinib of £34,400 per QALY gained. The committee heard from the assessment group, however, that the adjustments made by Bristol-Myers Squibb did not include the removal of dasatinib as a second- and third-line treatment option in line with the guidance on dasatinib, high-dose imatinib and nilotinib when imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241). It was also noted that the removal of second- and third-line dasatinib would increase the ICER for dasatinib compared with standard-dose imatinib considerably. Following the second appraisal committee meeting, the committee was made aware of errors in the assessment report in the calculation of some of the relative risks and 95% confidence intervals. So the assessment group sent the committee an erratum to the assessment report, which outlined the incorrect and corrected values. This showed that correcting the errors did not affect the statistical significance of any of the results from the trials. The committee also heard that none of the incorrect values had any impact on the results of the assessment group's cost-effectiveness analyses so the ICERs remained unchanged. Therefore the committee did not alter its view that imatinib and nilotinib, but not dasatinib, could be recommended as cost-effective first-line treatments for adults with chronic-phase CML. The committee considered the comments received from some consultees after consultation on the appraisal consultation document that it was inappropriate to exclude dasatinib as a second or third-line treatment from the modelling. However, the committee agreed that, with the publication of the guidance on dasatinib, high-dose imatinib and nilotinib when imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241), it would not be appropriate to include dasatinib as a second or third-line treatment in the modelling for this appraisal. The committee was aware that NICE technology appraisal guidance 241 considered the use of the tyrosine kinase inhibitors in cases of imatinib resistance or intolerance only but had not considered their use following first-line treatment with nilotinib or dasatinib. The committee considered that this was because standard-dose imatinib was the only recommended first-line tyrosine kinase inhibitor for the treatment of chronic-phase CML at the time of appraisal, and it agreed that the same rationale that underpinned the recommendations in the guidance on dasatinib, high-dose imatinib and nilotinib when imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241) should also apply to the use of dasatinib after first-line treatment with an alternative first-line tyrosine kinase inhibitor. The committee noted that further adjustments to Bristol-Myers Squibb's model by the assessment group, to remove dasatinib as a second- and third-line treatment option in line with NICE technology appraisal guidance 241, resulted in an ICER for first-line dasatinib compared with standard-dose imatinib of at least £75,000 per QALY gained. The committee concluded that Bristol-Myers Squibb's modelling results, when adjusted by the assessment group to reflect second-line treatments approved by NICE, supported the results generated by the assessment group's model. The committee heard from the clinical experts and some consultees that, for a small group of people with specific kinase domain mutations that would make their CML resistant to nilotinib, dasatinib would be offered as second-line treatment. However, the committee considered that, because these mutations would be determined after first-line treatment failure, this would not be relevant to the first-line treatment decision for people presenting with chronic-phase CML. Furthermore, this subgroup of people with specific kinase domain mutations was not distinguished in the evidence base for dasatinib. The committee also heard from consultees after consultation on the appraisal consultation document that there are other important subgroups for whom dasatinib would be used rather than nilotinib, including people with long QT syndrome or diabetes. However, the committee noted that it had not been presented with any evidence to support this and therefore could not make any recommendations for dasatinib in these subgroups. The committee concluded that the ICERs for dasatinib were substantially outside the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained), and that dasatinib could not be recommended as a cost-effective use of NHS resources for the first-line treatment of adults with chronic-phase CML. The committee recognised the innovative nature and substantial change in the treatment of CML that imatinib has provided since it has been introduced and recommended for use by NICE in the guidance on imatinib in CML (NICE technology appraisal guidance 70), and discussed whether dasatinib and nilotinib should be considered innovative treatments. The committee considered that while the introduction of dasatinib and nilotinib was also an important development in terms of pharmacological progress beyond imatinib, the critical innovation was the first-generation tyrosine kinase inhibitor. Furthermore, the committee had not been made aware of any benefits from this progress that were not captured in the QALYs modelled. # Equality issues (NICE technology appraisal guidance 251) The committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. The committee considered that there were no issues directly relating to the equalities legislation. However, the committee noted that in both companies' submissions, stem cell transplantation would be considered for people for whom first- and second-line tyrosine kinase inhibitor treatment fails and, because only a small number of people would be eligible for stem cell transplantation, this could raise potential equity issues in relation to race, age (older people), and people with comorbidities. However, the committee concluded that the recommendations do not differentiate between any groups of people, and therefore there was not considered to be an equalities issue. # Cancer Drugs Fund partial reconsideration of NICE technology appraisal guidance 251 This appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia. The committee considered the company's (Bristol-Myers Squibb) submission for the Cancer Drugs Fund reconsideration that included: a revised patient access scheme that provides a simple discount to the list price of dasatinib longer follow-up data from the DASISION study an updated systematic literature review, the results of which were used to inform a network meta-analysis of dasatinib, nilotinib and imatinib a cost-minimisation analysis of dasatinib compared with nilotinib and imatinib. ## Clinical and cost effectiveness The committee discussed the appropriateness of the company's cost-minimisation analysis for dasatinib compared with nilotinib. The evidence review group (ERG) had highlighted that the use of a cost-minimisation analysis assumes that all health outcomes and treatment costs (other than drug acquisition) are equivalent. The committee recalled its judgement that dasatinib was slightly clinically superior to imatinib (see section 4.6), and that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness (see section 4.7). The committee discussed the new evidence the company submitted as part of the reconsideration. It concluded that there was no new evidence that would change the conclusions it made during the previous technology appraisal. Therefore, the committee considered that, if drug acquisition costs of dasatinib were shown to be less than those of imatinib, it was likely that dasatinib would dominate imatinib (that is, be both more effective and less costly). Furthermore, it is plausible that a cost-minimisation analysis is appropriate because treatment with dasatinib is sufficiently similar to nilotinib. The committee noted that nilotinib is available with a patient access scheme, which provides a simple discount to the list price of nilotinib. The level of the discount is commercial in confidence. The committee discussed the results of the ERG's cost-minimisation analysis, which took into account the list price of imatinib and the patient access schemes of both nilotinib and dasatinib. It concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended for untreated Philadelphia-chromosome-positive CML. ## Pharmaceutical Price Regulation Scheme 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA426 Appraisal title: Dasatinib, nilotinib and imatinib for untreated chronic myeloid leukaemia Section Key conclusion Imatinib is recommended as an option for untreated, chronic-phase Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in adults. Dasatinib and nilotinib are recommended, within their marketing authorisations, as options for untreated chronic-phase Philadelphia-chromosome-positive CML in adults. The drugs are recommended only if the companies provide them with the discounts agreed in the relevant patient access schemes. The committee concluded that the available evidence suggested that dasatinib and nilotinib provided superior clinical benefit as measured by surrogate outcome measures, to standard-dose imatinib in the first-line treatment of people with chronic-phase CML. Overall, the committee concluded that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness. The committee noted that the incremental cost-effectiveness ratio (ICER) for first-line nilotinib was £11,000 per quality-adjusted life year (QALY) gained and concluded that the results of the assessment group's analyses indicated that nilotinib represented a cost-effective first-line treatment for people with chronic-phase CML. The committee noted that changes to some input parameters, notably adjusting the modelled dose intensity of first-line nilotinib to levels recommended in the summary of product characteristics reversed the relative cost effectiveness of nilotinib and imatinib. In addition, the committee noted that imatinib has a proven longer-term record of safety and efficacy: there were 7‑year survival data for first-line standard-dose imatinib from the IRIS trial (versus STI571), with favourable results for complete cytogenetic response and disease progression, while there were still only short-term survival data for dasatinib and nilotinib. The committee considered that it would be important to have an alternative tyrosine kinase inhibitor treatment available if it is no more expensive than alternatives. The committee therefore concluded that it would be appropriate to recommend both nilotinib and standard-dose imatinib as options for the first-line treatment of people with chronic-phase CML. In addition, it recognised that, given that imatinib and nilotinib have comparable cost effectiveness, should one of the drugs become significantly cheaper, it should be preferred (taking into consideration administration costs, required dose and product price per dose). The committee noted that the ICERs for first-line treatment with dasatinib followed either by nilotinib or imatinib compared with first-line treatment with standard-dose imatinib followed by nilotinib exceeded £300,000 per QALY gained. The committee concluded that the ICERs for dasatinib were substantially outside the range normally considered a cost-effective use of NHS resources and that dasatinib could not be recommended as a cost-effective use of NHS resources for the first-line treatment of adults with chronic-phase CML. The committee concluded that the ICERs for dasatinib were substantially outside the range normally considered a cost-effective use of NHS resources and that dasatinib could not be recommended as a cost-effective use of NHS resources for the first-line treatment of adults with chronic-phase CML. Cancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended for untreated Philadelphia-chromosome-positive CML. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard from the clinical experts that standard-dose imatinib is the usual first-line treatment for people presenting with chronic-phase CML, and that clinical experience of dasatinib and nilotinib for chronic-phase CML is largely restricted to the context of clinical trials. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee considered that while the introduction of dasatinib and nilotinib was also an important development in terms of pharmacological progress beyond imatinib, the critical innovation was the first-generation tyrosine kinase inhibitor. Furthermore, the committee had not been made aware of any benefits from this progress that was not captured in the QALYs modelled. What is the position of the treatment in the pathway of care for the condition? The committee heard from the clinical experts that standard-dose imatinib is the usual first-line treatment for chronic-phase CML, in line with the guidance on first-line imatinib for CML (NICE technology appraisal guidance 70), and that clinical experience of dasatinib and nilotinib for chronic-phase CML is largely restricted to the context of clinical trials. Adverse effects The committee noted from the clinical trials that dasatinib, nilotinib and standard-dose imatinib were well tolerated and that stopping rates because of adverse events for people taking dasatinib and nilotinib compared with standard-dose imatinib were similar. The committee heard from patient experts that, in their experience, side effects associated with tyrosine kinase inhibitors were considered to be easily manageable over time. The committee was also aware that QT interval prolongation was listed in the special warnings and precautions for use in the summary of product characteristics for both dasatinib and nilotinib. However, the committee was reassured by the views of the clinical experts that there was no increased cardiovascular risk at the licensed doses. The committee concluded that all 3 drugs appeared to be well tolerated and represented important treatments for people with CML. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee was aware of 2 comparative clinical trials, 1 that compared dasatinib with imatinib and 1 that compared nilotinib with imatinib. It also noted that no trials directly comparing dasatinib and nilotinib were available. The committee considered that both trials were good quality international randomised controlled trials and that the demographic characteristics of the participants and the overall trial designs were sufficiently similar to enable indirect comparison of dasatinib and nilotinib. Relevance to general clinical practice in the NHS The committee noted that the populations in the 2 clinical trials may not be completely representative of a UK CML population, because of the lower age at diagnosis compared with the general population. However, the committee was reassured by the views of the clinical experts that the age difference was not a major factor, and it concluded that the populations included in the trials were broadly relevant to UK clinical practice. Uncertainties generated by the evidence The committee noted that the clinical trials were of short duration and provided only short-term data on progression-free and overall survival and that surrogate outcome measures were used. The committee noted that the clinical evidence used in the assessment group's analysis of short-term surrogate response markers as predictors of longer-term patient-relevant outcomes was taken from a mixture of longer-term randomised and observational studies of imatinib only. However, the committee agreed that the results of the analysis could be potentially applied to people receiving dasatinib or nilotinib. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No clinically relevant subgroups for which there is evidence of differential effectiveness were identified by the committee. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee considered the results of the clinical trials, which showed that statistically significantly more people receiving dasatinib and nilotinib had a complete cytogenetic response and a major molecular response than people receiving imatinib at 12-month follow-up. The committee also noted the views of the clinical and patient experts that nilotinib and dasatinib are more effective drugs with a theoretically superior mechanism of action to standard-dose imatinib, although imatinib remains very effective for the majority of patients. The committee concluded that the available evidence suggests that dasatinib and nilotinib provided superior clinical benefit as measured by surrogate outcome measures than standard-line imatinib in the first-line treatment of people with chronic-phase CML. The committee considered the results of the indirect comparison of dasatinib and nilotinib conducted by the assessment group, which showed no statistically significant differences in rates of complete cytogenetic response and major molecular response by 12 months between the 2 treatments. The committee was also aware of another published study, which conducted a matching-adjusted indirect comparison of dasatinib and nilotinib, and showed statistically significantly higher major molecular response rates and overall survival by 12 months for people taking nilotinib compared with dasatinib. The committee noted the comment from the clinical specialist that this study had been sponsored by Novartis. Overall, the committee concluded that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness. Evidence for cost effectiveness Availability and nature of evidence The committee considered the economic models provided by the companies, Bristol-Myers Squibb and Novartis and also by the assessment group. It noted key differences in the treatment pathways and approaches to modelling overall survival in the 3 models. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee noted that the assessment group's modelling included a range of scenarios because of uncertainty about the impact of dasatinib and nilotinib on long-term survival and about subsequent lines of treatment. It noted that 4 base-case scenarios were modelled, which varied according to the methodology used to estimate overall survival, subsequent second- and third-line treatment options and whether costs and QALYs per person progressing beyond the first- and second-line tyrosine kinase inhibitor should be considered equal across treatment arms. The committee was aware that nilotinib was the only tyrosine kinase inhibitor considered as a possible second-line treatment in the assessment group's model (in 2 of the 4 base-case scenarios), and that this reflected the guidance on dasatinib, high-dose imatinib and nilotinib when standard-dose imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241). The committee further noted that the assessment group had conducted extensive deterministic sensitivity analyses to explore uncertainty around key structural assumptions in its model. The committee concluded that, although assumptions in the modelling around survival and subsequent lines of treatment were associated with substantial uncertainty, the assessment group, by considering the impact of alternative assumptions, had made considerable effort to address this. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? No potential significant and substantial health-related benefits that had not been included in the economic models were identified. Are there specific groups of people for whom the technology is particularly cost effective? No specific groups of people for whom the technologies are particularly cost effective were identified. What are the key drivers of cost effectiveness? The committee noted that the acquisition costs of dasatinib and nilotinib were in excess of £30,000 per person per year, and that the cost of standard-dose imatinib had recently increased to approximately £20,000 per person per year. The committee was aware that the ICERs for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib were sensitive to a number of parameters, including assumptions about the dose intensity of nilotinib and the average time spent on second-line nilotinib or imatinib treatment. The committee noted that the cost effectiveness of dasatinib was unaltered by changes to all input parameters in the deterministic sensitivity analyses. Most likely cost-effectiveness estimate (given as an ICER) The committee acknowledged the wide variation in the cost-effectiveness results across the scenarios presented by the assessment group, which reflected the considerable structural uncertainty in the modelling of first-line tyrosine kinase inhibitors for CML. The committee concluded that the assessment group's original base-case cost-effectiveness results indicated that dasatinib was not cost effective and that nilotinib was on the border of cost effectiveness in many of the analyses presented when the patient access scheme was applied. The committee was satisfied that the assessment group had appropriately addressed comments received from the companies on its economic model and that the ICERs generated from the assessment group's revised analysis provided a suitable basis for recommendation. The committee accepted that hydroxyurea and stem cell transplantation would not be used routinely in the second-line setting in place of a tyrosine kinase inhibitor and that therefore scenarios 1 and 2 of the assessment group's model provided only relatively approximate estimates of the cost effectiveness of first-line treatment with tyrosine kinase inhibitors. The committee noted that the assessment group had modelled 2 additional scenarios – 1 comprising first-line treatment with nilotinib followed by second-line standard-dose imatinib, and the other comprising first-line treatment with dasatinib followed by second-line standard-dose imatinib. The committee agreed that these analyses were an important addition to the assessment group's model because they enabled a comparison in scenarios 3 and 4 of all the relevant first- and second-line treatment sequences. The committee noted that the ICER for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib was £11,000 per QALY gained in scenarios 3 and 4 of the assessment group's model and that this was within the range normally considered a cost-effective use of NHS resources. The committee noted that dasatinib was associated with fewer QALYs and was more costly than nilotinib in all scenarios and that the ICERs for dasatinib compared with standard-dose imatinib exceeded £200,000 per QALY gained. The committee recognised that, although more of the sensitivity analyses in the assessment group's model produced favourable ICERs for nilotinib compared with standard-dose imatinib, imatinib has a proven longer-term record of safety and efficacy: there were 7 years of survival data for first-line imatinib from the IRIS trial, with positive results for complete cytogenetic response and disease progression, while there were still only short-term survival data for dasatinib and nilotinib. The committee acknowledged that the additional analyses by the assessment group produced apparently inconsistent results (with NICE technology appraisal guidance 241) about the cost effectiveness of second-line treatment with a tyrosine kinase inhibitor but accepted that consideration of second-line treatments was outside the remit of this appraisal. Cancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources. Additional factors taken into account Patient access schemes (PPRS) The committee noted that the Department of Health had approved a patient access scheme for nilotinib, which makes it available with a discount applied to all invoices. The size of the discount is commercial in confidence. Cancer Drugs Fund reconsideration: the committee noted that the Department of Health had approved a patient access scheme for dasatinib, which makes it available with a discount on the list price. The size of the discount is commercial in confidence. End-of-life considerations Equalities considerations and social value judgements The committee concluded that the recommendations do not differentiate between any groups of people, and therefore there was not considered to be an equalities issue.	{'Recommendations': 'Imatinib is recommended as an option for untreated, chronic-phase Philadelphia-chromosome-positive chronic myeloid leukaemia in adults.\n\nDasatinib and nilotinib are recommended, within their marketing authorisations, as options for untreated chronic-phase Philadelphia-chromosome-positive chronic myeloid leukaemia in adults. The drugs are recommended only if the companies provide them with the discounts agreed in the relevant patient access schemes.', 'The technologies': "Description of the technologies\n\nDasatinib (Sprycel, Bristol-Myers Squibb), a tyrosine kinase inhibitor, is an orally active inhibitor of Src and the Src family of tyrosine kinases. These are involved in cell growth, differentiation, migration and survival, and many are involved in oncogenesis, tumour metastasis and angiogenesis.\n\nImatinib (Glivec, Novartis Pharmaceuticals) is an orally active tyrosine kinase inhibitor, designed to competitively inhibit Bcr‑Abl tyrosine kinase activity. By blocking specific signals in cells expressing Bcr‑Abl, imatinib reduces the uncontrolled proliferation of white blood cells that is a characteristic feature of chronic myeloid leukaemia (CML).\n\nNilotinib (Tasigna, Novartis Pharmaceuticals), a tyrosine kinase inhibitor, is an orally active phenylaminopyrimidine derivative of imatinib. Studies suggest that nilotinib inhibits 32 of 33 mutant Bcr‑Abl forms that are resistant to imatinib.\n\nMarketing authorisations\n\nDasatinib has a marketing authorisation for the treatment of 'adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase' and adult patients with 'chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate'.\n\nImatinib has a marketing authorisation for the treatment of adult and paediatric patients with 'newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment' and for 'adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis'.\n\nNilotinib has a marketing authorisation for the treatment of adult patients with 'newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase' and adult patients with 'chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib'.\n\nAdverse reactions\n\nThe most common reported side effects with dasatinib are headache, pleural effusion, shortness of breath, cough, diarrhoea, nausea, vomiting, abdominal pain, skin rash, musculoskeletal pain, infections, haemorrhage, superficial oedema, fatigue, fever, neutropenia, thrombocytopenia and anaemia. The summary of product characteristics states: 'Dasatinib should be administered with caution to patients who have or may develop prolongation of the QT interval'.\n\nThe most common side effects with imatinib are nausea, vomiting, oedema (fluid retention), muscle cramps, skin rash, diarrhoea, abdominal pain, headache and fatigue.\n\nThe most common side effects with nilotinib are thrombocytopenia, neutropenia, anaemia, headache, nausea, constipation, diarrhoea, rash, pruritus, fatigue and increased blood levels of lipase and bilirubin. Nilotinib prolongs the QT interval and is therefore contraindicated in people with hypokalaemia, hypomagnesaemia or long QT syndrome.\n\nFor full details of adverse reactions and contraindications, see the summary of product characteristics of the respective technologies.\n\nRecommended doses and schedules\n\nDasatinib is administered orally. The recommended starting dosage is 100\xa0mg once daily in the chronic phase and treatment should continue until disease progression or until no longer tolerated by the patient. Dose increase or reduction is recommended based on patient response and tolerability.\n\nImatinib is administered orally. The recommended starting dosage is 400\xa0mg once daily in the chronic phase and treatment should be continued as long as the patient continues to benefit.\n\nNilotinib is administered orally. The recommended starting dosage is 300\xa0mg twice daily for newly diagnosed chronic-phase CML and treatment should be continued as long as the patient continues to benefit.\n\nPrices\n\nDasatinib is available at a cost of £2,504.96 for a pack of 30 100-mg tablets (excluding VAT; 'British national formulary' [BNF] online, accessed October 2016). The cost of dasatinib treatment is £30,477.00 per year, assuming a treatment regimen of 100\xa0mg once daily once daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of dasatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\nImatinib was available at a cost of £1,604.00 for a 400-mg 30‑tablet pack (excluding VAT; BNF edition 61) resulting in an annual cost of imatinib treatment of £39,033.00, assuming a treatment regimen of 400 mg twice daily. The cost of imatinib has increased to £1,836.48 for a 400-mg 30‑tablet pack (excluding VAT; BNF online, accessed October 2016). The cost of imatinib treatment is now £44,718.00 per year assuming a treatment regimen of 400\xa0mg twice daily. Costs may vary in different settings because of negotiated procurement discounts.\n\nNilotinib is available at a cost of £2,432.85 for a pack of 112 150-mg tablets (excluding VAT; BNF online, accessed October 2016). The cost of nilotinib treatment is £31,715.00 per year, assuming a treatment regimen of 300\xa0mg twice daily. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nilotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia. Sections 4.1 to 4.28 reflect the committee's consideration of the evidence submitted in the original appraisal (NICE technology appraisal guidance 251). Sections 4.29 to\xa04.32 reflect the committee's consideration of the additional evidence submitted for the Cancer Drugs Fund reconsideration. It focused on a cost-minimisation analysis using a revised patient access scheme, which provides a simple discount to the list price of dasatinib. The level of the discount is commercial in confidence.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of dasatinib, having considered evidence on the nature of chronic myeloid leukaemia (CML) and the value placed on the benefits of dasatinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0251)\n\nThe committee discussed current clinical practice for the treatment of CML. The committee heard from the clinical experts that standard-dose imatinib is the usual first-line treatment for chronic-phase CML, in line with the guidance on first-line imatinib for CML (NICE technology appraisal guidance\xa070), and that clinical experience of dasatinib and nilotinib for chronic-phase CML is largely restricted to the context of clinical trials.\n\nTo understand the full CML treatment pathway, the committee discussed the possible treatment pathway for chronic-phase CML that has failed to respond to first-line tyrosine kinase inhibitor treatment. It was noted by the committee that nilotinib, but not dasatinib or high-dose imatinib, was recommended in the guidance on dasatinib, high-dose imatinib and nilotinib when standard-dose imatinib has failed because of resistance or intolerance. However, the clinical experts stated that, for a very small proportion of people whose CML is resistant to standard-dose imatinib or who are intolerant of imatinib, there may be clinical reasons for the use of dasatinib, including comorbidities and disease resistance to nilotinib. The committee also heard from the clinical experts that standard-dose imatinib could be a potential second-line treatment if dasatinib or nilotinib were to replace it as the standard first-line treatment. The committee noted the views of the clinical experts that the use of standard-dose imatinib in the second-line setting would preferably be limited to people who were intolerant to first-line dasatinib or nilotinib, and that standard-dose imatinib would be less likely to be offered to people with resistance to first-line dasatinib or nilotinib because the clinical experts believed it is a less effective agent. The clinical experts also commented that hydroxyurea would not be used as a second-line treatment for CML in place of a tyrosine kinase inhibitor because it does not affect the progression of the disease and is used for palliative purposes or as a short-term measure between lines of treatment.\n\nThe committee discussed the clinical-effectiveness evidence for dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of CML. It was aware of 2\xa0comparative trials, 1\xa0that compared dasatinib with imatinib (DASISION) and 1 that compared nilotinib with imatinib (ENESTnd). It noted that no trials directly comparing dasatinib and nilotinib were available.\n\nThe committee considered that both trials were good quality international randomised controlled trials and that the demographic characteristics of the participants and the overall trial designs were sufficiently similar to enable indirect comparison of dasatinib and nilotinib. However, it was also noted that both the clinical trials were of short duration and provided only short-term data on progression-free and overall survival and that surrogate outcome measures were used. The committee also noted that the trial populations may not be completely representative of a UK CML population, because of the lower age at diagnosis compared with the general population. However, the committee was reassured by the views of the clinical experts that the age difference was not a major factor, and it concluded that the populations included in the trials were broadly relevant to UK clinical practice.\n\nThe committee considered the results of the clinical trials, which showed that statistically significantly more people receiving dasatinib and nilotinib had a complete cytogenetic response and a major molecular response than people receiving standard-dose imatinib at 12‑month follow-up. The committee also noted the views of the clinical and patient experts that nilotinib and dasatinib are more effective drugs with a theoretically superior mechanism of action to standard-dose imatinib, although imatinib remains very effective for most patients. The committee concluded that the available evidence suggests that dasatinib and nilotinib provided superior clinical benefit, as measured by surrogate outcome measures, to standard-dose imatinib in the first-line treatment chronic-phase CML.\n\nThe committee considered the results of the indirect comparison of dasatinib and nilotinib conducted by the assessment group, which showed no statistically significant differences in rates of complete cytogenetic response and major molecular response by 12\xa0months between the 2\xa0treatments. The committee was also aware of another published study, which conducted a matching-adjusted indirect comparison of dasatinib and nilotinib, and showed statistically significantly higher major molecular response rates and overall survival by 12\xa0months for people taking nilotinib compared with dasatinib. The committee noted the comment from the clinical specialist that this study had been sponsored by Novartis. Overall, the committee concluded that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness.\n\nThe committee considered the assessment group's analysis of short-term surrogate response markers as predictors of longer-term patient-relevant outcomes. The committee noted that the clinical evidence was taken from a mixture of longer-term randomised and observational studies of imatinib only. However, the committee accepted that the results of the analysis, which showed that people with either a complete cytogenetic response or major molecular response after 12\xa0months experienced better long-term survival, could be potentially applied to people receiving dasatinib or nilotinib.\n\nThe committee discussed the adverse side effects of tyrosine kinase inhibitors for people with CML. It noted from the clinical trials that all 3\xa0drugs were well tolerated and that stopping rates because of adverse events for people taking dasatinib and nilotinib compared with standard-dose imatinib were similar. However, the committee noted that health-related quality of life was not reported in either trial. The committee also heard from the patient experts that, in their experience, side effects associated with tyrosine kinase inhibitors were considered to be easily manageable over time, were not a major concern for people with CML, and that, although dasatinib and nilotinib were associated with different adverse effects, tolerability was similar between both drugs. The committee also noted that QT interval prolongation was listed in the special warnings and precautions for use in the summary of product characteristics for both dasatinib and nilotinib. However, the committee was reassured by the views of the clinical experts that there was no increased cardiovascular risk at the licensed doses. The committee concluded that all 3\xa0drugs appeared to be well tolerated and represented important treatments for people with CML.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0251)\n\nThe committee discussed the cost effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of CML. The committee noted that the acquisition costs of dasatinib and nilotinib were in excess of £30,000 per person per year, and that the cost of standard-dose imatinib had recently increased to approximately £20,000 per person per year. It also noted that the Department of Health had approved a patient access scheme for nilotinib, the details of which are commercial in confidence. The patient access scheme discount was reflected in the acquisition cost of nilotinib used in both the assessment group's and Novartis' cost-effectiveness analyses.\n\nThe committee considered the economic models provided by the companies, Bristol-Myers Squibb and Novartis, and also by the assessment group. It noted key differences in the treatment pathways and approaches to modelling overall survival in the 3\xa0economic models. The committee also considered the comments received from both companies on the assessment group's economic model and the responses provided by the assessment group to these comments.\n\nThe committee noted that the assessment group's economic model included a range of scenarios because of uncertainty about the impact of dasatinib and nilotinib on long-term survival and about subsequent lines of treatment at the time of modelling. It noted that 4\xa0base-case scenarios were modelled, which varied according to the methodology used to estimate overall survival, subsequent second- and third-line treatment options and whether costs and quality-adjusted life years (QALYs) per person progressing beyond the first- and second-line tyrosine kinase inhibitor should be considered equal across treatment arms. The committee was aware that nilotinib was the only tyrosine kinase inhibitor considered as a possible second-line treatment in the assessment group's original economic analyses (in 2\xa0of the 4\xa0base-case scenarios), and that this reflected the guidance on dasatinib, high-dose imatinib and nilotinib when standard-dose imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241). The committee further noted that the assessment group had conducted extensive deterministic sensitivity analyses to explore uncertainty around key structural assumptions in its model. The committee concluded that, although assumptions in the modelling around survival and subsequent lines of treatment were associated with substantial uncertainty, the assessment group, by considering the impact of alternative assumptions, had made considerable effort to address this.\n\nThe committee considered the original outputs of the economic model developed by the assessment group as part of its assessment report sent for consultation (before revisions were made following the comments received on the assessment report). The committee acknowledged the wide variation in the cost-effectiveness results across the scenarios presented by the assessment group, which reflected the considerable structural uncertainty in the modelling of first-line tyrosine kinase inhibitors for CML. However, it also noted that in the base-case analysis for all scenarios, dasatinib was either dominated by nilotinib or generated incremental cost-effectiveness ratios (ICER) of more than £300,000 per QALY gained compared with imatinib. The committee noted that in the 2\xa0scenarios that did not consider the use of second-line nilotinib following first-line treatment with dasatinib or standard-dose imatinib, the ICERs for nilotinib compared with standard-dose imatinib were £36,000 per QALY gained (scenario\xa01) and £26,000 per QALY gained (scenario\xa02). The committee also noted that in the scenarios that did consider second-line nilotinib following first-line treatment with dasatinib or standard-dose imatinib (that is, scenarios 3 and 4), nilotinib generated fewer QALYs but generated substantial cost savings compared with imatinib followed by second-line nilotinib. The committee concluded that the assessment group's original base-case cost-effectiveness results indicated that dasatinib was not cost effective and that nilotinib was on the border of cost effectiveness (the range usually considered a cost-effective use of NHS resources is between £20,000 and £30,000 per QALY gained) in many of the analyses presented when the patient access scheme was applied.\n\nThe committee carefully considered the comments received from consultees on the assessment group's economic model and the assessment group's response to these comments. The committee noted the key criticisms from Bristol-Myers Squibb about the different modelling approaches used to estimate survival on first- and second-line treatment, which Bristol-Myers Squibb argued were inconsistent with the underlying disease and resulted in incorrect or unreliable treatment durations being modelled. However, the committee agreed that only short-term data were available for survival on first-line dasatinib and nilotinib and that the assessment group had adequately acknowledged and addressed the advantages and disadvantages of different survival modelling approaches by presenting a range of scenarios rather than a single base-case cost-effectiveness analysis. It noted that, by using a cumulative survival approach in its base-case scenario analyses, the assessment group had used a similar approach to modelling survival as Novartis in its economic model and that the surrogate survival approach used in its sensitivity analyses was similar to the approach used by Bristol-Myers Squibb in its model. The committee also noted that many of the weaknesses associated with these alternative approaches to modelling survival that were highlighted by Bristol-Myers Squibb were clearly acknowledged by the assessment group and were also reflected in both companies' models. It agreed with the assessment group that, although probabilistic sensitivity analysis has an important role in exploring parameter uncertainty in NICE appraisals, its usefulness is limited in situations in which there is substantial structural uncertainty: in this case there is extensive uncertainty around the possible treatment sequences following first-line tyrosine kinase inhibitor treatment failure and modelling of short-term survival data. The committee therefore concluded that the assessment group had adequately addressed this structural uncertainty by presenting a range of deterministic scenario analyses.\n\nThe committee also considered the comments received from Novartis about the assessment group's economic model. The committee noted that the assessment group had accepted Novartis' comments in relation to the costs of medical management in the chronic phase and had subsequently reduced the cost in its model. The committee noted that when these changes were made, the revised base-case ICERs for the scenarios that compared nilotinib with imatinib followed by no second-line nilotinib were £25,000 (scenario\xa01) and £20,000 per QALY gained (scenario\xa02). The committee also noted that, in response to additional comments received from Novartis, the assessment group had also explored the effect of adjustments to the mean dose intensity of imatinib (increased from 100% to 106%) and mean survival after stem cell transplantation (reduced from 17.0\xa0years to 7.5\xa0years). The committee agreed that the adjustment to mean survival after stem cell transplantation, which resulted in ICERs of £17,000 and £18,000 per QALY gained in scenarios\xa01 and\xa02, was plausible, but that an increased dose of imatinib taken from a single time point in 1\xa0trial could not be assumed to reflect the evidence as a whole or clinical practice. For all scenarios, dasatinib continued to be dominated by nilotinib or to generate ICERs of over £200,000 per QALY gained compared with imatinib. The committee was satisfied that the assessment group had appropriately addressed comments received from the companies on its economic model and that the ICERs generated from the assessment group's revised analysis provided a suitable basis for recommendation.\n\nThe committee considered which of the scenarios modelled by the assessment group gave the most realistic estimates of cost effectiveness for dasatinib, nilotinib and standard-dose imatinib. At the time of the first appraisal committee meeting, the committee was aware that there was considerable uncertainty about which treatments would be given to people with chronic-phase CML following first-line treatment – this was driven by uncertainty about the final guidance that would be issued by NICE on the second-line treatment of chronic and accelerated phase CML; that is, in adults whose CML is resistant to standard-dose imatinib or who are intolerant of imatinib (published as NICE technology appraisal guidance 241 by the time of the second appraisal committee meeting). The committee was also aware at the first appraisal committee meeting that a scenario of second-line imatinib following first-line treatment with nilotinib or dasatinib had not been modelled by the assessment group despite clinical specialist opinion that this would be a plausible treatment pathway for people with CML that is intolerant to a first-line second-generation tyrosine kinase inhibitor. The committee also considered the comments received from consultees following consultation on the assessment consultation document that scenarios\xa01 and\xa02 of the assessment group's model did not reflect clinical practice and should not be used to inform the recommendations. The committee accepted that hydroxyurea and stem cell transplantation would not be routinely used in the second-line setting in place of a tyrosine kinase inhibitor. The committee therefore considered that scenarios\xa03 and\xa04 were initially incomplete (at the time of the first appraisal committee meeting) but that scenarios\xa01 and\xa02 of the assessment group's model provided only relatively approximate estimates of the cost effectiveness of first-line treatment with tyrosine kinase inhibitors.\n\nThe committee therefore considered the further additional analyses carried out by the assessment group after consultation on the appraisal consultation document. It noted that the assessment group had modelled 2\xa0additional scenarios – 1\xa0comprising first-line treatment with nilotinib followed by second-line standard-dose imatinib, and the other comprising first-line treatment with dasatinib followed by second-line standard-dose imatinib. In both scenarios, hydroxyurea and stem cell transplantation were only considered as third-line treatments. The committee agreed that these analyses were an important addition to the assessment group's model because they enabled a comparison in scenarios\xa03 and\xa04 of all the relevant first- and second-line treatment sequences.\n\nThe committee thus considered the ICERs from scenarios\xa03 and\xa04 of the assessment group's model, including the results from the further additional analyses presented by the assessment group following the first appraisal committee meeting. The committee noted that the ICER for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib was £11,000 per QALY gained for both scenarios and that this was in the range normally considered a cost-effective use of NHS resources. It also noted that treatment with first-line nilotinib followed by imatinib resulted in more QALYs and lower costs than first-line treatment with dasatinib followed either by imatinib or nilotinib (that is, nilotinib dominated dasatinib). The implications of these results were consistent with those from scenarios\xa01 and\xa02. The committee concluded that the results of the assessment group's analyses indicated that nilotinib represented a cost-effective first-line treatment for people with chronic-phase CML, and that dasatinib did not.\n\nWith regard to imatinib, the committee was aware that the ICERs for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib were sensitive to a number of parameters, including assumptions about the dose intensity of nilotinib and the average time spent on second-line nilotinib or imatinib treatment. The committee noted that changes to these input parameters, notably adjusting the modelled dose intensity of first-line nilotinib to levels recommended in the summary of product characteristics, reversed the relative cost effectiveness of nilotinib and imatinib. In addition, the committee recognised that, although more of the sensitivity analyses produced favourable ICERs for nilotinib when compared with standard-dose imatinib, imatinib has a proven longer-term record of safety and efficacy: there were 7\xa0years of survival data for first-line imatinib from the IRIS trial, with positive results for complete cytogenetic response and disease progression, while there were still only short-term survival data for dasatinib and nilotinib. Finally, the committee considered that it was important to have an alternative tyrosine kinase inhibitor treatment available if it is no more expensive than alternatives. The committee therefore concluded that it would be appropriate to recommend both nilotinib and standard-dose imatinib as options for the first-line treatment of people with chronic-phase CML. In addition it recognised that, given that imatinib and nilotinib have comparable cost effectiveness, should one of the drugs become significantly cheaper, it should be preferred (taking into consideration administration costs, required dose and product price per dose).\n\nThe committee further concluded that the recommendations for first-line tyrosine kinase inhibitors should be considered for review in 2\xa0years' time when the price of standard-dose imatinib may be affected by the entry of new companies.\n\nThe committee was aware that the additional analyses produced by the assessment group following the first appraisal committee meeting indicated that the ICERs for first-line nilotinib followed by imatinib compared with first-line nilotinib and no subsequent tyrosine kinase inhibitor were £57,000 and £31,000 per QALY gained using the assessment group's non-simplified method and simplified method, respectively. The committee also noted that the original analyses produced by the assessment group indicated that the ICERs for first-line imatinib followed by nilotinib compared with first-line nilotinib and no subsequent tyrosine kinase inhibitor were £213,000 and £50,000 per QALY gained using the non-simplified method and simplified method, respectively. The committee acknowledged that the analyses produced apparently inconsistent results (with NICE technology appraisal guidance\xa0241) about the cost effectiveness of second-line treatment with a tyrosine kinase inhibitor but accepted that consideration of second-line treatments was outside the remit of this appraisal. It also accepted that the evidence on which to reach a definite conclusion was insufficient and conflicting, that there was considerable uncertainty around these ICERs, and that more data were needed to fully assess the cost effectiveness of first and second-line tyrosine kinase inhibitor treatments. Meanwhile it considered the implication of this appraisal, that both imatinib and nilotinib (with the agreed discount under the patient access scheme) should be available first and second line, to be reasonable.\n\nThe committee gave further consideration to its conclusion on the cost effectiveness of dasatinib compared with imatinib and nilotinib from the assessment group's model in the light of consultation points raised by Bristol-Myers Squibb. The committee noted that the ICERs for first-line treatment with dasatinib followed either by nilotinib or imatinib compared with first-line treatment with standard-dose imatinib followed by nilotinib exceeded £300,000 per QALY gained. The committee further noted that this result was broadly unaltered by changes to all input parameters in the deterministic sensitivity analyses. As described in section\xa04.18, it was also aware that first-line treatment with dasatinib followed either by imatinib or nilotinib was dominated by first-line nilotinib followed by imatinib. The committee also noted that the conclusions from these estimates were corroborated by the results generated by the Bristol-Myers Squibb model, when corrected by the assessment group. These corrections (which concerned formulae errors and included the patient access scheme discount for nilotinib) resulted in an ICER of £46,000 per QALY gained for dasatinib compared with imatinib, with nilotinib dominating dasatinib. When the model was further adjusted by the assessment group so that dasatinib was not taken as a second- or third-line treatment after imatinib or nilotinib, the committee noted that the ICER for dasatinib compared with imatinib increased to £96,000 per QALY gained, which it agreed could not be considered cost effective.\n\nThe committee was aware that, as part of its response to the consultation on the appraisal consultation document, Bristol-Myers Squibb had made some adjustments to its model by incorporating changes that the assessment group had made to its own model following feedback from Novartis (see section\xa04.14). The committee noted from the information submitted from Bristol-Myers Squibb incorporating identical medical management costs to those used in the assessment group's model, correcting formulae errors, and incorporating an estimate of the discount for nilotinib agreed under the patient access scheme, led to an ICER for dasatinib compared with standard-dose imatinib of £34,400 per QALY gained. The committee heard from the assessment group, however, that the adjustments made by Bristol-Myers Squibb did not include the removal of dasatinib as a second- and third-line treatment option in line with the guidance on dasatinib, high-dose imatinib and nilotinib when imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241). It was also noted that the removal of second- and third-line dasatinib would increase the ICER for dasatinib compared with standard-dose imatinib considerably.\n\nFollowing the second appraisal committee meeting, the committee was made aware of errors in the assessment report in the calculation of some of the relative risks and 95% confidence intervals. So the assessment group sent the committee an erratum to the assessment report, which outlined the incorrect and corrected values. This showed that correcting the errors did not affect the statistical significance of any of the results from the trials. The committee also heard that none of the incorrect values had any impact on the results of the assessment group's cost-effectiveness analyses so the ICERs remained unchanged. Therefore the committee did not alter its view that imatinib and nilotinib, but not dasatinib, could be recommended as cost-effective first-line treatments for adults with chronic-phase CML.\n\nThe committee considered the comments received from some consultees after consultation on the appraisal consultation document that it was inappropriate to exclude dasatinib as a second or third-line treatment from the modelling. However, the committee agreed that, with the publication of the guidance on dasatinib, high-dose imatinib and nilotinib when imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241), it would not be appropriate to include dasatinib as a second or third-line treatment in the modelling for this appraisal. The committee was aware that NICE technology appraisal guidance 241 considered the use of the tyrosine kinase inhibitors in cases of imatinib resistance or intolerance only but had not considered their use following first-line treatment with nilotinib or dasatinib. The committee considered that this was because standard-dose imatinib was the only recommended first-line tyrosine kinase inhibitor for the treatment of chronic-phase CML at the time of appraisal, and it agreed that the same rationale that underpinned the recommendations in the guidance on dasatinib, high-dose imatinib and nilotinib when imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241) should also apply to the use of dasatinib after first-line treatment with an alternative first-line tyrosine kinase inhibitor. The committee noted that further adjustments to Bristol-Myers Squibb's model by the assessment group, to remove dasatinib as a second- and third-line treatment option in line with NICE technology appraisal guidance 241, resulted in an ICER for first-line dasatinib compared with standard-dose imatinib of at least £75,000 per QALY gained. The committee concluded that Bristol-Myers Squibb's modelling results, when adjusted by the assessment group to reflect second-line treatments approved by NICE, supported the results generated by the assessment group's model.\n\nThe committee heard from the clinical experts and some consultees that, for a small group of people with specific kinase domain mutations that would make their CML resistant to nilotinib, dasatinib would be offered as second-line treatment. However, the committee considered that, because these mutations would be determined after first-line treatment failure, this would not be relevant to the first-line treatment decision for people presenting with chronic-phase CML. Furthermore, this subgroup of people with specific kinase domain mutations was not distinguished in the evidence base for dasatinib. The committee also heard from consultees after consultation on the appraisal consultation document that there are other important subgroups for whom dasatinib would be used rather than nilotinib, including people with long QT syndrome or diabetes. However, the committee noted that it had not been presented with any evidence to support this and therefore could not make any recommendations for dasatinib in these subgroups. The committee concluded that the ICERs for dasatinib were substantially outside the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained), and that dasatinib could not be recommended as a cost-effective use of NHS resources for the first-line treatment of adults with chronic-phase CML.\n\nThe committee recognised the innovative nature and substantial change in the treatment of CML that imatinib has provided since it has been introduced and recommended for use by NICE in the guidance on imatinib in CML (NICE technology appraisal guidance 70), and discussed whether dasatinib and nilotinib should be considered innovative treatments. The committee considered that while the introduction of dasatinib and nilotinib was also an important development in terms of pharmacological progress beyond imatinib, the critical innovation was the first-generation tyrosine kinase inhibitor. Furthermore, the committee had not been made aware of any benefits from this progress that were not captured in the QALYs modelled.\n\n# Equality issues (NICE technology appraisal guidance\xa0251)\n\nThe committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. The committee considered that there were no issues directly relating to the equalities legislation. However, the committee noted that in both companies' submissions, stem cell transplantation would be considered for people for whom first- and second-line tyrosine kinase inhibitor treatment fails and, because only a small number of people would be eligible for stem cell transplantation, this could raise potential equity issues in relation to race, age (older people), and people with comorbidities. However, the committee concluded that the recommendations do not differentiate between any groups of people, and therefore there was not considered to be an equalities issue.\n\n# Cancer Drugs Fund partial reconsideration of NICE technology appraisal guidance\xa0251\n\nThis appraisal was a Cancer Drugs Fund partial reconsideration of the published NICE technology appraisal guidance on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia. The committee considered the company's (Bristol-Myers Squibb) submission for the Cancer Drugs Fund reconsideration that included:\n\na revised patient access scheme that provides a simple discount to the list price of dasatinib\n\nlonger follow-up data from the DASISION study\n\nan updated systematic literature review, the results of which were used to inform a network meta-analysis of dasatinib, nilotinib and imatinib\n\na cost-minimisation analysis of dasatinib compared with nilotinib and imatinib.\n\n## Clinical and cost effectiveness\n\nThe committee discussed the appropriateness of the company's cost-minimisation analysis for dasatinib compared with nilotinib. The evidence review group (ERG) had highlighted that the use of a cost-minimisation analysis assumes that all health outcomes and treatment costs (other than drug acquisition) are equivalent. The committee recalled its judgement that dasatinib was slightly clinically superior to imatinib (see section\xa04.6), and that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness (see section\xa04.7). The committee discussed the new evidence the company submitted as part of the reconsideration. It concluded that there was no new evidence that would change the conclusions it made during the previous technology appraisal. Therefore, the committee considered that, if drug acquisition costs of dasatinib were shown to be less than those of imatinib, it was likely that dasatinib would dominate imatinib (that is, be both more effective and less costly). Furthermore, it is plausible that a cost-minimisation analysis is appropriate because treatment with dasatinib is sufficiently similar to nilotinib.\n\nThe committee noted that nilotinib is available with a patient access scheme, which provides a simple discount to the list price of nilotinib. The level of the discount is commercial in confidence. The committee discussed the results of the ERG's cost-minimisation analysis, which took into account the list price of imatinib and the patient access schemes of both nilotinib and dasatinib. It concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended for untreated Philadelphia-chromosome-positive CML.\n\n## Pharmaceutical Price Regulation Scheme 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA426\n\nAppraisal title: Dasatinib, nilotinib and imatinib for untreated chronic myeloid leukaemia\n\nSection\n\nKey conclusion\n\nImatinib is recommended as an option for untreated, chronic-phase Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in adults.\n\n\n\nDasatinib and nilotinib are recommended, within their marketing authorisations, as options for untreated chronic-phase Philadelphia-chromosome-positive CML in adults. The drugs are recommended only if the companies provide them with the discounts agreed in the relevant patient access schemes.\n\n\n\nThe committee concluded that the available evidence suggested that dasatinib and nilotinib provided superior clinical benefit as measured by surrogate outcome measures, to standard-dose imatinib in the first-line treatment of people with chronic-phase CML.\n\n\n\nOverall, the committee concluded that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness.\n\n\n\nThe committee noted that the incremental cost-effectiveness ratio (ICER) for first-line nilotinib was £11,000 per quality-adjusted life year (QALY) gained and concluded that the results of the assessment group's analyses indicated that nilotinib represented a cost-effective first-line treatment for people with chronic-phase CML.\n\n\n\nThe committee noted that changes to some input parameters, notably adjusting the modelled dose intensity of first-line nilotinib to levels recommended in the summary of product characteristics reversed the relative cost effectiveness of nilotinib and imatinib. In addition, the committee noted that imatinib has a proven longer-term record of safety and efficacy: there were 7‑year survival data for first-line standard-dose imatinib from the IRIS trial (versus STI571), with favourable results for complete cytogenetic response and disease progression, while there were still only short-term survival data for dasatinib and nilotinib. The committee considered that it would be important to have an alternative tyrosine kinase inhibitor treatment available if it is no more expensive than alternatives. The committee therefore concluded that it would be appropriate to recommend both nilotinib and standard-dose imatinib as options for the first-line treatment of people with chronic-phase CML. In addition, it recognised that, given that imatinib and nilotinib have comparable cost effectiveness, should one of the drugs become significantly cheaper, it should be preferred (taking into consideration administration costs, required dose and product price per dose).\n\n\n\nThe committee noted that the ICERs for first-line treatment with dasatinib followed either by nilotinib or imatinib compared with first-line treatment with standard-dose imatinib followed by nilotinib exceeded £300,000 per QALY gained. The committee concluded that the ICERs for dasatinib were substantially outside the range normally considered a cost-effective use of NHS resources and that dasatinib could not be recommended as a cost-effective use of NHS resources for the first-line treatment of adults with chronic-phase CML.\n\n\n\nThe committee concluded that the ICERs for dasatinib were substantially outside the range normally considered a cost-effective use of NHS resources and that dasatinib could not be recommended as a cost-effective use of NHS resources for the first-line treatment of adults with chronic-phase CML.\n\n\n\nCancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources and so should be recommended for untreated Philadelphia-chromosome-positive CML.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the clinical experts that standard-dose imatinib is the usual first-line treatment for people presenting with chronic-phase CML, and that clinical experience of dasatinib and nilotinib for chronic-phase CML is largely restricted to the context of clinical trials.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee considered that while the introduction of dasatinib and nilotinib was also an important development in terms of pharmacological progress beyond imatinib, the critical innovation was the first-generation tyrosine kinase inhibitor. Furthermore, the committee had not been made aware of any benefits from this progress that was not captured in the QALYs modelled.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard from the clinical experts that standard-dose imatinib is the usual first-line treatment for chronic-phase CML, in line with the guidance on first-line imatinib for CML (NICE technology appraisal guidance 70), and that clinical experience of dasatinib and nilotinib for chronic-phase CML is largely restricted to the context of clinical trials.\n\n\n\nAdverse effects\n\nThe committee noted from the clinical trials that dasatinib, nilotinib and standard-dose imatinib were well tolerated and that stopping rates because of adverse events for people taking dasatinib and nilotinib compared with standard-dose imatinib were similar. The committee heard from patient experts that, in their experience, side effects associated with tyrosine kinase inhibitors were considered to be easily manageable over time.\n\nThe committee was also aware that QT interval prolongation was listed in the special warnings and precautions for use in the summary of product characteristics for both dasatinib and nilotinib. However, the committee was reassured by the views of the clinical experts that there was no increased cardiovascular risk at the licensed doses. The committee concluded that all 3 drugs appeared to be well tolerated and represented important treatments for people with CML.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee was aware of 2 comparative clinical trials, 1 that compared dasatinib with imatinib and 1 that compared nilotinib with imatinib. It also noted that no trials directly comparing dasatinib and nilotinib were available.\n\nThe committee considered that both trials were good quality international randomised controlled trials and that the demographic characteristics of the participants and the overall trial designs were sufficiently similar to enable indirect comparison of dasatinib and nilotinib.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe committee noted that the populations in the 2 clinical trials may not be completely representative of a UK CML population, because of the lower age at diagnosis compared with the general population. However, the committee was reassured by the views of the clinical experts that the age difference was not a major factor, and it concluded that the populations included in the trials were broadly relevant to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that the clinical trials were of short duration and provided only short-term data on progression-free and overall survival and that surrogate outcome measures were used.\n\nThe committee noted that the clinical evidence used in the assessment group's analysis of short-term surrogate response markers as predictors of longer-term patient-relevant outcomes was taken from a mixture of longer-term randomised and observational studies of imatinib only. However, the committee agreed that the results of the analysis could be potentially applied to people receiving dasatinib or nilotinib.\n\n, 4.8\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo clinically relevant subgroups for which there is evidence of differential effectiveness were identified by the committee.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee considered the results of the clinical trials, which showed that statistically significantly more people receiving dasatinib and nilotinib had a complete cytogenetic response and a major molecular response than people receiving imatinib at 12-month follow-up. The committee also noted the views of the clinical and patient experts that nilotinib and dasatinib are more effective drugs with a theoretically superior mechanism of action to standard-dose imatinib, although imatinib remains very effective for the majority of patients. The committee concluded that the available evidence suggests that dasatinib and nilotinib provided superior clinical benefit as measured by surrogate outcome measures than standard-line imatinib in the first-line treatment of people with chronic-phase CML.\n\nThe committee considered the results of the indirect comparison of dasatinib and nilotinib conducted by the assessment group, which showed no statistically significant differences in rates of complete cytogenetic response and major molecular response by 12 months between the 2 treatments. The committee was also aware of another published study, which conducted a matching-adjusted indirect comparison of dasatinib and nilotinib, and showed statistically significantly higher major molecular response rates and overall survival by 12 months for people taking nilotinib compared with dasatinib. The committee noted the comment from the clinical specialist that this study had been sponsored by Novartis. Overall, the committee concluded that there was insufficient evidence to distinguish between dasatinib and nilotinib in terms of clinical effectiveness.\n\n, 4.7\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee considered the economic models provided by the companies, Bristol-Myers Squibb and Novartis and also by the assessment group. It noted key differences in the treatment pathways and approaches to modelling overall survival in the 3 models.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee noted that the assessment group's modelling included a range of scenarios because of uncertainty about the impact of dasatinib and nilotinib on long-term survival and about subsequent lines of treatment. It noted that 4 base-case scenarios were modelled, which varied according to the methodology used to estimate overall survival, subsequent second- and third-line treatment options and whether costs and QALYs per person progressing beyond the first- and second-line tyrosine kinase inhibitor should be considered equal across treatment arms.\n\nThe committee was aware that nilotinib was the only tyrosine kinase inhibitor considered as a possible second-line treatment in the assessment group's model (in 2 of the 4 base-case scenarios), and that this reflected the guidance on dasatinib, high-dose imatinib and nilotinib when standard-dose imatinib has failed because of resistance or intolerance (NICE technology appraisal guidance 241).\n\nThe committee further noted that the assessment group had conducted extensive deterministic sensitivity analyses to explore uncertainty around key structural assumptions in its model. The committee concluded that, although assumptions in the modelling around survival and subsequent lines of treatment were associated with substantial uncertainty, the assessment group, by considering the impact of alternative assumptions, had made considerable effort to address this.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo potential significant and substantial health-related benefits that had not been included in the economic models were identified.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific groups of people for whom the technologies are particularly cost effective were identified.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee noted that the acquisition costs of dasatinib and nilotinib were in excess of £30,000 per person per year, and that the cost of standard-dose imatinib had recently increased to approximately £20,000 per person per year.\n\n\n\nThe committee was aware that the ICERs for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib were sensitive to a number of parameters, including assumptions about the dose intensity of nilotinib and the average time spent on second-line nilotinib or imatinib treatment.\n\n\n\nThe committee noted that the cost effectiveness of dasatinib was unaltered by changes to all input parameters in the deterministic sensitivity analyses.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee acknowledged the wide variation in the cost-effectiveness results across the scenarios presented by the assessment group, which reflected the considerable structural uncertainty in the modelling of first-line tyrosine kinase inhibitors for CML.\n\nThe committee concluded that the assessment group's original base-case cost-effectiveness results indicated that dasatinib was not cost effective and that nilotinib was on the border of cost effectiveness in many of the analyses presented when the patient access scheme was applied.\n\n\n\nThe committee was satisfied that the assessment group had appropriately addressed comments received from the companies on its economic model and that the ICERs generated from the assessment group's revised analysis provided a suitable basis for recommendation.\n\n\n\nThe committee accepted that hydroxyurea and stem cell transplantation would not be used routinely in the second-line setting in place of a tyrosine kinase inhibitor and that therefore scenarios 1 and 2 of the assessment group's model provided only relatively approximate estimates of the cost effectiveness of first-line treatment with tyrosine kinase inhibitors.\n\n\n\nThe committee noted that the assessment group had modelled 2 additional scenarios – 1 comprising first-line treatment with nilotinib followed by second-line standard-dose imatinib, and the other comprising first-line treatment with dasatinib followed by second-line standard-dose imatinib. The committee agreed that these analyses were an important addition to the assessment group's model because they enabled a comparison in scenarios 3 and 4 of all the relevant first- and second-line treatment sequences.\n\n\n\nThe committee noted that the ICER for first-line nilotinib followed by imatinib compared with first-line imatinib followed by nilotinib was £11,000 per QALY gained in scenarios 3 and 4 of the assessment group's model and that this was within the range normally considered a cost-effective use of NHS resources.\n\n\n\nThe committee noted that dasatinib was associated with fewer QALYs and was more costly than nilotinib in all scenarios and that the ICERs for dasatinib compared with standard-dose imatinib exceeded £200,000 per QALY gained.\n\n, 4.18, 4.22\n\nThe committee recognised that, although more of the sensitivity analyses in the assessment group's model produced favourable ICERs for nilotinib compared with standard-dose imatinib, imatinib has a proven longer-term record of safety and efficacy: there were 7 years of survival data for first-line imatinib from the IRIS trial, with positive results for complete cytogenetic response and disease progression, while there were still only short-term survival data for dasatinib and nilotinib.\n\n\n\nThe committee acknowledged that the additional analyses by the assessment group produced apparently inconsistent results (with NICE technology appraisal guidance 241) about the cost effectiveness of second-line treatment with a tyrosine kinase inhibitor but accepted that consideration of second-line treatments was outside the remit of this appraisal.\n\n\n\nCancer Drugs Fund reconsideration: the committee concluded that, with the revised patient access scheme, it was likely that dasatinib was a cost-effective use of NHS resources.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee noted that the Department of Health had approved a patient access scheme for nilotinib, which makes it available with a discount applied to all invoices. The size of the discount is commercial in confidence.\n\n\n\nCancer Drugs Fund reconsideration: the committee noted that the Department of Health had approved a patient access scheme for dasatinib, which makes it available with a discount on the list price. The size of the discount is commercial in confidence.\n\n\n\nEnd-of-life considerations\n\n–\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee concluded that the recommendations do not differentiate between any groups of people, and therefore there was not considered to be an equalities issue.\n\n"}	https://www.nice.org.uk/guidance/ta426	Evidence-based recommendations on dasatinib (Sprycel), nilotinib (Tasigna) and imatinib (Glivec) for untreated chronic myeloid leukaemia in adults.
f3981990971936359a544aa0fb1304effd22b03f	nice	Organ donation for transplantation: improving donor identification and consent rates for deceased organ donation	Organ donation for transplantation: improving donor identification and consent rates for deceased organ donation This guideline covers identifying people who wish to donate their organs after their death. It offers advice on how to approach families and carers of people who are nearing the end of life and how to seek consent for organ donation. It aims to promote discussion of organ donation as part of end-of-life care and to increase the number of organs available for people waiting for a transplant. # Introduction A significant proportion of people in England and Wales would wish to donate their organs after death for the purpose of transplantation. This guideline recognises the complexities that arise owing to the majority of potential organ donors lacking the capacity to be directly involved in decision making at the time of their death. This guideline seeks to promote the identification and fulfilment of these wishes through: more effective and expedient identification and referral of potential organ donors a more informed, considered and timely approach to consent for donation that is based primarily on identifying the wishes of the individual whenever known and however recorded. The General Medical Council guidance on treatment and care towards the end of life: good practice in decision making requires that consultant staff who have clinical responsibility for patients who are potential donors exercise a duty to consider organ donation as part of end-of-life care. Although donation occurs after death, there are steps that healthcare professionals may need to take before the death of the patient if donation is to take place. This guidance covers such steps, and in the case of clinical triggers for referral, refers to actions that might take place even before the inevitability of death has been recognised. These actions may result in challenges and tensions for the healthcare teams but they can and indeed should be incorporated into local hospital policies in order to better promote donation as part of end-of-life care. Organ donation for transplantation is a complex area and one to which conventional clinical research methods cannot be easily applied. Consequently, much of the evidence included in this guideline is of a qualitative nature and does not lend itself to conventional use of GRADE assessment. A modified version of the GRADE assessment tool has been used to assess study limitations, indirectness and inconsistency. Recognising the ethical and legal context in this area, legal advice was sought and incorporated during the development of the guideline.# Person-centred care This guideline offers best practice advice on improving donor identification and consent rates. Treatment and care should take into account people's needs and preferences. Where the person at the end of their life has the capacity to make decisions, they should have the opportunity to make informed decisions about their care, in partnership with their healthcare professionals. In many cases parents, families and guardians are an important part of the consent process and, unless the person has expressed otherwise, should be involved in decisions about consent. If potential donors do not have the capacity to make decisions, healthcare professionals should follow the Department of Health's advice on consent and the code of practice that accompanies the Mental Capacity Act. In Wales, healthcare professionals should follow advice on consent from the Welsh government. If the potential donor is under 16, healthcare professionals should follow the Department of Health's Seeking consent: working with children guide. The Human Tissue Authority has produced codes of practice for consent and for donation of solid organs for transplantation, and the NHS has produced a code of practice on confidentiality. NHS blood and transplant has produced policies on care of the donor family, and standards of practice for donor transplant coordinators. Good communication between healthcare professionals and people is essential. It should be supported by evidence-based written information tailored to the person's needs. The information people are given about their care should be culturally appropriate. It should also be accessible to people with additional needs such as physical, sensory or learning disabilities, and to people who do not speak or read English. Parents, families and guardians should also be given the information and support they need.# Recommendations # Identifying patients who are potential donors Organ donation should be considered as a usual part of end-of-life care planning. Identify all patients who are potentially suitable donors as early as possible, through a systematic approach. While recognising that clinical situations vary identification should be based on either of the following criteria: defined clinical trigger factors in patients who have had a catastrophic brain injury, namely: the absence of one or more cranial nerve reflexes and a Glasgow Coma Scale (GCS) score of 4 or less that is not explained by sedationunless there is a clear reason why the above clinical triggers are not met (for example because of sedation) and/or a decision has been made to perform brainstem death tests, whichever is the earlier (it is recognised that a proportion of the patients who are identified by these clinical triggers will survive; see also the Royal College of Paediatrics and Child Health guideline on the diagnosis of death by neurological criteria (DNC) in infants less than two months old, published in 2015). the intention to withdraw life-sustaining treatment in patients with a life-threatening or life-limiting condition which will, or is expected to, result in circulatory death. The healthcare team caring for the patient should initiate discussions about potential organ donation with the specialist nurse for organ donation at the time the criteria in recommendation 1.1.2 are met. # Patients who have capacity In circumstances where a patient has the capacity to make their own decisions, obtain their views on, and consent to, organ donation.If the potential donor is under 16, healthcare professionals should follow the Department of Health's guide on Seeking consent: working with children. # Assessing best interests If a patient lacks capacity to make decisions about their end-of life-care, seek to establish whether taking steps, before death, to facilitate organ donation would be in the best interests of the patient. While assessing the patient's best interests clinically stabilise the patient in an appropriate critical care setting while the assessment for donation is performed – for example, an adult intensive care unit or in discussion with a regional paediatric intensive care unit (see recommendation 1.1.8). Provided that delay is in the patient's overall best interests, life-sustaining treatments should not be withdrawn or limited until the patient's wishes around organ donation have been explored and the clinical potential for the patient to donate has been assessed in accordance with legal and professional guidance.See the government's guidance on legal issues relevant to non-heartbeating organ donation, the Donation after Circulatory Death steering group's 2010 Consensus Meeting Report and the General Medical Council guidance on treatment and care towards the end of life: good practice in decision making. In assessing a patient's best interests, consider: the patient's known wishes and feelings, in particular any advance statement or registration on the NHS organ donor register but also any views expressed by the patient to those close to the patient the beliefs or values that would be likely to influence the patient's decision if they had the capacity to make it any other factors they would be likely to consider if they were able to do so the views of the patient's family, friends and anyone involved in their care as appropriate as to what would be in the patient's best interests; and anyone named by the patient to be consulted about such decisions.Visit the NHS organ donation website for further information. # Seeking consent to organ donation If a patient lacks the capacity to consent to organ donation seek to establish the patient's prior consent by: referring to an advance statement if available establishing whether the patient has registered and recorded their consent to donate on the NHS organ donor register and exploring with those close to the patient whether the patient had expressed any views about organ donation.See the General Medical Council guidance on treatment and care towards the end of life: good practice in decision making, and the NHS organ donation website for more information about consent. If the patient's prior consent has not already been ascertained, and in the absence of a person or persons having been appointed as nominated representative(s), consent for organ donation should be sought from those in a qualifying relationship with the patient. Where a nominated representative has been appointed and the person had not already made a decision about donation prior to their death, then consent should be sought after death from the said nominated representative(s). # Approach to those close to the patient ## The multidisciplinary team A multidisciplinary team (MDT) should be responsible for planning the approach and discussing organ donation with those close to the patient. The MDT should include: the medical and nursing staff involved in the care of the patient, led throughout the process by an identifiable consultant the specialist nurse for organ donation local faith representative(s) where relevant. Whenever possible, continuity of care should be provided by team members who have been directly involved in caring for the patient. The MDT involved in the initial approach should have the necessary skills and knowledge to provide to those close to the patient appropriate support and accurate information about organ donation (see recommendations 1.1.30 and 1.1.31 in the section on organisation of the identification, referral and consent processes). # Discussions in all cases Before approaching those close to the patient: identify a patient's potential for donation in consultation with the specialist nurse for organ donation check the NHS organ donor register and any advance statements or Lasting Power of Attorney for health and welfare clarify coronial, legal and safeguarding issues. Before approaching those close to the patient, try to seek information on all of the following: knowledge of the clinical history of the patient who is a potential donor identification of key family members assessment of whether family support is required – for example faith representative, family liaison officer, bereavement service, trained interpreter, advocate identification of other key family issues identification of cultural and religious issues that may have an impact on consent. Approach those close to the patient in a setting suitable for private and compassionate discussion. Every approach to those close to the patient should be planned with the MDT and at a time that suits the family's circumstances. In all cases those close to the patient should be approached in a professional, compassionate and caring manner and given sufficient time to consider the information. Discussions about organ donation with those close to the patient should only take place when it has been clearly established that they understand that death is inevitable or has occurred. When approaching those close to the patient: discuss with them that donation is a usual part of the end-of-life care use open-ended questions – for example 'how do you think your relative would feel about organ donation?' use positive ways to describe organ donation, especially when patients are on the NHS organ donor register or they have expressed a wish to donate during their lifetime – for example 'by becoming a donor your relative has a chance to save and transform the lives of many others' avoid the use of apologetic or negative language (for example 'I am asking you because it is policy' or 'I am sorry to have to ask you'). The healthcare team providing care for the patient should provide those close to the patient who is a potential donor with the following, as appropriate: assurance that the primary focus is on the care and dignity of the patient (whether the donation occurs or not) explicit confirmation and reassurance that the standard of care received will be the same whether they consider giving consent for organ donation or not the rationale behind the decision to withdraw or withhold life-sustaining treatment and how the timing will be coordinated to support organ donation a clear explanation of, and information on: the process of organ donation and retrieval, including post-retrieval arrangements what interventions may be required between consent and organ retrieval where and when organ retrieval is likely to occur how current legislation (for example, the Mental Capacity Act 2005 and the Human Tissue Act 2004) applies to their situation, including the status of being on the NHS organ donor register or any advance statement how the requirements for coronial referral apply to their situation consent documentation reasons why organ donation may not take place, even if consent is granted. Allow sufficient time for those close to the patient to understand the inevitability of the death or anticipated death and to spend time with the patient. Discuss withdrawal of life-sustaining treatment or neurological death before, and at a different time from, discussing organ donation unless those close to the patient initiate these discussions in the same conversation. For discussions where circulatory death is anticipated, provide a clear explanation on: what end-of-life care involves and where it will take place – for example, theatre, critical care department how death is confirmed and what happens next what happens if death does not occur within a defined time period. For discussions where neurological death is anticipated, provide a clear explanation on: how death is diagnosed using neurological criteria how this is confirmed and what happens next. # Organisation of the identification, referral and consent processes Each hospital should have a policy and protocol that is consistent with these recommendations for identifying patients who are potential donors and managing the consent process. Each hospital should identify a clinical team to ensure the development, implementation and regular review of their policies. Adult and paediatric intensive care units should have a named lead consultant with responsibility for organ donation. The MDT involved in the identification, referral to a specialist nurse for organ donation, and consent should have the specialist skills and competencies necessary to deliver the recommended process for organ donation outlined in this guideline. The skills and competencies required of the individual members of the team will depend on their role in the process. However, all healthcare professionals involved in identification, referral to a specialist nurse for organ donation, and consent processes should: have knowledge of the basic principles and the relative benefits of, donation after circulatory death (DCD) versus donation after brainstem death (DBD) understand the principles of the diagnosis of death using neurological or cardiorespiratory criteria and how this relates to the organ donation process be able to explain neurological death clearly to families understand the use of clinical triggers to identify patients who may be potential organ donors understand the processes, policies and protocols relating to donor management adhere to relevant professional standards of practice regarding organ donation and end-of-life care. Consultant staff should have specific knowledge and skills in: the law surrounding organ donation medical ethics as applied to organ donation the diagnosis and confirmation of death using neurological or cardiorespiratory criteria the greater potential for transplantation of organs retrieved from DBD donors compared with organs from DCD donors legally and ethically appropriate clinical techniques to secure physiological optimisation in patients who are potential organ donors communication skills and knowledge necessary to improve consent ratios for organ donation.# Recommendations for research We have made the following recommendations for research, based on our review of evidence, to improve NICE guidance and patient care in the future. # Reasons for refusal for consent Why do families refuse to give permission for organ donation? ## Why this is important High-quality research using mixed methodology is needed to identify the reasons behind family refusal to see if there are factors that are changeable (for example, poor understanding of the process, medical mistrust, 'knee-jerk' response that is later regretted). The study could be, for example, a multi-centre observational study where all family members (those that did and those that did not give permission for their deceased loved one's organ donation) are followed up 6 months later. Such research could determine whether those participants who gave permission for donation have higher perceived benefits scores, lower prolonged grief scores and higher quality-of-life scores than those who did not. # Improving rates of identification and referral of potential donors What are the key components of an intervention to improve identification and referral rates? ## Why this is important Currently, the evidence for improving identification and referral rates consists mainly of observational reports of complex interventions, with most studies being of limited follow-up. Further research is needed to identify the components, or combinations of components, of the interventions that are effective in increasing identification and referral rates. These studies should have an appropriate length of follow-up to ensure a sustained impact in the longer term. # Improving consent rates What are the key components of an intervention to improve consent rates? ## Why this is important Currently, the evidence for improving consent rates consists mainly of observational reports of complex interventions, with most studies being of limited follow-up. Further research is needed to identify the components, or combinations of components, of the identified interventions that are effective in increasing consent rates. These studies should have an appropriate length of follow-up to ensure a sustained impact in the longer term. # The experience of consenting for organ donation Does a positive experience of approach and process of consent for families increase consent rates? ## Why this is important It is generally accepted that if families have a more positive experience of the approach and process of consenting, then rates of consent will increase. However, no high-quality evidence was identified to support this perception. Further research is needed to confirm this assumption and, if true, to identify those components of the approach and process that are key to improving the experience, and hence the consent rate.	{'Introduction': 'A significant proportion of people in England and Wales would wish to donate their organs after death for the purpose of transplantation. This guideline recognises the complexities that arise owing to the majority of potential organ donors lacking the capacity to be directly involved in decision making at the time of their death. This guideline seeks to promote the identification and fulfilment of these wishes through:\n\nmore effective and expedient identification and referral of potential organ donors\n\na more informed, considered and timely approach to consent for donation that is based primarily on identifying the wishes of the individual whenever known and however recorded.\n\nThe General Medical Council guidance on treatment and care towards the end of life: good practice in decision making requires that consultant staff who have clinical responsibility for patients who are potential donors exercise a duty to consider organ donation as part of end-of-life care.\n\nAlthough donation occurs after death, there are steps that healthcare professionals may need to take before the death of the patient if donation is to take place. This guidance covers such steps, and in the case of clinical triggers for referral, refers to actions that might take place even before the inevitability of death has been recognised. These actions may result in challenges and tensions for the healthcare teams but they can and indeed should be incorporated into local hospital policies in order to better promote donation as part of end-of-life care.\n\nOrgan donation for transplantation is a complex area and one to which conventional clinical research methods cannot be easily applied. Consequently, much of the evidence included in this guideline is of a qualitative nature and does not lend itself to conventional use of GRADE assessment. A modified version of the GRADE assessment tool has been used to assess study limitations, indirectness and inconsistency.\n\nRecognising the ethical and legal context in this area, legal advice was sought and incorporated during the development of the guideline.', 'Person-centred care': "This guideline offers best practice advice on improving donor identification and consent rates.\n\nTreatment and care should take into account people's needs and preferences. Where the person at the end of their life has the capacity to make decisions, they should have the opportunity to make informed decisions about their care, in partnership with their healthcare professionals. In many cases parents, families and guardians are an important part of the consent process and, unless the person has expressed otherwise, should be involved in decisions about consent. If potential donors do not have the capacity to make decisions, healthcare professionals should follow the Department of Health's advice on consent and the code of practice that accompanies the Mental Capacity Act. In Wales, healthcare professionals should follow advice on consent from the Welsh government.\n\nIf the potential donor is under 16, healthcare professionals should follow the Department of Health's Seeking consent: working with children guide.\n\nThe Human Tissue Authority has produced codes of practice for consent and for donation of solid organs for transplantation, and the NHS has produced a code of practice on confidentiality. NHS blood and transplant has produced policies on care of the donor family, and standards of practice for donor transplant coordinators.\n\nGood communication between healthcare professionals and people is essential. It should be supported by evidence-based written information tailored to the person's needs. The information people are given about their care should be culturally appropriate. It should also be accessible to people with additional needs such as physical, sensory or learning disabilities, and to people who do not speak or read English.\n\nParents, families and guardians should also be given the information and support they need.", 'Recommendations': "# Identifying patients who are potential donors\n\nOrgan donation should be considered as a usual part of end-of-life care planning.\n\nIdentify all patients who are potentially suitable donors as early as possible, through a systematic approach. While recognising that clinical situations vary identification should be based on either of the following criteria:\n\ndefined clinical trigger factors in patients who have had a catastrophic brain injury, namely:\n\n\n\nthe absence of one or more cranial nerve reflexes and\n\na Glasgow Coma Scale (GCS) score of 4 or less that is not explained by sedationunless there is a clear reason why the above clinical triggers are not met (for example because of sedation) and/or a decision has been made to perform brainstem death tests, whichever is the earlier (it is recognised that a proportion of the patients who are identified by these clinical triggers will survive; see also the Royal College of Paediatrics and Child Health guideline on the diagnosis of death by neurological criteria (DNC) in infants less than two months old, published in 2015).\n\n\n\nthe intention to withdraw life-sustaining treatment in patients with a life-threatening or life-limiting condition which will, or is expected to, result in circulatory death.\n\nThe healthcare team caring for the patient should initiate discussions about potential organ donation with the specialist nurse for organ donation at the time the criteria in recommendation 1.1.2 are met.\n\n# Patients who have capacity\n\nIn circumstances where a patient has the capacity to make their own decisions, obtain their views on, and consent to, organ donation.If the potential donor is under 16, healthcare professionals should follow the Department of Health's guide on Seeking consent: working with children.\n\n# Assessing best interests\n\nIf a patient lacks capacity to make decisions about their end-of life-care, seek to establish whether taking steps, before death, to facilitate organ donation would be in the best interests of the patient.\n\nWhile assessing the patient's best interests clinically stabilise the patient in an appropriate critical care setting while the assessment for donation is performed – for example, an adult intensive care unit or in discussion with a regional paediatric intensive care unit (see recommendation 1.1.8).\n\nProvided that delay is in the patient's overall best interests, life-sustaining treatments should not be withdrawn or limited until the patient's wishes around organ donation have been explored and the clinical potential for the patient to donate has been assessed in accordance with legal and professional guidance.See the government's guidance on legal issues relevant to non-heartbeating organ donation, the Donation after Circulatory Death steering group's 2010 Consensus Meeting Report and the General Medical Council guidance on treatment and care towards the end of life: good practice in decision making.\n\nIn assessing a patient's best interests, consider:\n\nthe patient's known wishes and feelings, in particular any advance statement or registration on the NHS organ donor register but also any views expressed by the patient to those close to the patient\n\nthe beliefs or values that would be likely to influence the patient's decision if they had the capacity to make it\n\nany other factors they would be likely to consider if they were able to do so\n\nthe views of the patient's family, friends and anyone involved in their care as appropriate as to what would be in the patient's best interests; and\n\nanyone named by the patient to be consulted about such decisions.Visit the NHS organ donation website for further information.\n\n# Seeking consent to organ donation\n\nIf a patient lacks the capacity to consent to organ donation seek to establish the patient's prior consent by:\n\nreferring to an advance statement if available\n\nestablishing whether the patient has registered and recorded their consent to donate on the NHS organ donor register and\n\nexploring with those close to the patient whether the patient had expressed any views about organ donation.See the General Medical Council guidance on treatment and care towards the end of life: good practice in decision making, and the NHS organ donation website for more information about consent.\n\nIf the patient's prior consent has not already been ascertained, and in the absence of a person or persons having been appointed as nominated representative(s), consent for organ donation should be sought from those in a qualifying relationship with the patient. Where a nominated representative has been appointed and the person had not already made a decision about donation prior to their death, then consent should be sought after death from the said nominated representative(s).\n\n# Approach to those close to the patient\n\n## The multidisciplinary team\n\nA multidisciplinary team (MDT) should be responsible for planning the approach and discussing organ donation with those close to the patient.\n\nThe MDT should include:\n\nthe medical and nursing staff involved in the care of the patient, led throughout the process by an identifiable consultant\n\nthe specialist nurse for organ donation\n\nlocal faith representative(s) where relevant.\n\nWhenever possible, continuity of care should be provided by team members who have been directly involved in caring for the patient.\n\nThe MDT involved in the initial approach should have the necessary skills and knowledge to provide to those close to the patient appropriate support and accurate information about organ donation (see recommendations 1.1.30 and 1.1.31 in the section on organisation of the identification, referral and consent processes).\n\n# Discussions in all cases\n\nBefore approaching those close to the patient:\n\nidentify a patient's potential for donation in consultation with the specialist nurse for organ donation\n\ncheck the NHS organ donor register and any advance statements or Lasting Power of Attorney for health and welfare\n\nclarify coronial, legal and safeguarding issues.\n\nBefore approaching those close to the patient, try to seek information on all of the following:\n\nknowledge of the clinical history of the patient who is a potential donor\n\nidentification of key family members\n\nassessment of whether family support is required – for example faith representative, family liaison officer, bereavement service, trained interpreter, advocate\n\nidentification of other key family issues\n\nidentification of cultural and religious issues that may have an impact on consent.\n\nApproach those close to the patient in a setting suitable for private and compassionate discussion.\n\nEvery approach to those close to the patient should be planned with the MDT and at a time that suits the family's circumstances.\n\nIn all cases those close to the patient should be approached in a professional, compassionate and caring manner and given sufficient time to consider the information.\n\nDiscussions about organ donation with those close to the patient should only take place when it has been clearly established that they understand that death is inevitable or has occurred.\n\nWhen approaching those close to the patient:\n\ndiscuss with them that donation is a usual part of the end-of-life care\n\nuse open-ended questions – for example 'how do you think your relative would feel about organ donation?'\n\nuse positive ways to describe organ donation, especially when patients are on the NHS organ donor register or they have expressed a wish to donate during their lifetime – for example 'by becoming a donor your relative has a chance to save and transform the lives of many others'\n\navoid the use of apologetic or negative language (for example 'I am asking you because it is policy' or 'I am sorry to have to ask you').\n\nThe healthcare team providing care for the patient should provide those close to the patient who is a potential donor with the following, as appropriate:\n\nassurance that the primary focus is on the care and dignity of the patient (whether the donation occurs or not)\n\nexplicit confirmation and reassurance that the standard of care received will be the same whether they consider giving consent for organ donation or not\n\nthe rationale behind the decision to withdraw or withhold life-sustaining treatment and how the timing will be coordinated to support organ donation\n\na clear explanation of, and information on:\n\n\n\nthe process of organ donation and retrieval, including post-retrieval arrangements\n\nwhat interventions may be required between consent and organ retrieval\n\nwhere and when organ retrieval is likely to occur\n\nhow current legislation (for example, the Mental Capacity Act 2005 and the Human Tissue Act 2004) applies to their situation, including the status of being on the NHS organ donor register or any advance statement\n\nhow the requirements for coronial referral apply to their situation\n\n\n\nconsent documentation\n\nreasons why organ donation may not take place, even if consent is granted.\n\nAllow sufficient time for those close to the patient to understand the inevitability of the death or anticipated death and to spend time with the patient.\n\nDiscuss withdrawal of life-sustaining treatment or neurological death before, and at a different time from, discussing organ donation unless those close to the patient initiate these discussions in the same conversation.\n\nFor discussions where circulatory death is anticipated, provide a clear explanation on:\n\nwhat end-of-life care involves and where it will take place – for example, theatre, critical care department\n\nhow death is confirmed and what happens next\n\nwhat happens if death does not occur within a defined time period.\n\nFor discussions where neurological death is anticipated, provide a clear explanation on:\n\nhow death is diagnosed using neurological criteria\n\nhow this is confirmed and what happens next.\n\n# Organisation of the identification, referral and consent processes\n\nEach hospital should have a policy and protocol that is consistent with these recommendations for identifying patients who are potential donors and managing the consent process.\n\nEach hospital should identify a clinical team to ensure the development, implementation and regular review of their policies.\n\nAdult and paediatric intensive care units should have a named lead consultant with responsibility for organ donation.\n\nThe MDT involved in the identification, referral to a specialist nurse for organ donation, and consent should have the specialist skills and competencies necessary to deliver the recommended process for organ donation outlined in this guideline.\n\nThe skills and competencies required of the individual members of the team will depend on their role in the process. However, all healthcare professionals involved in identification, referral to a specialist nurse for organ donation, and consent processes should:\n\nhave knowledge of the basic principles and the relative benefits of, donation after circulatory death (DCD) versus donation after brainstem death (DBD)\n\nunderstand the principles of the diagnosis of death using neurological or cardiorespiratory criteria and how this relates to the organ donation process\n\nbe able to explain neurological death clearly to families\n\nunderstand the use of clinical triggers to identify patients who may be potential organ donors\n\nunderstand the processes, policies and protocols relating to donor management\n\nadhere to relevant professional standards of practice regarding organ donation and end-of-life care.\n\nConsultant staff should have specific knowledge and skills in:\n\nthe law surrounding organ donation\n\nmedical ethics as applied to organ donation\n\nthe diagnosis and confirmation of death using neurological or cardiorespiratory criteria\n\nthe greater potential for transplantation of organs retrieved from DBD donors compared with organs from DCD donors\n\nlegally and ethically appropriate clinical techniques to secure physiological optimisation in patients who are potential organ donors\n\ncommunication skills and knowledge necessary to improve consent ratios for organ donation.", 'Recommendations for research': "We have made the following recommendations for research, based on our review of evidence, to improve NICE guidance and patient care in the future.\n\n# Reasons for refusal for consent\n\nWhy do families refuse to give permission for organ donation?\n\n## Why this is important\n\nHigh-quality research using mixed methodology is needed to identify the reasons behind family refusal to see if there are factors that are changeable (for example, poor understanding of the process, medical mistrust, 'knee-jerk' response that is later regretted). The study could be, for example, a multi-centre observational study where all family members (those that did and those that did not give permission for their deceased loved one's organ donation) are followed up 6 months later.\n\nSuch research could determine whether those participants who gave permission for donation have higher perceived benefits scores, lower prolonged grief scores and higher quality-of-life scores than those who did not.\n\n# Improving rates of identification and referral of potential donors\n\nWhat are the key components of an intervention to improve identification and referral rates?\n\n## Why this is important\n\nCurrently, the evidence for improving identification and referral rates consists mainly of observational reports of complex interventions, with most studies being of limited follow-up. Further research is needed to identify the components, or combinations of components, of the interventions that are effective in increasing identification and referral rates. These studies should have an appropriate length of follow-up to ensure a sustained impact in the longer term.\n\n# Improving consent rates\n\nWhat are the key components of an intervention to improve consent rates?\n\n## Why this is important\n\nCurrently, the evidence for improving consent rates consists mainly of observational reports of complex interventions, with most studies being of limited follow-up. Further research is needed to identify the components, or combinations of components, of the identified interventions that are effective in increasing consent rates. These studies should have an appropriate length of follow-up to ensure a sustained impact in the longer term.\n\n# The experience of consenting for organ donation\n\nDoes a positive experience of approach and process of consent for families increase consent rates?\n\n## Why this is important\n\nIt is generally accepted that if families have a more positive experience of the approach and process of consenting, then rates of consent will increase. However, no high-quality evidence was identified to support this perception. Further research is needed to confirm this assumption and, if true, to identify those components of the approach and process that are key to improving the experience, and hence the consent rate."}	https://www.nice.org.uk/guidance/cg135	This guideline covers identifying people who wish to donate their organs after their death. It offers advice on how to approach families and carers of people who are nearing the end of life and how to seek consent for organ donation. It aims to promote discussion of organ donation as part of end-of-life care and to increase the number of organs available for people waiting for a transplant.
82d74430aa27cc6126104a80baf85000591d131b	nice	Extracorporeal shockwave therapy for Achilles tendinopathy	Extracorporeal shockwave therapy for Achilles tendinopathy Evidence-based recommendations on extracorporeal shockwave therapy for treating Achilles tendinopathy in adults. This involves passing shockwaves through the skin to the affected area. # Recommendations The evidence on extracorporeal shockwave therapy (ESWT) for Achilles tendinopathy raises no major safety concerns. Current evidence on efficacy of the procedure is inconsistent and limited in quality and quantity. Therefore, ESWT for Achilles tendinopathy should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to do ESWT for Achilles tendinopathy should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having ESWT for Achilles tendinopathy (see section 7.2). NICE encourages further research into ESWT for Achilles tendinopathy, which may include comparative data collection. Studies should clearly describe patient selection, treatment protocols, use of local anaesthesia and the type and duration of energy applied (see section 3). Studies should include validated outcome measures and have a minimum of 1 year of follow-up. NICE may update the guidance on publication of further evidence.# Indications and current treatments Achilles tendinopathy is characterised by chronic degeneration of the Achilles tendon and is usually associated with injury or overuse. Symptoms include pain, swelling, weakness and stiffness over the Achilles tendon and tenderness over the heel. Achilles tendinopathy is classified as insertional or non-insertional. Insertional Achilles tendinopathy occurs at the bone–tendon junction in more active people, and non-insertional (or mid-portion) Achilles tendinopathy occurs more proximally in older, less active and overweight people. Conservative treatments include rest, application of ice, non-steroidal anti-inflammatory drugs (NSAIDs), orthotic devices and splints, physiotherapy, Achilles tendon exercises or stretching, topical nitroglycerin, low‑level laser therapy and injections with corticosteroid or autologous blood. Surgery may rarely be considered in patients with refractory symptoms with the aim of repairing partial tears in the Achilles tendon.# The procedure Extracorporeal shockwave therapy (ESWT) is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance may be used to assist with positioning of the device. The shockwaves can be either focused or unfocused (often referred to as radial shock waves). The focused shockwaves are generated using electrohydraulic, electromagnetic or piezoelectric energy. The unfocused shockwaves are generated pneumatically. Treatment protocols for ESWT vary according to the energy density and frequency of shockwaves. ESWT may be applied in a series of treatments or a single session. Local anaesthesia may be administered before treatment because high-energy ESWT (>0.12 mJ/mm2) can be painful; however, there is evidence that the use of local anaesthesia may adversely influence the outcome of ESWT. Low-energy ESWT (EFD ≤0.12 mJ/mm2) can be used repeatedly and does not need local anaesthesia. The mechanism by which this therapy might affect tendinopathy is not known.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. # Extracorporeal shockwave therapy (ESWT) for non-insertional (mid-portion) Achilles tendinopathy In a systematic review and meta-analysis on ESWT (n=633), evidence for mid-portion Achilles tendinopathy (tendinopathy 2 to 6cm from the insertion into the calcaneus) was reported from 2 randomised controlled trials (RCTs) of 75 and 68 patients respectively (Rompe 2007, Rompe 2009). The RCT of 75 patients (Rompe 2007) compared ESWT (n=25) with eccentric loading exercise (n=25) and found no statistically significant effects on pain and functional outcomes at 4‑month follow-up (Visual analogue scale score standard mean difference 0.17, 95% confidence interval −0.38 to 0.73; Victorian institute of sport assessment questionnaire–Achilles score SMD 0.29, 95% CI −0.27 to 0.85; Likert scale risk ratio 1.20, 95% CI 0.64 to 2.25). The study also compared ESWT (n=25) with a 'wait and see' group (no-treatment control, n=25) and found statistically significant effects that favoured ESWT at 4‑month follow-up (VAS score SMD −0.93, 95% CI −1.52 to −0.34; VISA-A score SMD −1.03, 95% CI −1.62 to −0.44; Likert scale risk ratio 0.63, 95% CI 0.40 to 1.00). The RCT of 68 patients (Rompe 2009) comparing combined ESWT and eccentric loading exercise in mid-portion Achilles tendinopathy (n=34) with eccentric loading exercise alone (n=34) found greater improvement in pain and function at 4‑month follow-up (VAS score SMD −0.53, 95% CI −1.01 to −0.05; VISA-A score SMD −0.76, 95% CI −1.25 to −0.27; Likert scale risk ratio 0.40, 95% CI 0.18 to 0.91). The systematic review also reported evidence from a case-control study of 68 patients (Furia 2008) comparing ESWT (n=34) with conservative treatment including rest, footwear modification, anti-inflammatory medication, and gastrocnemius-soleus stretching and strengthening (n=34) and found that ESWT was statistically significantly better in improving pain and functional outcomes at 3–month follow‑up (VAS score SMD −3.75, 95% CI −4.56 to −2.95; Roles and Maudsley score SMD 0.20, 95% CI 0.09 to 0.46) and after follow up of at least 12 months (VAS score SMD −3.42, 95% CI −4.18 to −2.66; Roles and Maudsley score risk ratio 0.20, 95% CI 0.09 to 0.46). # ESWT for insertional Achilles tendinopathy In the systematic review and meta-analysis on ESWT (n=633), evidence for insertional Achilles tendinopathy (tendinopathy up to 2 cm from the insertion into the calcaneus) was reported from 1 RCT of 50 patients (Rompe 2008) comparing ESWT (n=25) to eccentric loading exercise (n=25). It found statistically significant improvement for outcomes of pain and function at 4‑month follow-up (VAS score SMD −0.86, 95% CI −1.44 to −0.27; VISA-A score SMD −1.54, 95% CI −2.18 to −0.91; Likert scale risk ratio 0.50, 95% CI 0.28 to 0.89).The systematic review also reported evidence from 1 case-control study of 68 patients (Furia 2006) comparing ESWT (n=34) with conservative treatment including rest, footwear modification, anti-inflammatory medication, and gastrocnemius-soleus stretching and strengthening (n=34) and found that ESWT was statistically significantly better in improving pain and functional outcomes at 3‑month follow‑up (VAS score SMD −2.42, 95% CI −3.05 to −1.78; Roles and Maudsley score SMD 0.28, 95% CI 0.13 to 0.62) and after follow-up of at least 12 months (VAS score SMD −2.39, 95% CI −3.02 to −1.76; Roles and Maudsley score risk ratio 0.28, 95% CI 0.13 to 0.62). The effect of ESWT was diminished when a local anaesthetic was administered before treatment in this study. # ESWT for non-insertional (mid-portion) or insertional Achilles tendinopathy In a systematic review and meta-analysis of 246 patients, evidence from meta-analysis of data from 2 RCTs (Rompe 2007, patients with mid-portion tendinopathy; Rompe 2008, patients with insertional tendinopathy) found no significant effects on pain and functional outcomes at 16‑week follow‑up (VISA-A score SMD −0.55, 95% CI −2.21 to 1.11). In the systematic review and meta-analysis on ESWT (n=633), evidence for mid-portion or insertional Achilles tendinopathy was reported from 2 RCTs of 49 and 48 patients respectively (Costa 2005, Rasmussen 2008) comparing ESWT with no treatment (placebo). The RCT of 49 patients (Costa 2005) found no significant difference between ESWT (n=22) and sham treatment (n=27) at 3‑month follow-up (VAS score SMD −0.44, 95% CI −1.01 to 0.13; Functional index of lower limb activity SMD −1.05, 95% CI −1.65 to −0.45; EQ-5D SMD −0.21, 95% CI −0.77 to 0.36). The RCT of 48 patients (Rasmussen 2008) used the same intervention as Costa 2005 but with a higher energy level and an extra treatment session. It found that patients in the ESWT group had significantly better American orthopaedic foot and ankle society (AOFAS) scores than the sham group at 3‑month follow-up (SMD −0.52, 95% CI −1.09 to 0.06). The 3 prospective studies (Firdman 2008, Saxena 2011, Vulpiani 2009) included in this systematic review reported improvements in pain and functional outcomes at an average follow up of 20 to 24 months. The specialist advisers listed key efficacy outcomes as pain reduction, pain relief and improved function. Twelve commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Transient skin reddening occurred in all patients treated by extracorporeal shockwave therapy (ESWT) in 1 RCT (Rompe 2007) and in 3 patients each in the 2 case-control studies (Furia 2006 and 2008) included in a systematic review of 11 studies. Some patients reported the presence of cutaneous bruises after the applications of ESWT in the case series of 102 patients with Achilles tendinopathy (number not reported). Pain during ESWT in 2 patients and transient numbness for 24 hours after ESWT in 1 patient was reported in a case-control study (Furia 2006) included in the systematic review of 11 studies. Calf ache was reported in some patients who had eccentric loading exercise in 1 RCT (Rompe 2007, numbers not reported), and in an equal number ('the majority') of patients in both groups in another RCT (Costa 2005, numbers not reported) included in the systematic review of 11 studies. Achilles tendon rupture 2 weeks after the first ESWT treatment session, associated with falls, was reported in 2 patients in 1 RCT (Costa 2005) included in the systematic review of 11 studies. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers considered that the following were theoretical adverse events: persistent or worsening symptoms and damage to the soft tissues. Twelve commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information For related NICE guidance, see the NICE website. This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2240-6	{'Recommendations': "The evidence on extracorporeal shockwave therapy (ESWT) for Achilles tendinopathy raises no major safety concerns. Current evidence on efficacy of the procedure is inconsistent and limited in quality and quantity. Therefore, ESWT for Achilles tendinopathy should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do ESWT for Achilles tendinopathy should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having ESWT for Achilles tendinopathy (see section 7.2).\n\nNICE encourages further research into ESWT for Achilles tendinopathy, which may include comparative data collection. Studies should clearly describe patient selection, treatment protocols, use of local anaesthesia and the type and duration of energy applied (see section 3). Studies should include validated outcome measures and have a minimum of 1\xa0year of follow-up. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Achilles tendinopathy is characterised by chronic degeneration of the Achilles tendon and is usually associated with injury or overuse. Symptoms include pain, swelling, weakness and stiffness over the Achilles tendon and tenderness over the heel. Achilles tendinopathy is classified as insertional or non-insertional. Insertional Achilles tendinopathy occurs at the bone–tendon junction in more active people, and non-insertional (or mid-portion) Achilles tendinopathy occurs more proximally in older, less active and overweight people.\n\nConservative treatments include rest, application of ice, non-steroidal anti-inflammatory drugs (NSAIDs), orthotic devices and splints, physiotherapy, Achilles tendon exercises or stretching, topical nitroglycerin, low‑level laser therapy and injections with corticosteroid or autologous blood. Surgery may rarely be considered in patients with refractory symptoms with the aim of repairing partial tears in the Achilles tendon.', 'The procedure': 'Extracorporeal shockwave therapy (ESWT) is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance may be used to assist with positioning of the device. The shockwaves can be either focused or unfocused (often referred to as radial shock waves). The focused shockwaves are generated using electrohydraulic, electromagnetic or piezoelectric energy. The unfocused shockwaves are generated pneumatically.\n\nTreatment protocols for ESWT vary according to the energy density and frequency of shockwaves. ESWT may be applied in a series of treatments or a single session. Local anaesthesia may be administered before treatment because high-energy ESWT (>0.12 mJ/mm2) can be painful; however, there is evidence that the use of local anaesthesia may adversely influence the outcome of ESWT. Low-energy ESWT (EFD ≤0.12 mJ/mm2) can be used repeatedly and does not need local anaesthesia.\n\nThe mechanism by which this therapy might affect tendinopathy is not known.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\n# Extracorporeal shockwave therapy (ESWT) for non-insertional (mid-portion) Achilles tendinopathy\n\nIn a systematic review and meta-analysis on ESWT (n=633), evidence for mid-portion Achilles tendinopathy (tendinopathy 2\xa0to\xa06cm from the insertion into the calcaneus) was reported from 2\xa0randomised controlled trials (RCTs) of 75 and 68\xa0patients respectively (Rompe 2007, Rompe 2009). The RCT of 75\xa0patients (Rompe 2007) compared ESWT (n=25) with eccentric loading exercise (n=25) and found no statistically significant effects on pain and functional outcomes at 4‑month follow-up (Visual analogue scale [VAS] score standard mean difference [SMD] 0.17, 95% confidence interval [CI] −0.38 to 0.73; Victorian institute of sport assessment questionnaire–Achilles [VISA-A] score SMD 0.29, 95% CI −0.27 to 0.85; Likert scale risk ratio 1.20, 95% CI 0.64 to 2.25). The study also compared ESWT (n=25) with a 'wait and see' group (no-treatment control, n=25) and found statistically significant effects that favoured ESWT at 4‑month follow-up (VAS score SMD −0.93, 95% CI −1.52 to −0.34; VISA-A score SMD −1.03, 95% CI −1.62 to −0.44; Likert scale risk ratio 0.63, 95% CI 0.40 to 1.00). The RCT of 68\xa0patients (Rompe 2009) comparing combined ESWT and eccentric loading exercise in mid-portion Achilles tendinopathy (n=34) with eccentric loading exercise alone (n=34) found greater improvement in pain and function at 4‑month follow-up (VAS score SMD −0.53, 95% CI −1.01 to −0.05; VISA-A score SMD −0.76, 95% CI −1.25 to −0.27; Likert scale risk ratio 0.40, 95% CI 0.18 to 0.91).\n\nThe systematic review also reported evidence from a case-control study of 68\xa0patients (Furia 2008) comparing ESWT (n=34) with conservative treatment including rest, footwear modification, anti-inflammatory medication, and gastrocnemius-soleus stretching and strengthening (n=34) and found that ESWT was statistically significantly better in improving pain and functional outcomes at 3–month follow‑up (VAS score SMD −3.75, 95% CI −4.56 to −2.95; Roles and Maudsley score SMD 0.20, 95% CI 0.09 to 0.46) and after follow up of at least 12\xa0months (VAS score SMD −3.42, 95% CI −4.18 to −2.66; Roles and Maudsley score risk ratio 0.20, 95% CI 0.09 to 0.46).\n\n# ESWT for insertional Achilles tendinopathy\n\nIn the systematic review and meta-analysis on ESWT (n=633), evidence for insertional Achilles tendinopathy (tendinopathy up to 2\xa0cm from the insertion into the calcaneus) was reported from 1\xa0RCT of 50\xa0patients (Rompe 2008) comparing ESWT (n=25) to eccentric loading exercise (n=25). It found statistically significant improvement for outcomes of pain and function at 4‑month follow-up (VAS score SMD −0.86, 95% CI −1.44 to −0.27; VISA-A score SMD −1.54, 95% CI −2.18 to −0.91; Likert scale risk ratio 0.50, 95% CI 0.28 to 0.89).The systematic review also reported evidence from 1\xa0case-control study of 68\xa0patients (Furia 2006) comparing ESWT (n=34) with conservative treatment including rest, footwear modification, anti-inflammatory medication, and gastrocnemius-soleus stretching and strengthening (n=34) and found that ESWT was statistically significantly better in improving pain and functional outcomes at 3‑month follow‑up (VAS score SMD −2.42, 95% CI −3.05 to −1.78; Roles and Maudsley score SMD 0.28, 95% CI 0.13 to 0.62) and after follow-up of at least 12\xa0months (VAS score SMD −2.39, 95% CI −3.02 to −1.76; Roles and Maudsley score risk ratio 0.28, 95% CI 0.13 to 0.62). The effect of ESWT was diminished when a local anaesthetic was administered before treatment in this study.\n\n# ESWT for non-insertional (mid-portion) or insertional Achilles tendinopathy\n\nIn a systematic review and meta-analysis of 246\xa0patients, evidence from meta-analysis of data from 2\xa0RCTs (Rompe 2007, patients with mid-portion tendinopathy; Rompe 2008, patients with insertional tendinopathy) found no significant effects on pain and functional outcomes at 16‑week follow‑up (VISA-A score SMD −0.55, 95% CI −2.21 to 1.11).\n\nIn the systematic review and meta-analysis on ESWT (n=633), evidence for mid-portion or insertional Achilles tendinopathy was reported from 2\xa0RCTs of 49 and 48\xa0patients respectively (Costa 2005, Rasmussen 2008) comparing ESWT with no treatment (placebo). The RCT of 49\xa0patients (Costa 2005) found no significant difference between ESWT (n=22) and sham treatment (n=27) at 3‑month follow-up (VAS score SMD −0.44, 95% CI −1.01 to 0.13; Functional index of lower limb activity [FILA] SMD −1.05, 95% CI −1.65 to −0.45; EQ-5D SMD −0.21, 95% CI −0.77 to 0.36). The RCT of 48\xa0patients (Rasmussen 2008) used the same intervention as Costa 2005 but with a higher energy level and an extra treatment session. It found that patients in the ESWT group had significantly better American orthopaedic foot and ankle society (AOFAS) scores than the sham group at 3‑month follow-up (SMD −0.52, 95% CI −1.09 to 0.06). The 3\xa0prospective studies (Firdman 2008, Saxena 2011, Vulpiani 2009) included in this systematic review reported improvements in pain and functional outcomes at an average follow up of 20 to 24\xa0months.\n\nThe specialist advisers listed key efficacy outcomes as pain reduction, pain relief and improved function.\n\nTwelve commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nTransient skin reddening occurred in all patients treated by extracorporeal shockwave therapy (ESWT) in 1\xa0RCT (Rompe 2007) and in 3\xa0patients each in the 2\xa0case-control studies (Furia 2006 and 2008) included in a systematic review of 11\xa0studies. Some patients reported the presence of cutaneous bruises after the applications of ESWT in the case series of 102\xa0patients with Achilles tendinopathy (number not reported).\n\nPain during ESWT in 2\xa0patients and transient numbness for 24\xa0hours after ESWT in 1\xa0patient was reported in a case-control study (Furia 2006) included in the systematic review of 11\xa0studies.\n\nCalf ache was reported in some patients who had eccentric loading exercise in 1\xa0RCT (Rompe 2007, numbers not reported), and in an equal number ('the majority') of patients in both groups in another RCT (Costa 2005, numbers not reported) included in the systematic review of 11\xa0studies.\n\nAchilles tendon rupture 2\xa0weeks after the first ESWT treatment session, associated with falls, was reported in 2\xa0patients in 1\xa0RCT (Costa 2005) included in the systematic review of 11\xa0studies.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers considered that the following were theoretical adverse events: persistent or worsening symptoms and damage to the soft tissues.\n\nTwelve commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Further information': 'For related NICE guidance, see the NICE website.\n\nThis guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2240-6'}	https://www.nice.org.uk/guidance/ipg571	Evidence-based recommendations on extracorporeal shockwave therapy for treating Achilles tendinopathy in adults. This involves passing shockwaves through the skin to the affected area.
b8bd54f763da3f807100ffc893aaa8d694c94698	nice	Radiation therapy for early Dupuytren's disease	Radiation therapy for early Dupuytren's disease Evidence-based recommendations on radiation therapy for early Dupuytren’s contractures in adults. This involves directing low energy X-rays at the affected tissue. # Recommendations The evidence on radiation therapy for early Dupuytren's disease raises no major safety concerns. Current evidence on its efficacy is inadequate in quantity and quality, and is difficult to interpret because of uncertainty about the natural history of Dupuytren's disease. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to do radiation therapy for early Dupuytren's disease should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's efficacy, the unpredictability of progression of early Dupuytren's disease, and that there is a theoretical risk of malignancy in the long term after any type of radiation therapy. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having radiation therapy for early Dupuytren's disease (see section 7.1). NICE encourages further research into radiation therapy for early Dupuytren's disease, including randomised controlled trials. Because of the uncertainty over the natural history of the disease, this should include studies comparing the long-term efficacy of radiation therapy with no radiation therapy. Studies should include details of patient selection, stage of disease progression, duration and types of treatment, patient-reported outcomes, and long-term efficacy and safety data. NICE may update the guidance on publication of further evidence.# Indications and current treatments Dupuytren's disease is a benign fibroproliferative disorder of the fascia of the hand and fingers. Its aetiology is unknown. It is characterised by connective tissue thickening in the palm of the hand, forming nodules. These nodules are thought to progress to form cords, which cause difficulty in extending the fingers. Symptoms include reduced range of motion, reduced hand function and pain. It most commonly affects the fourth and fifth fingers. Most patients are affected in both hands. There is no formal clinical definition of early disease but the term is generally used for patients with contractures of 30 degrees or less, with or without palmar disease. Not all patients have progressive disease, and the natural history of the disease is not well understood. Treatments for Dupuytren's disease aim to restore hand function and prevent progression. These include needle aponeurotomy (percutaneous needle fasciotomy) in earlier disease, and open surgical correction (fasciotomy or fasciectomy) in later disease when secondary changes to tendons and joints have developed. Limited fasciectomy is the most commonly used open surgical treatment. Dermofasciectomy is used for advanced cases. A non-surgical treatment using injectable collagenase clostridium histolyticum is also sometimes used.# The procedure The aim of this procedure is to prevent or postpone disease progression, and reduce the need for surgical intervention. The mechanism of action of radiation therapy is uncertain, but it is thought to affect the development and growth rate of fibroblasts in the palmar fascia. Radiation therapy is delivered to the nodules and cords that have formed in the hands. The usual regimen is 30 Gy in 10 fractions, consisting of 2 phases of 15 Gy in 5 fractions with a gap of 6–12 weeks between the 2 phases. Alternatively, 21 Gy may be given in 7 fractions on alternate days over 2 weeks.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a randomised controlled trial (RCT) of 129 patients (198 hands), in which both groups had radiation therapy, objective symptom assessment (number and consistency of cords and nodules, and degree of extension deficit) showed regression of Dupuytren's disease at 1‑year follow-up in 56% (53/95) of hands treated with 30 Gy of radiation and in 53% (55/103) of hands treated with 21 Gy (p<0.01 for the before-after change in both groups; no statistically significant difference between groups). The symptoms remained stable in a further 37% (35/95) of hands treated with 30 Gy of radiation and a further 38% (39/103) of hands treated with 21 Gy (no statistically significant difference between groups). Overall disease progression rate at 1 year was 8% (16/198). New nodules were reported in 6% (11/198) of hands, new cords in 4% (7/198) and increased flexion deformity in 6% (12/198). The same trial reported that subjective symptom assessment (not otherwise defined) showed statistically significant regression of Dupuytren's disease at 1‑year follow-up in 65% (41/63) of patients in the group treated with 30 Gy of radiation, and 53% (35/66) of patients treated with 21 Gy (p<0.01 for the within group change; level of statistical significance between groups not reported). The condition remained stable in a further 30% (19/63) of patients in the 30 Gy group and a further 41% (27/66) of patients in the 21 Gy group (level of statistical significance between groups not reported). In a case series of 206 patients treated with 32 Gy of radiation, which collected self-reported questionnaire data at a median follow-up of 40 months, symptoms regressed in 45% (93/206) of patients and there was no further disease progression (including in patients with regression) in 80% (165/206) of patients. In a case series of 135 patients (208 hands) treated with 30 Gy of radiation, clinical evaluation after a median follow-up of 13 years showed complete relief of symptoms in 16% (14/87) of patients, good relief in symptoms in 18% (16/87), minor relief in 32% (28/87), unchanged symptoms in 14% (12/87) and progression of symptoms in 20% (17/87). In the same case series, clinical evaluation after a median follow-up of 13 years showed regression of the disease in 10% (20/208) of hands, stable disease in 59% (123/208) of hands and progression in 31% (65/208) of hands. In a case series of 33 patients (60 treated sites), which collected self-reported survey data after a median follow-up of 31 months, the disease progressed at any location within or outside the radiation therapy treatment field in 61% (20/33) of patients. In-field progression occurred in 23% (14/60) of sites but 4 sites were successfully re-irradiated with final local control in 83% (50/60) of sites. In the same study, the symptoms improved or remained stable in 93% of sites (relative numbers not given). In the RCT of 129 patients (198 hands) treated with 30 Gy or 21 Gy of radiation, 3% (4/129) of patients needed hand surgery for disease progression within 1 year of follow-up. In the case series of 135 patients (208 hands), 20% (42/208) of hands needed surgery within a median follow-up of 13 years. In the case series of 33 patients, 6% (2/33) of patients needed surgery within a median follow-up of 31 months. In the case series of 206 patients, the mean (± standard deviation) score for satisfaction with the therapy (measured with a visual analogue scale from 0 to 10 ) was 7.9±2.7 points (n=198 patients) at a median follow-up of 40 months. In the case series of 33 patients, 94% (31/33) of patients considered radiation therapy successful (defined by patient report indicating whether patients felt that radiation therapy had been successful or not) at a median follow-up of 31 months. The specialist advisers listed the following key efficacy outcomes: absence of progression, time to recurrence or progression to a functionally significant contracture, and rates of subsequent surgery. Thirty four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. # Acute toxicity Overall, acute toxicity including skin tenderness, redness, peeling, or mild pain was reported in 50% (n=8, denominator not stated) of patients in a case series of 17 patients (treated with 21 Gy of radiation) that collected self-report questionnaire data. Dry skin or redness was reported in 38% (76/198) of hands in a randomised controlled trial (RCT) of 129 patients treated with 30 Gy or 21 Gy of radiation within a 4‑week follow-up. Dry desquamation was reported in 5% (10/198) of hands and wet desquamation in 2% (3/198) of hands in the RCT of 129 patients treated with 30 Gy or 21 Gy of radiation within a 4‑week follow-up. Extensive erythema was reported in 6% (12/198) of hands in the RCT of 129 patients treated with 30 Gy or 21 Gy of radiation within a 4‑week follow-up. Erythema was reported in 20% (42/206) of patients in a case series of 206 patients treated with 32 Gy of radiation within a 4-week follow-up. Pronounced swelling was reported in 2% (3/198) of hands in the RCT of 129 patients treated with 30 Gy or 21 Gy of radiation within a 4‑week follow-up. Tenderness was reported in 3% (2/60) of sites in a case series of 33 patients. # Chronic toxicity Overall, chronic toxicity including mild tightness of the skin, dryness, skin thickening, mild swelling and decreased sensation was reported in 31% (n=5, denominator not stated) of patients in the case series of 17 patients, with a mean follow-up of 35 months. Overall, chronic toxicity events occurred in 16% (15/95) of hands treated with 30 Gy of radiation and in 11% (11/103) of hands treated with 21 Gy within 3 months and in 4% (4/95), and 5% (5/103) of hands treated with 30 Gy or 21 Gy respectively within 12 months of radiation therapy, in the RCT of 129 patients. Most of these events were skin dryness, increased desquamation, mild skin atrophy or slight subcutaneous fibrosis needing topical treatment (type of treatment not stated). Dry skin was reported in 20% (41/206) of patients in the case series of 206 patients treated with 32 Gy of radiation, in more than 4 weeks of follow-up. Desquamation was reported in 2% (5/206) of patients in the same case series of 206 patients. Dry skin and increased desquamation were reported in 23% (47/208) of hands in a case series of 135 patients within a median follow-up of 13 years. Lack of sweating was reported in 4% (8/206) of patients in the case series of 206 patients treated with 32 Gy of radiation within a median follow-up of 40 months. Skin atrophy was reported in 3% (7/206) of patients in the case series of 206 patients treated with 32 Gy of radiation, in more than 4 weeks of follow-up. In the same study, telangiectasia was reported in 3% (6/206) of patients, in more than 4 weeks of follow-up. Mild skin atrophy with occasional telangiectasia was reported in 7% (14/208) of hands in the case series of 135 patients within a median follow-up of 13 years. Alteration of heat and pain sensation was reported in 4% (8/198) of hands in the RCT of 129 patients treated with 30 Gy or 21 Gy (minimum follow-up of 1 year). Sensory affection was reported in 2% (4/206) of patients in the case series of 206 patients treated with 32 Gy of radiation, in more than 4 weeks of follow‑up. Erythema was reported in 2% (5/208) of patients in the case series of 135 patients at up to 1 year. Weakness (subjective 10–20% reduction in strength) was reported in 3% (2/60) of sites in the case series of 33 patients within a median follow-up of 31 months. Reduced nail health was reported in 3% (2/60) of sites in the case series of 33 patients within a median follow-up of 31 months. Hyperpigmentation was reported in 3% (2/60) of sites in the case series of 33 patients within a median follow-up of 31 months. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any new anecdotal adverse events. They considered that the following were theoretical adverse events: radiation‑induced malignancy and adverse surgical outcome due to poor wound healing in irradiated skin. Thirty-four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2246-8	{'Recommendations': "The evidence on radiation therapy for early Dupuytren's disease raises no major safety concerns. Current evidence on its efficacy is inadequate in quantity and quality, and is difficult to interpret because of uncertainty about the natural history of Dupuytren's disease. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do radiation therapy for early Dupuytren's disease should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy, the unpredictability of progression of early Dupuytren's disease, and that there is a theoretical risk of malignancy in the long term after any type of radiation therapy. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having radiation therapy for early Dupuytren's disease (see section 7.1).\n\nNICE encourages further research into radiation therapy for early Dupuytren's disease, including randomised controlled trials. Because of the uncertainty over the natural history of the disease, this should include studies comparing the long-term efficacy of radiation therapy with no radiation therapy. Studies should include details of patient selection, stage of disease progression, duration and types of treatment, patient-reported outcomes, and long-term efficacy and safety data. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': "Dupuytren's disease is a benign fibroproliferative disorder of the fascia of the hand and fingers. Its aetiology is unknown. It is characterised by connective tissue thickening in the palm of the hand, forming nodules. These nodules are thought to progress to form cords, which cause difficulty in extending the fingers. Symptoms include reduced range of motion, reduced hand function and pain. It most commonly affects the fourth and fifth fingers. Most patients are affected in both hands. There is no formal clinical definition of early disease but the term is generally used for patients with contractures of 30\xa0degrees or less, with or without palmar disease. Not all patients have progressive disease, and the natural history of the disease is not well understood.\n\nTreatments for Dupuytren's disease aim to restore hand function and prevent progression. These include needle aponeurotomy (percutaneous needle fasciotomy) in earlier disease, and open surgical correction (fasciotomy or fasciectomy) in later disease when secondary changes to tendons and joints have developed. Limited fasciectomy is the most commonly used open surgical treatment. Dermofasciectomy is used for advanced cases. A non-surgical treatment using injectable collagenase clostridium histolyticum is also sometimes used.", 'The procedure': 'The aim of this procedure is to prevent or postpone disease progression, and reduce the need for surgical intervention. The mechanism of action of radiation therapy is uncertain, but it is thought to affect the development and growth rate of fibroblasts in the palmar fascia.\n\nRadiation therapy is delivered to the nodules and cords that have formed in the hands. The usual regimen is 30\xa0Gy in 10\xa0fractions, consisting of 2\xa0phases of 15\xa0Gy in 5\xa0fractions with a gap of 6–12\xa0weeks between the 2\xa0phases. Alternatively, 21\xa0Gy may be given in 7\xa0fractions on alternate days over 2\xa0weeks.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 129\xa0patients (198\xa0hands), in which both groups had radiation therapy, objective symptom assessment (number and consistency of cords and nodules, and degree of extension deficit) showed regression of Dupuytren's disease at 1‑year follow-up in 56% (53/95) of hands treated with 30\xa0Gy of radiation and in 53% (55/103) of hands treated with 21\xa0Gy (p<0.01 for the before-after change in both groups; no statistically significant difference between groups). The symptoms remained stable in a further 37% (35/95) of hands treated with 30\xa0Gy of radiation and a further 38% (39/103) of hands treated with 21\xa0Gy (no statistically significant difference between groups). Overall disease progression rate at 1\xa0year was 8% (16/198). New nodules were reported in 6% (11/198) of hands, new cords in 4% (7/198) and increased flexion deformity in 6% (12/198). The same trial reported that subjective symptom assessment (not otherwise defined) showed statistically significant regression of Dupuytren's disease at 1‑year follow-up in 65% (41/63) of patients in the group treated with 30\xa0Gy of radiation, and 53% (35/66) of patients treated with 21\xa0Gy (p<0.01 for the within group change; level of statistical significance between groups not reported). The condition remained stable in a further 30% (19/63) of patients in the 30\xa0Gy group and a further 41% (27/66) of patients in the 21\xa0Gy group (level of statistical significance between groups not reported).\n\nIn a case series of 206\xa0patients treated with 32\xa0Gy of radiation, which collected self-reported questionnaire data at a median follow-up of 40\xa0months, symptoms regressed in 45% (93/206) of patients and there was no further disease progression (including in patients with regression) in 80% (165/206) of patients.\n\nIn a case series of 135\xa0patients (208\xa0hands) treated with 30\xa0Gy of radiation, clinical evaluation after a median follow-up of 13\xa0years showed complete relief of symptoms in 16% (14/87) of patients, good relief in symptoms in 18% (16/87), minor relief in 32% (28/87), unchanged symptoms in 14% (12/87) and progression of symptoms in 20% (17/87). In the same case series, clinical evaluation after a median follow-up of 13\xa0years showed regression of the disease in 10% (20/208) of hands, stable disease in 59% (123/208) of hands and progression in 31% (65/208) of hands.\n\nIn a case series of 33\xa0patients (60\xa0treated sites), which collected self-reported survey data after a median follow-up of 31\xa0months, the disease progressed at any location within or outside the radiation therapy treatment field in 61% (20/33) of patients. In-field progression occurred in 23% (14/60) of sites but 4\xa0sites were successfully re-irradiated with final local control in 83% (50/60) of sites. In the same study, the symptoms improved or remained stable in 93% of sites (relative numbers not given).\n\nIn the RCT of 129\xa0patients (198\xa0hands) treated with 30\xa0Gy or 21\xa0Gy of radiation, 3% (4/129) of patients needed hand surgery for disease progression within 1\xa0year of follow-up. In the case series of 135\xa0patients (208\xa0hands), 20% (42/208) of hands needed surgery within a median follow-up of 13\xa0years. In the case series of 33\xa0patients, 6% (2/33) of patients needed surgery within a median follow-up of 31\xa0months.\n\nIn the case series of 206\xa0patients, the mean (± standard deviation) score for satisfaction with the therapy (measured with a visual analogue scale from 0 [not satisfied] to 10 [extremely satisfied]) was 7.9±2.7\xa0points (n=198\xa0patients) at a median follow-up of 40\xa0months. In the case series of 33\xa0patients, 94% (31/33) of patients considered radiation therapy successful (defined by patient report indicating whether patients felt that radiation therapy had been successful or not) at a median follow-up of 31\xa0months.\n\nThe specialist advisers listed the following key efficacy outcomes: absence of progression, time to recurrence or progression to a functionally significant contracture, and rates of subsequent surgery.\n\nThirty four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\n# Acute toxicity\n\nOverall, acute toxicity including skin tenderness, redness, peeling, or mild pain was reported in 50% (n=8, denominator not stated) of patients in a case series of 17\xa0patients (treated with 21\xa0Gy of radiation) that collected self-report questionnaire data.\n\nDry skin or redness was reported in 38% (76/198) of hands in a randomised controlled trial (RCT) of 129\xa0patients treated with 30\xa0Gy or 21\xa0Gy of radiation within a 4‑week follow-up.\n\nDry desquamation was reported in 5% (10/198) of hands and wet desquamation in 2% (3/198) of hands in the RCT of 129\xa0patients treated with 30\xa0Gy or 21\xa0Gy of radiation within a 4‑week follow-up.\n\nExtensive erythema was reported in 6% (12/198) of hands in the RCT of 129\xa0patients treated with 30\xa0Gy or 21\xa0Gy of radiation within a 4‑week follow-up. Erythema was reported in 20% (42/206) of patients in a case series of 206\xa0patients treated with 32\xa0Gy of radiation within a 4-week follow-up.\n\nPronounced swelling was reported in 2% (3/198) of hands in the RCT of 129\xa0patients treated with 30\xa0Gy or 21\xa0Gy of radiation within a 4‑week follow-up.\n\nTenderness was reported in 3% (2/60) of sites in a case series of 33\xa0patients.\n\n# Chronic toxicity\n\nOverall, chronic toxicity including mild tightness of the skin, dryness, skin thickening, mild swelling and decreased sensation was reported in 31% (n=5, denominator not stated) of patients in the case series of 17\xa0patients, with a mean follow-up of 35\xa0months.\n\nOverall, chronic toxicity events occurred in 16% (15/95) of hands treated with 30\xa0Gy of radiation and in 11% (11/103) of hands treated with 21\xa0Gy within 3\xa0months and in 4% (4/95), and 5% (5/103) of hands treated with 30\xa0Gy or 21\xa0Gy respectively within 12\xa0months of radiation therapy, in the RCT of 129\xa0patients. Most of these events were skin dryness, increased desquamation, mild skin atrophy or slight subcutaneous fibrosis needing topical treatment (type of treatment not stated).\n\nDry skin was reported in 20% (41/206) of patients in the case series of 206\xa0patients treated with 32\xa0Gy of radiation, in more than 4\xa0weeks of follow-up. Desquamation was reported in 2% (5/206) of patients in the same case series of 206\xa0patients. Dry skin and increased desquamation were reported in 23% (47/208) of hands in a case series of 135\xa0patients within a median follow-up of 13\xa0years.\n\nLack of sweating was reported in 4% (8/206) of patients in the case series of 206\xa0patients treated with 32\xa0Gy of radiation within a median follow-up of 40\xa0months.\n\nSkin atrophy was reported in 3% (7/206) of patients in the case series of 206\xa0patients treated with 32\xa0Gy of radiation, in more than 4\xa0weeks of follow-up. In the same study, telangiectasia was reported in 3% (6/206) of patients, in more than 4\xa0weeks of follow-up. Mild skin atrophy with occasional telangiectasia was reported in 7% (14/208) of hands in the case series of 135\xa0patients within a median follow-up of 13\xa0years.\n\nAlteration of heat and pain sensation was reported in 4% (8/198) of hands in the RCT of 129\xa0patients treated with 30\xa0Gy or 21\xa0Gy (minimum follow-up of 1\xa0year). Sensory affection was reported in 2% (4/206) of patients in the case series of 206\xa0patients treated with 32\xa0Gy of radiation, in more than 4\xa0weeks of follow‑up. Erythema was reported in 2% (5/208) of patients in the case series of 135\xa0patients at up to 1\xa0year.\n\nWeakness (subjective 10–20% reduction in strength) was reported in 3% (2/60) of sites in the case series of 33\xa0patients within a median follow-up of 31\xa0months.\n\nReduced nail health was reported in 3% (2/60) of sites in the case series of 33\xa0patients within a median follow-up of 31\xa0months.\n\nHyperpigmentation was reported in 3% (2/60) of sites in the case series of 33\xa0patients within a median follow-up of 31\xa0months.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any new anecdotal adverse events. They considered that the following were theoretical adverse events: radiation‑induced malignancy and adverse surgical outcome due to poor wound healing in irradiated skin.\n\nThirty-four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Further information': 'This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2246-8'}	https://www.nice.org.uk/guidance/ipg573	Evidence-based recommendations on radiation therapy for early Dupuytren’s contractures in adults. This involves directing low energy X-rays at the affected tissue.
9b127ede857a3d27f6f9dc30a18c4fdd490cf80f	nice	Everolimus with exemestane for treating advanced breast cancer after endocrine therapy	Everolimus with exemestane for treating advanced breast cancer after endocrine therapy Evidence-based recommendations on everolimus (Afinitor) for treating advanced breast cancer in adults after endocrine therapy. # Recommendations Everolimus, in combination with exemestane, is recommended within its marketing authorisation, as an option for treating advanced human epidermal growth factor receptor 2 (HER2)-negative, hormone-receptor-positive breast cancer in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non-steroidal aromatase inhibitor. Everolimus is recommended only if the company provides it with the discount agreed in the patient access scheme.# The technology Description of the technology Everolimus (Afinitor, Novartis Pharmaceuticals) inhibits the mammalian target of rapamycin, a protein that regulates the division of tumour cells and growth of blood vessels. Marketing authorisation Everolimus has a UK marketing authorisation for the 'treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor'. Adverse reactions The summary of product characteristics lists the most frequently reported grade 3 or 4 adverse reactions including: anaemia, fatigue, diarrhoea, infections, stomatitis, hyperglycaemia, thrombocytopenia, lymphopenia, neutropenia, hypophosphataemia, hypercholesterolaemia, diabetes mellitus and pneumonitis. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Everolimus is administered orally. The recommended dosage is 10 mg once daily and treatment should continue as long as patients benefit clinically, or until they have unacceptable adverse reactions. Adverse reactions that are severe and/or intolerable may be managed by reducing the dosage to 5 mg daily or temporarily stopping treatment then reintroducing it at 5 mg daily. Price The price for a pack (30 tablets per pack) of 10-mg tablets and 5-mg tablets is £2,673 and £2,250 respectively (excluding VAT; 'British national formulary' ). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of everolimus with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Novartis and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on everolimus in combination with exemestane for treating advanced HER2-negative hormone receptor-positive breast cancer after endocrine therapy. It focused on updated overall survival data from the BOLERO‑2 trial and cost-effectiveness analyses using a patient access scheme, which provides everolimus at a reduced cost. The level of the discount is commercial in confidence. Sections 4.1 to 4.27 cover the committee's consideration of the evidence submitted in the original appraisal. Sections 4.28 to 4.33 cover the committee's consideration of the additional evidence submitted for the Cancer Drugs Fund reconsideration. In BOLERO‑2 postmenopausal women with advanced human epidermal growth factor receptor 2 (HER2)-negative hormone receptor-positive breast cancer without symptomatic visceral disease who had previously had a non-steroidal aromatase inhibitor were randomised to either everolimus plus exemestane or to exemestane alone. The primary end point of the trial was progression-free survival as assessed by a local radiologist (study site specific). See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on everolimus in combination with exemestane for treating advanced HER2-negative hormone receptor-positive breast cancer after endocrine therapy.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of everolimus plus exemestane, having considered evidence on the nature of advanced human epidermal growth factor receptor 2 (HER2)-negative hormone receptor-positive breast cancer after endocrine therapy and the value placed on the benefits of everolimus plus exemestane by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee considered the views of the patient expert on their experience of everolimus as a treatment for advanced breast cancer. It heard that patients would value everolimus plus exemestane as a treatment option because it is offered when limited treatment options exist after a woman's disease becomes resistant to endocrine therapy, and because everolimus plus exemestane may delay the need for chemotherapy and its associated toxicity. The committee also heard from the patient expert that patients value increased survival and improved quality of life. The committee was aware of comments from consultees that everolimus is considered to be the 'biggest development in years for treating breast cancer' and also that 'length of life is only worth having if there is a quality of life as well'. The committee recognised the importance of having a range of treatment options for postmenopausal women with advanced breast cancer. The committee considered the marketing authorisation, which specifies that everolimus can be used for 'postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor'. The committee noted that patients in the BOLERO‑2 trial may have had visceral disease, but that it was unclear whether these patients were also symptomatic. The committee heard from the clinical experts that patients with visceral disease may or may not have symptoms but that, for patients with life-threatening symptomatic visceral disease, chemotherapy is the preferred treatment option, usually with an anthracycline-containing regimen (doxorubicin or epirubicin) or a taxane. The committee understood that, in accordance with the marketing authorisation, everolimus was not being appraised for patients with symptomatic visceral disease. The committee considered the likely position of everolimus plus exemestane in the treatment pathway for women with advanced HER2-negative hormone receptor-positive breast cancer. The committee heard from the clinical experts that, in general, clinical practice reflects the recommendations in NICE's guideline on advanced breast cancer, but that patients whose disease progresses after a non-steroidal aromatase inhibitor (such as anastrozole or letrozole) are often offered further endocrine treatments rather than chemotherapy. The clinical experts confirmed that everolimus plus exemestane would be offered to patients whose disease has progressed on a non-steroidal aromatase inhibitor at a point when a patient might otherwise receive either further endocrine therapy or chemotherapy. The committee considered the chemotherapy treatments that the company had included as comparators in its submission. It understood that the scope listed 'chemotherapy in accordance with NICE guidance' and that the company had included comparisons with docetaxel, doxorubicin and capecitabine, and after consultation, vinorelbine. The committee heard from the clinical experts that the most relevant chemotherapy comparators for everolimus plus exemestane are likely to be capecitabine and vinorelbine because anthracyclines (doxorubicin) and taxanes (docetaxel) are generally used to treat metastatic breast cancer in patients who have symptomatic and life-threatening visceral disease (see section 4.3). The committee concluded that, of the chemotherapies, the comparison of everolimus plus exemestane with capecitabine was the most relevant for the population in the appraisal, and that a comparison with vinorelbine was also appropriate. The committee then discussed the endocrine treatments included as comparators by the company. It heard from the clinical experts that, although fulvestrant is available through the Cancer Drugs Fund, NICE has not recommended it. The committee did not hear any evidence that fulvestrant can be considered routine practice when non-steroidal aromatase inhibitors have failed. The clinical experts stated that tamoxifen and exemestane (alone) were appropriate comparators for everolimus plus exemestane, although tamoxifen is often offered after exemestane. Also, the committee understood from the clinical experts that, although exemestane is used, there are concerns that it is not effective in the population considered in this appraisal because the disease will have already progressed on a non-steroidal aromatase inhibitor. The committee noted that this concern was acknowledged by the European Medicines Agency in the European public assessment report, which stated that patients in the exemestane arm of BOLERO‑2 may have received suboptimal treatment. On this basis, the European Medicines Agency requested that the company complete a trial comparing everolimus plus exemestane with everolimus alone and with capecitabine alone. Despite these issues, the committee concluded that exemestane alone was the most relevant endocrine comparator for everolimus plus exemestane for the purpose of this appraisal. # Clinical effectiveness (NICE technology appraisal guidance 295) The committee discussed the data on clinical effectiveness from BOLERO‑2. It heard from the clinical experts that the trial population represented patients who would be offered everolimus in the UK. The committee understood from the trial publication and from the statistical analysis plan of the trial that the primary end point of the trial was progression-free survival based on radiographic assessment by local investigators, and that central assessment by an independent radiology committee was used in supportive analyses. However, in its submission, and at the committee meeting, the company stated that the primary end point was progression-free survival based both on local and central radiological assessment. The committee noted that the company's statistical analysis plan stated that the primary end point of BOLERO‑2 was amended to local assessment from central assessment 5 months after the original protocol was approved. The company explained that this protocol amendment was implemented after approximately 100 events, but could not provide the reasons for the change. The committee was aware that median progression-free survival was longer (both relatively and absolutely) when estimated using central rather than local assessment and that the company had chosen to use centrally assessed estimates of progression-free survival in its economic model. The committee heard from the company that central assessment was associated with fewer biases. However, it was aware that women in the UK who would receive everolimus plus exemestane would have progression assessed locally, not centrally. The company agreed with the committee that disease progression would be assessed locally in routine clinical practice. The committee was aware that, ideally, trials give unbiased estimates of relative treatment effects, but that biases with central assessment may have existed in this particular trial. The committee agreed that it was important to consider in detail the different approaches related to, and issues around, local and central assessment. The committee then discussed the approaches to analysing the BOLERO‑2 data when assessed locally or centrally. It was aware that the trial protocol stipulated that, once a patient's disease was assessed locally as having progressed, study treatment would have stopped (and the patient may have gone on to other treatments), whether or not the central radiological committee had considered the disease to have progressed. The committee heard from the company that the analysis followed the statistical analysis plan, that patients deemed to have progressed only by local assessment were censored in Kaplan–Meier analyses based on central assessment, and that the company's statistical analysis plan acknowledged the potential for informative censoring when the analysis was based on central review. The committee understood that censoring occurs in a trial when the event of interest, in this case, disease progression, is not seen during the follow‑up. It appreciated that censoring in some circumstances can be 'informative', that is, patients censored for one reason are more likely to have disease progression than patients censored for another reason. The censoring in the analysis based on central assessment may have been informative because these patients would plausibly fare more poorly (given that they had disease severe enough for the local radiologists to have deemed their disease to have progressed) than would patients censored by other means. The committee heard from the evidence review group (ERG) that informative censoring may have biased the treatment effect because it violates the statistical assumption that censoring is random and therefore unrelated to prognosis. The ERG noted that this is of greater concern in unblinded trials, but the committee was also aware of the analysis provided by the ERG that concluded there was no evidence that local investigators acted in a way to suggest that unblinding occurred in BOLERO‑2. The committee was also aware of analyses presented by the company after consultation, in which patients randomised to everolimus and censored by central review were instead recorded as having progressed which, according to the company, did not reveal informative censoring. However, the committee noted that these sensitivity analyses resulted in a hazard ratio of 0.55, reflecting a smaller treatment effect compared with when effectiveness was addressed centrally (0.36) or locally (0.43). The ERG explained to the committee that it could not verify the sensitivity analysis described by the company without access to the Kaplan–Meier analyses requested at the clarification stage. It concluded that, as a means to avoid informative censoring, local assessment without risk of informative censoring was superior to central assessment with imputed data. In addition, the committee was aware of a meta-analysis by Amit et al. (2011), which showed that local evaluation provides a reliable measure of treatment effect when compared with central assessment, even when trials are unblinded. The committee concluded that it was more appropriate to use effectiveness data derived from local assessment in the modelling than from central assessment because local assessment represented the primary end point of the trial, reflected clinical practice and minimised the potential for bias from informative censoring. Overall, the committee concluded that everolimus plus exemestane is effective in prolonging progression-free survival compared with exemestane alone. The committee considered the results for overall survival in BOLERO‑2 and that the median overall survival had not yet been reached. It therefore agreed that the immaturity of the data resulted in considerable uncertainty associated with the longer-term benefits of everolimus plus exemestane. The committee considered the safety data from BOLERO‑2, which showed that patients receiving everolimus plus exemestane had more adverse reactions, specifically stomatitis and anaemia, than patients receiving exemestane alone. The committee heard from the clinical experts that, although everolimus can lead to several different adverse reactions, it is generally well tolerated. The clinical experts noted that, because everolimus was associated with pneumonitis, it was likely that patients would need additional monitoring. The committee heard from the patient expert that people vary in their willingness to accept the risks of treatment with chemotherapy because it can significantly worsen a patient's health-related quality of life, and highlighted the importance of providing information on treatments to patients. The committee discussed the results of the indirect treatment comparison that estimates the clinical effectiveness of everolimus plus exemestane compared with fulvestrant. It heard from the ERG that it should regard the results with caution. The committee was aware that the company's indirect treatment comparison included studies that may have assessed progression-free survival locally (which differed from the company's preference for central assessment for everolimus plus exemestane), and that the estimated incremental cost-effectiveness ratio (ICER) for everolimus plus exemestane compared with fulvestrant depended on the results of the indirect treatment comparison. The committee noted its previous conclusion that, because fulvestrant is not used routinely in clinical practice (see section 4.6), and is not currently recommended by NICE (NICE's technology appraisal guidance on fulvestrant included a different patient population), it did not consider fulvestrant to be a relevant comparator. The committee concluded that, for this technology appraisal, the results of the indirect treatment comparison were not key to its decision-making. The committee discussed the company's approach of using the TAMRAD trial, which compared everolimus plus tamoxifen with tamoxifen alone, to inform a comparison of everolimus plus exemestane with tamoxifen alone. The committee understood from the company that it used the hazard ratios from TAMRAD in its economic model and assumed that the hazard ratios for everolimus plus exemestane compared with tamoxifen alone would be the same as those for everolimus plus tamoxifen compared with tamoxifen alone. The clinical experts noted that they could not determine whether the assumption was valid because exemestane and tamoxifen have different mechanisms of action. The committee concluded that there was considerable uncertainty about the validity of the comparison of everolimus plus exemestane with tamoxifen. Therefore no conclusions were possible on the effectiveness of everolimus plus exemestane compared with tamoxifen. The committee considered the results of the naive chained indirect analysis, which estimated the clinical effectiveness of everolimus plus exemestane compared with chemotherapy. It heard from the ERG that it had several concerns about the methodology associated with this analysis, which relied on untested assumptions and on a systematic review (Wilcken et al. 2003) that included studies that no longer reflect clinical practice. The clinical experts agreed that the studies in the systematic review reflect outdated clinical practice, but also stated there was little evidence comparing endocrine therapies with chemotherapies. Indeed, the ERG had not identified any evidence that would have allowed the company to have completed a more appropriate analysis. The committee concluded that it was not possible to make robust comparisons between everolimus plus exemestane and chemotherapy based on the available evidence. Therefore it was not possible to separately develop recommendations for everolimus plus exemestane compared with chemotherapy. # Cost effectiveness (NICE technology appraisal guidance 295) The committee considered the company's economic model and the ERG's critique of the company's comparison of everolimus plus exemestane and exemestane alone. Firstly, it discussed the company's economic model and their choice of a Weibull function to extrapolate overall survival data from BOLERO‑2. It noted that the Weibull function did not provide the best statistical fit, but heard from the company that its clinical advisers suggested that the Weibull function estimated the proportion of patients alive over time more accurately than the other functions explored. The committee was aware of numerous uncertainties about extrapolating survival beyond the end of BOLERO‑2, for example, that few patients died during the median 18‑month follow‑up of BOLERO‑2, making data sparse, and whether mortality rates would plausibly differ after treatment stops between postmenopausal women who had or did not have previous treatment with everolimus. The committee concluded that statistical fit is only one way to choose a parametric function, and that how well a curve fits the natural history of advanced breast cancer treated with standard treatment would also be important, particularly when overall survival data are immature. The committee discussed whether it was appropriate for the company to adjust overall survival with a factor it took from Beauchemin et al. (2012) to address the anomalous result when estimating the number of women in the 'progressed disease' health state from the progression-free survival and overall survival data, and whether it was appropriate to apply this adjustment only to people who had everolimus plus exemestane. The committee heard from the ERG that this adjustment increased the length of overall survival in the everolimus plus exemestane arm of the economic model by 17%. The company clarified that it took the factor from a conference poster, which it considered to be the most up‑to‑date source of evidence. The committee understood that the most recent evidence was not necessarily the most robust, and that other studies exist and had been reviewed by the NICE Decision Support Unit (a review of studies examining the relationship between progression-free survival and overall survival in advanced or metastatic cancer). Also, the committee concluded that it was not reasonable for the company to apply this adjustment factor only to the everolimus plus exemestane arm of the economic model, and that the anomalous result for post-progression survival showed that the company had either used the wrong parametric model or had applied the functions incorrectly in the model. The committee noted that the company had removed the adjustment in the additional analyses it provided after consultation. The committee noted that the company had originally applied a background mortality rate (age-related mortality) after 4 years in the economic model. It heard from the ERG that this double counted deaths from causes other than advanced breast cancer because these were seen in BOLERO‑2. The committee concluded that it was not appropriate for the company to model additional background mortality and noted that this was removed in the additional analyses provided by the company after consultation. The committee discussed the implications of using local or central assessment for progression-free survival in the modelling. It would expect progression-free survival from the economic model and the trial to be similar, but noted that the centrally assessed mean progression-free survival with everolimus plus exemestane was 3.8 months longer than that observed in BOLERO‑2, whereas progression-free survival for exemestane alone was only 0.5 months longer in the economic model than in the trial. The committee noted that this indicated that the economic model did not reflect the patient population in BOLERO‑2. Also, the committee noted that the estimates for locally assessed progression-free survival were similar between the economic model and the trial. The committee concluded that the company's economic model based on centrally assessed progression-free survival is unlikely to provide a robust basis for calculating a valid estimate of cost effectiveness. The committee discussed the ERG's exploratory survival analyses. The ERG chose a 'piecewise approach' because the mortality risk associated with advanced breast cancer is likely to be different before progression than it is after progression when a treatment has stopped. The committee understood from the ERG that the company did not provide the post-progression survival data that it requested and therefore the ERG could not assess whether everolimus prolongs survival after disease progression. The committee agreed that fitting multiple parametric curves to the overall survival data may be appropriate when there is a high degree of uncertainty associated with estimating the survival gain from immature data. However, the committee could not be confident that this markedly diminished the uncertainty inherent in the data. It noted the ERG's observation that mortality rates were similar in both treatment arms after approximately 10 months, and so the ERG fitted an exponential model that assumed parallel long-term hazard trends and, after consultation, an alternative scenario that assumed everolimus plus exemestane provides a survival benefit compared with exemestane alone (that is, the 'non-parallel exponential model'). The committee heard from the ERG that it was unable to assess the goodness of fit of the exploratory survival analyses because the company did not provide access to the patient-level data. It agreed that the company's estimated 10.5 months' survival benefit with the Weibull analysis was likely to be optimistic, and that the estimated 1.4 months' survival benefit with the ERG's exploratory parallel exponential model was likely to be pessimistic. The committee acknowledged that the overall survival benefit of everolimus plus exemestane is uncertain but probably lies between these estimates, as seen in the overall survival benefit from the ERG's non-parallel exponential model (4.6 months), which reflects the longer progression-free survival with everolimus plus exemestane compared with exemestane alone. The committee agreed to use the ERG's exploratory non-parallel exponential survival analyses in its discussions. The committee discussed the utility values for the 'stable disease' health state used by the company in its economic model. It noted that, in its original submission, the company had chosen utility values (taken from Lloyd et al. 2006) for the health states that were not estimated in line with the NICE reference case because it used vignettes to describe the health states and the standard gamble technique to estimate the utility values. The committee was aware that these utility values had been used by other companies in NICE's previous appraisal of breast cancer (fulvestrant for the treatment of locally advanced or metastatic breast cancer). The ERG noted that the company had incorrectly calculated the utility estimate for 'stable disease' in its original submission because it had not calculated utility separately for each treatment. The committee understood that correcting this had a small effect on the ICER. It understood that the company had measured health-related quality of life using a disease-specific instrument, but made no attempt to map this to the preferred generic EQ‑5D instrument, despite several algorithms being available. It heard from the company that this was because BOLERO‑2 evaluated health-related quality of life only until disease progressed. The committee acknowledged this limitation, but concluded that it would have been appropriate for the company to present estimates for the 'stable disease' health state from BOLERO‑2 alongside its base-case analysis. In its meeting after consultation, the committee discussed the alternative utility value from Launois et al. (1997) included by the company for the 'progressed disease' health state. The committee heard from the company that it had increased the utility value for 'progressed disease' after discussions with the Scottish Medicines Consortium. The company explained that Launois et al. was the only publication relevant to advanced breast cancer that it could find. The committee discussed the anomalous finding in Launois et al., which showed a lower quality of life for 'early progression' compared with 'progression'. It heard from the clinical experts that this was unlikely to reflect reality. The committee further discussed whether it is more valid to assume a decrease in utility from stable to progressed disease of approximately 0.28 (if using Lloyd et al. 2006) or approximately 0.12 (if using Launois et al.). The patient expert commented that they were unable to approximate the decrease in quality of life resulting from disease progression in patients with advanced breast cancer. The committee stated that the estimates for quality of life for the 'progressed disease' state from both Lloyd et al. and Launois et al. relied on the descriptions used for the vignettes in the studies but the company could not provide information on how the vignettes had been described. The committee heard from the ERG that Lloyd et al. better reflected NICE's guide to the methods of technology appraisal (2008), in that it used valuations from the UK general public, than did Launois et al., which surveyed French nurses. The committee concluded that neither valuation of utility for the 'progressed disease' health state was without uncertainty, but that the data from Lloyd et al. were more appropriate than the data from Launois et al. The committee discussed whether the company provided valid cost inputs for the 'stable' and 'progressed' health states in its economic model. It was aware that the company may have used drug costs of chemotherapy (particularly docetaxel) that were higher than the costs in the NHS, achieved through national agreements. The committee agreed with the ERG's decision to adjust the time on treatment to reflect the longer follow‑up period of BOLERO‑2, and to include costs for a quarterly appointment to assess whether patients with stable disease had progressed. The committee was aware that these exploratory analyses decreased and increased the base-case ICER respectively. It noted that the univariate sensitivity analysis included in the company's economic model (although not presented in its written submission) showed that the ICERs were sensitive to the costs for the 'progressed disease' health state but that this did not include costs associated with subsequent therapies (namely, chemotherapy). After consultation, the company included the costs associated with subsequent therapies in its economic model. It heard from the ERG that there is no evidence to suggest the probability of receiving subsequent therapies after disease progression differed significantly between treatment arms. The committee concluded that the inclusion of costs associated with subsequent therapies would have a small effect on the estimation of the ICER. The committee discussed whether it was appropriate to include costs and disutilities associated with adverse events in the model, noting that the company had included these in its analyses of everolimus plus exemestane compared with chemotherapies, but not when compared with endocrine therapies. The committee heard from the clinical experts that mild adverse events would not lead to a break from treatment, but that patients may need other medicines (for example, mouthwash for stomatitis). The clinical experts noted that patients who have grade 3 or 4 adverse events would need a temporary break in treatment and that the cost of pneumonitis appeared to be underestimated in the company's model for both diagnosis and treatment. Having previously concluded that, given the side-effect profile of everolimus, costs and disutilities associated with adverse events should be included for each of the comparisons in its economic model, the committee noted that the company included them in the additional analyses it provided after consultation. The committee discussed the most plausible ICER, noting that a robust comparison was available only for everolimus plus exemestane compared with exemestane alone. It agreed that the most plausible ICER should be based on an analysis using the following assumptions: using exponential functions to estimate progression-free survival and the non-parallel model of overall survival -mitting the adjustment factor from Beauchemin et al. (2012) using locally assessed trial data including adverse reactions using rates of adverse reactions as documented in the European public assessment report recalculating time on treatment including costs of monitoring disease that has not progressed correcting discounting and utility values for stable disease using the utility value for 'progressed disease' from Lloyd et al. (2006) and omitting extra mortality from non-cancer causes.The committee noted that the ICER was most sensitive to the modelling of overall survival and the progression-free survival assessment method. The committee concluded that the ERG's estimate of the ICER (including the patient access scheme for everolimus) of £68,000 per quality-adjusted life year (QALY) gained for everolimus plus exemestane compared with exemestane alone was more plausible than the company's base-case estimate. The committee concluded that everolimus (plus exemestane) could not be considered a cost-effective use of NHS resources for treating advanced HER2-negative hormone receptor-positive breast cancer, after recurrence or progression following a non-steroidal aromatase inhibitor. The committee discussed the innovative nature of everolimus and whether the economic analysis had captured all changes in health-related quality of life. In its submission, the company stated that everolimus was innovative because it is administered orally, may slow the rate of disease progression in the bone, increases productivity and reduces healthcare resource use when compared with chemotherapy. The committee noted that a number of the comparator treatments are also administered orally, that bone markers were only an exploratory end point in BOLERO‑2, and that gains in productivity were currently outside of the NICE reference case. The committee considered that differences in the use of healthcare resource are expected to be adequately captured in the company's economic model. Although the committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring the sensitivity of the tumour to endocrine therapy, it concluded that the company had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the QALY, as defined in NICE's guide to the methods of technology appraisal (2008). The committee concluded that the case for innovation made by the company did not change the committee's conclusions about the cost effectiveness of everolimus plus exemestane. The committee considered supplementary advice from NICE, which should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all of the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to show that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The committee discussed whether everolimus plus exemestane fulfilled the criteria for a life-extending end-of-life treatment. It acknowledged the uncertainty associated with estimated life expectancy but, given that the company's model estimated a mean overall survival of 28.9 months for exemestane alone, the committee was not convinced that the life expectancy of women offered everolimus plus exemestane based on the marketing authorisation was convincingly less than 24 months. The committee heard from the company that it chose not to present a case for end-of-life treatment in its original submission because discussions with the clinical experts identified no clinically plausible subgroups of patients with a life expectancy of less than 24 months. The committee was aware that the meta-analysis of the SoFEA and EFECT trials provided by the company during consultation suggested a median survival of 22.6 months in patients with advanced breast cancer treated with exemestane alone. However, the committee understood that the company's original submission showed at least a third of the patients in the SoFEA trial had HER2-positive tumours (the EFECT trial did not report the proportion of patients with HER2-negative tumours). It heard from the clinical experts that HER2-positive tumours have a worse prognosis, that is, patients with HER2-positive tumours on average die sooner than patients with HER2-negative tumours. The committee concluded that these 2 trials were not relevant in determining life expectancy in women with HER2-negative tumours, and that everolimus plus exemestane did not convincingly fulfil this criterion for an end-of-life therapy as defined. Having established that everolimus did not meet the short life expectancy criterion, the committee decided that it was not necessary to make a decision about the extension-to-life or population size criteria. It concluded that, on this basis, everolimus plus exemestane did not fulfil the criteria for being a life-extending, end-of-life treatment. The committee discussed whether subgroups existed in which everolimus plus exemestane offered a cost-effective use of NHS resources. The ERG had identified 3 subgroups. The committee noted that, although the statistical analysis plan of the trial included no plans to test for interaction, the company had stated that it had not identified any statistically significant differences in progression-free survival between subgroups. The committee heard from the ERG that it believed these subgroups may be relevant because, even though the relative effectiveness of everolimus plus exemestane might be similar across subgroups, differences in baseline risk could improve the cost effectiveness. The committee noted that the ERG had been unable to quantify the effect on the ICER of the different subgroups. The committee was also aware that the efficacy analyses in subgroups performed by the company were purely exploratory and intended to explore the uniformity of any overall treatment effects, and that the company had not included any cost-effectiveness analyses for subgroups in its original or revised submission. The committee concluded that the available evidence did not allow it to make any recommendations specific to subgroups of patients. # Cancer Drugs Fund reconsideration of NICE technology appraisal guidance 295 This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on everolimus in combination with exemestane for treating advanced HER2-negative hormone receptor-positive breast cancer after endocrine therapy. The committee considered the company's submission for the Cancer Drugs Fund reconsideration that: included a patient access scheme that provides a simple discount to the list price of everolimus provided new analyses reflecting longer follow-up data on overall survival from BOLERO‑2 revised the approaches for extrapolating progression-free survival and overall survival in the economic model addressed the committee's preferred assumptions (see section 4.23) used up-to-date unit cost data.The committee also considered the ERG's critique of the company's reconsideration submission and the ERG's exploratory analyses. The committee was aware that the ERG had corrected an error when implementing the time horizon in the company's economic model. ## Extrapolating progression-free survival from BOLERO‑2 The committee noted that the company used progression-free survival based on assessment by a local radiologist, as preferred in the original appraisal (see section 4.8 and section 4.17). It also noted that the company used the same data cut for progression-free survival in its original submission and its reconsideration submission. The committee understood that this was because the data were already mature at the time of the original data cut. However, the committee was aware that the company and ERG used different methods to model the same progression-free survival data in this reconsideration compared with the original appraisal. The committee asked why the company and ERG had chosen to change their methods. The committee understood that the company now used the function that provided the best statistical fit (log-logistic) rather than the function that was considered the most plausible by the company's clinical advisers (Weibull) and used it to extrapolate, but also to replace, the trial Kaplan‒Meier data. The committee considered that the log-logistic function was likely to overestimate the progression-free survival benefits of everolimus plus exemestane compared with exemestane alone beyond the end of BOLERO‑2. The committee noted that the ERG took a different approach to modelling progression-free survival by using the Kaplan–Meier data directly from BOLERO‑2 and then applying a simple exponential model to both treatment arms from the time when the number of data events from BOLERO‑2 was small. The committee heard from the ERG that the trial data and the simple exponential model corresponded closely. The committee agreed that the ERG's approach was reasonable given the maturity of the progression-free survival data and the ERG's preference for using real data when possible. It concluded that it preferred the ERG's method for modelling progression-free survival rather than the company's method. ## Extrapolating overall survival from BOLERO‑2 The committee noted that the company had submitted more mature evidence for overall survival in its Cancer Drugs Fund reconsideration submission than it had originally. The committee recognised that new data would mean that the company would revisit the most appropriate method for modelling overall survival. The new data were based on a median follow-up of 39.3 months, by which time 56.6% of patients had died. This compared with the company's original submission based on a median follow-up of 16 months, when 25.1% of patients had died. Noting that the hazard ratio changed from 0.77 to 0.89 in the analyses, the committee highlighted that the more mature overall survival data suggested everolimus plus exemestane compared with exemestane alone was less clinically effective than it appeared in the company's original submission. The committee recognised that the company fitted a log-logistic function to the curve representing the more mature data to model overall survival. It commented that the company chose the log-logistic function because it considered this to be the best statistical fit. The committee understood that the ERG modelled overall survival differently using a landmark analysis based on the assumption that patients would not gain benefit (increased life expectancy) from everolimus after disease progression and after stopping treatment. The committee agreed that the ERG's approach was reasonable and the landmark method was likely to provide a reasonable approximation of the incremental survival, which reflected BOLERO‑2. The committee noted that both the company's and ERG's methods for modelling overall survival had a small effect on the ICER. However, it concluded that it preferred the ERG's method for modelling overall survival rather than the company's method. ## Probabilistic ICERs The committee noted that the company only provided ICERs estimated from deterministic analyses in its response to the appraisal consultation document. The committee preferred probabilistic sensitivity analyses because most economic models are non-linear. It concluded that it would have preferred to have seen probabilistic ICERs as defined in NICE's guide to the methods of technology appraisal (2013). ## End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the company provided a subgroup analysis of people with HER2-negative hormone receptor-positive tumours randomised to exemestane alone in the SoFEA trial. Median overall survival was less than 24 months. The committee was aware that the mean life expectancy would exceed the median life expectancy. The committee noted that the median overall survival for people receiving exemestane alone was 26.6 months in BOLERO‑2. It was also aware that the company's model had estimated a mean survival of over 30 months. The committee was aware that the ERG's exploratory analyses similarly estimated a mean life expectancy of more than 30 months for exemestane alone. Therefore, the committee agreed with its conclusion in the original technology appraisal that everolimus plus exemestane did not fulfil the short life expectancy criterion for an end-of-life therapy (see section 4.26). It concluded that everolimus plus exemestane did not fulfil the criteria for being a life-extending, end-of-life treatment. ## Conclusion The committee discussed the most plausible ICER for everolimus plus exemestane compared with exemestane alone. The committee agreed that the most plausible ICER should be based on the ERG's exploratory analyses to estimate progression-free survival and overall survival and the longer time horizon. In its response to the appraisal consultation document, the company provided an updated cost-effectiveness analysis including an increased discount in the patient access scheme and survival analyses of both progression-free and overall survival using ERG methods. It also used the longer time horizon. The ICERs including the revised patient access scheme are commercial in confidence to protect the level of discount, and cannot be presented here. The committee concluded that everolimus plus exemestane with the revised patient access scheme was a cost-effective use of NHS resources and could be recommended for routine commissioning in the NHS for treating advanced HER2-negative hormone receptor-positive breast cancer in postmenopausal women that has recurred or progressed after a non-steroidal aromatase inhibitor. # Summary of appraisal committee's key conclusions TA421 Appraisal title: Everolimus with exemestane for treating advanced breast cancer after endocrine therapy Section Key conclusion: Cancer Drugs Fund reconsideration of TA295 Everolimus, in combination with exemestane, is recommended within its marketing authorisation as an option for treating advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non-steroidal aromatase inhibitor. Everolimus is recommended only if the company provides it with the discount agreed in the patient access scheme. In its response to the appraisal consultation document, the company provided an updated cost-effectiveness analysis. The committee concluded that everolimus plus exemestane with the revised patient access scheme was a cost-effective use of NHS resources and could be recommended for routine commissioning in the NHS for treating advanced HER2-negative hormone receptor-positive breast cancer in postmenopausal women that has recurred or progressed after a non-steroidal aromatase inhibitor. Current practice (TA295) Clinical need of patients, including the availability of alternative treatments The committee heard from the patient expert that patients would value everolimus plus exemestane as a treatment option because it is offered when limited treatment options exist after a woman's disease becomes resistant to endocrine therapy, and because everolimus plus exemestane may delay the need for chemotherapy and its associated toxicity. The committee also heard from the patient expert that patients value increased survival and improved quality of life. The committee heard from clinical experts that the most relevant chemotherapy comparators for everolimus are likely to be capecitabine and vinorelbine because anthracyclines (doxorubicin) and taxanes (docetaxel) are generally used to treat metastatic breast cancer in people who have symptomatic and life-threatening visceral disease. The committee heard from clinical experts that, although fulvestrant is available through the Cancer Drugs Fund, NICE has not recommended fulvestrant following treatment with tamoxifen. Also, the committee did not hear any evidence that fulvestrant can be considered routine practice when non-steroidal aromatase inhibitors have failed. The clinical experts stated that tamoxifen and exemestane (alone) were appropriate comparators for everolimus plus exemestane, although tamoxifen is often offered after exemestane. The committee concluded that exemestane alone was the most relevant endocrine comparator for everolimus plus exemestane. The technology (TA295) Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy. What is the position of the treatment in the pathway of care for the condition? The clinical experts confirmed that everolimus plus exemestane would be offered to patients whose disease has progressed on a non-steroidal aromatase inhibitor at a point when a patient might receive either further endocrine therapy or chemotherapy. Adverse reactions The committee noted that the BOLERO‑2 trial showed that patients receiving everolimus plus exemestane had more adverse reactions, specifically stomatitis and anaemia, than patients receiving exemestane alone. However, the committee heard that everolimus is generally well tolerated. Evidence for clinical effectiveness (TA295) Availability, nature and quality of evidence The committee concluded that the indirect treatment comparison that estimated the clinical effectiveness of everolimus plus exemestane compared with fulvestrant should be regarded with caution. The committee noted that the TAMRAD trial did not compare everolimus within its licensed indication (that is, in combination with exemestane) with tamoxifen. The committee noted that no conclusions on the effectiveness of everolimus plus exemestane compared with tamoxifen were possible. The committee concluded that the 'naive chained indirect analysis', which estimated the clinical effectiveness of everolimus plus exemestane compared with chemotherapy, relied on untested assumptions and on a systematic review that included studies that no longer reflect clinical practice. Relevance to general clinical practice in the NHS The committee heard from the clinical experts that the BOLERO‑2 trial population represented patients who would be offered everolimus in the UK. Uncertainties generated by the evidence The committee agreed that the immaturity of the overall survival data from the BOLERO-2 trial generated considerable uncertainty associated with the longer-term benefits of everolimus plus exemestane. The committee concluded that there was considerable uncertainty about the validity of the comparison of everolimus plus exemestane with tamoxifen, but noted its previous conclusions that, of the endocrine therapies, the comparison of everolimus plus exemestane with exemestane alone was the most relevant to the appraisal. The committee concluded that it was not possible to make robust comparisons between everolimus plus exemestane and chemotherapies based on the available evidence. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee noted that, although the company included no plans to test for interaction in its statistical analysis plan, it had stated that it had not identified any statistically significant differences in progression-free survival between subgroups. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that everolimus plus exemestane is effective in prolonging progression-free survival compared with exemestane alone. The committee agreed that the immaturity of the overall survival data resulted in considerable uncertainty associated with the longer-term benefits of everolimus plus exemestane. Evidence for cost effectiveness (TA295) Availability and nature of evidence The committee considered the company's economic model and the evidence review group's (ERG) critique of the company's comparison of everolimus plus exemestane and exemestane alone. The committee noted that the incremental cost-effectiveness ratio (ICER) was most sensitive to the modelling of overall survival and the progression-free survival assessment method. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee agreed that the most plausible ICER should be based on an analysis using the following assumptions: using exponential functions to estimate progression-free survival; omitting the adjustment factor from Beauchemin et al. (2012); using locally assessed trial data; including adverse reactions; using rates of adverse reactions as documented in the European public assessment report; recalculating time on treatment; including costs of monitoring disease that has not progressed; correcting discounting and utility values for stable disease; using the utility value for 'progressed disease' from Lloyd et al. (2006); and omitting extra mortality from non-cancer causes. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee concluded that neither valuation of utility for the 'progressed disease' health state was without uncertainty, but that the data from Lloyd et al. were more appropriate than the data from Launois et al. (1997). Although the committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy, it concluded that the company had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the quality-adjusted life year (QALY). Are there specific groups of people for whom the technology is particularly cost effective? The committee concluded that the available evidence did not allow it to make any recommendations specific to subgroups of patients. What are the key drivers of cost effectiveness? Using local or central assessment for progression-free survival in the modelling: The committee concluded that it was more appropriate to use effectiveness data derived from local assessment in the modelling than from central assessment because local assessment represented the primary end point of the trial, reflected clinical practice and minimised the potential for bias from informative censoring. Choice of survival modelling: The committee agreed that the company's estimated 10.5 months' survival benefit with the Weibull analysis was likely to be optimistic, and that the estimated 1.4 months' survival benefit with the ERG's exploratory parallel exponential model was likely to be pessimistic. It acknowledged that the overall survival benefit of everolimus plus exemestane is uncertain but probably lies between these estimates. The committee noted that it is also similar to the overall survival benefit from the ERG's non-parallel exponential model (4.6 months), which reflects the longer progression-free survival with everolimus plus exemestane than with exemestane alone. Most likely cost-effectiveness estimate (given as an ICER) The committee concluded that the ERG's estimate of the ICER (including the patient access scheme for everolimus) of £68,000 per QALY gained for everolimus plus exemestane compared with exemestane alone was more plausible than the company's base-case estimate. Additional factors taken into account (TA295) Patient access schemes (PPRS) Novartis has agreed a patient access scheme with the Department of Health. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End-of-life considerations The committee acknowledged the uncertainty associated with estimated life expectancy but, given that the company's model estimated a mean overall survival of 28.9 months for exemestane alone, the committee was not convinced that the life expectancy of women to whom everolimus plus exemestane would be offered was convincingly less than 24 months. The committee therefore concluded that everolimus plus exemestane did not fulfil the criteria for an end-of-life therapy. Equalities considerations and social value judgements The only potential issue raised was that everolimus should be available to male patients. However, the UK marketing authorisation includes only postmenopausal women and therefore this issue could not be addressed within the remit of this NICE technology appraisal. Cancer Drugs Fund reconsideration of TA295 Evidence for clinical effectiveness The committee discussed the data on clinical effectiveness from BOLERO‑2. The committee noted that the company had submitted more mature evidence for overall survival in its Cancer Drugs Fund reconsideration submission than it had originally. The committee was aware that the company and ERG used different methods to model the same progression-free survival data in this reconsideration compared with the original appraisal. Noting that the hazard ratio changed from 0.77 to 0.89 in the analyses, the committee highlighted that the more mature overall survival data suggested everolimus plus exemestane compared with exemestane alone was less clinically effective than it appeared in the company's original submission. Evidence for cost effectiveness The committee considered the company's submission for the Cancer Drugs Fund reconsideration that included a patient access scheme, provided new analyses reflecting longer follow-up data on overall survival from BOLERO 2, revised the approaches for extrapolating progression-free survival and overall survival in the economic model, addressed the committee's preferred assumptions and used up-to-date unit cost data. The committee also considered the ERG's critique of the company's reconsideration submission and the ERG's exploratory analyses. The committee noted that the company only provided ICERs estimated from deterministic analyses in its response to the appraisal consultation document. The committee preferred probabilistic sensitivity analyses because most economic models are non-linear. The committee agreed that the most plausible ICER should be based on the ERG's exploratory analyses to estimate progression-free survival and overall survival and the longer time horizon. Although the committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy, it concluded that the company had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the quality-adjusted life year (QALY). The ICERs including the patient access scheme are commercial in confidence, and cannot be presented here. Additional factors taken into account Novartis has agreed a patient access scheme for everolimus with the Department of Health.	{'Recommendations': 'Everolimus, in combination with exemestane, is recommended within its marketing authorisation, as an option for treating advanced human epidermal growth factor receptor\xa02 (HER2)-negative, hormone-receptor-positive breast cancer in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non-steroidal aromatase inhibitor. Everolimus is recommended only if the company provides it with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nEverolimus (Afinitor, Novartis Pharmaceuticals) inhibits the mammalian target of rapamycin, a protein that regulates the division of tumour cells and growth of blood vessels.\n\nMarketing authorisation\n\nEverolimus has a UK marketing authorisation for the 'treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor'.\n\nAdverse reactions\n\nThe summary of product characteristics lists the most frequently reported grade\xa03 or\xa04 adverse reactions including: anaemia, fatigue, diarrhoea, infections, stomatitis, hyperglycaemia, thrombocytopenia, lymphopenia, neutropenia, hypophosphataemia, hypercholesterolaemia, diabetes mellitus and pneumonitis. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nEverolimus is administered orally. The recommended dosage is 10\xa0mg once daily and treatment should continue as long as patients benefit clinically, or until they have unacceptable adverse reactions. Adverse reactions that are severe and/or intolerable may be managed by reducing the dosage to 5\xa0mg daily or temporarily stopping treatment then reintroducing it at 5\xa0mg daily.\n\nPrice\n\nThe price for a pack (30\xa0tablets per pack) of 10-mg tablets and 5-mg tablets is £2,673 and £2,250 respectively (excluding VAT; 'British national formulary' [BNF]). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of everolimus with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Novartis and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on everolimus in combination with exemestane for treating advanced HER2-negative hormone receptor-positive breast cancer after endocrine therapy. It focused on updated overall survival data from the BOLERO‑2 trial and cost-effectiveness analyses using a patient access scheme, which provides everolimus at a reduced cost. The level of the discount is commercial in confidence. Sections\xa04.1 to 4.27 cover the committee's consideration of the evidence submitted in the original appraisal. Sections\xa04.28 to 4.33 cover the committee's consideration of the additional evidence submitted for the Cancer Drugs Fund reconsideration.\n\nIn BOLERO‑2 postmenopausal women with advanced human epidermal growth factor receptor\xa02 (HER2)-negative hormone receptor-positive breast cancer without symptomatic visceral disease who had previously had a non-steroidal aromatase inhibitor were randomised to either everolimus plus exemestane or to exemestane alone. The primary end point of the trial was progression-free survival as assessed by a local radiologist (study site specific).\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on everolimus in combination with exemestane for treating advanced HER2-negative hormone receptor-positive breast cancer after endocrine therapy.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of everolimus plus exemestane, having considered evidence on the nature of advanced human epidermal growth factor receptor\xa02 (HER2)-negative hormone receptor-positive breast cancer after endocrine therapy and the value placed on the benefits of everolimus plus exemestane by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee considered the views of the patient expert on their experience of everolimus as a treatment for advanced breast cancer. It heard that patients would value everolimus plus exemestane as a treatment option because it is offered when limited treatment options exist after a woman's disease becomes resistant to endocrine therapy, and because everolimus plus exemestane may delay the need for chemotherapy and its associated toxicity. The committee also heard from the patient expert that patients value increased survival and improved quality of life. The committee was aware of comments from consultees that everolimus is considered to be the 'biggest development in years for treating breast cancer' and also that 'length of life is only worth having if there is a quality of life as well'. The committee recognised the importance of having a range of treatment options for postmenopausal women with advanced breast cancer.\n\nThe committee considered the marketing authorisation, which specifies that everolimus can be used for 'postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor'. The committee noted that patients in the BOLERO‑2 trial may have had visceral disease, but that it was unclear whether these patients were also symptomatic. The committee heard from the clinical experts that patients with visceral disease may or may not have symptoms but that, for patients with life-threatening symptomatic visceral disease, chemotherapy is the preferred treatment option, usually with an anthracycline-containing regimen (doxorubicin or epirubicin) or a taxane. The committee understood that, in accordance with the marketing authorisation, everolimus was not being appraised for patients with symptomatic visceral disease.\n\nThe committee considered the likely position of everolimus plus exemestane in the treatment pathway for women with advanced HER2-negative hormone receptor-positive breast cancer. The committee heard from the clinical experts that, in general, clinical practice reflects the recommendations in NICE's guideline on advanced breast cancer, but that patients whose disease progresses after a non-steroidal aromatase inhibitor (such as anastrozole or letrozole) are often offered further endocrine treatments rather than chemotherapy. The clinical experts confirmed that everolimus plus exemestane would be offered to patients whose disease has progressed on a non-steroidal aromatase inhibitor at a point when a patient might otherwise receive either further endocrine therapy or chemotherapy.\n\nThe committee considered the chemotherapy treatments that the company had included as comparators in its submission. It understood that the scope listed 'chemotherapy in accordance with NICE guidance' and that the company had included comparisons with docetaxel, doxorubicin and capecitabine, and after consultation, vinorelbine. The committee heard from the clinical experts that the most relevant chemotherapy comparators for everolimus plus exemestane are likely to be capecitabine and vinorelbine because anthracyclines (doxorubicin) and taxanes (docetaxel) are generally used to treat metastatic breast cancer in patients who have symptomatic and life-threatening visceral disease (see section\xa04.3). The committee concluded that, of the chemotherapies, the comparison of everolimus plus exemestane with capecitabine was the most relevant for the population in the appraisal, and that a comparison with vinorelbine was also appropriate.\n\nThe committee then discussed the endocrine treatments included as comparators by the company. It heard from the clinical experts that, although fulvestrant is available through the Cancer Drugs Fund, NICE has not recommended it. The committee did not hear any evidence that fulvestrant can be considered routine practice when non-steroidal aromatase inhibitors have failed. The clinical experts stated that tamoxifen and exemestane (alone) were appropriate comparators for everolimus plus exemestane, although tamoxifen is often offered after exemestane. Also, the committee understood from the clinical experts that, although exemestane is used, there are concerns that it is not effective in the population considered in this appraisal because the disease will have already progressed on a non-steroidal aromatase inhibitor. The committee noted that this concern was acknowledged by the European Medicines Agency in the European public assessment report, which stated that patients in the exemestane arm of BOLERO‑2 may have received suboptimal treatment. On this basis, the European Medicines Agency requested that the company complete a trial comparing everolimus plus exemestane with everolimus alone and with capecitabine alone. Despite these issues, the committee concluded that exemestane alone was the most relevant endocrine comparator for everolimus plus exemestane for the purpose of this appraisal.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0295)\n\nThe committee discussed the data on clinical effectiveness from BOLERO‑2. It heard from the clinical experts that the trial population represented patients who would be offered everolimus in the UK. The committee understood from the trial publication and from the statistical analysis plan of the trial that the primary end point of the trial was progression-free survival based on radiographic assessment by local investigators, and that central assessment by an independent radiology committee was used in supportive analyses. However, in its submission, and at the committee meeting, the company stated that the primary end point was progression-free survival based both on local and central radiological assessment. The committee noted that the company's statistical analysis plan stated that the primary end point of BOLERO‑2 was amended to local assessment from central assessment 5\xa0months after the original protocol was approved. The company explained that this protocol amendment was implemented after approximately 100\xa0events, but could not provide the reasons for the change. The committee was aware that median progression-free survival was longer (both relatively and absolutely) when estimated using central rather than local assessment and that the company had chosen to use centrally assessed estimates of progression-free survival in its economic model. The committee heard from the company that central assessment was associated with fewer biases. However, it was aware that women in the UK who would receive everolimus plus exemestane would have progression assessed locally, not centrally. The company agreed with the committee that disease progression would be assessed locally in routine clinical practice. The committee was aware that, ideally, trials give unbiased estimates of relative treatment effects, but that biases with central assessment may have existed in this particular trial. The committee agreed that it was important to consider in detail the different approaches related to, and issues around, local and central assessment.\n\nThe committee then discussed the approaches to analysing the BOLERO‑2 data when assessed locally or centrally. It was aware that the trial protocol stipulated that, once a patient's disease was assessed locally as having progressed, study treatment would have stopped (and the patient may have gone on to other treatments), whether or not the central radiological committee had considered the disease to have progressed. The committee heard from the company that the analysis followed the statistical analysis plan, that patients deemed to have progressed only by local assessment were censored in Kaplan–Meier analyses based on central assessment, and that the company's statistical analysis plan acknowledged the potential for informative censoring when the analysis was based on central review. The committee understood that censoring occurs in a trial when the event of interest, in this case, disease progression, is not seen during the follow‑up. It appreciated that censoring in some circumstances can be 'informative', that is, patients censored for one reason are more likely to have disease progression than patients censored for another reason. The censoring in the analysis based on central assessment may have been informative because these patients would plausibly fare more poorly (given that they had disease severe enough for the local radiologists to have deemed their disease to have progressed) than would patients censored by other means. The committee heard from the evidence review group (ERG) that informative censoring may have biased the treatment effect because it violates the statistical assumption that censoring is random and therefore unrelated to prognosis. The ERG noted that this is of greater concern in unblinded trials, but the committee was also aware of the analysis provided by the ERG that concluded there was no evidence that local investigators acted in a way to suggest that unblinding occurred in BOLERO‑2. The committee was also aware of analyses presented by the company after consultation, in which patients randomised to everolimus and censored by central review were instead recorded as having progressed which, according to the company, did not reveal informative censoring. However, the committee noted that these sensitivity analyses resulted in a hazard ratio of\xa00.55, reflecting a smaller treatment effect compared with when effectiveness was addressed centrally (0.36) or locally (0.43). The ERG explained to the committee that it could not verify the sensitivity analysis described by the company without access to the Kaplan–Meier analyses requested at the clarification stage. It concluded that, as a means to avoid informative censoring, local assessment without risk of informative censoring was superior to central assessment with imputed data. In addition, the committee was aware of a meta-analysis by Amit et al. (2011), which showed that local evaluation provides a reliable measure of treatment effect when compared with central assessment, even when trials are unblinded. The committee concluded that it was more appropriate to use effectiveness data derived from local assessment in the modelling than from central assessment because local assessment represented the primary end point of the trial, reflected clinical practice and minimised the potential for bias from informative censoring. Overall, the committee concluded that everolimus plus exemestane is effective in prolonging progression-free survival compared with exemestane alone.\n\nThe committee considered the results for overall survival in BOLERO‑2 and that the median overall survival had not yet been reached. It therefore agreed that the immaturity of the data resulted in considerable uncertainty associated with the longer-term benefits of everolimus plus exemestane.\n\nThe committee considered the safety data from BOLERO‑2, which showed that patients receiving everolimus plus exemestane had more adverse reactions, specifically stomatitis and anaemia, than patients receiving exemestane alone. The committee heard from the clinical experts that, although everolimus can lead to several different adverse reactions, it is generally well tolerated. The clinical experts noted that, because everolimus was associated with pneumonitis, it was likely that patients would need additional monitoring. The committee heard from the patient expert that people vary in their willingness to accept the risks of treatment with chemotherapy because it can significantly worsen a patient's health-related quality of life, and highlighted the importance of providing information on treatments to patients.\n\nThe committee discussed the results of the indirect treatment comparison that estimates the clinical effectiveness of everolimus plus exemestane compared with fulvestrant. It heard from the ERG that it should regard the results with caution. The committee was aware that the company's indirect treatment comparison included studies that may have assessed progression-free survival locally (which differed from the company's preference for central assessment for everolimus plus exemestane), and that the estimated incremental cost-effectiveness ratio (ICER) for everolimus plus exemestane compared with fulvestrant depended on the results of the indirect treatment comparison. The committee noted its previous conclusion that, because fulvestrant is not used routinely in clinical practice (see section\xa04.6), and is not currently recommended by NICE (NICE's technology appraisal guidance on fulvestrant included a different patient population), it did not consider fulvestrant to be a relevant comparator. The committee concluded that, for this technology appraisal, the results of the indirect treatment comparison were not key to its decision-making.\n\nThe committee discussed the company's approach of using the TAMRAD trial, which compared everolimus plus tamoxifen with tamoxifen alone, to inform a comparison of everolimus plus exemestane with tamoxifen alone. The committee understood from the company that it used the hazard ratios from TAMRAD in its economic model and assumed that the hazard ratios for everolimus plus exemestane compared with tamoxifen alone would be the same as those for everolimus plus tamoxifen compared with tamoxifen alone. The clinical experts noted that they could not determine whether the assumption was valid because exemestane and tamoxifen have different mechanisms of action. The committee concluded that there was considerable uncertainty about the validity of the comparison of everolimus plus exemestane with tamoxifen. Therefore no conclusions were possible on the effectiveness of everolimus plus exemestane compared with tamoxifen.\n\nThe committee considered the results of the naive chained indirect analysis, which estimated the clinical effectiveness of everolimus plus exemestane compared with chemotherapy. It heard from the ERG that it had several concerns about the methodology associated with this analysis, which relied on untested assumptions and on a systematic review (Wilcken et al. 2003) that included studies that no longer reflect clinical practice. The clinical experts agreed that the studies in the systematic review reflect outdated clinical practice, but also stated there was little evidence comparing endocrine therapies with chemotherapies. Indeed, the ERG had not identified any evidence that would have allowed the company to have completed a more appropriate analysis. The committee concluded that it was not possible to make robust comparisons between everolimus plus exemestane and chemotherapy based on the available evidence. Therefore it was not possible to separately develop recommendations for everolimus plus exemestane compared with chemotherapy.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0295)\n\nThe committee considered the company's economic model and the ERG's critique of the company's comparison of everolimus plus exemestane and exemestane alone. Firstly, it discussed the company's economic model and their choice of a Weibull function to extrapolate overall survival data from BOLERO‑2. It noted that the Weibull function did not provide the best statistical fit, but heard from the company that its clinical advisers suggested that the Weibull function estimated the proportion of patients alive over time more accurately than the other functions explored. The committee was aware of numerous uncertainties about extrapolating survival beyond the end of BOLERO‑2, for example, that few patients died during the median 18‑month follow‑up of BOLERO‑2, making data sparse, and whether mortality rates would plausibly differ after treatment stops between postmenopausal women who had or did not have previous treatment with everolimus. The committee concluded that statistical fit is only one way to choose a parametric function, and that how well a curve fits the natural history of advanced breast cancer treated with standard treatment would also be important, particularly when overall survival data are immature.\n\nThe committee discussed whether it was appropriate for the company to adjust overall survival with a factor it took from Beauchemin et al. (2012) to address the anomalous result when estimating the number of women in the 'progressed disease' health state from the progression-free survival and overall survival data, and whether it was appropriate to apply this adjustment only to people who had everolimus plus exemestane. The committee heard from the ERG that this adjustment increased the length of overall survival in the everolimus plus exemestane arm of the economic model by 17%. The company clarified that it took the factor from a conference poster, which it considered to be the most up‑to‑date source of evidence. The committee understood that the most recent evidence was not necessarily the most robust, and that other studies exist and had been reviewed by the NICE Decision Support Unit (a review of studies examining the relationship between progression-free survival and overall survival in advanced or metastatic cancer). Also, the committee concluded that it was not reasonable for the company to apply this adjustment factor only to the everolimus plus exemestane arm of the economic model, and that the anomalous result for post-progression survival showed that the company had either used the wrong parametric model or had applied the functions incorrectly in the model. The committee noted that the company had removed the adjustment in the additional analyses it provided after consultation.\n\nThe committee noted that the company had originally applied a background mortality rate (age-related mortality) after 4\xa0years in the economic model. It heard from the ERG that this double counted deaths from causes other than advanced breast cancer because these were seen in BOLERO‑2. The committee concluded that it was not appropriate for the company to model additional background mortality and noted that this was removed in the additional analyses provided by the company after consultation.\n\nThe committee discussed the implications of using local or central assessment for progression-free survival in the modelling. It would expect progression-free survival from the economic model and the trial to be similar, but noted that the centrally assessed mean progression-free survival with everolimus plus exemestane was 3.8\xa0months longer than that observed in BOLERO‑2, whereas progression-free survival for exemestane alone was only 0.5\xa0months longer in the economic model than in the trial. The committee noted that this indicated that the economic model did not reflect the patient population in BOLERO‑2. Also, the committee noted that the estimates for locally assessed progression-free survival were similar between the economic model and the trial. The committee concluded that the company's economic model based on centrally assessed progression-free survival is unlikely to provide a robust basis for calculating a valid estimate of cost effectiveness.\n\nThe committee discussed the ERG's exploratory survival analyses. The ERG chose a 'piecewise approach' because the mortality risk associated with advanced breast cancer is likely to be different before progression than it is after progression when a treatment has stopped. The committee understood from the ERG that the company did not provide the post-progression survival data that it requested and therefore the ERG could not assess whether everolimus prolongs survival after disease progression. The committee agreed that fitting multiple parametric curves to the overall survival data may be appropriate when there is a high degree of uncertainty associated with estimating the survival gain from immature data. However, the committee could not be confident that this markedly diminished the uncertainty inherent in the data. It noted the ERG's observation that mortality rates were similar in both treatment arms after approximately 10\xa0months, and so the ERG fitted an exponential model that assumed parallel long-term hazard trends and, after consultation, an alternative scenario that assumed everolimus plus exemestane provides a survival benefit compared with exemestane alone (that is, the 'non-parallel exponential model'). The committee heard from the ERG that it was unable to assess the goodness of fit of the exploratory survival analyses because the company did not provide access to the patient-level data. It agreed that the company's estimated 10.5\xa0months' survival benefit with the Weibull analysis was likely to be optimistic, and that the estimated 1.4\xa0months' survival benefit with the ERG's exploratory parallel exponential model was likely to be pessimistic. The committee acknowledged that the overall survival benefit of everolimus plus exemestane is uncertain but probably lies between these estimates, as seen in the overall survival benefit from the ERG's non-parallel exponential model (4.6\xa0months), which reflects the longer progression-free survival with everolimus plus exemestane compared with exemestane alone. The committee agreed to use the ERG's exploratory non-parallel exponential survival analyses in its discussions.\n\nThe committee discussed the utility values for the 'stable disease' health state used by the company in its economic model. It noted that, in its original submission, the company had chosen utility values (taken from Lloyd et al. 2006) for the health states that were not estimated in line with the NICE reference case because it used vignettes to describe the health states and the standard gamble technique to estimate the utility values. The committee was aware that these utility values had been used by other companies in NICE's previous appraisal of breast cancer (fulvestrant for the treatment of locally advanced or metastatic breast cancer). The ERG noted that the company had incorrectly calculated the utility estimate for 'stable disease' in its original submission because it had not calculated utility separately for each treatment. The committee understood that correcting this had a small effect on the ICER. It understood that the company had measured health-related quality of life using a disease-specific instrument, but made no attempt to map this to the preferred generic EQ‑5D instrument, despite several algorithms being available. It heard from the company that this was because BOLERO‑2 evaluated health-related quality of life only until disease progressed. The committee acknowledged this limitation, but concluded that it would have been appropriate for the company to present estimates for the 'stable disease' health state from BOLERO‑2 alongside its base-case analysis.\n\nIn its meeting after consultation, the committee discussed the alternative utility value from Launois et al. (1997) included by the company for the 'progressed disease' health state. The committee heard from the company that it had increased the utility value for 'progressed disease' after discussions with the Scottish Medicines Consortium. The company explained that Launois et al. was the only publication relevant to advanced breast cancer that it could find. The committee discussed the anomalous finding in Launois et al., which showed a lower quality of life for 'early progression' compared with 'progression'. It heard from the clinical experts that this was unlikely to reflect reality. The committee further discussed whether it is more valid to assume a decrease in utility from stable to progressed disease of approximately 0.28 (if using Lloyd et al. 2006) or approximately 0.12 (if using Launois et al.). The patient expert commented that they were unable to approximate the decrease in quality of life resulting from disease progression in patients with advanced breast cancer. The committee stated that the estimates for quality of life for the 'progressed disease' state from both Lloyd et al. and Launois et al. relied on the descriptions used for the vignettes in the studies but the company could not provide information on how the vignettes had been described. The committee heard from the ERG that Lloyd et al. better reflected NICE's guide to the methods of technology appraisal (2008), in that it used valuations from the UK general public, than did Launois et al., which surveyed French nurses. The committee concluded that neither valuation of utility for the 'progressed disease' health state was without uncertainty, but that the data from Lloyd et al. were more appropriate than the data from Launois et al.\n\nThe committee discussed whether the company provided valid cost inputs for the 'stable' and 'progressed' health states in its economic model. It was aware that the company may have used drug costs of chemotherapy (particularly docetaxel) that were higher than the costs in the NHS, achieved through national agreements. The committee agreed with the ERG's decision to adjust the time on treatment to reflect the longer follow‑up period of BOLERO‑2, and to include costs for a quarterly appointment to assess whether patients with stable disease had progressed. The committee was aware that these exploratory analyses decreased and increased the base-case ICER respectively. It noted that the univariate sensitivity analysis included in the company's economic model (although not presented in its written submission) showed that the ICERs were sensitive to the costs for the 'progressed disease' health state but that this did not include costs associated with subsequent therapies (namely, chemotherapy). After consultation, the company included the costs associated with subsequent therapies in its economic model. It heard from the ERG that there is no evidence to suggest the probability of receiving subsequent therapies after disease progression differed significantly between treatment arms. The committee concluded that the inclusion of costs associated with subsequent therapies would have a small effect on the estimation of the ICER.\n\nThe committee discussed whether it was appropriate to include costs and disutilities associated with adverse events in the model, noting that the company had included these in its analyses of everolimus plus exemestane compared with chemotherapies, but not when compared with endocrine therapies. The committee heard from the clinical experts that mild adverse events would not lead to a break from treatment, but that patients may need other medicines (for example, mouthwash for stomatitis). The clinical experts noted that patients who have grade\xa03 or\xa04 adverse events would need a temporary break in treatment and that the cost of pneumonitis appeared to be underestimated in the company's model for both diagnosis and treatment. Having previously concluded that, given the side-effect profile of everolimus, costs and disutilities associated with adverse events should be included for each of the comparisons in its economic model, the committee noted that the company included them in the additional analyses it provided after consultation.\n\nThe committee discussed the most plausible ICER, noting that a robust comparison was available only for everolimus plus exemestane compared with exemestane alone. It agreed that the most plausible ICER should be based on an analysis using the following assumptions:\n\nusing exponential functions to estimate progression-free survival and the non-parallel model of overall survival\n\nomitting the adjustment factor from Beauchemin et al. (2012)\n\nusing locally assessed trial data\n\nincluding adverse reactions\n\nusing rates of adverse reactions as documented in the European public assessment report\n\nrecalculating time on treatment\n\nincluding costs of monitoring disease that has not progressed\n\ncorrecting discounting and utility values for stable disease\n\nusing the utility value for 'progressed disease' from Lloyd et al. (2006) and omitting extra mortality from non-cancer causes.The committee noted that the ICER was most sensitive to the modelling of overall survival and the progression-free survival assessment method. The committee concluded that the ERG's estimate of the ICER (including the patient access scheme for everolimus) of £68,000 per quality-adjusted life year (QALY) gained for everolimus plus exemestane compared with exemestane alone was more plausible than the company's base-case estimate. The committee concluded that everolimus (plus exemestane) could not be considered a cost-effective use of NHS resources for treating advanced HER2-negative hormone receptor-positive breast cancer, after recurrence or progression following a non-steroidal aromatase inhibitor.\n\nThe committee discussed the innovative nature of everolimus and whether the economic analysis had captured all changes in health-related quality of life. In its submission, the company stated that everolimus was innovative because it is administered orally, may slow the rate of disease progression in the bone, increases productivity and reduces healthcare resource use when compared with chemotherapy. The committee noted that a number of the comparator treatments are also administered orally, that bone markers were only an exploratory end point in BOLERO‑2, and that gains in productivity were currently outside of the NICE reference case. The committee considered that differences in the use of healthcare resource are expected to be adequately captured in the company's economic model. Although the committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring the sensitivity of the tumour to endocrine therapy, it concluded that the company had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the QALY, as defined in NICE's guide to the methods of technology appraisal (2008). The committee concluded that the case for innovation made by the company did not change the committee's conclusions about the cost effectiveness of everolimus plus exemestane.\n\nThe committee considered supplementary advice from NICE, which should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all of the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to show that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe committee discussed whether everolimus plus exemestane fulfilled the criteria for a life-extending end-of-life treatment. It acknowledged the uncertainty associated with estimated life expectancy but, given that the company's model estimated a mean overall survival of 28.9\xa0months for exemestane alone, the committee was not convinced that the life expectancy of women offered everolimus plus exemestane based on the marketing authorisation was convincingly less than 24\xa0months. The committee heard from the company that it chose not to present a case for end-of-life treatment in its original submission because discussions with the clinical experts identified no clinically plausible subgroups of patients with a life expectancy of less than 24\xa0months. The committee was aware that the meta-analysis of the SoFEA and EFECT trials provided by the company during consultation suggested a median survival of 22.6\xa0months in patients with advanced breast cancer treated with exemestane alone. However, the committee understood that the company's original submission showed at least a third of the patients in the SoFEA trial had HER2-positive tumours (the EFECT trial did not report the proportion of patients with HER2-negative tumours). It heard from the clinical experts that HER2-positive tumours have a worse prognosis, that is, patients with HER2-positive tumours on average die sooner than patients with HER2-negative tumours. The committee concluded that these 2\xa0trials were not relevant in determining life expectancy in women with HER2-negative tumours, and that everolimus plus exemestane did not convincingly fulfil this criterion for an end-of-life therapy as defined. Having established that everolimus did not meet the short life expectancy criterion, the committee decided that it was not necessary to make a decision about the extension-to-life or population size criteria. It concluded that, on this basis, everolimus plus exemestane did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\nThe committee discussed whether subgroups existed in which everolimus plus exemestane offered a cost-effective use of NHS resources. The ERG had identified 3\xa0subgroups. The committee noted that, although the statistical analysis plan of the trial included no plans to test for interaction, the company had stated that it had not identified any statistically significant differences in progression-free survival between subgroups. The committee heard from the ERG that it believed these subgroups may be relevant because, even though the relative effectiveness of everolimus plus exemestane might be similar across subgroups, differences in baseline risk could improve the cost effectiveness. The committee noted that the ERG had been unable to quantify the effect on the ICER of the different subgroups. The committee was also aware that the efficacy analyses in subgroups performed by the company were purely exploratory and intended to explore the uniformity of any overall treatment effects, and that the company had not included any cost-effectiveness analyses for subgroups in its original or revised submission. The committee concluded that the available evidence did not allow it to make any recommendations specific to subgroups of patients.\n\n# Cancer Drugs Fund reconsideration of NICE technology appraisal guidance\xa0295\n\nThis appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on everolimus in combination with exemestane for treating advanced HER2-negative hormone receptor-positive breast cancer after endocrine therapy. The committee considered the company's submission for the Cancer Drugs Fund reconsideration that:\n\nincluded a patient access scheme that provides a simple discount to the list price of everolimus\n\nprovided new analyses reflecting longer follow-up data on overall survival from BOLERO‑2\n\nrevised the approaches for extrapolating progression-free survival and overall survival in the economic model\n\naddressed the committee's preferred assumptions (see section\xa04.23)\n\nused up-to-date unit cost data.The committee also considered the ERG's critique of the company's reconsideration submission and the ERG's exploratory analyses. The committee was aware that the ERG had corrected an error when implementing the time horizon in the company's economic model.\n\n## Extrapolating progression-free survival from BOLERO‑2\n\nThe committee noted that the company used progression-free survival based on assessment by a local radiologist, as preferred in the original appraisal (see section\xa04.8 and section\xa04.17). It also noted that the company used the same data cut for progression-free survival in its original submission and its reconsideration submission. The committee understood that this was because the data were already mature at the time of the original data cut. However, the committee was aware that the company and ERG used different methods to model the same progression-free survival data in this reconsideration compared with the original appraisal. The committee asked why the company and ERG had chosen to change their methods. The committee understood that the company now used the function that provided the best statistical fit (log-logistic) rather than the function that was considered the most plausible by the company's clinical advisers (Weibull) and used it to extrapolate, but also to replace, the trial Kaplan‒Meier data. The committee considered that the log-logistic function was likely to overestimate the progression-free survival benefits of everolimus plus exemestane compared with exemestane alone beyond the end of BOLERO‑2. The committee noted that the ERG took a different approach to modelling progression-free survival by using the Kaplan–Meier data directly from BOLERO‑2 and then applying a simple exponential model to both treatment arms from the time when the number of data events from BOLERO‑2 was small. The committee heard from the ERG that the trial data and the simple exponential model corresponded closely. The committee agreed that the ERG's approach was reasonable given the maturity of the progression-free survival data and the ERG's preference for using real data when possible. It concluded that it preferred the ERG's method for modelling progression-free survival rather than the company's method.\n\n## Extrapolating overall survival from BOLERO‑2\n\nThe committee noted that the company had submitted more mature evidence for overall survival in its Cancer Drugs Fund reconsideration submission than it had originally. The committee recognised that new data would mean that the company would revisit the most appropriate method for modelling overall survival. The new data were based on a median follow-up of 39.3\xa0months, by which time 56.6% of patients had died. This compared with the company's original submission based on a median follow-up of 16\xa0months, when 25.1% of patients had died. Noting that the hazard ratio changed from\xa00.77 to\xa00.89 in the analyses, the committee highlighted that the more mature overall survival data suggested everolimus plus exemestane compared with exemestane alone was less clinically effective than it appeared in the company's original submission. The committee recognised that the company fitted a log-logistic function to the curve representing the more mature data to model overall survival. It commented that the company chose the log-logistic function because it considered this to be the best statistical fit. The committee understood that the ERG modelled overall survival differently using a landmark analysis based on the assumption that patients would not gain benefit (increased life expectancy) from everolimus after disease progression and after stopping treatment. The committee agreed that the ERG's approach was reasonable and the landmark method was likely to provide a reasonable approximation of the incremental survival, which reflected BOLERO‑2. The committee noted that both the company's and ERG's methods for modelling overall survival had a small effect on the ICER. However, it concluded that it preferred the ERG's method for modelling overall survival rather than the company's method.\n\n## Probabilistic ICERs\n\nThe committee noted that the company only provided ICERs estimated from deterministic analyses in its response to the appraisal consultation document. The committee preferred probabilistic sensitivity analyses because most economic models are non-linear. It concluded that it would have preferred to have seen probabilistic ICERs as defined in NICE's guide to the methods of technology appraisal (2013).\n\n## End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the company provided a subgroup analysis of people with HER2-negative hormone receptor-positive tumours randomised to exemestane alone in the SoFEA trial. Median overall survival was less than 24\xa0months. The committee was aware that the mean life expectancy would exceed the median life expectancy. The committee noted that the median overall survival for people receiving exemestane alone was 26.6\xa0months in BOLERO‑2. It was also aware that the company's model had estimated a mean survival of over 30\xa0months. The committee was aware that the ERG's exploratory analyses similarly estimated a mean life expectancy of more than 30\xa0months for exemestane alone. Therefore, the committee agreed with its conclusion in the original technology appraisal that everolimus plus exemestane did not fulfil the short life expectancy criterion for an end-of-life therapy (see section\xa04.26). It concluded that everolimus plus exemestane did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\n## Conclusion\n\nThe committee discussed the most plausible ICER for everolimus plus exemestane compared with exemestane alone. The committee agreed that the most plausible ICER should be based on the ERG's exploratory analyses to estimate progression-free survival and overall survival and the longer time horizon. In its response to the appraisal consultation document, the company provided an updated cost-effectiveness analysis including an increased discount in the patient access scheme and survival analyses of both progression-free and overall survival using ERG methods. It also used the longer time horizon. The ICERs including the revised patient access scheme are commercial in confidence to protect the level of discount, and cannot be presented here. The committee concluded that everolimus plus exemestane with the revised patient access scheme was a cost-effective use of NHS resources and could be recommended for routine commissioning in the NHS for treating advanced HER2-negative hormone receptor-positive breast cancer in postmenopausal women that has recurred or progressed after a non-steroidal aromatase inhibitor.\n\n# Summary of appraisal committee's key conclusions\n\nTA421\n\nAppraisal title: Everolimus with exemestane for treating advanced breast cancer after endocrine therapy\n\nSection\n\nKey conclusion: Cancer Drugs Fund reconsideration of TA295\n\nEverolimus, in combination with exemestane, is recommended within its marketing authorisation as an option for treating advanced human epidermal growth factor receptor 2 (HER2)-negative hormone-receptor-positive breast cancer in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non-steroidal aromatase inhibitor. Everolimus is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\n\n\n\n\nIn its response to the appraisal consultation document, the company provided an updated cost-effectiveness analysis. The committee concluded that everolimus plus exemestane with the revised patient access scheme was a cost-effective use of NHS resources and could be recommended for routine commissioning in the NHS for treating advanced HER2-negative hormone receptor-positive breast cancer in postmenopausal women that has recurred or progressed after a non-steroidal aromatase inhibitor.\n\n\n\nCurrent practice (TA295)\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the patient expert that patients would value everolimus plus exemestane as a treatment option because it is offered when limited treatment options exist after a woman's disease becomes resistant to endocrine therapy, and because everolimus plus exemestane may delay the need for chemotherapy and its associated toxicity. The committee also heard from the patient expert that patients value increased survival and improved quality of life.\n\n\n\nThe committee heard from clinical experts that the most relevant chemotherapy comparators for everolimus are likely to be capecitabine and vinorelbine because anthracyclines (doxorubicin) and taxanes (docetaxel) are generally used to treat metastatic breast cancer in people who have symptomatic and life-threatening visceral disease.\n\n\n\nThe committee heard from clinical experts that, although fulvestrant is available through the Cancer Drugs Fund, NICE has not recommended fulvestrant following treatment with tamoxifen. Also, the committee did not hear any evidence that fulvestrant can be considered routine practice when non-steroidal aromatase inhibitors have failed. The clinical experts stated that tamoxifen and exemestane (alone) were appropriate comparators for everolimus plus exemestane, although tamoxifen is often offered after exemestane. The committee concluded that exemestane alone was the most relevant endocrine comparator for everolimus plus exemestane.\n\n\n\nThe technology (TA295)\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe clinical experts confirmed that everolimus plus exemestane would be offered to patients whose disease has progressed on a non-steroidal aromatase inhibitor at a point when a patient might receive either further endocrine therapy or chemotherapy.\n\n\n\nAdverse reactions\n\nThe committee noted that the BOLERO‑2 trial showed that patients receiving everolimus plus exemestane had more adverse reactions, specifically stomatitis and anaemia, than patients receiving exemestane alone. However, the committee heard that everolimus is generally well tolerated.\n\n\n\nEvidence for clinical effectiveness (TA295)\n\nAvailability, nature and quality of evidence\n\nThe committee concluded that the indirect treatment comparison that estimated the clinical effectiveness of everolimus plus exemestane compared with fulvestrant should be regarded with caution.\n\n\n\nThe committee noted that the TAMRAD trial did not compare everolimus within its licensed indication (that is, in combination with exemestane) with tamoxifen. The committee noted that no conclusions on the effectiveness of everolimus plus exemestane compared with tamoxifen were possible.\n\n\n\nThe committee concluded that the 'naive chained indirect analysis', which estimated the clinical effectiveness of everolimus plus exemestane compared with chemotherapy, relied on untested assumptions and on a systematic review that included studies that no longer reflect clinical practice.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee heard from the clinical experts that the BOLERO‑2 trial population represented patients who would be offered everolimus in the UK.\n\n\n\nUncertainties generated by the evidence\n\nThe committee agreed that the immaturity of the overall survival data from the BOLERO-2 trial generated considerable uncertainty associated with the longer-term benefits of everolimus plus exemestane.\n\n\n\nThe committee concluded that there was considerable uncertainty about the validity of the comparison of everolimus plus exemestane with tamoxifen, but noted its previous conclusions that, of the endocrine therapies, the comparison of everolimus plus exemestane with exemestane alone was the most relevant to the appraisal.\n\n\n\nThe committee concluded that it was not possible to make robust comparisons between everolimus plus exemestane and chemotherapies based on the available evidence.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee noted that, although the company included no plans to test for interaction in its statistical analysis plan, it had stated that it had not identified any statistically significant differences in progression-free survival between subgroups.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that everolimus plus exemestane is effective in prolonging progression-free survival compared with exemestane alone.\n\n\n\nThe committee agreed that the immaturity of the overall survival data resulted in considerable uncertainty associated with the longer-term benefits of everolimus plus exemestane.\n\n\n\nEvidence for cost effectiveness (TA295)\n\nAvailability and nature of evidence\n\nThe committee considered the company's economic model and the evidence review group's (ERG) critique of the company's comparison of everolimus plus exemestane and exemestane alone.\n\n\n\nThe committee noted that the incremental cost-effectiveness ratio (ICER) was most sensitive to the modelling of overall survival and the progression-free survival assessment method.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee agreed that the most plausible ICER should be based on an analysis using the following assumptions: using exponential functions to estimate progression-free survival; omitting the adjustment factor from Beauchemin et al. (2012); using locally assessed trial data; including adverse reactions; using rates of adverse reactions as documented in the European public assessment report; recalculating time on treatment; including costs of monitoring disease that has not progressed; correcting discounting and utility values for stable disease; using the utility value for 'progressed disease' from Lloyd et al. (2006); and omitting extra mortality from non-cancer causes.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee concluded that neither valuation of utility for the 'progressed disease' health state was without uncertainty, but that the data from Lloyd et al. were more appropriate than the data from Launois et al. (1997).\n\n\n\nAlthough the committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy, it concluded that the company had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the quality-adjusted life year (QALY).\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee concluded that the available evidence did not allow it to make any recommendations specific to subgroups of patients.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nUsing local or central assessment for progression-free survival in the modelling: The committee concluded that it was more appropriate to use effectiveness data derived from local assessment in the modelling than from central assessment because local assessment represented the primary end point of the trial, reflected clinical practice and minimised the potential for bias from informative censoring.\n\n, 4.17\n\nChoice of survival modelling: The committee agreed that the company's estimated 10.5\xa0months' survival benefit with the Weibull analysis was likely to be optimistic, and that the estimated 1.4\xa0months' survival benefit with the ERG's exploratory parallel exponential model was likely to be pessimistic. It acknowledged that the overall survival benefit of everolimus plus exemestane is uncertain but probably lies between these estimates. The committee noted that it is also similar to the overall survival benefit from the ERG's non-parallel exponential model (4.6\xa0months), which reflects the longer progression-free survival with everolimus plus exemestane than with exemestane alone.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that the ERG's estimate of the ICER (including the patient access scheme for everolimus) of £68,000 per QALY gained for everolimus plus exemestane compared with exemestane alone was more plausible than the company's base-case estimate.\n\n\n\nAdditional factors taken into account (TA295)\n\nPatient access schemes (PPRS)\n\nNovartis has agreed a patient access scheme with the Department of Health. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nThe committee acknowledged the uncertainty associated with estimated life expectancy but, given that the company's model estimated a mean overall survival of 28.9\xa0months for exemestane alone, the committee was not convinced that the life expectancy of women to whom everolimus plus exemestane would be offered was convincingly less than 24\xa0months. The committee therefore concluded that everolimus plus exemestane did not fulfil the criteria for an end-of-life therapy.\n\n, 4.26\n\nEqualities considerations and social value judgements\n\nThe only potential issue raised was that everolimus should be available to male patients. However, the UK marketing authorisation includes only postmenopausal women and therefore this issue could not be addressed within the remit of this NICE technology appraisal.\n\n–\n\nCancer Drugs Fund reconsideration of TA295\n\nEvidence for clinical effectiveness\n\nThe committee discussed the data on clinical effectiveness from BOLERO‑2.\n\nThe committee noted that the company had submitted more mature evidence for overall survival in its Cancer Drugs Fund reconsideration submission than it had originally.\n\nThe committee was aware that the company and ERG used different methods to model the same progression-free survival data in this reconsideration compared with the original appraisal.\n\nNoting that the hazard ratio changed from 0.77 to 0.89 in the analyses, the committee highlighted that the more mature overall survival data suggested everolimus plus exemestane compared with exemestane alone was less clinically effective than it appeared in the company's original submission.\n\n, 4.30\n\nEvidence for cost effectiveness\n\nThe committee considered the company's submission for the Cancer Drugs Fund reconsideration that included a patient access scheme, provided new analyses reflecting longer follow-up data on overall survival from BOLERO 2, revised the approaches for extrapolating progression-free survival and overall survival in the economic model, addressed the committee's preferred assumptions and used up-to-date unit cost data.\n\nThe committee also considered the ERG's critique of the company's reconsideration submission and the ERG's exploratory analyses.\n\n\n\nThe committee noted that the company only provided ICERs estimated from deterministic analyses in its response to the appraisal consultation document. The committee preferred probabilistic sensitivity analyses because most economic models are non-linear.\n\n\n\nThe committee agreed that the most plausible ICER should be based on the ERG's exploratory analyses to estimate progression-free survival and overall survival and the longer time horizon.\n\n\n\nAlthough the committee acknowledged that the mechanism of action of everolimus may offer a step change in treatment by restoring sensitivity of the tumour to endocrine therapy, it concluded that the company had not submitted convincing evidence that everolimus (plus exemestane) provides health-related quality-of-life benefits exceeding that calculated in the quality-adjusted life year (QALY).\n\n\n\nThe ICERs including the patient access scheme are commercial in confidence, and cannot be presented here.\n\n\n\nAdditional factors taken into account\n\nNovartis has agreed a patient access scheme for everolimus with the Department of Health.\n\n"}	https://www.nice.org.uk/guidance/ta421	Evidence-based recommendations on everolimus (Afinitor) for treating advanced breast cancer in adults after endocrine therapy.
e96289d0ea6cdbaff131656c0d46edc6a70f9095	nice	Crizotinib for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer	Crizotinib for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer Evidence-based recommendations on crizotinib (Xalkori) for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. # Recommendations Crizotinib is recommended, within its marketing authorisation, as an option for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.# The technology Description of the technology Crizotinib (Xalkori, Pfizer) is an inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor and its variants. Marketing authorisation Crizotinib has a marketing authorisation in the UK which includes 'adults with previously treated ALK-positive advanced non-small-cell lung cancer'. Adverse reactions The summary of product characteristics lists the following as the most common adverse reactions associated with crizotinib: visual disorder, diarrhoea, nausea, vomiting, constipation, oedema, fatigue, decreased appetite, neutropenia, elevated aminotransferases, anaemia, leukopenia, neuropathy, dysgeusia, dizziness, bradycardia, abdominal pain and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended dosage of crizotinib is 250 mg twice daily. Price The list price of crizotinib is £4,689 for 60 capsules (excluding VAT; 'British national formulary' online, accessed October 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of crizotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Pfizer and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. It focused on cost-effectiveness analyses using a revised patient access scheme, which provides a simple discount to the list price of crizotinib. The level of the discount is commercial in confidence. See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of crizotinib, having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of crizotinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness (NICE technology appraisal guidance 296) The committee heard from clinical experts and patient experts that there are limited treatment options for people with non-small-cell lung cancer whose disease has progressed after chemotherapy. It heard from the patient experts and clinical experts that non-small-cell lung cancer associated with an anaplastic lymphoma kinase (ALK) fusion gene is an uncommon subtype of non-small-cell lung cancer and noted the views of the patient experts and clinical experts on the severity of the disease. The committee also heard from the clinical experts and patient experts that people with ALK-positive non-small-cell lung cancer would particularly value the availability of an effective targeted therapy and the convenience of an oral formulation; neither of these features apply to docetaxel. It also heard from the clinical experts that most patients would tolerate the side effects associated with crizotinib. The committee concluded that crizotinib offers potential benefits to people with ALK-positive non-small-cell lung cancer. The committee discussed the decision problem as presented in the company's submission. It noted that this was the same as the scope for the appraisal, except that the scope listed erlotinib as a comparator, but the company had not included a comparison of crizotinib and erlotinib in the submission. The committee understood that erlotinib is a treatment that targets the activated epidermal growth factor receptor (EGFR) gene mutation in non-small-cell lung cancer and that it is very rare for people with non-small-cell lung cancer to have both the EGFR mutation and ALK fusion gene. It therefore accepted the company's position that an EGFR-targeted medicine would not be expected to be standard of care in clinical practice for patients with ALK-positive disease. The committee was aware of a comment received during consultation that if crizotinib were not available, ALK testing would not be carried out and patients would be likely to receive erlotinib as second-line treatment in preference to docetaxel. However, the committee did not consider this to be a reason for insisting on a comparison between crizotinib and erlotinib, given that the decision problem, as defined in the NICE scope, was to appraise crizotinib in a population of patients with ALK-positive disease. Therefore, the committee agreed with the company's position that erlotinib should not be considered as a comparator for crizotinib for previously treated ALK-positive non-small-cell lung cancer. It also noted that pemetrexed was not in the scope and was not a valid comparator as a second-line treatment because patients are likely to have pemetrexed before being considered for crizotinib. The committee was also aware that pemetrexed is not recommended by NICE as a second-line treatment. It concluded that docetaxel and best supportive care are the appropriate comparators for crizotinib. The committee discussed the characteristics of the population in the PROFILE 1007 trial. It noted that most of the trial population had been diagnosed with adenocarcinoma, had a good performance status, was relatively young and had never smoked. The committee considered that these characteristics generally indicate better prognosis and therefore discussed whether the trial population represented people with ALK-positive non-small-cell lung cancer in clinical practice. It heard from the clinical experts that the modest benefits of docetaxel in PROFILE 1007 were consistent with what would be expected in clinical practice. The committee noted the lack of evidence available either to determine the survival of patients with ALK-positive disease who had not received treatment with crizotinib or to assess the separate impact on survival of the features of non-small-cell lung cancer that accompany ALK-positive disease (young age, mainly women, nearly always adenocarcinoma, and a high proportion of people who have never smoked). Although it questioned whether such patients might have a better prognosis than patients with ALK-negative disease because of these favourable prognostic factors, the committee accepted that the PROFILE 1007 population was likely to be similar to people considered for treatment with crizotinib in UK clinical practice. The committee considered treatment duration with crizotinib. It noted that a large proportion of patients in PROFILE 1007 continued to receive crizotinib treatment after radiographically determined disease progression. It noted that the summary of product characteristics states that 'prolongation of treatment after objective disease progression in selected patients may be considered on an individual basis, but no additional benefit has been demonstrated'. The committee discussed whether treatment would be discontinued on radiographic disease progression in clinical practice. It heard from the clinical experts that if a tumour has progressed, it would indicate reduced sensitivity to treatment and there would be a need to switch to another therapy. However, at present there is no standard third-line therapy. Without further treatment options, the committee understood that symptomatic progression, rather than radiographic progression, is likely to be the trigger for treatment change or discontinuation. The committee was informed of an abstract presented at the American Society of Clinical Oncology reporting that 53% of patients in PROFILE 1001 and PROFILE 1005 received crizotinib after disease progression for at least 2 weeks (range 2–84 weeks, median 10 weeks). The committee was persuaded by the evidence from PROFILE 1007 and the American Society of Clinical Oncology abstract that treatment would most likely continue until symptomatic progression. It did not find any reason from the evidence provided by the clinical experts to suggest that treatment would routinely stop at radiographic progression. The committee therefore concluded that the treatment protocol of PROFILE 1007, in which patients could continue treatment after radiographic progression, reflected the likely treatment duration for crizotinib in UK clinical practice. The committee discussed the evidence for the clinical efficacy of crizotinib. It noted the median progression-free survival gains of 4.7 and 5.1 months with crizotinib compared with chemotherapy and docetaxel respectively from PROFILE 1007, and considered that this represented a noteworthy extension to progression-free survival in advanced non-small-cell lung cancer. It noted the objective response rate of around 65% and considered this to be a very high response rate for a second-line non-small-cell lung cancer treatment. The committee went on to discuss the overall survival estimates from PROFILE 1007. It noted that the results did not identify a statistically significant difference in overall survival between crizotinib and chemotherapy. However, the committee acknowledged that this was based on relatively immature data and subject to a high rate of crossover from chemotherapy to crizotinib. It heard from the company that more mature and therefore more reliable overall survival data would be available for PROFILE 1007. However, it noted that this would not be within the timeframe of this appraisal. The committee therefore considered the results of the company's crossover analyses in which the estimate of overall survival gain with crizotinib compared with chemotherapy ranged from 5.8 months to 21.7 months. The committee considered that the range of results from the crossover analyses suggested a high degree of uncertainty around the estimate of overall survival gain. It heard from the clinical experts that the estimated gain in overall survival with treatment might be expected to be 8 or 9 months. The committee noted that this was approximately midway between the results of the rank-preserving structural failure time (RPSFT) method and the company's chosen method for crossover analysis (inverse probability of treatment and censoring weighted 5; IPTCW5) as discussed in section 4.8. It therefore accepted that treatment with crizotinib would result in an overall survival gain compared with docetaxel but the exact size of the gain was uncertain because of the immaturity of the PROFILE 1007 data and the impact of crossover in the study. Overall, the committee concluded that, based on the evidence for progression-free survival and response rate, crizotinib is a clinically efficacious treatment for ALK-positive advanced non-small-cell lung cancer compared with chemotherapy. The committee noted the number of adverse events associated with crizotinib treatment from the PROFILE studies. However, it was advised by the patient experts and clinical experts that crizotinib would be tolerated by most people with non-small-cell lung cancer. The committee concluded that crizotinib is associated with some adverse reactions but these would be tolerable for most patients and generally easily managed. The committee discussed the results of the company's mixed treatment comparison in which crizotinib was compared with best supportive care. It noted the evidence review group's (ERG's) assertion that there were substantial underlying differences in the populations of patients with non-small-cell lung cancer in the included studies. The committee was aware of the company's comment that the median progression-free survival values in the chemotherapy arms of the different trials included in the network were consistent. However, the committee remained concerned about the relevance of the trial populations to a population of people with ALK-positive non-small-cell lung cancer who would receive best supportive care. This was because the trials in the mixed treatment comparison included patients who were well enough for chemotherapy, and therefore their prognostic factors would not represent those of patients receiving best supportive care. In addition, only PROFILE 1007 was carried out in patients with ALK-positive non-small-cell lung cancer; the other trials were in unselected disease. Therefore, the committee concluded that the results from the mixed treatment comparison were subject to uncertainty given the significant heterogeneity in the included studies. It further concluded that the resulting hazard ratio for overall survival for crizotinib compared with best supportive care should be viewed with considerable caution and that as a result, the relative effect of crizotinib compared with best supportive care remained an area of substantial uncertainty. The committee discussed the company's preferred approach to crossover (IPTCW5) in more detail, noting that this had been used to obtain the overall survival hazard ratio for docetaxel. The committee noted the ERG's main concern that the different approaches to crossover had resulted in survival gain for crizotinib varying between 5.8 months (using the RPSFT method) and 21.7 months (using the real world data method). The ERG reiterated its concern at the meeting that this variation suggested a high degree of uncertainty associated with all the results from the various crossover analyses. The committee discussed the company's justification for preferring one method, noting that, of the different statistical methods, IPTCW5 gave the most favourable overall survival benefit for crizotinib. It heard from the company that the decision was based on their view that the chemotherapy overall survival which resulted from using the hazard ratio from the IPTCW5 method applied to the extrapolated overall survival data for crizotinib, most closely reflected the overall survival from other trials of docetaxel and pemetrexed. Therefore, the company asserted that the IPTCW5 method was the most appropriate based on the face validity of the results. However, the committee was concerned that the other trials of second-line treatment with pemetrexed or docetaxel were in potentially very different populations of patients. The committee noted that the company's chosen method resulted in a modelled progression-free survival gain of 5.7 months, and an overall survival gain of 12.3 months for crizotinib and that this large gain in overall survival compared with progression-free survival was not supported by any evidence. The committee also considered the application of the company's method of adjustment for crossover, questioning why the type of chemotherapy had not been included as a covariant, given that pemetrexed had been given as the first choice treatment in the chemotherapy group. It heard from the company that this had not been considered. The committee considered that this could lead to flaws in the analysis. It did not accept the company's assertion of face validity to justify using one particular crossover adjustment method because it remained concerned that the choice of data and parametric extrapolation method also influenced the outcome. The committee concluded that the company's application of the chosen method for adjusting for crossover (IPTCW5) produced an overly optimistic overall survival benefit for crizotinib, for which there was no supporting evidence. The committee further discussed the most likely projection of the overall survival benefit for crizotinib compared with docetaxel. It discussed comments by the company that it is biologically plausible that the overall survival to progression-free survival ratio would be higher with targeted therapy than with chemotherapy. The clinical experts confirmed that in some patients there was a dramatic response to treatment and that targeted therapies such as crizotinib could reduce tumour size to below that at the beginning of therapy. Therefore, at progression, the size of the tumour could still be smaller than at the beginning of therapy and as a result, benefit would continue into the progressed disease stage. The committee was persuaded by this evidence. It went on to discuss the outcome from the RPSFT method, in which the overall survival benefit for crizotinib was 5.8 months. In view of the evidence from the clinical experts relating to the expected gain in survival with crizotinib (see section 4.5), the committee concluded that the RPSFT method might underestimate overall survival. The committee recognised the limitations of the crossover adjustment methods, particularly when applied to a small trial with crossover in both directions and with immature data. It considered that the IPTCW2 method, which resulted in an overall survival benefit of 7.1 months, may be a reasonable assumption given the lack of robust data. This method produced a result between the 2 extremes of the IPTCW5 and RPSFT methods, broadly in agreement with clinical opinion (see section 4.5). The committee concluded that the exact gain in overall survival from treatment with crizotinib was very uncertain and an exact value could not be reliably established from the available data; however for the purposes of the economic model the IPTCW2 was the most reasonable method on which to base its decision. # Cost effectiveness (NICE technology appraisal guidance 296) The committee discussed the utility estimates in the model. It welcomed the collection of EQ-5D data in PROFILE 1007. The committee noted that the baseline utility estimates were different between the groups at entry into the study, and specifically that the mean baseline utility value for crizotinib was higher than for chemotherapy. The company confirmed that this had not been adjusted for in the model. The committee also noted the difference in utility values between crizotinib and chemotherapy for the progressed disease health state and observed that these post-progression utilities had been measured at the outset of the progressed disease state and continued at that value until death. It first discussed whether a treatment benefit with crizotinib might be expected to continue after treatment was stopped. The committee heard from the clinical experts that patients with progressed disease would continue to have some additional health-related quality-of-life benefit for some time after treatment was withdrawn compared with those on chemotherapy, but that this would deteriorate over time. It accepted that some utility benefit might be expected from crizotinib discontinued at disease progression, though there are no data to suggest how great a benefit this might be or for how long it would persist. The committee was also aware that there might be a utility benefit of continuing crizotinib, but there were no data to show whether such continued treatment benefits patients or for how long. The committee considered the company's revised model, incorporating a step change in post-progression utilities. It recognised that this was a more conservative assumption than in the original model because the initial difference in post-progression utility reduced rather than persisted over time. However, the company did not justify the approach used to model a reduction in post-progression utilities. The ERG commented that, without any further evidence, the size and duration of post-progression benefit remained uncertain. In addition the approach used by the company to characterise the reduction is likely to overestimate the quality-adjusted life year (QALY) benefits because of the impact of discounting and of differences in the baseline values. The committee concluded that the company's revised post-progression utilities represented a partial solution to the estimation of these values but that the utility estimates in the post-progression health state remained uncertain because of the lack of utility data in the post-progression period. The committee discussed the cost estimates in the company's economic model. The committee noted that CT scans were performed every 6 weeks in PROFILE 1007. The committee heard from the clinical experts that on average, patients would initially have a CT scan every 2 months and this would probably be reduced to every 3 months at a later stage if the patient was clearly benefitting from treatment. The committee considered that the costs of CT scans in the original model had been underestimated. It noted that in the revised base-case model the company updated the costs to assume a CT scan every 3 months for all patients in the progression-free health state. The committee noted that the costs of docetaxel in the model were based on its use in the post hoc subgroup in PROFILE 1007 (presented as confidential in the company's submission and not reported here). Based on the clinical experts' opinion, the committee thought it very unlikely that in England and Wales, patients would receive more than 6 cycles of docetaxel. The committee noted that in the revised base-case model the company capped the costs of docetaxel at 6 cycles. The committee considered the administration costs, noting that the model assumed no cost to the NHS associated with administration of crizotinib. It agreed that there would be some administrative costs to the NHS associated with treatment with crizotinib and that the SB11Z healthcare resource group code for oral chemotherapy of £126 should have been included for each crizotinib treatment cycle in the progression-free state. The committee considered the company's view that no administration costs would be incurred because this treatment is taken at home and that this administration cost had not been included in other appraisals involving oral chemotherapies. The committee was also aware of current inconsistencies in the healthcare resource group codes highlighted by the ERG, who pointed out that the administration cost for docetaxel was £102. However, the committee agreed that an administration cost was appropriate for crizotinib and since SB11Z was the only available healthcare resource group code for oral chemotherapy cost it accepted this value as appropriate. The committee recognised that this cost is not a key driver of the cost effectiveness of crizotinib. Finally, the committee considered the acquisition cost of docetaxel, noting the substantial discrepancy between the published price in the 'British national formulary' (BNF) and the range of prices paid by the NHS across the country as reported in the electronic Market Information Tool (eMIT) from the NHS Commercial Medicines Unit. It noted the company's view that the eMIT costs did not meet NICE's criteria for inclusion in the base case. However, the committee agreed that the eMIT costs were appropriate because the NICE methods guide states that a reduced price should be used in the base case when nationally available price reductions exist.Overall, the committee agreed that the costs in the revised base-case model were likely to be underestimated in favour of crizotinib because of the use of the BNF price for docetaxel and the exclusion of crizotinib administration costs. The committee considered the impact of these 2 parameter inputs and noted that the ERG had carried out exploratory analyses. These analyses demonstrated that the use of the eMIT price for docetaxel would increase the incremental cost-effectiveness ratio (ICER) by about £5,000 per QALY gained and including the £126 crizotinib administration cost would increase the ICER by about £2,200 per QALY gained. The committee concluded that the impact of these factors would increase the ICER in the company's revised base-case model. The committee further considered the cost-effectiveness estimates of crizotinib compared with docetaxel. It expressed a preference to base its decision on probabilistic estimates of the ICER whenever possible. In addition, the committee decided that the most relevant ICER would assume the same treatment duration for crizotinib as in PROFILE 1007 (see section 4.4). The committee considered the company's revised base-case probabilistic estimate of the ICER of £70,000 per QALY gained. It was aware that this was based on the company's preferred method for adjusting for crossover (IPTCW5). Based on its earlier discussions about the approach to crossover (see sections 4.8 and 4.9) the committee then considered the probabilistic estimates of the ICER using the IPTCW2 and RPSFT methods, available from the ERG's exploratory analyses (£96,000 and £111,800 per QALY gained respectively). The committee considered that, given the limited evidence, it was reasonable to assume that the ICER would be closer to £96,000 per QALY gained because the overall survival gain obtained using IPTCW2 was broadly in agreement with clinical opinion. However, the committee noted that these estimates did not use the eMIT price for docetaxel or an administration cost of £126 for crizotinib (see section 4.11). The committee was aware that when the ERG had carried out these 2 amendments to the company's revised base case individually, the combined result was to increase the ICER by approximately £7,000 per QALY gained. The committee therefore concluded that the ICER on which to base a decision for crizotinib compared with docetaxel would be more than £100,000 per QALY gained. The committee further considered the cost-effectiveness estimates of crizotinib compared with best supportive care. In line with its consideration of the ICER for the comparison with docetaxel, the committee expressed a preference for a probabilistic estimate of the ICER and one that assumed the same treatment duration for crizotinib as in PROFILE 1007. The committee considered the company's revised base-case probabilistic estimate of the ICER of £50,200 per QALY gained. It was aware that this was based on the company's preferred approach to crossover (IPTCW5). Having previously concluded that the IPTCW5 method would be overly optimistic towards crizotinib, the committee reasoned that this ICER would be likely to be underestimated. In addition, the committee had reservations that this ICER was based on a hazard ratio from a mixed treatment comparison in which the patients in the included trials had been eligible for chemotherapy (see section 4.7). The committee considered that this introduced substantial uncertainty around any estimates of the ICER. The committee therefore concluded that the ICER on which to base a decision for crizotinib compared with best supportive care would be more than £50,200 per QALY gained. However, the committee further concluded that this ICER was associated with substantial uncertainty, which it was not possible to quantify because of the lack of a robust mixed treatment comparison between crizotinib and best supportive care. # Innovation (NICE technology appraisal guidance 296) The committee considered whether crizotinib offers benefits because of its innovative nature, as the first targeted drug for ALK-positive non-small-cell lung cancer. It heard from the company that crizotinib is innovative because the ability to target patients who are most likely to benefit can be seen as a step change in the management of non-small-cell lung cancer. It further heard from the clinical experts and patient experts that crizotinib delivers high response rates and a substantial benefit in at least progression-free survival in lung cancer and is also well tolerated, particularly when compared with current standard cytotoxic therapy for non-small-cell lung cancer. The committee agreed with these observations but considered that the potential extension to life and the convenience of an oral treatment compared with intravenous second-line therapy would already be captured in the QALY calculation. The committee was not made aware of any significant and substantial impact on health-related benefits which are not already captured in the QALY calculation, and therefore concluded that no additional value judgements needed to be made for innovation. # End-of-life considerations (NICE technology appraisal guidance 296) The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The committee considered the life expectancy of patients with advanced non-small-cell lung cancer associated with an ALK fusion gene. It noted the results from the company's statistical crossover analyses, which gave a range of estimates between 20 and 27 months for the chemotherapy group. Based on its discussions around the crossover methods explored by the company (see section 4.8), it considered that there was some uncertainty around these estimates. It further acknowledged that there is a lack of overall survival data for patients with ALK-positive non-small-cell lung cancer who have not received treatment with crizotinib. However, on balance, the committee considered that the life expectancy of patients with ALK-positive non-small-cell lung cancer after first-line chemotherapy would be less than 24 months. It then discussed the criterion relating to extension to life. The committee noted that the median progression-free survival results from PROFILE 1007 indicated an extension to life of 4.7 months for crizotinib compared with chemotherapy, and that this was not affected by crossover. It agreed that crizotinib would extend life by an additional 3 months. The committee then considered the size of the population, noting the company's estimate of around 500 patients. It accepted that crizotinib is licensed for a small population. The committee accepted that, on the basis of these 3 criteria, the supplementary advice from NICE for life-extending treatments could be considered for crizotinib, even though there was considerable uncertainty in the exact overall survival gain, and therefore in the resulting ICER. The committee considered its recommendations to the NHS. Based on the most plausible ICERs (see sections 4.12 and 4.13), the committee concluded that even allowing for the supplementary advice to the committee for life-extending treatments, the size of additional weight that would need to be assigned to the QALY gains would be too great for crizotinib to be considered a cost-effective use of NHS resources. Also, the committee was not satisfied that the assumptions used in the economic modelling for the comparison with best supportive care, in particular the hazard ratio from the mixed treatment comparison, were plausible and robust. The committee concluded that treatment with crizotinib for previously treated ALK-positive advanced non-small-cell lung cancer should not be recommended for use within the NHS. # Equality issues (NICE technology appraisal guidance 296) The committee considered whether its recommendations were associated with any potential issues related to equality. The committee noted the potential equality issue raised during scoping that testing could be restricted to patients with a diagnosis of adenocarcinoma. The committee heard from the clinical experts that there is currently no established ALK testing strategy in UK clinical practice. The committee then considered the potential equality issues raised by clinical experts during consultation. The clinical experts were concerned that, if this treatment is not recommended, patients in the NHS will not have access to a targeted therapy that is routinely available elsewhere and so survival rates in England and Wales will continue to lag behind other countries. Lung cancer patients are also a particularly disadvantaged group, with a high proportion from more socially disadvantaged groups. The committee discussed whether these potential equality issues affected NICE's duties under the equality legislation and concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations. # Cancer Drugs Fund reconsideration This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. Crizotinib has been available through the Cancer Drugs Fund because it was not recommended in the original guidance. In its revised submission updating its cost-effectiveness analysis, the company: re-analysed data for overall survival using more mature data from PROFILE 1007 included a revised patient access scheme (a simple discount to the list price as in NICE's technology appraisal guidance on crizotinib for untreated anaplastic lymphoma kinase-positive non-small-cell lung cancer) applied the same values for post-regression utility for crizotinib and docetaxel did not present new analyses comparing crizotinib with best supportive care updated all unit costs data to 2016 values (including the eMIT price for docetaxel) assumed in its base case that clinicians would not continue to offer crizotinib after disease progression and presented scenario analyses to address areas of uncertainty. ## Clinical management The committee recognised that the treatment pathway for ALK-positive non-small-cell lung cancer has changed since the publication of NICE's technology appraisal guidance on crizotinib (TA296). New treatments recommended by NICE are now available. For example, crizotinib is recommended as a treatment option for untreated (that is, first-line treatment) anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults (TA406) and ceritinib is recommended for treating advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer in adults who have previously had crizotinib. Before crizotinib was recommended as first-line treatment, it was available as a second- or subsequent-line treatment, after platinum-based combination chemotherapy, through the Cancer Drugs Fund. The committee heard from clinical experts that now that crizotinib is recommended for untreated disease, significantly fewer patients would have crizotinib as a second-line treatment. Also, the committee heard from the clinical experts that they would like to offer crizotinib as an option to patients whose ALK-positive tumour status became known after they had received first-line chemotherapy. The committee concluded that the changes in the treatment pathway resulted in a smaller population for crizotinib as second-line treatment. ## New analyses The company submitted a new model which included all the committee's preferred assumptions, except treatment with crizotinib extending beyond disease progression (the company included treatment after progression only as a scenario analysis). The company also included a revised patient access scheme. The model compared crizotinib with docetaxel only, but used evidence from the combined docetaxel and pemetrexed arm of PROFILE 1007. The resulting ICERs cannot be reported here because they are commercial in confidence. The committee discussed the lack of analyses comparing crizotinib with best supportive care in the company submission. The company proposed that if crizotinib were cost effective compared with docetaxel, it would also be cost effective compared with best supportive care. The ERG commented that although some uncertainty existed, the company's statement appeared reasonable. The committee concluded that if crizotinib were cost effective compared with docetaxel, it would also be cost effective compared with best supportive care. The committee discussed the company's approach to crossover using the more mature overall survival data from PROFILE 1007. The mature data were based on median follow-up of 51 and 53 months, by which time 67% and 73% of patients had died in the crizotinib and chemotherapy arms respectively. This compared with the company's original submission based on a median follow-up of 12.2 months in each arm, when 28% and 27% of patients had died in the crizotinib and chemotherapy arms respectively. The committee noted that in the mature dataset there was a higher proportion of patients who switched to other treatments when their disease progressed. In the chemotherapy arm (n=174), 87% and 64% of patients in the mature and the previous dataset, respectively, switched from chemotherapy to crizotinib or other drugs. The committee was aware that the company had revisited the most appropriate method for modelling overall survival when using the mature data. The company argued that because of the high degree of crossover, the small number of patients remaining on chemotherapy in the control arm, and the variation in post-progression therapies, the IPTCW method was no longer appropriate. The company therefore adjusted the survival data using the RPSFT method. Unlike IPTCW, the RPSFT method relies on the assumption of a 'common treatment effect', meaning that a therapy is as effective when given later (for example, at progression) as it would be earlier (before progression). The committee asked the company whether it had tested this assumption. The company was unable to satisfactorily answer the committee. The ERG agreed that the RPSFT method was a better choice than the IPTCW approach, but it noted that the company had not explored other methods, for example the iterative parameter estimation and 2-stage methods. Noting that in the analyses the hazard ratio declined from 0.79 (adjusted for crossover, less mature data) to 0.38 (adjusted for crossover, more mature data), the ERG highlighted that the more mature data suggested that crizotinib (compared with docetaxel) appeared to be much more effective than in the company's original submission. The committee agreed that irrespective of the method of crossover adjustment used, and despite the longer follow-up, the size of the overall survival estimate associated with crizotinib is uncertain. The committee considered the ERG's scenario analyses, which used 2 different estimates of overall survival hazard ratio: In the first scenario the ERG used an overall survival hazard ratio of 0.49, which the ERG chose to be the same value as the progression-free survival hazard ratio reported in PROFILE 1007. Progression-free survival is normally not affected by crossover, because crossover usually happens after progression. Also, according to the ERG, the hazard ratio for overall survival is normally less strongly associated with a treatment than is progression-free survival. The second scenario used an overall survival hazard ratio of 0.60, which reflected the hazard ratio for overall survival reported for crizotinib for untreated disease. The ERG assumed that in this scenario crizotinib was equally effective in delaying death in people with either untreated or previously treated disease.The committee noted that both scenarios increased the ICERs. Further scenario analyses presented by both the company and the ERG assumed that crizotinib continues to be given beyond disease progression. These analyses again increased the ICERs. Because of the uncertainty around the estimate of overall survival, the committee agreed, the ERG's scenario analyses rather than the company's base-case model are more appropriate for decision-making. The committee preferred the ERG's first scenario (with an overall survival hazard ratio of 0.49) because it used PROFILE 1007 data and the hazard ratio for progression-free survival was not confounded by crossover. The committee heard from the clinical experts that because ceritinib is now recommended third line after crizotinib, clinicians would be unlikely to offer continued treatment with crizotinib after disease progression. However, the committee was aware that the evidence from PROFILE 1007 included treatment with crizotinib after progression, and therefore the estimates of effectiveness (as well as the costs) reflect this. The committee considered that if a shorter duration of treatment were assumed than seen in the trial, then it would also be reasonable to assume lower effectiveness. Therefore, for consistency between the effectiveness and the cost estimates, the committee chose to consider analyses which included crizotinib treatment after progression, as in the original appraisal. The committee concluded that its preferred base case was the ERG's scenario analysis including an overall survival hazard ratio of 0.49 and allowing for crizotinib treatment after progression. The committee considered the most plausible ICER for crizotinib compared with docetaxel for people with previously treated anaplastic-lymphoma-kinase-positive advanced non-small-cell lung cancer. It noted that the updated analyses submitted by the company included the costs of administering crizotinib, which were estimated using the costs for administering chemotherapy. The committee was aware that the company did not think that it was appropriate to include these costs and that it considered the resulting ICER to be conservative, that is, higher than it would otherwise be. The committee also heard from the ERG that the company used what the ERG considered to be a conservative health utility assumption after progression on crizotinib (including the treatment after progression scenario). The committee concluded that the most plausible ICER for crizotinib compared with docetaxel would be less than £50,000 per QALY gained including the revised patient access scheme, assuming a hazard ratio of 0.49 for overall survival and allowing for crizotinib treatment after progression. The committee had previously concluded that if crizotinib were cost effective compared with docetaxel, it was also likely to be cost effective compared with best supportive care. ## End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It noted the committee's previous conclusion that the end-of-life criteria had been met (see section 4.16). The criterion that the treatment is licensed or otherwise indicated for small patient populations is no longer relevant. The committee did not see new evidence to change its original decision and considered the end-of-life criteria to be fulfilled. ## Conclusion Taking into account the new cost-effectiveness analyses, which apply to a population that is likely to be getting smaller, including the revised patient access scheme, and considering the end-of-life criteria, the committee recommended crizotinib as a cost-effective use of NHS resources for people with previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. # Summary of appraisal committee's key conclusions TA422 Appraisal title: Crizotinib for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer Section Key conclusion (Cancer Drugs Fund reconsideration of TA296) Crizotinib is recommended, within its marketing authorisation, as an option for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme. The committee understood that in the company's Cancer Drugs Fund (CDF) reconsideration submission, it provided an updated cost-effectiveness analysis. The committee concluded that allowing for the supplementary advice to the committee for life-extending treatments, crizotinib was a cost-effective use of NHS resources. Current practice (TA296) Clinical need of patients, including the availability of alternative treatments The committee heard from clinical experts and patient experts that there are limited treatment options for people with non-small-cell lung cancer whose disease has failed chemotherapy. The committee also heard from the clinical experts and patient experts that people with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer would particularly value the availability of an effective targeted therapy and the convenience of an oral formulation; neither of these features apply to docetaxel. The technology (TA296) Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee considered that the potential extension to life and the convenience of an oral treatment compared with intravenous second-line therapy would already be captured in the quality-adjusted life year (QALY) calculation. The committee was not made aware of any significant and substantial impact on health-related benefits which are not already captured in the QALY calculation, and therefore concluded that no additional value judgements needed to be made for innovation. What is the position of the treatment in the pathway of care for the condition? The committee concluded that docetaxel and best supportive care are the appropriate comparators for crizotinib. Adverse reactions The committee noted the number of adverse reactions associated with crizotinib treatment from the PROFILE studies. The committee concluded that crizotinib is associated with some adverse reactions but these would be tolerable for most patients and generally easily managed. Evidence for clinical effectiveness (TA296) Availability, nature and quality of evidence The main evidence came from 1 multicentre, randomised phase III efficacy and safety study in patients with previously treated ALK-positive non-small-cell lung cancer (PROFILE 1007). Relevance to general clinical practice in the NHS The committee accepted that the PROFILE 1007 population was likely to be similar to people considered for treatment with crizotinib in UK clinical practice. The committee concluded that the treatment protocol of PROFILE 1007, in which patients could continue treatment after radiographic progression, reflected the likely treatment duration for crizotinib in UK clinical practice. Uncertainties generated by the evidence The committee acknowledged that the overall survival data from the crizotinib studies were relatively immature and, for PROFILE 1007, subject to a high rate of crossover from chemotherapy to crizotinib. The committee heard from the company that more mature and therefore more reliable overall survival data would be available for PROFILE 1007. However, it noted that this would not be within the timeframe of this appraisal. The committee concluded that the exact gain in overall survival from treatment with crizotinib was very uncertain and an exact value could not be reliably established from the available data. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Subgroups of patients receiving treatment with crizotinib were not in the scope, or identified during the appraisal. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee noted the median gain in progression-free survival of 5.1 months with crizotinib compared with docetaxel from PROFILE 1007, and considered that this represented a noteworthy extension to progression-free survival in advanced non-small-cell lung cancer. The committee accepted that treatment with crizotinib would result in an overall survival gain compared with docetaxel but the exact size of the gain was uncertain because of the immaturity of the PROFILE 1007 data and the impact of crossover in the study. Overall, the committee concluded that, based on the evidence for progression-free survival and response rate, crizotinib is a clinically efficacious treatment for ALK-positive non-small-cell lung cancer compared with chemotherapy. Evidence for cost effectiveness (TA296) Availability and nature of evidence The company developed a 3-state model, which it referred to as a semi-Markov area-under-the-curve analysis. The model used estimates of treatment effectiveness from PROFILE 1005, PROFILE 1007 and a mixed treatment comparison. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee discussed the company's justification for preferring one crossover adjustment method, noting that, of the different statistical methods, inverse probability of treatment and censoring weighted 5 (IPTCW5) gave the most favourable overall survival benefit for crizotinib. The committee noted that the company's chosen method resulted in a modelled progression-free survival gain of 5.7 months, and an overall survival gain of 12.3 months for crizotinib and that this large gain in overall survival compared with progression-free survival was not supported by any evidence. The committee concluded that the company's application of the chosen method for adjusting for crossover (IPTCW5) produced an overly optimistic overall survival benefit for crizotinib, for which there was no supporting evidence. The committee concluded that the results from the mixed treatment comparison were subject to uncertainty given the significant heterogeneity in the included studies. It further concluded that the resulting hazard ratio for overall survival for crizotinib compared with best supportive care should be viewed with considerable caution and that as a result, the relative effect of crizotinib compared with best supportive care remained an area of substantial uncertainty. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee discussed the utility estimates in the model. It noted that the baseline utility estimates were different between the groups at entry into the study, and specifically that the mean baseline utility value for crizotinib was higher than for chemotherapy. The company confirmed that this had not been adjusted for in the model. The committee also noted the difference in utility values for the progressed disease health state between crizotinib and chemotherapy and observed that these post-progression utilities had been measured at the outset of the progressed disease state and continued at that value until death. The committee accepted that some utility benefit might be expected from crizotinib discontinued at disease progression, though there are no data to suggest how great a benefit this might be or for how long it would persist. The committee concluded that the company's revised post-progression utilities represented a partial solution to the estimation of these values but that the utility estimates in the post-progression state remained uncertain because of the lack of data in the post-progression period. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? The committee considered the most plausible cost-effectiveness estimates of crizotinib compared with docetaxel and best supportive care. The committee agreed that the exact gain in overall survival from treatment with crizotinib was very uncertain and an exact value could not be reliably established from the available data; however for the purposes of the economic model the IPTCW2 was the most reasonable method on which to base its decision. This method produced a result between the 2 extremes of the IPTCW5 and rank-preserving structural failure time (RPSFT) methods, broadly in agreement with clinical opinion (see section 4.5). For the comparison with best supportive care, the committee concluded that the incremental cost-effectiveness ratio (ICER) was associated substantial uncertainty, which it was not possible to quantify because of the lack of a robust mixed treatment comparison between crizotinib and best supportive care. to 4.13 Most likely cost-effectiveness estimate (given as an ICER) (TA296) The committee concluded that the ICER on which to base a decision for crizotinib compared with docetaxel would be more than £100,000 per QALY gained. The committee concluded that the ICER on which to base a decision for crizotinib compared with best supportive care would be more than £50,200 per QALY gained. However, the committee further concluded that this ICER was associated with a substantial amount of uncertainty, which it was not possible to quantify because of the lack of a robust mixed treatment comparison between crizotinib and best supportive care. Additional factors taken into account (TA296) Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health. This involves a discount applied to the list price of crizotinib. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End-of-life considerations The committee accepted that the supplementary advice from NICE for life-extending treatments could be considered for crizotinib compared with chemotherapy, even though there was considerable uncertainty in the exact overall survival gain, and therefore in the resulting ICER. Equalities considerations and social value judgements The committee concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations. Cancer Drugs Fund reconsideration of TA296 Current practice The committee noted that the treatment pathway for ALK-positive non-small-cell lung cancer has changed since the original appraisal (TA296). New treatments recommended by NICE are now available. Evidence for clinical effectiveness The committee noted that more mature data were available in the CDF reconsideration submission. Evidence for cost effectiveness The company submitted a new model which included all the committee's preferred assumptions, except treatment with crizotinib extending beyond disease progression. The committee noted that no analyses comparing crizotinib with best supportive care were presented in the CDF reconsideration submission. The committee concluded that the most plausible ICER for crizotinib compared with docetaxel would be less than £50,000 per QALY gained including the revised patient access scheme, assuming a hazard ratio of 0.49 for overall survival and allowing for crizotinib treatment after progression. Additional factors taken into account The committee acknowledged that the CDF reconsideration submission included the patient access scheme as in NICE's technology appraisal guidance on crizotinib for untreated anaplastic lymphoma kinase-positive non-small-cell lung cancer. The committee considered the end-of-life criteria to be fulfilled.	{'Recommendations': 'Crizotinib is recommended, within its marketing authorisation, as an option for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nCrizotinib (Xalkori, Pfizer) is an inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor and its variants.\n\nMarketing authorisation\n\nCrizotinib has a marketing authorisation in the UK which includes 'adults with previously treated ALK-positive advanced non-small-cell lung cancer'.\n\nAdverse reactions\n\nThe summary of product characteristics lists the following as the most common adverse reactions associated with crizotinib: visual disorder, diarrhoea, nausea, vomiting, constipation, oedema, fatigue, decreased appetite, neutropenia, elevated aminotransferases, anaemia, leukopenia, neuropathy, dysgeusia, dizziness, bradycardia, abdominal pain and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dosage of crizotinib is 250\xa0mg twice daily.\n\nPrice\n\nThe list price of crizotinib is £4,689 for 60\xa0capsules (excluding VAT; 'British national formulary' [BNF] online, accessed October 2016).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of crizotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Pfizer and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. It focused on cost-effectiveness analyses using a revised patient access scheme, which provides a simple discount to the list price of crizotinib. The level of the discount is commercial in confidence.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of crizotinib, having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of crizotinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0296)\n\nThe committee heard from clinical experts and patient experts that there are limited treatment options for people with non-small-cell lung cancer whose disease has progressed after chemotherapy. It heard from the patient experts and clinical experts that non-small-cell lung cancer associated with an anaplastic lymphoma kinase (ALK) fusion gene is an uncommon subtype of non-small-cell lung cancer and noted the views of the patient experts and clinical experts on the severity of the disease. The committee also heard from the clinical experts and patient experts that people with ALK-positive non-small-cell lung cancer would particularly value the availability of an effective targeted therapy and the convenience of an oral formulation; neither of these features apply to docetaxel. It also heard from the clinical experts that most patients would tolerate the side effects associated with crizotinib. The committee concluded that crizotinib offers potential benefits to people with ALK-positive non-small-cell lung cancer.\n\nThe committee discussed the decision problem as presented in the company's submission. It noted that this was the same as the scope for the appraisal, except that the scope listed erlotinib as a comparator, but the company had not included a comparison of crizotinib and erlotinib in the submission. The committee understood that erlotinib is a treatment that targets the activated epidermal growth factor receptor (EGFR) gene mutation in non-small-cell lung cancer and that it is very rare for people with non-small-cell lung cancer to have both the EGFR mutation and ALK fusion gene. It therefore accepted the company's position that an EGFR-targeted medicine would not be expected to be standard of care in clinical practice for patients with ALK-positive disease. The committee was aware of a comment received during consultation that if crizotinib were not available, ALK testing would not be carried out and patients would be likely to receive erlotinib as second-line treatment in preference to docetaxel. However, the committee did not consider this to be a reason for insisting on a comparison between crizotinib and erlotinib, given that the decision problem, as defined in the NICE scope, was to appraise crizotinib in a population of patients with ALK-positive disease. Therefore, the committee agreed with the company's position that erlotinib should not be considered as a comparator for crizotinib for previously treated ALK-positive non-small-cell lung cancer. It also noted that pemetrexed was not in the scope and was not a valid comparator as a second-line treatment because patients are likely to have pemetrexed before being considered for crizotinib. The committee was also aware that pemetrexed is not recommended by NICE as a second-line treatment. It concluded that docetaxel and best supportive care are the appropriate comparators for crizotinib.\n\nThe committee discussed the characteristics of the population in the PROFILE\xa01007 trial. It noted that most of the trial population had been diagnosed with adenocarcinoma, had a good performance status, was relatively young and had never smoked. The committee considered that these characteristics generally indicate better prognosis and therefore discussed whether the trial population represented people with ALK-positive non-small-cell lung cancer in clinical practice. It heard from the clinical experts that the modest benefits of docetaxel in PROFILE\xa01007 were consistent with what would be expected in clinical practice. The committee noted the lack of evidence available either to determine the survival of patients with ALK-positive disease who had not received treatment with crizotinib or to assess the separate impact on survival of the features of non-small-cell lung cancer that accompany ALK-positive disease (young age, mainly women, nearly always adenocarcinoma, and a high proportion of people who have never smoked). Although it questioned whether such patients might have a better prognosis than patients with ALK-negative disease because of these favourable prognostic factors, the committee accepted that the PROFILE\xa01007 population was likely to be similar to people considered for treatment with crizotinib in UK clinical practice.\n\nThe committee considered treatment duration with crizotinib. It noted that a large proportion of patients in PROFILE\xa01007 continued to receive crizotinib treatment after radiographically determined disease progression. It noted that the summary of product characteristics states that 'prolongation of treatment after objective disease progression in selected patients may be considered on an individual basis, but no additional benefit has been demonstrated'. The committee discussed whether treatment would be discontinued on radiographic disease progression in clinical practice. It heard from the clinical experts that if a tumour has progressed, it would indicate reduced sensitivity to treatment and there would be a need to switch to another therapy. However, at present there is no standard third-line therapy. Without further treatment options, the committee understood that symptomatic progression, rather than radiographic progression, is likely to be the trigger for treatment change or discontinuation. The committee was informed of an abstract presented at the American Society of Clinical Oncology reporting that 53% of patients in PROFILE\xa01001 and PROFILE\xa01005 received crizotinib after disease progression for at least 2\xa0weeks (range 2–84\xa0weeks, median 10\xa0weeks). The committee was persuaded by the evidence from PROFILE\xa01007 and the American Society of Clinical Oncology abstract that treatment would most likely continue until symptomatic progression. It did not find any reason from the evidence provided by the clinical experts to suggest that treatment would routinely stop at radiographic progression. The committee therefore concluded that the treatment protocol of PROFILE\xa01007, in which patients could continue treatment after radiographic progression, reflected the likely treatment duration for crizotinib in UK clinical practice.\n\nThe committee discussed the evidence for the clinical efficacy of crizotinib. It noted the median progression-free survival gains of 4.7 and 5.1\xa0months with crizotinib compared with chemotherapy and docetaxel respectively from PROFILE\xa01007, and considered that this represented a noteworthy extension to progression-free survival in advanced non-small-cell lung cancer. It noted the objective response rate of around 65% and considered this to be a very high response rate for a second-line non-small-cell lung cancer treatment. The committee went on to discuss the overall survival estimates from PROFILE\xa01007. It noted that the results did not identify a statistically significant difference in overall survival between crizotinib and chemotherapy. However, the committee acknowledged that this was based on relatively immature data and subject to a high rate of crossover from chemotherapy to crizotinib. It heard from the company that more mature and therefore more reliable overall survival data would be available for PROFILE\xa01007. However, it noted that this would not be within the timeframe of this appraisal. The committee therefore considered the results of the company's crossover analyses in which the estimate of overall survival gain with crizotinib compared with chemotherapy ranged from 5.8\xa0months to 21.7\xa0months. The committee considered that the range of results from the crossover analyses suggested a high degree of uncertainty around the estimate of overall survival gain. It heard from the clinical experts that the estimated gain in overall survival with treatment might be expected to be 8 or 9\xa0months. The committee noted that this was approximately midway between the results of the rank-preserving structural failure time (RPSFT) method and the company's chosen method for crossover analysis (inverse probability of treatment and censoring weighted 5; IPTCW5) as discussed in section\xa04.8. It therefore accepted that treatment with crizotinib would result in an overall survival gain compared with docetaxel but the exact size of the gain was uncertain because of the immaturity of the PROFILE\xa01007 data and the impact of crossover in the study. Overall, the committee concluded that, based on the evidence for progression-free survival and response rate, crizotinib is a clinically efficacious treatment for ALK-positive advanced non-small-cell lung cancer compared with chemotherapy.\n\nThe committee noted the number of adverse events associated with crizotinib treatment from the PROFILE studies. However, it was advised by the patient experts and clinical experts that crizotinib would be tolerated by most people with non-small-cell lung cancer. The committee concluded that crizotinib is associated with some adverse reactions but these would be tolerable for most patients and generally easily managed.\n\nThe committee discussed the results of the company's mixed treatment comparison in which crizotinib was compared with best supportive care. It noted the evidence review group's (ERG's) assertion that there were substantial underlying differences in the populations of patients with non-small-cell lung cancer in the included studies. The committee was aware of the company's comment that the median progression-free survival values in the chemotherapy arms of the different trials included in the network were consistent. However, the committee remained concerned about the relevance of the trial populations to a population of people with ALK-positive non-small-cell lung cancer who would receive best supportive care. This was because the trials in the mixed treatment comparison included patients who were well enough for chemotherapy, and therefore their prognostic factors would not represent those of patients receiving best supportive care. In addition, only PROFILE\xa01007 was carried out in patients with ALK-positive non-small-cell lung cancer; the other trials were in unselected disease. Therefore, the committee concluded that the results from the mixed treatment comparison were subject to uncertainty given the significant heterogeneity in the included studies. It further concluded that the resulting hazard ratio for overall survival for crizotinib compared with best supportive care should be viewed with considerable caution and that as a result, the relative effect of crizotinib compared with best supportive care remained an area of substantial uncertainty.\n\nThe committee discussed the company's preferred approach to crossover (IPTCW5) in more detail, noting that this had been used to obtain the overall survival hazard ratio for docetaxel. The committee noted the ERG's main concern that the different approaches to crossover had resulted in survival gain for crizotinib varying between 5.8\xa0months (using the RPSFT method) and 21.7\xa0months (using the real world data method). The ERG reiterated its concern at the meeting that this variation suggested a high degree of uncertainty associated with all the results from the various crossover analyses. The committee discussed the company's justification for preferring one method, noting that, of the different statistical methods, IPTCW5 gave the most favourable overall survival benefit for crizotinib. It heard from the company that the decision was based on their view that the chemotherapy overall survival which resulted from using the hazard ratio from the IPTCW5 method applied to the extrapolated overall survival data for crizotinib, most closely reflected the overall survival from other trials of docetaxel and pemetrexed. Therefore, the company asserted that the IPTCW5 method was the most appropriate based on the face validity of the results. However, the committee was concerned that the other trials of second-line treatment with pemetrexed or docetaxel were in potentially very different populations of patients. The committee noted that the company's chosen method resulted in a modelled progression-free survival gain of 5.7\xa0months, and an overall survival gain of 12.3\xa0months for crizotinib and that this large gain in overall survival compared with progression-free survival was not supported by any evidence. The committee also considered the application of the company's method of adjustment for crossover, questioning why the type of chemotherapy had not been included as a covariant, given that pemetrexed had been given as the first choice treatment in the chemotherapy group. It heard from the company that this had not been considered. The committee considered that this could lead to flaws in the analysis. It did not accept the company's assertion of face validity to justify using one particular crossover adjustment method because it remained concerned that the choice of data and parametric extrapolation method also influenced the outcome. The committee concluded that the company's application of the chosen method for adjusting for crossover (IPTCW5) produced an overly optimistic overall survival benefit for crizotinib, for which there was no supporting evidence.\n\nThe committee further discussed the most likely projection of the overall survival benefit for crizotinib compared with docetaxel. It discussed comments by the company that it is biologically plausible that the overall survival to progression-free survival ratio would be higher with targeted therapy than with chemotherapy. The clinical experts confirmed that in some patients there was a dramatic response to treatment and that targeted therapies such as crizotinib could reduce tumour size to below that at the beginning of therapy. Therefore, at progression, the size of the tumour could still be smaller than at the beginning of therapy and as a result, benefit would continue into the progressed disease stage. The committee was persuaded by this evidence. It went on to discuss the outcome from the RPSFT method, in which the overall survival benefit for crizotinib was 5.8\xa0months. In view of the evidence from the clinical experts relating to the expected gain in survival with crizotinib (see section\xa04.5), the committee concluded that the RPSFT method might underestimate overall survival. The committee recognised the limitations of the crossover adjustment methods, particularly when applied to a small trial with crossover in both directions and with immature data. It considered that the IPTCW2 method, which resulted in an overall survival benefit of 7.1\xa0months, may be a reasonable assumption given the lack of robust data. This method produced a result between the 2\xa0extremes of the IPTCW5 and RPSFT methods, broadly in agreement with clinical opinion (see section\xa04.5). The committee concluded that the exact gain in overall survival from treatment with crizotinib was very uncertain and an exact value could not be reliably established from the available data; however for the purposes of the economic model the IPTCW2 was the most reasonable method on which to base its decision.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0296)\n\nThe committee discussed the utility estimates in the model. It welcomed the collection of EQ-5D data in PROFILE\xa01007. The committee noted that the baseline utility estimates were different between the groups at entry into the study, and specifically that the mean baseline utility value for crizotinib was higher than for chemotherapy. The company confirmed that this had not been adjusted for in the model. The committee also noted the difference in utility values between crizotinib and chemotherapy for the progressed disease health state and observed that these post-progression utilities had been measured at the outset of the progressed disease state and continued at that value until death. It first discussed whether a treatment benefit with crizotinib might be expected to continue after treatment was stopped. The committee heard from the clinical experts that patients with progressed disease would continue to have some additional health-related quality-of-life benefit for some time after treatment was withdrawn compared with those on chemotherapy, but that this would deteriorate over time. It accepted that some utility benefit might be expected from crizotinib discontinued at disease progression, though there are no data to suggest how great a benefit this might be or for how long it would persist. The committee was also aware that there might be a utility benefit of continuing crizotinib, but there were no data to show whether such continued treatment benefits patients or for how long. The committee considered the company's revised model, incorporating a step change in post-progression utilities. It recognised that this was a more conservative assumption than in the original model because the initial difference in post-progression utility reduced rather than persisted over time. However, the company did not justify the approach used to model a reduction in post-progression utilities. The ERG commented that, without any further evidence, the size and duration of post-progression benefit remained uncertain. In addition the approach used by the company to characterise the reduction is likely to overestimate the quality-adjusted life year (QALY) benefits because of the impact of discounting and of differences in the baseline values. The committee concluded that the company's revised post-progression utilities represented a partial solution to the estimation of these values but that the utility estimates in the post-progression health state remained uncertain because of the lack of utility data in the post-progression period.\n\nThe committee discussed the cost estimates in the company's economic model.\n\nThe committee noted that CT scans were performed every 6\xa0weeks in PROFILE\xa01007. The committee heard from the clinical experts that on average, patients would initially have a CT scan every 2\xa0months and this would probably be reduced to every 3\xa0months at a later stage if the patient was clearly benefitting from treatment. The committee considered that the costs of CT scans in the original model had been underestimated. It noted that in the revised base-case model the company updated the costs to assume a CT scan every 3\xa0months for all patients in the progression-free health state.\n\nThe committee noted that the costs of docetaxel in the model were based on its use in the post hoc subgroup in PROFILE\xa01007 (presented as confidential in the company's submission and not reported here). Based on the clinical experts' opinion, the committee thought it very unlikely that in England and Wales, patients would receive more than 6\xa0cycles of docetaxel. The committee noted that in the revised base-case model the company capped the costs of docetaxel at 6\xa0cycles.\n\nThe committee considered the administration costs, noting that the model assumed no cost to the NHS associated with administration of crizotinib. It agreed that there would be some administrative costs to the NHS associated with treatment with crizotinib and that the SB11Z healthcare resource group code for oral chemotherapy of £126 should have been included for each crizotinib treatment cycle in the progression-free state. The committee considered the company's view that no administration costs would be incurred because this treatment is taken at home and that this administration cost had not been included in other appraisals involving oral chemotherapies. The committee was also aware of current inconsistencies in the healthcare resource group codes highlighted by the ERG, who pointed out that the administration cost for docetaxel was £102. However, the committee agreed that an administration cost was appropriate for crizotinib and since SB11Z was the only available healthcare resource group code for oral chemotherapy cost it accepted this value as appropriate. The committee recognised that this cost is not a key driver of the cost effectiveness of crizotinib.\n\nFinally, the committee considered the acquisition cost of docetaxel, noting the substantial discrepancy between the published price in the 'British national formulary' (BNF) and the range of prices paid by the NHS across the country as reported in the electronic Market Information Tool (eMIT) from the NHS Commercial Medicines Unit. It noted the company's view that the eMIT costs did not meet NICE's criteria for inclusion in the base case. However, the committee agreed that the eMIT costs were appropriate because the NICE methods guide states that a reduced price should be used in the base case when nationally available price reductions exist.Overall, the committee agreed that the costs in the revised base-case model were likely to be underestimated in favour of crizotinib because of the use of the BNF price for docetaxel and the exclusion of crizotinib administration costs. The committee considered the impact of these 2\xa0parameter inputs and noted that the ERG had carried out exploratory analyses. These analyses demonstrated that the use of the eMIT price for docetaxel would increase the incremental cost-effectiveness ratio (ICER) by about £5,000 per QALY gained and including the £126 crizotinib administration cost would increase the ICER by about £2,200 per QALY gained. The committee concluded that the impact of these factors would increase the ICER in the company's revised base-case model.\n\nThe committee further considered the cost-effectiveness estimates of crizotinib compared with docetaxel. It expressed a preference to base its decision on probabilistic estimates of the ICER whenever possible. In addition, the committee decided that the most relevant ICER would assume the same treatment duration for crizotinib as in PROFILE\xa01007 (see section\xa04.4). The committee considered the company's revised base-case probabilistic estimate of the ICER of £70,000 per QALY gained. It was aware that this was based on the company's preferred method for adjusting for crossover (IPTCW5). Based on its earlier discussions about the approach to crossover (see sections\xa04.8 and 4.9) the committee then considered the probabilistic estimates of the ICER using the IPTCW2 and RPSFT methods, available from the ERG's exploratory analyses (£96,000 and £111,800 per QALY gained respectively). The committee considered that, given the limited evidence, it was reasonable to assume that the ICER would be closer to £96,000 per QALY gained because the overall survival gain obtained using IPTCW2 was broadly in agreement with clinical opinion. However, the committee noted that these estimates did not use the eMIT price for docetaxel or an administration cost of £126 for crizotinib (see section\xa04.11). The committee was aware that when the ERG had carried out these 2\xa0amendments to the company's revised base case individually, the combined result was to increase the ICER by approximately £7,000 per QALY gained. The committee therefore concluded that the ICER on which to base a decision for crizotinib compared with docetaxel would be more than £100,000 per QALY gained.\n\nThe committee further considered the cost-effectiveness estimates of crizotinib compared with best supportive care. In line with its consideration of the ICER for the comparison with docetaxel, the committee expressed a preference for a probabilistic estimate of the ICER and one that assumed the same treatment duration for crizotinib as in PROFILE\xa01007. The committee considered the company's revised base-case probabilistic estimate of the ICER of £50,200 per QALY gained. It was aware that this was based on the company's preferred approach to crossover (IPTCW5). Having previously concluded that the IPTCW5 method would be overly optimistic towards crizotinib, the committee reasoned that this ICER would be likely to be underestimated. In addition, the committee had reservations that this ICER was based on a hazard ratio from a mixed treatment comparison in which the patients in the included trials had been eligible for chemotherapy (see section\xa04.7). The committee considered that this introduced substantial uncertainty around any estimates of the ICER. The committee therefore concluded that the ICER on which to base a decision for crizotinib compared with best supportive care would be more than £50,200 per QALY gained. However, the committee further concluded that this ICER was associated with substantial uncertainty, which it was not possible to quantify because of the lack of a robust mixed treatment comparison between crizotinib and best supportive care.\n\n# Innovation (NICE technology appraisal guidance 296)\n\nThe committee considered whether crizotinib offers benefits because of its innovative nature, as the first targeted drug for ALK-positive non-small-cell lung cancer. It heard from the company that crizotinib is innovative because the ability to target patients who are most likely to benefit can be seen as a step change in the management of non-small-cell lung cancer. It further heard from the clinical experts and patient experts that crizotinib delivers high response rates and a substantial benefit in at least progression-free survival in lung cancer and is also well tolerated, particularly when compared with current standard cytotoxic therapy for non-small-cell lung cancer. The committee agreed with these observations but considered that the potential extension to life and the convenience of an oral treatment compared with intravenous second-line therapy would already be captured in the QALY calculation. The committee was not made aware of any significant and substantial impact on health-related benefits which are not already captured in the QALY calculation, and therefore concluded that no additional value judgements needed to be made for innovation.\n\n# End-of-life considerations (NICE technology appraisal guidance\xa0296)\n\nThe committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe committee considered the life expectancy of patients with advanced non-small-cell lung cancer associated with an ALK fusion gene. It noted the results from the company's statistical crossover analyses, which gave a range of estimates between 20 and 27\xa0months for the chemotherapy group. Based on its discussions around the crossover methods explored by the company (see section\xa04.8), it considered that there was some uncertainty around these estimates. It further acknowledged that there is a lack of overall survival data for patients with ALK-positive non-small-cell lung cancer who have not received treatment with crizotinib. However, on balance, the committee considered that the life expectancy of patients with ALK-positive non-small-cell lung cancer after first-line chemotherapy would be less than 24\xa0months. It then discussed the criterion relating to extension to life. The committee noted that the median progression-free survival results from PROFILE\xa01007 indicated an extension to life of 4.7\xa0months for crizotinib compared with chemotherapy, and that this was not affected by crossover. It agreed that crizotinib would extend life by an additional 3\xa0months. The committee then considered the size of the population, noting the company's estimate of around 500\xa0patients. It accepted that crizotinib is licensed for a small population. The committee accepted that, on the basis of these 3\xa0criteria, the supplementary advice from NICE for life-extending treatments could be considered for crizotinib, even though there was considerable uncertainty in the exact overall survival gain, and therefore in the resulting ICER.\n\nThe committee considered its recommendations to the NHS. Based on the most plausible ICERs (see sections\xa04.12 and 4.13), the committee concluded that even allowing for the supplementary advice to the committee for life-extending treatments, the size of additional weight that would need to be assigned to the QALY gains would be too great for crizotinib to be considered a cost-effective use of NHS resources. Also, the committee was not satisfied that the assumptions used in the economic modelling for the comparison with best supportive care, in particular the hazard ratio from the mixed treatment comparison, were plausible and robust. The committee concluded that treatment with crizotinib for previously treated ALK-positive advanced non-small-cell lung cancer should not be recommended for use within the NHS.\n\n# Equality issues (NICE technology appraisal guidance\xa0296)\n\nThe committee considered whether its recommendations were associated with any potential issues related to equality. The committee noted the potential equality issue raised during scoping that testing could be restricted to patients with a diagnosis of adenocarcinoma. The committee heard from the clinical experts that there is currently no established ALK testing strategy in UK clinical practice. The committee then considered the potential equality issues raised by clinical experts during consultation. The clinical experts were concerned that, if this treatment is not recommended, patients in the NHS will not have access to a targeted therapy that is routinely available elsewhere and so survival rates in England and Wales will continue to lag behind other countries. Lung cancer patients are also a particularly disadvantaged group, with a high proportion from more socially disadvantaged groups. The committee discussed whether these potential equality issues affected NICE's duties under the equality legislation and concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations.\n\n# Cancer Drugs Fund reconsideration\n\nThis appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. Crizotinib has been available through the Cancer Drugs Fund because it was not recommended in the original guidance. In its revised submission updating its cost-effectiveness analysis, the company:\n\nre-analysed data for overall survival using more mature data from PROFILE\xa01007\n\nincluded a revised patient access scheme (a simple discount to the list price as in NICE's technology appraisal guidance on crizotinib for untreated anaplastic lymphoma kinase-positive non-small-cell lung cancer)\n\napplied the same values for post-regression utility for crizotinib and docetaxel\n\ndid not present new analyses comparing crizotinib with best supportive care\n\nupdated all unit costs data to 2016 values (including the eMIT price for docetaxel)\n\nassumed in its base case that clinicians would not continue to offer crizotinib after disease progression and\n\npresented scenario analyses to address areas of uncertainty.\n\n## Clinical management\n\nThe committee recognised that the treatment pathway for ALK-positive non-small-cell lung cancer has changed since the publication of NICE's technology appraisal guidance on crizotinib (TA296). New treatments recommended by NICE are now available. For example, crizotinib is recommended as a treatment option for untreated (that is, first-line treatment) anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults (TA406) and ceritinib is recommended for treating advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer in adults who have previously had crizotinib. Before crizotinib was recommended as first-line treatment, it was available as a second- or subsequent-line treatment, after platinum-based combination chemotherapy, through the Cancer Drugs Fund. The committee heard from clinical experts that now that crizotinib is recommended for untreated disease, significantly fewer patients would have crizotinib as a second-line treatment. Also, the committee heard from the clinical experts that they would like to offer crizotinib as an option to patients whose ALK-positive tumour status became known after they had received first-line chemotherapy. The committee concluded that the changes in the treatment pathway resulted in a smaller population for crizotinib as second-line treatment.\n\n## New analyses\n\nThe company submitted a new model which included all the committee's preferred assumptions, except treatment with crizotinib extending beyond disease progression (the company included treatment after progression only as a scenario analysis). The company also included a revised patient access scheme. The model compared crizotinib with docetaxel only, but used evidence from the combined docetaxel and pemetrexed arm of PROFILE\xa01007. The resulting ICERs cannot be reported here because they are commercial in confidence. The committee discussed the lack of analyses comparing crizotinib with best supportive care in the company submission. The company proposed that if crizotinib were cost effective compared with docetaxel, it would also be cost effective compared with best supportive care. The ERG commented that although some uncertainty existed, the company's statement appeared reasonable. The committee concluded that if crizotinib were cost effective compared with docetaxel, it would also be cost effective compared with best supportive care.\n\nThe committee discussed the company's approach to crossover using the more mature overall survival data from PROFILE\xa01007. The mature data were based on median follow-up of 51 and 53\xa0months, by which time 67% and 73% of patients had died in the crizotinib and chemotherapy arms respectively. This compared with the company's original submission based on a median follow-up of 12.2\xa0months in each arm, when 28% and 27% of patients had died in the crizotinib and chemotherapy arms respectively. The committee noted that in the mature dataset there was a higher proportion of patients who switched to other treatments when their disease progressed. In the chemotherapy arm (n=174), 87% and 64% of patients in the mature and the previous dataset, respectively, switched from chemotherapy to crizotinib or other drugs. The committee was aware that the company had revisited the most appropriate method for modelling overall survival when using the mature data. The company argued that because of the high degree of crossover, the small number of patients remaining on chemotherapy in the control arm, and the variation in post-progression therapies, the IPTCW method was no longer appropriate. The company therefore adjusted the survival data using the RPSFT method. Unlike IPTCW, the RPSFT method relies on the assumption of a 'common treatment effect', meaning that a therapy is as effective when given later (for example, at progression) as it would be earlier (before progression). The committee asked the company whether it had tested this assumption. The company was unable to satisfactorily answer the committee. The ERG agreed that the RPSFT method was a better choice than the IPTCW approach, but it noted that the company had not explored other methods, for example the iterative parameter estimation and 2-stage methods. Noting that in the analyses the hazard ratio declined from 0.79 (adjusted for crossover, less mature data) to 0.38 (adjusted for crossover, more mature data), the ERG highlighted that the more mature data suggested that crizotinib (compared with docetaxel) appeared to be much more effective than in the company's original submission. The committee agreed that irrespective of the method of crossover adjustment used, and despite the longer follow-up, the size of the overall survival estimate associated with crizotinib is uncertain.\n\nThe committee considered the ERG's scenario analyses, which used 2\xa0different estimates of overall survival hazard ratio:\n\nIn the first scenario the ERG used an overall survival hazard ratio of 0.49, which the ERG chose to be the same value as the progression-free survival hazard ratio reported in PROFILE\xa01007. Progression-free survival is normally not affected by crossover, because crossover usually happens after progression. Also, according to the ERG, the hazard ratio for overall survival is normally less strongly associated with a treatment than is progression-free survival.\n\nThe second scenario used an overall survival hazard ratio of 0.60, which reflected the hazard ratio for overall survival reported for crizotinib for untreated disease. The ERG assumed that in this scenario crizotinib was equally effective in delaying death in people with either untreated or previously treated disease.The committee noted that both scenarios increased the ICERs. Further scenario analyses presented by both the company and the ERG assumed that crizotinib continues to be given beyond disease progression. These analyses again increased the ICERs. Because of the uncertainty around the estimate of overall survival, the committee agreed, the ERG's scenario analyses rather than the company's base-case model are more appropriate for decision-making. The committee preferred the ERG's first scenario (with an overall survival hazard ratio of 0.49) because it used PROFILE 1007 data and the hazard ratio for progression-free survival was not confounded by crossover. The committee heard from the clinical experts that because ceritinib is now recommended third line after crizotinib, clinicians would be unlikely to offer continued treatment with crizotinib after disease progression. However, the committee was aware that the evidence from PROFILE\xa01007 included treatment with crizotinib after progression, and therefore the estimates of effectiveness (as well as the costs) reflect this. The committee considered that if a shorter duration of treatment were assumed than seen in the trial, then it would also be reasonable to assume lower effectiveness. Therefore, for consistency between the effectiveness and the cost estimates, the committee chose to consider analyses which included crizotinib treatment after progression, as in the original appraisal. The committee concluded that its preferred base case was the ERG's scenario analysis including an overall survival hazard ratio of 0.49 and allowing for crizotinib treatment after progression.\n\nThe committee considered the most plausible ICER for crizotinib compared with docetaxel for people with previously treated anaplastic-lymphoma-kinase-positive advanced non-small-cell lung cancer. It noted that the updated analyses submitted by the company included the costs of administering crizotinib, which were estimated using the costs for administering chemotherapy. The committee was aware that the company did not think that it was appropriate to include these costs and that it considered the resulting ICER to be conservative, that is, higher than it would otherwise be. The committee also heard from the ERG that the company used what the ERG considered to be a conservative health utility assumption after progression on crizotinib (including the treatment after progression scenario). The committee concluded that the most plausible ICER for crizotinib compared with docetaxel would be less than £50,000 per QALY gained including the revised patient access scheme, assuming a hazard ratio of 0.49 for overall survival and allowing for crizotinib treatment after progression. The committee had previously concluded that if crizotinib were cost effective compared with docetaxel, it was also likely to be cost effective compared with best supportive care.\n\n## End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It noted the committee's previous conclusion that the end-of-life criteria had been met (see section\xa04.16). The criterion that the treatment is licensed or otherwise indicated for small patient populations is no longer relevant. The committee did not see new evidence to change its original decision and considered the end-of-life criteria to be fulfilled.\n\n## Conclusion\n\nTaking into account the new cost-effectiveness analyses, which apply to a population that is likely to be getting smaller, including the revised patient access scheme, and considering the end-of-life criteria, the committee recommended crizotinib as a cost-effective use of NHS resources for people with previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer.\n\n# Summary of appraisal committee's key conclusions\n\nTA422\n\nAppraisal title: Crizotinib for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer\n\nSection\n\nKey conclusion (Cancer Drugs Fund reconsideration of TA296)\n\nCrizotinib is recommended, within its marketing authorisation, as an option for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\n\n\nThe committee understood that in the company's Cancer Drugs Fund (CDF) reconsideration submission, it provided an updated cost-effectiveness analysis. The committee concluded that allowing for the supplementary advice to the committee for life-extending treatments, crizotinib was a cost-effective use of NHS resources.\n\n, 4.26\n\nCurrent practice (TA296)\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from clinical experts and patient experts that there are limited treatment options for people with non-small-cell lung cancer whose disease has failed chemotherapy.\n\nThe committee also heard from the clinical experts and patient experts that people with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer would particularly value the availability of an effective targeted therapy and the convenience of an oral formulation; neither of these features apply to docetaxel.\n\n\n\nThe technology (TA296)\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee considered that the potential extension to life and the convenience of an oral treatment compared with intravenous second-line therapy would already be captured in the quality-adjusted life year (QALY) calculation. The committee was not made aware of any significant and substantial impact on health-related benefits which are not already captured in the QALY calculation, and therefore concluded that no additional value judgements needed to be made for innovation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that docetaxel and best supportive care are the appropriate comparators for crizotinib.\n\n\n\nAdverse reactions\n\nThe committee noted the number of adverse reactions associated with crizotinib treatment from the PROFILE studies. The committee concluded that crizotinib is associated with some adverse reactions but these would be tolerable for most patients and generally easily managed.\n\n\n\nEvidence for clinical effectiveness (TA296)\n\nAvailability, nature and quality of evidence\n\nThe main evidence came from 1\xa0multicentre, randomised phase\xa0III efficacy and safety study in patients with previously treated ALK-positive non-small-cell lung cancer (PROFILE\xa01007).\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee accepted that the PROFILE\xa01007 population was likely to be similar to people considered for treatment with crizotinib in UK clinical practice.\n\n\n\nThe committee concluded that the treatment protocol of PROFILE\xa01007, in which patients could continue treatment after radiographic progression, reflected the likely treatment duration for crizotinib in UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee acknowledged that the overall survival data from the crizotinib studies were relatively immature and, for PROFILE\xa01007, subject to a high rate of crossover from chemotherapy to crizotinib. The committee heard from the company that more mature and therefore more reliable overall survival data would be available for PROFILE\xa01007. However, it noted that this would not be within the timeframe of this appraisal. The committee concluded that the exact gain in overall survival from treatment with crizotinib was very uncertain and an exact value could not be reliably established from the available data.\n\n, 4.8, 4.9\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nSubgroups of patients receiving treatment with crizotinib were not in the scope, or identified during the appraisal.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee noted the median gain in progression-free survival of 5.1\xa0months with crizotinib compared with docetaxel from PROFILE\xa01007, and considered that this represented a noteworthy extension to progression-free survival in advanced non-small-cell lung cancer.\n\nThe committee accepted that treatment with crizotinib would result in an overall survival gain compared with docetaxel but the exact size of the gain was uncertain because of the immaturity of the PROFILE\xa01007 data and the impact of crossover in the study.\n\nOverall, the committee concluded that, based on the evidence for progression-free survival and response rate, crizotinib is a clinically efficacious treatment for ALK-positive non-small-cell lung cancer compared with chemotherapy.\n\n\n\nEvidence for cost effectiveness (TA296)\n\nAvailability and nature of evidence\n\nThe company developed a 3-state model, which it referred to as a semi-Markov area-under-the-curve analysis. The model used estimates of treatment effectiveness from PROFILE\xa01005, PROFILE\xa01007 and a mixed treatment comparison.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee discussed the company's justification for preferring one crossover adjustment method, noting that, of the different statistical methods, inverse probability of treatment and censoring weighted 5 (IPTCW5) gave the most favourable overall survival benefit for crizotinib. The committee noted that the company's chosen method resulted in a modelled progression-free survival gain of 5.7\xa0months, and an overall survival gain of 12.3\xa0months for crizotinib and that this large gain in overall survival compared with progression-free survival was not supported by any evidence. The committee concluded that the company's application of the chosen method for adjusting for crossover (IPTCW5) produced an overly optimistic overall survival benefit for crizotinib, for which there was no supporting evidence.\n\n\n\nThe committee concluded that the results from the mixed treatment comparison were subject to uncertainty given the significant heterogeneity in the included studies. It further concluded that the resulting hazard ratio for overall survival for crizotinib compared with best supportive care should be viewed with considerable caution and that as a result, the relative effect of crizotinib compared with best supportive care remained an area of substantial uncertainty.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee discussed the utility estimates in the model. It noted that the baseline utility estimates were different between the groups at entry into the study, and specifically that the mean baseline utility value for crizotinib was higher than for chemotherapy. The company confirmed that this had not been adjusted for in the model.\n\nThe committee also noted the difference in utility values for the progressed disease health state between crizotinib and chemotherapy and observed that these post-progression utilities had been measured at the outset of the progressed disease state and continued at that value until death. The committee accepted that some utility benefit might be expected from crizotinib discontinued at disease progression, though there are no data to suggest how great a benefit this might be or for how long it would persist. The committee concluded that the company's revised post-progression utilities represented a partial solution to the estimation of these values but that the utility estimates in the post-progression state remained uncertain because of the lack of data in the post-progression period.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee considered the most plausible cost-effectiveness estimates of crizotinib compared with docetaxel and best supportive care. The committee agreed that the exact gain in overall survival from treatment with crizotinib was very uncertain and an exact value could not be reliably established from the available data; however for the purposes of the economic model the IPTCW2 was the most reasonable method on which to base its decision. This method produced a result between the 2\xa0extremes of the IPTCW5 and rank-preserving structural failure time (RPSFT) methods, broadly in agreement with clinical opinion (see section\xa04.5). For the comparison with best supportive care, the committee concluded that the incremental cost-effectiveness ratio (ICER) was associated substantial uncertainty, which it was not possible to quantify because of the lack of a robust mixed treatment comparison between crizotinib and best supportive care.\n\nto 4.13\n\nMost likely cost-effectiveness estimate (given as an ICER) (TA296)\n\nThe committee concluded that the ICER on which to base a decision for crizotinib compared with docetaxel would be more than £100,000 per QALY gained.\n\nThe committee concluded that the ICER on which to base a decision for crizotinib compared with best supportive care would be more than £50,200 per QALY gained. However, the committee further concluded that this ICER was associated with a substantial amount of uncertainty, which it was not possible to quantify because of the lack of a robust mixed treatment comparison between crizotinib and best supportive care.\n\n, 4.13\n\nAdditional factors taken into account (TA296)\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This involves a discount applied to the list price of crizotinib. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nThe committee accepted that the supplementary advice from NICE for life-extending treatments could be considered for crizotinib compared with chemotherapy, even though there was considerable uncertainty in the exact overall survival gain, and therefore in the resulting ICER.\n\n, 4.17\n\nEqualities considerations and social value judgements\n\nThe committee concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations.\n\n\n\nCancer Drugs Fund reconsideration of TA296\n\nCurrent practice\n\nThe committee noted that the treatment pathway for ALK-positive non-small-cell lung cancer has changed since the original appraisal (TA296). New treatments recommended by NICE are now available.\n\n\n\nEvidence for clinical effectiveness\n\nThe committee noted that more mature data were available in the CDF reconsideration submission.\n\n\n\nEvidence for cost effectiveness\n\nThe company submitted a new model which included all the committee's preferred assumptions, except treatment with crizotinib extending beyond disease progression. The committee noted that no analyses comparing crizotinib with best supportive care were presented in the CDF reconsideration submission.\n\n, 4.21\n\nThe committee concluded that the most plausible ICER for crizotinib compared with docetaxel would be less than £50,000 per QALY gained including the revised patient access scheme, assuming a hazard ratio of 0.49 for overall survival and allowing for crizotinib treatment after progression.\n\n, 4.24\n\nAdditional factors taken into account\n\nThe committee acknowledged that the CDF reconsideration submission included the patient access scheme as in NICE's technology appraisal guidance on crizotinib for untreated anaplastic lymphoma kinase-positive non-small-cell lung cancer.\n\n\n\nThe committee considered the end-of-life criteria to be fulfilled.\n\n"}	https://www.nice.org.uk/guidance/ta422	Evidence-based recommendations on crizotinib (Xalkori) for previously treated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults.
3145042cf7edc7b84fdf3776da1f44d6e46e3631	nice	Eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens	Eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens Evidence-based recommendations on eribulin (Halaven) for locally advanced or metastatic (secondary) breast cancer in adults who have had 2 or more courses of chemotherapy. # Recommendations Eribulin is recommended as an option for treating locally advanced or metastatic breast cancer in adults, only when: it has progressed after at least 2 chemotherapy regimens (which may include an anthracycline or a taxane, and capecitabine) the company provides eribulin with the discount agreed in the patient access scheme. This guidance is not intended to affect the position of patients whose treatment with eribulin was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology # Description of the technology Eribulin (Halaven, Eisai) is a synthetic analogue of halichondrin B, which inhibits tubulin polymerisation. This disrupts the assembly and formation of microtubules, stopping cancer cell division. # Marketing authorisation Eribulin has a UK marketing authorisation for the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least 1 chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless these treatments were not suitable. This appraisal is only looking at locally advanced or metastatic breast cancer that has progressed after 2 or more chemotherapy regimens for advanced disease. # Adverse reactions The adverse reactions of eribulin include fatigue, alopecia, peripheral neuropathy, nausea, neutropenia, leukopenia and anaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics. # Recommended dose and schedule The recommended dosage of eribulin as the ready to use solution is 1.23 mg/m2 administered intravenously over 2 to 5 minutes on days 1 and 8 of every 21‑day cycle. # Price The cost of eribulin is £361.00 per 0.88 mg/2 ml solution for injection vial and £541.50 per 1.32 mg/3 ml solution for injection vial (excluding VAT; British national formulary online, accessed September 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of eribulin, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence This appraisal is a review of NICE's guidance TA250. The relevant evidence submitted by the company (Eisai) is the data for the subgroup of patients who had locally advanced or metastatic breast cancer that has progressed after 2 or more chemotherapy regimens for advanced disease, which includes capecitabine (if indicated, referred to as subgroup 2 in their submission). The appraisal committee considered this evidence alongside a review of the company submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of eribulin, having considered evidence on the nature of locally advanced or metastatic breast cancer and the value placed on the benefits of eribulin by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Symptoms and management of advanced breast cancer The committee heard from a patient expert that locally advanced or metastatic breast cancer is a debilitating condition that can affect women of all ages, and leads to premature death. It also heard that the symptoms of advanced breast cancer can differ substantially among patients, depending on the type of disease and the site of metastases, and the patient expert emphasised that living with advanced breast cancer is very difficult for patients and their families. The life expectancy of people for whom eribulin is licensed is short, and quality of life is very important. For some people even relatively short extensions to life are highly valued, particularly if they are able to experience important events like a child starting school or a family wedding, as long as their quality of life is maintained. The committee heard that having more treatment options available would be very important for patients, giving hope to them and their families. The committee recognised that the availability of additional treatment options for advanced disease would be valued by patients and their families. The committee discussed the management of advanced breast cancer with the clinical expert. It heard that the treatment of advanced disease is consistent with NICE's guideline on advanced breast cancer. Initially patients are offered an anthracycline, if they have not had one at an earlier stage in the treatment pathway, or they have a taxane. This is usually followed by capecitabine. The clinical expert estimated that about half of people will then be offered vinorelbine, and overall probably about three quarters of people will be offered either vinorelbine or gemcitabine. The committee was aware that eribulin has a marketing authorisation that covers both the treatment of HER2‑positive and HER2‑negative advanced breast cancer. People with HER2‑positive disease would initially be treated with targeted therapies, but might benefit from eribulin later in the treatment pathway. The committee noted that eribulin has been available through the Cancer Drugs Fund since 2011 for people with locally advanced or metastatic breast cancer, whose disease has progressed after at least 2 chemotherapy regimens. The committee concluded that eribulin is particularly valuable, and has been more widely used, for HER2‑negative disease because this has fewer treatment options. The committee considered the most relevant comparators for eribulin in clinical practice. It noted that although the comparators in the scope were defined as vinorelbine, capecitabine or gemcitabine, the comparator in the company submission was treatment of physician's choice (TPC), which was used in the EMBRACE clinical trial. This combined comparator included vinorelbine, gemcitabine, anthracyclines (doxorubicin) and taxanes (paclitaxel and docetaxel). The committee heard from the clinical expert that this reflects UK clinical practice because it includes all available options for this patient population, and most people would already have had capecitabine. The committee therefore concluded that TPC is a reasonable proxy for usual care in the NHS and a clinically relevant comparator for the population under consideration in this appraisal. It did however note that the majority of people (three quarters) would be offered vinorelbine or gemcitabine as an alternative to eribulin at this stage in the treatment pathway. # Clinical effectiveness The committee considered the clinical evidence for eribulin compared with TPC from the EMBRACE trial. This was a randomised controlled trial in women with locally advanced or metastatic breast cancer, who had had 2 to 5 chemotherapy regimens for advanced disease. The committee noted that the company presented data for the whole trial population and for a subgroup of people who previously had capecitabine, because they considered this population to be the most relevant to clinical practice in the UK. The committee agreed that the subgroup who had had capecitabine, from the company submission, was the most clinically relevant population and noted that approximately 80% of people having eribulin through the Cancer Drugs Fund had previously had capecitabine. It heard from the clinical expert that the design of EMBRACE reflects current clinical practice, and that the results are consistent with subsequent real-life use of eribulin through the Cancer Drugs Fund. The committee noted that the primary outcome of the trial was overall survival. At the submission 95% of the population in the subgroup had died and there was a 2.9 month difference in median overall survival favouring eribulin, which was statistically significant. The committee concluded that the results of EMBRACE are generalisable to the UK population, and agreed that the subgroup of people who had prior capecitabine is the most relevant population for this appraisal. It also concluded that based on the available evidence, eribulin is clinically effective and offers a statistically significant improvement in overall survival compared with TPC. Health-related quality-of-life data were not collected in EMBRACE, therefore the company presented results from another clinical trial for eribulin compared with capecitabine (Study 301). The committee noted that the population in Study 301 was less heavily pre-treated (had no more than 2 chemotherapy regimens, compared with 2 to 5 in EMBRACE) and had not previously had capecitabine. The committee also understood that the number of people completing the health-related quality-of-life questionnaire declined towards the end of the study period, and that data for 24 months is only available from 13 people in the eribulin arm. However it considered that this is a general problem in clinical trials, and welcomed the fact that there was data available directly from patients who had taken eribulin. The committee concluded that direct patient data on health-related quality of life from Study 301 is of value, but has inherent limitations. # Cost effectiveness The committee considered the cost-effectiveness evidence presented by the company and its critique by the ERG. It accepted the structure of the economic model developed by the company and went on to discuss some of the key assumptions within the model. ## Utility values The committee noted that the company used a mapping algorithm published by Crott and Briggs (2010) for estimating utility values from the health-related quality-of-life data from Study 301. It heard from the ERG that this algorithm was developed using data from people with locally advanced but not metastatic breast cancer and who had good baseline health status. The ERG also noted that this resulted in only a small decrease in the utility between the progression-free and post-progression health states in the company's model (approximately 3%), which it considered to be implausible. The ERG used the utility values from a study by Lloyd et al. (2006), which it considered to be more relevant. The study assessed UK-based societal preferences for different stages of metastatic breast cancer, and has been used in other NICE appraisals. This resulted in an approximate 20% decline in utility between the pre- and post-progression state, and an increase in the incremental cost-effectiveness ratio (ICER) of around £11,000 per QALY gained. The committee heard from the clinical expert that patients may have radiological evidence of disease progression without any immediate deterioration in symptoms or quality of life, although this would be expected to decline as the disease progressed further. The clinical expert said that some decline would be expected, but that an immediate decrease of 20% in health-related quality of life on progression seemed high. The committee considered that the very small decrement seen in the company's model, although generated directly from an eribulin trial, may be an underestimate. However, the estimate of 20% deterioration in quality of life on progression from the Lloyd et al. study also has limitations. The committee could not confidently determine whether the Lloyd et al. estimate was more or less accurate than that which resulted from the company's mapping. It concluded that the most plausible utility value for the progressed disease health state is likely to be somewhere between the company's and the ERG's estimates. ## Treatment costs The committee noted that the dose of eribulin and its comparators are dependent on body surface area. It heard from the ERG that the company calculated doses using the standard error instead of the standard deviation of the population, which is methodologically implausible, and resulted in a narrow range of body surface areas and drug dosages in the company model. The ERG changed this in its revised base case. The change in individual doses had little impact on cost of the drugs administered but increased the drug wastage, calculated from unused portions of vials, leading to an increase in total drug costs, especially of eribulin. The committee acknowledged that drug wastage is an issue when doses are individually calculated according to weight or body surface area and noted that some drug wastage had already been included in the company's base case (when the company excluded wastage in a sensitivity analysis the ICER decreased by 55%). The committee heard from the company that data on individual patient doses used in EMBRACE are not available. The committee heard from the clinical expert that in clinical practice drug wastage is recognised and efforts are made to minimise it by carefully scheduling patients for treatment where vial sharing is possible, although the proportion of drug cost saved through vial sharing in clinical practice is uncertain. The committee agreed that drug wastage may be higher than in the company's model, but that the ERG estimate is likely to be a conservative scenario. The committee noted that the company applied a 6‑month cap on the total treatments a patient could have in the model. The committee heard from the company that this was based on data on the proportion of breast cancer patients progressing from first to fifth-line therapy (Kantar Health, 2014) and is consistent with the results from EMBRACE, in which the majority of people had 3 to 6 cycles of eribulin. It heard from the ERG that a cap for all lines of treatment is implausible and likely to result in an underestimate of the costs of subsequent therapy. The ERG assumed that after progression 60% of patients would go on to have subsequent therapy until death, based on data on the proportion of breast cancer patients progressing from first to fifth-line therapy (Kantar Health, 2014). The committee heard from the clinical expert that the response to third-line treatment is variable; some people have chemotherapy sensitive disease and may continue on eribulin beyond 6 months, and these people may also respond well to subsequent lines of treatment. Others have disease that progresses quickly on eribulin, probably because they have chemotherapy insensitive disease, and these patients may decide not to have further treatments. The committee agreed with the ERG's reasoning on continuing treatment beyond 6 months, although it considered that there is significant uncertainty about the proportion of patients who might still be on treatment after 6 months, and the duration of subsequent lines of treatment. The committee acknowledged that the subsequent treatments are a source of significant uncertainty in the model, which it is not possible to resolve. It therefore concluded that although the assumptions in the company's model might have been optimistic, the ERG's assumption represents a worst-case scenario for the costs of subsequent therapy. The committee considered the sensitivity analysis presented by the company, which showed that if the percentage of people taking the comparators were changed to 50% gemcitabine and 50% vinorelbine, the ICER decreased substantially (by approximately 33%). It was mindful of its previous conclusion that most people would be offered vinorelbine or gemcitabine after 2 or more chemotherapy regimens (see section 4.2). It also noted that in EMBRACE only 65% of patients had these 2 agents and that assuming that 75% of patients would have gemcitabine or vinorelbine would reduce the ICER in favour of eribulin. ## Additional changes to the model by the ERG The committee considered the additional changes to the model, which included updating the progression-free survival and overall survival data, applying annual discounting, and correcting errors in the cost calculations. The committee noted that these were not cost drivers and did not have a major impact on the cost-effectiveness results. It accepted that these were methodological corrections and concluded that they were appropriate. ## Cost-effectiveness results The committee considered the most plausible ICER for eribulin compared with TPC. It was mindful of its previous considerations on the different assumptions and inputs to the model and concluded that the most plausible ICER for eribulin compared with TPC is likely to be between the company's base case ICER (£35,624 per quality-adjusted life year gained) and the ERG's revised base case (£62,672 per QALY gained). It also considered that there were a lot of uncertainties around the assumptions in the model, many of which could not be resolved. The committee noted that although it is not possible to determine a precise ICER for eribulin compared with TPC, some of the ERG's assumptions were based on highly conservative scenarios. The committee also noted that if the costs of TPC were increased (to account for a higher use of gemcitabine and vinorelbine in clinical practice than that in the model) this would further reduce the ICER for eribulin compared with TPC. # Innovation The committee heard from the company that it considers eribulin to be innovative because of its mechanism of action and convenient administration method (it is administered intravenously over 2 to 5 minutes with no special handling or tubing needed). The committee heard from the patient and clinical expert that a quick and easily administered preparation would enable appointments to be scheduled around normal daily life and activities (for example, work and carer commitments). However, the committee concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It considered that the evidence presented by the company showed that people with advanced breast cancer that has progressed after 2 lines of chemotherapy have a life expectancy of less than 24 months. The overall survival of people in EMBRACE was a mean of 13.53 months in the TPC arm. The committee also considered that both the company's and the ERG's models suggest that eribulin offers a mean overall survival benefit of more than 3 months. In light of the short life expectancy at this stage of breast cancer, the committee considered this overall survival benefit to be substantial. The committee therefore concluded that eribulin met the end-of-life criteria objectively and robustly and that it can be considered a life-extending, end-of-life treatment. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Conclusions The committee concluded that the correct modelling approach is uncertain but it found no evidence to indicate that the ERG's approach was based on more plausible assumptions than the company's approach. It noted that although it is not possible to determine a precise ICER for eribulin compared with TPC, some of the ERG's assumptions were based on highly conservative scenarios. The committee considered the most plausible ICER would be much lower than that calculated by the ERG, and was likely to be below £50,000 per QALY gained (see section 4.12). However it considered that if the percentage of people taking vinorelbine and gemcitabine in the TPC arm were increased, in line with UK clinical practice (see section 4.2), the ICER would be further reduced. It was satisfied that the ICER for eribulin was acceptable given the additional weight that can be assigned to QALY gains for a treatment that fulfils the end‑of‑life criteria. # Summary of appraisal committee's key conclusions ## Key conclusion Eribulin is recommended as an option for treating locally advanced or metastatic breast cancer in adults, only when: it has progressed after at least 2 chemotherapy regimens (which may include an anthracycline or a taxane and capecitabine) the company provides eribulin with the discount agreed in the patient access scheme. The committee concluded that the correct modelling approach is uncertain but it found no evidence to indicate that the evidence review group (ERG's) approach was based on more plausible assumptions than the company's approach. The most plausible incremental cost-effectiveness ratio (ICER) for eribulin compared with treatment of physician's choice (TPC) is likely to be between the company's base case ICER (£35,624 per quality-adjusted life year gained) and the ERG's revised base case (£62,672 per QALY gained). Although it is not possible to determine a precise ICER for eribulin compared with TPC, some of the ERG's assumptions were based on highly conservative scenarios. The committee considered the most plausible ICER would be much lower than that calculated by the ERG, and was likely to be below £50,000 per QALY gained. However it considered that if the percentage of people taking vinorelbine and gemcitabine in the TPC arm were increased, in line with UK clinical practice, the ICER would be further reduced. It was satisfied that the ICER for eribulin was acceptable given the additional weight that can be assigned to QALY gains for a treatment that fulfils the end of life criteria. See sections 1.1, 4.12 and 4.16 ## Current practice The majority of people (three quarters) would be offered vinorelbine or gemcitabine as an alternative to eribulin after 2 or more chemotherapy regimens. Eribulin has been available through the Cancer Drugs Fund since 2011 for people with locally advanced or metastatic breast cancer, whose disease has progressed after at least 2 chemotherapy regimens. The committee concluded that eribulin is particularly valuable, and has been more widely used, for HER2‑negative disease because this has fewer treatment options. It also recognised that the availability of additional treatment options for advanced disease would be valued by patients and their families. See sections 4.1 to 4.3 ## The technology Eribulin was associated with a statistically significant overall survival gain of 2.9 months, compared with TPC in the EMBRACE trial. The committee concluded that the results of EMBRACE are generalisable to the UK population, and agreed that the subgroup of people who had had capecitabine is the most relevant population for this appraisal. It also concluded that eribulin is clinically effective. The committee heard from the company that it considers eribulin to be innovative because of its mechanism of action and convenient administration method. However, it concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation. See sections 4.4 and 4.13 Initially patients with locally advanced or metastatic breast cancer are offered an anthracycline, if they have not had one at an earlier stage in the treatment pathway, or they have a taxane. This is usually followed by capecitabine. The clinical expert estimated that about half of people will then be offered vinorelbine, and overall about three quarters of people will be offered either vinorelbine or gemcitabine, as an alternative to eribulin. See section 4.2 The adverse reactions of eribulin include fatigue, alopecia, peripheral neuropathy, nausea, neutropenia, leukopenia and anaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics. See section 2 ## Evidence for clinical effectiveness The clinical evidence for eribulin compared with TPC comes from the EMBRACE trial. The committee noted that the company presented data for the whole trial population and for a subgroup of people who previously had capecitabine, because they considered this population to be the most relevant to clinical practice in the UK. The committee agreed that the subgroup who had had capecitabine, from the company submission, was the most clinically relevant population and noted that approximately 80% of people having eribulin through the Cancer Drugs Fund had previously had capecitabine. Health-related quality-of-life data was not collected in EMBRACE, therefore the company presented results from another clinical trial for eribulin compared with capecitabine (Study 301). The population in the study was less heavily pre-treated and had not previously had capecitabine. See sections 4.4 and 4.5 The committee concluded that the results of EMBRACE are generalisable to the UK population, and agreed that the subgroup of people who had had capecitabine is the most relevant population for this appraisal. It also concluded that TPC is a reasonable proxy for usual care in the NHS and a clinically relevant comparator for the population under consideration in this appraisal. It did however note that the majority of people (three quarters) would be offered vinorelbine or gemcitabine as an alternative to eribulin at this stage in the treatment pathway. See sections 4.2 and 4.4 Health-related quality-of-life data was not collected in EMBRACE, therefore the company presented results from another clinical trial for eribulin compared with capecitabine (Study 301). The population in Study 301 was less heavily pre-treated and had not previously had capecitabine. The committee considered that direct patient data on health-related quality of life is of value, but it has limitations. See section 4.5 The committee agreed that the subgroup of people who had had capecitabine is the most relevant population for this appraisal. See section 4.4 Eribulin was associated with a statistically significant overall survival benefit of 2.9 months when compared with TPC. See section 4.4 At the time of the appraisal for NICE's guidance TA250, evidence was available from a data-cut when 77% of patients in the trial had died. At the time of the submission for the current appraisal, 95% of the trial population had died and therefore more mature data was available. Health-related quality-of-life data was not collected in EMBRACE and in TA250 the company presented results from 2 phase 2, multi-centre, single-arm, open-label trials (Study 201 and Study 211). At the time of the current appraisal results from a phase 3, open label randomised controlled trial for eribulin compared with capecitabine had become available (Study 301). See sections 4.4 and 4.5 ## Evidence for cost effectiveness The committee accepted the structure of the economic model developed by the company and considered its critique by the ERG. See section 4.6 The committee considered the following key areas of uncertainty: utility values used in the model for the progressed disease health state, in both arms of the model the method used for calculating body surface area and dose of eribulin and its comparators the method used for calculating the costs of subsequent line of therapy the method used for calculating the costs of comparators. See sections 4.7 to 4.10 The company used a mapping algorithm published by Crott and Briggs (2010) for estimating utility values from the health-related quality-of-life data from Study 301. This resulted in only a small decrease in the utility between the progression-free and post-progression health states in the company's model (approximately 3%). The ERG considered this to be implausible and used utility values from a study by Lloyd at al. (2006), This resulted in an approximate 20% decline in utility between the pre- and post-progression state and increase in the ICER of around £11,000 per QALY gained. The committee considered that the very small decrement seen in the company's model, although generated directly from an eribulin trial, may be an underestimate but the 20% deterioration in quality of life on progression seemed to be too high. It concluded that the most plausible utility value for the progressed disease health state is likely to be somewhere between the company's and the ERG's estimates. The committee heard from the company that it considers eribulin to be innovative because of its mechanism of action and convenient administration method. However, it concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation. See sections 4.7 and 4.14 The committee considered that the subgroup of people who had had capecitabine is the most relevant population for this appraisal. See section 4.4 The key drivers of cost effectiveness in the company's model were the utility value used in the progressed disease heath state in both arms of the model and the price of eribulin. The committee concluded that the most plausible ICER for eribulin compared with TPC is likely to be between the company's base case ICER (£35,624 per QALY gained) and the ERG's revised base case (£62,672 per QALY gained). There were a lot of uncertainties around the assumptions in the model, therefore it was not possible to determine a precise ICER. The committee considered the most plausible ICER to be below £50,000 per QALY gained. The committee noted that if the costs of TPC were increased (to account for a higher use of gemcitabine and vinorelbine in clinical practice than that in the model) this would further reduce the ICER for eribulin compared with TPC. See sections 4.12 and 4.16 Eribulin was not recommended in NICE's guidance TA250 for the treatment of locally advanced or metastatic breast cancer that has progressed after at least 2 chemotherapy regimens for advanced disease, because the most plausible ICER was much higher than the range normally considered a cost‑effective use of NHS resources, even taking into account additional weights applied to QALY benefits for a life-extending treatment at the end of life. Updated survival results from the EMBRACE trial were incorporated in the current appraisal and also results for health-related quality-of-life from a phase 3, open label randomised controlled trial for eribulin compared with capecitabine (Study 301). The committee concluded that the correct modelling approach was uncertain and therefore the most plausible ICER for eribulin compared with TPC is likely to be between the company's base case ICER and the ERG's revised base case. There were a lot of uncertainties around the assumptions in the model, therefore it was not possible to determine a precise ICER. The committee considered the most plausible ICER to be below £50,000 per QALY gained. However it considered that if the percentage of people taking vinorelbine and gemcitabine in the TPC arm were increased, in line with UK clinical practice, the ICER would be further reduced. Therefore it was satisfied that the most plausible ICER was acceptable given the additional weight that can be assigned to QALY gains, for a treatment that fulfils the end-of-life criteria. See sections 4.12 and 4.16 ## Additional factors taken into account The PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. See section 4.15 The evidence shows that people with advanced breast cancer that has progressed after 2 lines of chemotherapy have a life expectancy of less than 24 months. The evidence also suggests that eribulin offers a mean overall survival benefit of more than 3 months. In light of the short life expectancy at this stage of breast cancer, the committee considered this overall survival benefit to be substantial. The committee concluded that eribulin met the end-of-life criteria objectively and robustly and that it can be considered a life-extending, end-of-life treatment. See section 4.14 No equality issues were raised during the appraisal.	{'Recommendations': 'Eribulin is recommended as an option for treating locally advanced or metastatic breast cancer in adults, only when:\n\nit has progressed after at least 2\xa0chemotherapy regimens (which may include an anthracycline or a taxane, and capecitabine)\n\nthe company provides eribulin with the discount agreed in the patient access scheme.\n\nThis guidance is not intended to affect the position of patients whose treatment with eribulin was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': '# Description of the technology\n\nEribulin (Halaven, Eisai) is a synthetic analogue of halichondrin\xa0B, which inhibits tubulin polymerisation. This disrupts the assembly and formation of microtubules, stopping cancer cell division.\n\n# Marketing authorisation\n\nEribulin has a UK marketing authorisation for the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least 1\xa0chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless these treatments were not suitable.\n\nThis appraisal is only looking at locally advanced or metastatic breast cancer that has progressed after 2\xa0or more chemotherapy regimens for advanced disease.\n\n# Adverse reactions\n\nThe adverse reactions of eribulin include fatigue, alopecia, peripheral neuropathy, nausea, neutropenia, leukopenia and anaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\n# Recommended dose and schedule\n\nThe recommended dosage of eribulin as the ready to use solution is 1.23\xa0mg/m2 administered intravenously over 2 to 5 minutes on days\xa01 and\xa08 of every 21‑day cycle.\n\n# Price\n\nThe cost of eribulin is £361.00 per 0.88\xa0mg/2\xa0ml solution for injection vial and £541.50 per 1.32\xa0mg/3\xa0ml solution for injection vial (excluding VAT; British national formulary [BNF] online, accessed September 2016).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of eribulin, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Evidence': "This appraisal is a review of NICE's guidance TA250. The relevant evidence submitted by the company (Eisai) is the data for the subgroup of patients who had locally advanced or metastatic breast cancer that has progressed after 2 or more chemotherapy regimens for advanced disease, which includes capecitabine (if indicated, referred to as subgroup\xa02 in their submission). The appraisal committee considered this evidence alongside a review of the company submission by the evidence review group (ERG). See the committee papers for full details of the evidence.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of eribulin, having considered evidence on the nature of locally advanced or metastatic breast cancer and the value placed on the benefits of eribulin by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Symptoms and management of advanced breast cancer\n\nThe committee heard from a patient expert that locally advanced or metastatic breast cancer is a debilitating condition that can affect women of all ages, and leads to premature death. It also heard that the symptoms of advanced breast cancer can differ substantially among patients, depending on the type of disease and the site of metastases, and the patient expert emphasised that living with advanced breast cancer is very difficult for patients and their families. The life expectancy of people for whom eribulin is licensed is short, and quality of life is very important. For some people even relatively short extensions to life are highly valued, particularly if they are able to experience important events like a child starting school or a family wedding, as long as their quality of life is maintained. The committee heard that having more treatment options available would be very important for patients, giving hope to them and their families. The committee recognised that the availability of additional treatment options for advanced disease would be valued by patients and their families.\n\nThe committee discussed the management of advanced breast cancer with the clinical expert. It heard that the treatment of advanced disease is consistent with NICE's guideline on advanced breast cancer. Initially patients are offered an anthracycline, if they have not had one at an earlier stage in the treatment pathway, or they have a taxane. This is usually followed by capecitabine. The clinical expert estimated that about half of people will then be offered vinorelbine, and overall probably about three quarters of people will be offered either vinorelbine or gemcitabine. The committee was aware that eribulin has a marketing authorisation that covers both the treatment of HER2‑positive and HER2‑negative advanced breast cancer. People with HER2‑positive disease would initially be treated with targeted therapies, but might benefit from eribulin later in the treatment pathway. The committee noted that eribulin has been available through the Cancer Drugs Fund since 2011 for people with locally advanced or metastatic breast cancer, whose disease has progressed after at least 2 chemotherapy regimens. The committee concluded that eribulin is particularly valuable, and has been more widely used, for HER2‑negative disease because this has fewer treatment options.\n\nThe committee considered the most relevant comparators for eribulin in clinical practice. It noted that although the comparators in the scope were defined as vinorelbine, capecitabine or gemcitabine, the comparator in the company submission was treatment of physician's choice (TPC), which was used in the EMBRACE clinical trial. This combined comparator included vinorelbine, gemcitabine, anthracyclines (doxorubicin) and taxanes (paclitaxel and docetaxel). The committee heard from the clinical expert that this reflects UK clinical practice because it includes all available options for this patient population, and most people would already have had capecitabine. The committee therefore concluded that TPC is a reasonable proxy for usual care in the NHS and a clinically relevant comparator for the population under consideration in this appraisal. It did however note that the majority of people (three quarters) would be offered vinorelbine or gemcitabine as an alternative to eribulin at this stage in the treatment pathway.\n\n# Clinical effectiveness\n\nThe committee considered the clinical evidence for eribulin compared with TPC from the EMBRACE trial. This was a randomised controlled trial in women with locally advanced or metastatic breast cancer, who had had 2\xa0to\xa05 chemotherapy regimens for advanced disease. The committee noted that the company presented data for the whole trial population and for a subgroup of people who previously had capecitabine, because they considered this population to be the most relevant to clinical practice in the UK. The committee agreed that the subgroup who had had capecitabine, from the company submission, was the most clinically relevant population and noted that approximately 80% of people having eribulin through the Cancer Drugs Fund had previously had capecitabine. It heard from the clinical expert that the design of EMBRACE reflects current clinical practice, and that the results are consistent with subsequent real-life use of eribulin through the Cancer Drugs Fund. The committee noted that the primary outcome of the trial was overall survival. At the submission 95% of the population in the subgroup had died and there was a 2.9\xa0month difference in median overall survival favouring eribulin, which was statistically significant. The committee concluded that the results of EMBRACE are generalisable to the UK population, and agreed that the subgroup of people who had prior capecitabine is the most relevant population for this appraisal. It also concluded that based on the available evidence, eribulin is clinically effective and offers a statistically significant improvement in overall survival compared with TPC.\n\nHealth-related quality-of-life data were not collected in EMBRACE, therefore the company presented results from another clinical trial for eribulin compared with capecitabine (Study\xa0301). The committee noted that the population in Study\xa0301 was less heavily pre-treated (had no more than 2 chemotherapy regimens, compared with 2\xa0to\xa05 in EMBRACE) and had not previously had capecitabine. The committee also understood that the number of people completing the health-related quality-of-life questionnaire declined towards the end of the study period, and that data for 24\xa0months is only available from 13\xa0people in the eribulin arm. However it considered that this is a general problem in clinical trials, and welcomed the fact that there was data available directly from patients who had taken eribulin. The committee concluded that direct patient data on health-related quality of life from Study\xa0301 is of value, but has inherent limitations.\n\n# Cost effectiveness\n\nThe committee considered the cost-effectiveness evidence presented by the company and its critique by the ERG. It accepted the structure of the economic model developed by the company and went on to discuss some of the key assumptions within the model.\n\n## Utility values\n\nThe committee noted that the company used a mapping algorithm published by Crott and Briggs (2010) for estimating utility values from the health-related quality-of-life data from Study\xa0301. It heard from the ERG that this algorithm was developed using data from people with locally advanced but not metastatic breast cancer and who had good baseline health status. The ERG also noted that this resulted in only a small decrease in the utility between the progression-free and post-progression health states in the company's model (approximately 3%), which it considered to be implausible. The ERG used the utility values from a study by Lloyd et al. (2006), which it considered to be more relevant. The study assessed UK-based societal preferences for different stages of metastatic breast cancer, and has been used in other NICE appraisals. This resulted in an approximate 20% decline in utility between the pre- and post-progression state, and an increase in the incremental cost-effectiveness ratio (ICER) of around £11,000 per QALY gained. The committee heard from the clinical expert that patients may have radiological evidence of disease progression without any immediate deterioration in symptoms or quality of life, although this would be expected to decline as the disease progressed further. The clinical expert said that some decline would be expected, but that an immediate decrease of 20% in health-related quality of life on progression seemed high. The committee considered that the very small decrement seen in the company's model, although generated directly from an eribulin trial, may be an underestimate. However, the estimate of 20% deterioration in quality of life on progression from the Lloyd et al. study also has limitations. The committee could not confidently determine whether the Lloyd et al. estimate was more or less accurate than that which resulted from the company's mapping. It concluded that the most plausible utility value for the progressed disease health state is likely to be somewhere between the company's and the ERG's estimates.\n\n## Treatment costs\n\nThe committee noted that the dose of eribulin and its comparators are dependent on body surface area. It heard from the ERG that the company calculated doses using the standard error instead of the standard deviation of the population, which is methodologically implausible, and resulted in a narrow range of body surface areas and drug dosages in the company model. The ERG changed this in its revised base case. The change in individual doses had little impact on cost of the drugs administered but increased the drug wastage, calculated from unused portions of vials, leading to an increase in total drug costs, especially of eribulin. The committee acknowledged that drug wastage is an issue when doses are individually calculated according to weight or body surface area and noted that some drug wastage had already been included in the company's base case (when the company excluded wastage in a sensitivity analysis the ICER decreased by 55%). The committee heard from the company that data on individual patient doses used in EMBRACE are not available. The committee heard from the clinical expert that in clinical practice drug wastage is recognised and efforts are made to minimise it by carefully scheduling patients for treatment where vial sharing is possible, although the proportion of drug cost saved through vial sharing in clinical practice is uncertain. The committee agreed that drug wastage may be higher than in the company's model, but that the ERG estimate is likely to be a conservative scenario.\n\nThe committee noted that the company applied a 6‑month cap on the total treatments a patient could have in the model. The committee heard from the company that this was based on data on the proportion of breast cancer patients progressing from first to fifth-line therapy (Kantar Health, 2014) and is consistent with the results from EMBRACE, in which the majority of people had 3\xa0to\xa06 cycles of eribulin. It heard from the ERG that a cap for all lines of treatment is implausible and likely to result in an underestimate of the costs of subsequent therapy. The ERG assumed that after progression 60% of patients would go on to have subsequent therapy until death, based on data on the proportion of breast cancer patients progressing from first to fifth-line therapy (Kantar Health, 2014). The committee heard from the clinical expert that the response to third-line treatment is variable; some people have chemotherapy sensitive disease and may continue on eribulin beyond 6\xa0months, and these people may also respond well to subsequent lines of treatment. Others have disease that progresses quickly on eribulin, probably because they have chemotherapy insensitive disease, and these patients may decide not to have further treatments. The committee agreed with the ERG's reasoning on continuing treatment beyond 6\xa0months, although it considered that there is significant uncertainty about the proportion of patients who might still be on treatment after 6\xa0months, and the duration of subsequent lines of treatment. The committee acknowledged that the subsequent treatments are a source of significant uncertainty in the model, which it is not possible to resolve. It therefore concluded that although the assumptions in the company's model might have been optimistic, the ERG's assumption represents a worst-case scenario for the costs of subsequent therapy.\n\nThe committee considered the sensitivity analysis presented by the company, which showed that if the percentage of people taking the comparators were changed to 50% gemcitabine and 50% vinorelbine, the ICER decreased substantially (by approximately 33%). It was mindful of its previous conclusion that most people would be offered vinorelbine or gemcitabine after 2 or more chemotherapy regimens (see section\xa04.2). It also noted that in EMBRACE only 65% of patients had these 2 agents and that assuming that 75% of patients would have gemcitabine or vinorelbine would reduce the ICER in favour of eribulin.\n\n## Additional changes to the model by the ERG\n\nThe committee considered the additional changes to the model, which included updating the progression-free survival and overall survival data, applying annual discounting, and correcting errors in the cost calculations. The committee noted that these were not cost drivers and did not have a major impact on the cost-effectiveness results. It accepted that these were methodological corrections and concluded that they were appropriate.\n\n## Cost-effectiveness results\n\nThe committee considered the most plausible ICER for eribulin compared with TPC. It was mindful of its previous considerations on the different assumptions and inputs to the model and concluded that the most plausible ICER for eribulin compared with TPC is likely to be between the company's base case ICER (£35,624 per quality-adjusted life year [QALY] gained) and the ERG's revised base case (£62,672 per QALY gained). It also considered that there were a lot of uncertainties around the assumptions in the model, many of which could not be resolved. The committee noted that although it is not possible to determine a precise ICER for eribulin compared with TPC, some of the ERG's assumptions were based on highly conservative scenarios. The committee also noted that if the costs of TPC were increased (to account for a higher use of gemcitabine and vinorelbine in clinical practice than that in the model) this would further reduce the ICER for eribulin compared with TPC.\n\n# Innovation\n\nThe committee heard from the company that it considers eribulin to be innovative because of its mechanism of action and convenient administration method (it is administered intravenously over 2 to 5\xa0minutes with no special handling or tubing needed). The committee heard from the patient and clinical expert that a quick and easily administered preparation would enable appointments to be scheduled around normal daily life and activities (for example, work and carer commitments). However, the committee concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It considered that the evidence presented by the company showed that people with advanced breast cancer that has progressed after 2\xa0lines of chemotherapy have a life expectancy of less than 24\xa0months. The overall survival of people in EMBRACE was a mean of 13.53\xa0months in the TPC arm. The committee also considered that both the company's and the ERG's models suggest that eribulin offers a mean overall survival benefit of more than 3\xa0months. In light of the short life expectancy at this stage of breast cancer, the committee considered this overall survival benefit to be substantial. The committee therefore concluded that eribulin met the end-of-life criteria objectively and robustly and that it can be considered a life-extending, end-of-life treatment.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Conclusions\n\nThe committee concluded that the correct modelling approach is uncertain but it found no evidence to indicate that the ERG's approach was based on more plausible assumptions than the company's approach. It noted that although it is not possible to determine a precise ICER for eribulin compared with TPC, some of the ERG's assumptions were based on highly conservative scenarios. The committee considered the most plausible ICER would be much lower than that calculated by the ERG, and was likely to be below £50,000 per QALY gained (see section\xa04.12). However it considered that if the percentage of people taking vinorelbine and gemcitabine in the TPC arm were increased, in line with UK clinical practice (see section\xa04.2), the ICER would be further reduced. It was satisfied that the ICER for eribulin was acceptable given the additional weight that can be assigned to QALY gains for a treatment that fulfils the end‑of‑life criteria.\n\n# Summary of appraisal committee's key conclusions\n\n## Key conclusion\n\nEribulin is recommended as an option for treating locally advanced or metastatic breast cancer in adults, only when:\n\nit has progressed after at least 2 chemotherapy regimens (which may include an anthracycline or a taxane and capecitabine)\n\nthe company provides eribulin with the discount agreed in the patient access scheme.\n\nThe committee concluded that the correct modelling approach is uncertain but it found no evidence to indicate that the evidence review group (ERG's) approach was based on more plausible assumptions than the company's approach.\n\nThe most plausible incremental cost-effectiveness ratio (ICER) for eribulin compared with treatment of physician's choice (TPC) is likely to be between the company's base case ICER (£35,624 per quality-adjusted life year [QALY] gained) and the ERG's revised base case (£62,672 per QALY gained). Although it is not possible to determine a precise ICER for eribulin compared with TPC, some of the ERG's assumptions were based on highly conservative scenarios. The committee considered the most plausible ICER would be much lower than that calculated by the ERG, and was likely to be below £50,000 per QALY gained. However it considered that if the percentage of people taking vinorelbine and gemcitabine in the TPC arm were increased, in line with UK clinical practice, the ICER would be further reduced. It was satisfied that the ICER for eribulin was acceptable given the additional weight that can be assigned to QALY gains for a treatment that fulfils the end of life criteria.\n\nSee sections 1.1, 4.12 and 4.16\n\n## Current practice\n\nThe majority of people (three quarters) would be offered vinorelbine or gemcitabine as an alternative to eribulin after 2\xa0or more chemotherapy regimens. Eribulin has been available through the Cancer Drugs Fund since 2011 for people with locally advanced or metastatic breast cancer, whose disease has progressed after at least 2 chemotherapy regimens. The committee concluded that eribulin is particularly valuable, and has been more widely used, for HER2‑negative disease because this has fewer treatment options. It also recognised that the availability of additional treatment options for advanced disease would be valued by patients and their families.\n\nSee sections 4.1 to 4.3\n\n## The technology\n\nEribulin was associated with a statistically significant overall survival gain of 2.9\xa0months, compared with TPC in the EMBRACE trial. The committee concluded that the results of EMBRACE are generalisable to the UK population, and agreed that the subgroup of people who had had capecitabine is the most relevant population for this appraisal. It also concluded that eribulin is clinically effective.\n\nThe committee heard from the company that it considers eribulin to be innovative because of its mechanism of action and convenient administration method. However, it concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation.\n\nSee sections 4.4 and 4.13\n\nInitially patients with locally advanced or metastatic breast cancer are offered an anthracycline, if they have not had one at an earlier stage in the treatment pathway, or they have a taxane. This is usually followed by capecitabine. The clinical expert estimated that about half of people will then be offered vinorelbine, and overall about three quarters of people will be offered either vinorelbine or gemcitabine, as an alternative to eribulin.\n\nSee section 4.2\n\nThe adverse reactions of eribulin include fatigue, alopecia, peripheral neuropathy, nausea, neutropenia, leukopenia and anaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nSee section 2\n\n## Evidence for clinical effectiveness\n\nThe clinical evidence for eribulin compared with TPC comes from the EMBRACE trial. The committee noted that the company presented data for the whole trial population and for a subgroup of people who previously had capecitabine, because they considered this population to be the most relevant to clinical practice in the UK. The committee agreed that the subgroup who had had capecitabine, from the company submission, was the most clinically relevant population and noted that approximately 80% of people having eribulin through the Cancer Drugs Fund had previously had capecitabine.\n\nHealth-related quality-of-life data was not collected in EMBRACE, therefore the company presented results from another clinical trial for eribulin compared with capecitabine (Study\xa0301). The population in the study was less heavily pre-treated and had not previously had capecitabine.\n\nSee sections 4.4 and 4.5\n\nThe committee concluded that the results of EMBRACE are generalisable to the UK population, and agreed that the subgroup of people who had had capecitabine is the most relevant population for this appraisal. It also concluded that TPC is a reasonable proxy for usual care in the NHS and a clinically relevant comparator for the population under consideration in this appraisal. It did however note that the majority of people (three quarters) would be offered vinorelbine or gemcitabine as an alternative to eribulin at this stage in the treatment pathway.\n\nSee sections 4.2 and 4.4\n\nHealth-related quality-of-life data was not collected in EMBRACE, therefore the company presented results from another clinical trial for eribulin compared with capecitabine (Study\xa0301). The population in Study\xa0301 was less heavily pre-treated and had not previously had capecitabine. The committee considered that direct patient data on health-related quality of life is of value, but it has limitations.\n\nSee section 4.5\n\nThe committee agreed that the subgroup of people who had had capecitabine is the most relevant population for this appraisal.\n\nSee section 4.4\n\nEribulin was associated with a statistically significant overall survival benefit of 2.9\xa0months when compared with TPC.\n\nSee section 4.4\n\nAt the time of the appraisal for NICE's guidance TA250, evidence was available from a data-cut when 77% of patients in the trial had died. At the time of the submission for the current appraisal, 95% of the trial population had died and therefore more mature data was available.\n\nHealth-related quality-of-life data was not collected in EMBRACE and in TA250 the company presented results from 2 phase\xa02, multi-centre, single-arm, open-label trials (Study\xa0201 and Study\xa0211). At the time of the current appraisal results from a phase 3, open label randomised controlled trial for eribulin compared with capecitabine had become available (Study\xa0301).\n\nSee sections 4.4 and 4.5\n\n## Evidence for cost effectiveness\n\nThe committee accepted the structure of the economic model developed by the company and considered its critique by the ERG.\n\nSee section 4.6\n\nThe committee considered the following key areas of uncertainty:\n\nutility values used in the model for the progressed disease health state, in both arms of the model\n\nthe method used for calculating body surface area and dose of eribulin and its comparators\n\nthe method used for calculating the costs of subsequent line of therapy the method used for calculating the costs of comparators.\n\nSee sections 4.7 to 4.10\n\nThe company used a mapping algorithm published by Crott and Briggs (2010) for estimating utility values from the health-related quality-of-life data from Study\xa0301. This resulted in only a small decrease in the utility between the progression-free and post-progression health states in the company's model (approximately 3%). The ERG considered this to be implausible and used utility values from a study by Lloyd at al. (2006), This resulted in an approximate 20% decline in utility between the pre- and post-progression state and increase in the ICER of around £11,000 per QALY gained.\n\nThe committee considered that the very small decrement seen in the company's model, although generated directly from an eribulin trial, may be an underestimate but the 20% deterioration in quality of life on progression seemed to be too high. It concluded that the most plausible utility value for the progressed disease health state is likely to be somewhere between the company's and the ERG's estimates.\n\nThe committee heard from the company that it considers eribulin to be innovative because of its mechanism of action and convenient administration method. However, it concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation.\n\nSee sections 4.7 and 4.14\n\nThe committee considered that the subgroup of people who had had capecitabine is the most relevant population for this appraisal.\n\nSee section 4.4\n\nThe key drivers of cost effectiveness in the company's model were the utility value used in the progressed disease heath state in both arms of the model and the price of eribulin.\n\nThe committee concluded that the most plausible ICER for eribulin compared with TPC is likely to be between the company's base case ICER (£35,624 per QALY gained) and the ERG's revised base case (£62,672 per QALY gained). There were a lot of uncertainties around the assumptions in the model, therefore it was not possible to determine a precise ICER. The committee considered the most plausible ICER to be below £50,000 per QALY gained. The committee noted that if the costs of TPC were increased (to account for a higher use of gemcitabine and vinorelbine in clinical practice than that in the model) this would further reduce the ICER for eribulin compared with TPC.\n\nSee sections 4.12 and 4.16\n\nEribulin was not recommended in NICE's guidance TA250 for the treatment of locally advanced or metastatic breast cancer that has progressed after at least 2 chemotherapy regimens for advanced disease, because the most plausible ICER was much higher than the range normally considered a cost‑effective use of NHS resources, even taking into account additional weights applied to QALY benefits for a life-extending treatment at the end of life.\n\nUpdated survival results from the EMBRACE trial were incorporated in the current appraisal and also results for health-related quality-of-life from a phase 3, open label randomised controlled trial for eribulin compared with capecitabine (Study\xa0301).\n\nThe committee concluded that the correct modelling approach was uncertain and therefore the most plausible ICER for eribulin compared with TPC is likely to be between the company's base case ICER and the ERG's revised base case. There were a lot of uncertainties around the assumptions in the model, therefore it was not possible to determine a precise ICER. The committee considered the most plausible ICER to be below £50,000 per QALY gained. However it considered that if the percentage of people taking vinorelbine and gemcitabine in the TPC arm were increased, in line with UK clinical practice, the ICER would be further reduced. Therefore it was satisfied that the most plausible ICER was acceptable given the additional weight that can be assigned to QALY gains, for a treatment that fulfils the end-of-life criteria.\n\nSee sections 4.12 and 4.16\n\n## Additional factors taken into account\n\nThe PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\nSee section 4.15\n\nThe evidence shows that people with advanced breast cancer that has progressed after 2 lines of chemotherapy have a life expectancy of less than 24\xa0months.\n\nThe evidence also suggests that eribulin offers a mean overall survival benefit of more than 3\xa0months. In light of the short life expectancy at this stage of breast cancer, the committee considered this overall survival benefit to be substantial.\n\nThe committee concluded that eribulin met the end-of-life criteria objectively and robustly and that it can be considered a life-extending, end-of-life treatment.\n\nSee section 4.14\n\nNo equality issues were raised during the appraisal."}	https://www.nice.org.uk/guidance/ta423	Evidence-based recommendations on eribulin (Halaven) for locally advanced or metastatic (secondary) breast cancer in adults who have had 2 or more courses of chemotherapy.
94e6425caae3c01cede589c0f8e198abfc353707	nice	Hypothermia: prevention and management in adults having surgery	Hypothermia: prevention and management in adults having surgery This guideline covers preventing and managing inadvertent hypothermia in people aged 18 and over having surgery. It offers advice on assessing patients’ risk of hypothermia, measuring and monitoring temperature, and devices for keeping patients warm before, during and after surgery. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Perioperative care Patients (and their families and carers) should be informed that: staying warm before surgery will lower the risk of postoperative complications the hospital environment may be colder than their own home they should bring additional clothing, such as a dressing gown, a vest, warm clothing and slippers, to help them keep comfortably warm they should tell staff if they feel cold at any time during their hospital stay. Pay particular attention to the comfort of patients with communication difficulties before, during and after surgery. When using any temperature recording or warming device, healthcare professionals should: be trained in their use maintain them in accordance with manufacturers' and suppliers' instructions comply with local infection control policies. When using any device to measure patient temperature, healthcare professionals should: be aware of, and carry out, any adjustments that need to be made in order to obtain an estimate of core temperature from that recorded at the site of measurement; core temperature is the temperature of the blood and internal organs. be aware of any such adjustments that are made automatically by the device used. Measure the patient's temperature using a site that produces either: a direct measurement of core temperature, or a direct estimate of core temperature that has been shown in research studies to be accurate to within 0.5ºC of direct measurement; a direct estimate of core temperature is the reading produced by a thermometer with no correction factors applied.At the time of publication these sites are: pulmonary artery catheter distal oesophagus urinary bladder zero heat-flux (deep forehead) sublingual; be aware of possible inaccuracies in core temperature estimation when using peripheral sites, such as sublingual or axilla, in patients whose core temperature is outside the normothermic range (36.5°C to 37.5°C). axilla; be aware of possible inaccuracies in core temperature estimation when using peripheral sites, such as sublingual or axilla, in patients whose core temperature is outside the normothermic range (36.5°C to 37.5°C). rectum. Do not use indirect estimates of core temperature in adults having surgery. An indirect estimate of core temperature is the reading produced by a thermometer after a correction factor has been applied. Examples include infrared tympanic, infrared temporal, infrared forehead and forehead strips. # Preoperative phase The preoperative phase is defined as the hour before induction of anaesthesia, during which the patient is prepared for surgery on the ward or in the emergency department, including possible use of premedication. Each patient should be assessed for their risk of inadvertent perioperative hypothermia and potential adverse consequences before transfer to the theatre suite. Patients should be managed as higher risk (see recommendation 1.3.7) if any 2 of the following apply: American Society of Anesthesiologists (ASA) grade 2 to 5 (the higher the grade, the greater the risk) preoperative temperature below 36.0°C (and preoperative warming is not possible because of clinical urgency) undergoing combined general and regional anaesthesia undergoing major or intermediate surgery at risk of cardiovascular complications. The patient's temperature should be measured and documented in the hour before they leave the ward or emergency department. If the patient's temperature is below 36.0°C, start active warming preoperatively on the ward or in the emergency department (unless there is a need to expedite surgery because of clinical urgency, for example bleeding or critical limb ischaemia). If the patient's temperature is 36.0°C or above, start active warming at least 30 minutes before induction of anaesthesia, unless this will delay emergency surgery. Maintain active warming throughout the intraoperative phase. The patient's temperature should be 36.0°C or above before they are transferred from the ward or emergency department (unless there is a need to expedite surgery because of clinical urgency, for example bleeding or critical limb ischaemia). On transfer to the theatre suite: active warming should be continued (or re-started as soon as possible) the patient should be encouraged to walk to theatre where appropriate. # Intraoperative phase The intraoperative phase is defined as total anaesthesia time, from the first anaesthetic intervention through to patient transfer to the recovery area of the theatre suite. The patient's temperature should be measured and documented before induction of anaesthesia and then every 30 minutes until the end of surgery. Standard critical incident reporting should be considered for any patient arriving at the theatre suite with a temperature below 36.0°C. Induction of anaesthesia should not begin unless the patient's temperature is 36.0°C or above (unless there is a need to expedite surgery because of clinical urgency, for example bleeding or critical limb ischaemia). In the theatre suite: the ambient temperature should be at least 21°C while the patient is exposed -nce active warming is established, the ambient temperature may be reduced to allow better working conditions using equipment to cool the surgical team should also be considered. The patient should be adequately covered throughout the intraoperative phase to conserve heat, and exposed only during surgical preparation. Intravenous fluids (500 ml or more) and blood products should be warmed to 37°C using a fluid warming device. Warm patients intraoperatively from induction of anaesthesia, using a forced-air warming device, if they are: having anaesthesia for more than 30 minutes or having anaesthesia for less than 30 minutes and are at higher risk of inadvertent perioperative hypothermia (see recommendation 1.2.1).Consider a resistive heating mattress or resistive heating blanket if a forced-air warming device is unsuitable. The temperature setting on forced-air warming devices should be set at maximum and then adjusted to maintain a patient temperature of at least 36.5°C. All irrigation fluids used intraoperatively should be warmed in a thermostatically controlled cabinet to a temperature of 38°C to 40°C. # Postoperative phase The postoperative phase is defined as the 24 hours after the patient has entered the recovery area of the theatre suite. The patient's temperature should be measured and documented on admission to the recovery room and then every 15 minutes. Ward transfer should not be arranged unless the patient's temperature is 36.0°C or above. If the patient's temperature is below 36.0°C, they should be actively warmed using forced-air warming until they are discharged from the recovery room or until they are comfortably warm. Patients should be kept comfortably warm when back on the ward. Their temperature should be measured and documented on arrival at the ward. Their temperature should then be measured and documented as part of routine 4‑hourly observations. They should be provided with at least 1 cotton sheet plus 2 blankets, or a duvet. If the patient's temperature falls below 36.0°C while on the ward: they should be warmed using forced-air warming until they are comfortably warm their temperature should be measured and documented at least every 30 minutes during warming. # Terms used in this guideline ## Active warming A process that transfers heat to the patient. ## Comfortably warm The expected normal temperature range of adult patients (between 36.5°C and 37.5°C). ## Core temperature The temperature of the blood and internal organs. ## Hypothermia Core temperature below 36.0°C. ## Temperature Core temperature.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations Here are some pointers to help put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Inadvertent perioperative hypothermia is a common but preventable complication of perioperative procedures, which is associated with poor outcomes for patients. Inadvertent perioperative hypothermia should be distinguished from the deliberate induction of hypothermia for medical reasons, which is not covered by this guideline. In this guideline, hypothermia is defined as a patient core temperature of below 36.0°C. 'Temperature' is used to denote core temperature. Adult surgical patients are at risk of developing hypothermia at any stage of the perioperative pathway. In the guideline, the perioperative pathway is divided into 3 phases: the preoperative phase is defined as the hour before induction of anaesthesia (when the patient is prepared for surgery on the ward or in the emergency department), the intraoperative phase is defined as total anaesthesia time, and the postoperative phase is defined as the 24 hours after entry into the recovery area in the theatre suite (which will include transfer to and time spent on the ward). The phrase 'comfortably warm' is used in recommendations relating to both the preoperative and postoperative phases, and refers to the expected normal temperature range of adult patients (between 36.5°C and 37.5°C). During the first 30 to 40 minutes of anaesthesia, a patient's temperature can drop to below 35.0°C. Reasons for this include loss of the behavioural response to cold and the impairment of thermoregulatory heat-preserving mechanisms under general or regional anaesthesia, anaesthesia-induced peripheral vasodilation (with associated heat loss), and the patient getting cold while waiting for surgery on the ward or in the emergency department. In 2016 we updated the guideline to take account of new evidence on active warming devices. We also added new recommendations on the site and method of measuring temperature, which had been identified as an area where guidance would be clinically useful.# Recommendations for research The guideline committee has made the following recommendations for research. As part of the 2016 update, the standing committee made 2 additional recommendations for research, on combined methods of intraoperative active warming compared with a single method, and forced-air warming compared with conductive fabric warming in laminar flow theatre. Three recommendations for research, on preoperative insulation and warming, comparison of intraoperative warming devices, and use of both preoperative and intraoperative warming, were removed. Details can be found in the addendum. # Combined methods of intraoperative active warming compared with a single method What is the clinical and cost effectiveness of combined methods of intraoperative active warming compared with a single method in preventing inadvertent perioperative hypothermia? ## Why this is important A combination of active warming devices, such as forced-air warming together with a resistive heating mattress, is usually used to warm patients during surgery. However, there is not enough evidence to show whether this is more clinically effective than a single active warming device, such as forced-air warming on its own. Randomised controlled trials (RCTs) should be carried out to compare combined methods of intraoperative active warming (such as forced-air warming together with a resistive heating mattress, or a resistive heating mattress together with a resistive heating blanket) with a single method of active warming (such as forced-air warming). All intravenous fluids should be warmed to 37°C. The RCTs should be sufficiently powered to show clinically significant differences. Primary outcomes should be core temperature at the end of surgery and incidence of hypothermia. Patients may be stratified by anaesthesia duration and type of surgery. Adverse effects and numbers of patients with complications of hypothermia (for example, cardiac events or wound infections) should be recorded. # Forced-air warming compared with conductive fabric warming in laminar flow theatre What is the clinical and cost effectiveness of intraoperative forced-air warming compared with conductive fabric warming in laminar flow theatre? ## Why this is important It has been suggested that forced-air warming may increase the risk of surgical site infection during implantation surgery (such as joint replacement) because the air flowing through the forced-air warming device disrupts the air flow around the surgical site. Research suggests that conductive warming devices are less likely to cause surgical site infection because the disruption to air flow is less than that caused by forced-air warming. More evidence is needed on the incidence of surgical site infection in implantation surgery using different warming devices. RCTs should be carried out to compare forced-air warming with conductive warming in laminar flow theatre. The RCTs should be sufficiently powered to show clinically significant differences. Primary outcomes should be surgical site infection and core temperature at the end of surgery. Adverse effects and numbers of patients with complications of hypothermia (for example, cardiac events or increased length of hospital stay) should be recorded. . # Temperature thresholds for preoperative warming What is the optimum temperature target when warming patients preoperatively? ## Why this is important Preoperative warming is intended to minimise the impact of redistribution hypothermia by reducing the temperature difference between the patient's core temperature and peripheral temperature. There is a lack of evidence for the optimum preoperative temperature for preventing intraoperative hypothermia. Large RCTs (with at least 100 patients in each arm) should be conducted in adults undergoing surgery to compare warming patients to 36.5°C and 37.0°C in the preoperative phase. Warming should be continued intraoperatively in all patients. All intravenous fluids given should be warmed to 37°C. Primary outcomes should be the incidence of hypothermia, and patient temperature intraoperatively (at 15, 30, 60 and 120 minutes) and in recovery. The duration of warming required to achieve the target preoperative temperature should be recorded. Adverse effects (including patient discomfort) and numbers of patients with complications of hypothermia (for example, morbid cardiac events, wound infection) should be recorded. # Effects of nutritional solutions Does the infusion of nutritional solutions such as amino acids and fructose further reduce the incidence of inadvertent perioperative hypothermia in patients receiving intraoperative warming? ## Why this is important Limited evidence suggests that infusion of amino acids or fructose in the preoperative and intraoperative phases may prevent hypothermia. Such infusions may also have additional benefits in fasted patients. A large RCT (with at least 100 patients in each arm) comparing infusions of amino acids, fructose and saline should be conducted in adults undergoing surgery. These infusions should be started before the induction of anaesthesia and continued throughout the intraoperative phase. All patients should receive forced-air warming intraoperatively and all intravenous fluids given should be warmed to 37°C. Primary outcomes should be the incidence of hypothermia, and patient temperature intraoperatively (at 15, 30, 60 and 120 minutes) and in recovery. Adverse effects and numbers of patients with complications of hypothermia (for example, morbid cardiac events, wound infections) should be recorded.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Perioperative care\n\nPatients (and their families and carers) should be informed that:\n\nstaying warm before surgery will lower the risk of postoperative complications\n\nthe hospital environment may be colder than their own home\n\nthey should bring additional clothing, such as a dressing gown, a vest, warm clothing and slippers, to help them keep comfortably warm\n\nthey should tell staff if they feel cold at any time during their hospital stay. \n\nPay particular attention to the comfort of patients with communication difficulties before, during and after surgery. [new 2016]\n\nWhen using any temperature recording or warming device, healthcare professionals should:\n\nbe trained in their use\n\nmaintain them in accordance with manufacturers' and suppliers' instructions\n\ncomply with local infection control policies. \n\nWhen using any device to measure patient temperature, healthcare professionals should:\n\nbe aware of, and carry out, any adjustments that need to be made in order to obtain an estimate of core temperature from that recorded at the site of measurement; core temperature is the temperature of the blood and internal organs.\n\nbe aware of any such adjustments that are made automatically by the device used. \n\nMeasure the patient's temperature using a site that produces either:\n\na direct measurement of core temperature, or\n\na direct estimate of core temperature that has been shown in research studies to be accurate to within 0.5ºC of direct measurement; a direct estimate of core temperature is the reading produced by a thermometer with no correction factors applied.At the time of publication these sites are:\n\n\n\npulmonary artery catheter\n\ndistal oesophagus\n\nurinary bladder\n\nzero heat-flux (deep forehead)\n\nsublingual; be aware of possible inaccuracies in core temperature estimation when using peripheral sites, such as sublingual or axilla, in patients whose core temperature is outside the normothermic range (36.5°C to 37.5°C).\n\naxilla; be aware of possible inaccuracies in core temperature estimation when using peripheral sites, such as sublingual or axilla, in patients whose core temperature is outside the normothermic range (36.5°C to 37.5°C).\n\nrectum. [new 2016]\n\n\n\nDo not use indirect estimates of core temperature in adults having surgery. An indirect estimate of core temperature is the reading produced by a thermometer after a correction factor has been applied. Examples include infrared tympanic, infrared temporal, infrared forehead and forehead strips. [new 2016]\n\n# Preoperative phase\n\nThe preoperative phase is defined as the hour before induction of anaesthesia, during which the patient is prepared for surgery on the ward or in the emergency department, including possible use of premedication.\n\nEach patient should be assessed for their risk of inadvertent perioperative hypothermia and potential adverse consequences before transfer to the theatre suite. Patients should be managed as higher risk (see recommendation\xa01.3.7) if any 2 of the following apply:\n\nAmerican Society of Anesthesiologists (ASA) grade 2\xa0to 5 (the higher the grade, the greater the risk)\n\npreoperative temperature below 36.0°C (and preoperative warming is not possible because of clinical urgency)\n\nundergoing combined general and regional anaesthesia\n\nundergoing major or intermediate surgery\n\nat risk of cardiovascular complications. \n\nThe patient's temperature should be measured and documented in the hour before they leave the ward or emergency department. \n\nIf the patient's temperature is below 36.0°C, start active warming preoperatively on the ward or in the emergency department (unless there is a need to expedite surgery because of clinical urgency, for example bleeding or critical limb ischaemia). [2008, amended 2016]\n\nIf the patient's temperature is 36.0°C or above, start active warming at least 30\xa0minutes before induction of anaesthesia, unless this will delay emergency surgery. [new 2016]\n\nMaintain active warming throughout the intraoperative phase. [2008, amended 2016]\n\nThe patient's temperature should be 36.0°C or above before they are transferred from the ward or emergency department (unless there is a need to expedite surgery because of clinical urgency, for example bleeding or critical limb ischaemia). \n\nOn transfer to the theatre suite:\n\nactive warming should be continued (or re-started as soon as possible)\n\nthe patient should be encouraged to walk to theatre where appropriate. [2008, amended 2016]\n\n# Intraoperative phase\n\nThe intraoperative phase is defined as total anaesthesia time, from the first anaesthetic intervention through to patient transfer to the recovery area of the theatre suite.\n\nThe patient's temperature should be measured and documented before induction of anaesthesia and then every 30\xa0minutes until the end of surgery. \n\nStandard critical incident reporting should be considered for any patient arriving at the theatre suite with a temperature below 36.0°C. \n\nInduction of anaesthesia should not begin unless the patient's temperature is 36.0°C or above (unless there is a need to expedite surgery because of clinical urgency, for example bleeding or critical limb ischaemia). \n\nIn the theatre suite:\n\nthe ambient temperature should be at least 21°C while the patient is exposed\n\nonce active warming is established, the ambient temperature may be reduced to allow better working conditions\n\nusing equipment to cool the surgical team should also be considered. [2008, amended 2016]\n\nThe patient should be adequately covered throughout the intraoperative phase to conserve heat, and exposed only during surgical preparation. \n\nIntravenous fluids (500\xa0ml or more) and blood products should be warmed to 37°C using a fluid warming device. \n\nWarm patients intraoperatively from induction of anaesthesia, using a forced-air warming device, if they are:\n\nhaving anaesthesia for more than 30\xa0minutes or\n\nhaving anaesthesia for less than 30\xa0minutes and are at higher risk of inadvertent perioperative hypothermia (see recommendation 1.2.1).Consider a resistive heating mattress or resistive heating blanket if a forced-air warming device is unsuitable. [new 2016]\n\nThe temperature setting on forced-air warming devices should be set at maximum and then adjusted to maintain a patient temperature of at least 36.5°C. \n\nAll irrigation fluids used intraoperatively should be warmed in a thermostatically controlled cabinet to a temperature of 38°C\xa0to 40°C. \n\n# Postoperative phase\n\nThe postoperative phase is defined as the 24\xa0hours after the patient has entered the recovery area of the theatre suite.\n\nThe patient's temperature should be measured and documented on admission to the recovery room and then every 15\xa0minutes.\n\nWard transfer should not be arranged unless the patient's temperature is 36.0°C or above.\n\nIf the patient's temperature is below 36.0°C, they should be actively warmed using forced-air warming until they are discharged from the recovery room or until they are comfortably warm. \n\nPatients should be kept comfortably warm when back on the ward.\n\nTheir temperature should be measured and documented on arrival at the ward.\n\nTheir temperature should then be measured and documented as part of routine 4‑hourly observations.\n\nThey should be provided with at least 1\xa0cotton sheet plus 2\xa0blankets, or a duvet. \n\nIf the patient's temperature falls below 36.0°C while on the ward:\n\nthey should be warmed using forced-air warming until they are comfortably warm\n\ntheir temperature should be measured and documented at least every 30\xa0minutes during warming. \n\n# Terms used in this guideline\n\n## Active warming\n\nA process that transfers heat to the patient.\n\n## Comfortably warm\n\nThe expected normal temperature range of adult patients (between 36.5°C and 37.5°C).\n\n## Core temperature\n\nThe temperature of the blood and internal organs.\n\n## Hypothermia\n\nCore temperature below 36.0°C.\n\n## Temperature\n\nCore temperature.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations\n\nHere are some pointers to help put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "Inadvertent perioperative hypothermia is a common but preventable complication of perioperative procedures, which is associated with poor outcomes for patients. Inadvertent perioperative hypothermia should be distinguished from the deliberate induction of hypothermia for medical reasons, which is not covered by this guideline.\n\nIn this guideline, hypothermia is defined as a patient core temperature of below 36.0°C. 'Temperature' is used to denote core temperature. Adult surgical patients are at risk of developing hypothermia at any stage of the perioperative pathway. In the guideline, the perioperative pathway is divided into 3\xa0phases: the preoperative phase is defined as the hour before induction of anaesthesia (when the patient is prepared for surgery on the ward or in the emergency department), the intraoperative phase is defined as total anaesthesia time, and the postoperative phase is defined as the 24\xa0hours after entry into the recovery area in the theatre suite (which will include transfer to and time spent on the ward). The phrase 'comfortably warm' is used in recommendations relating to both the preoperative and postoperative phases, and refers to the expected normal temperature range of adult patients (between 36.5°C and 37.5°C).\n\nDuring the first 30\xa0to 40\xa0minutes of anaesthesia, a patient's temperature can drop to below 35.0°C. Reasons for this include loss of the behavioural response to cold and the impairment of thermoregulatory heat-preserving mechanisms under general or regional anaesthesia, anaesthesia-induced peripheral vasodilation (with associated heat loss), and the patient getting cold while waiting for surgery on the ward or in the emergency department.\n\nIn 2016 we updated the guideline to take account of new evidence on active warming devices. We also added new recommendations on the site and method of measuring temperature, which had been identified as an area where guidance would be clinically useful.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\nAs part of the 2016 update, the standing committee made 2\xa0additional recommendations for research, on combined methods of intraoperative active warming compared with a single method, and forced-air warming compared with conductive fabric warming in laminar flow theatre. Three recommendations for research, on preoperative insulation and warming, comparison of intraoperative warming devices, and use of both preoperative and intraoperative warming, were removed. Details can be found in the addendum.\n\n# Combined methods of intraoperative active warming compared with a single method\n\nWhat is the clinical and cost effectiveness of combined methods of intraoperative active warming compared with a single method in preventing inadvertent perioperative hypothermia?\n\n## Why this is important\n\nA combination of active warming devices, such as forced-air warming together with a resistive heating mattress, is usually used to warm patients during surgery. However, there is not enough evidence to show whether this is more clinically effective than a single active warming device, such as forced-air warming on its own. Randomised controlled trials (RCTs) should be carried out to compare combined methods of intraoperative active warming (such as forced-air warming together with a resistive heating mattress, or a resistive heating mattress together with a resistive heating blanket) with a single method of active warming (such as forced-air warming). All intravenous fluids should be warmed to 37°C. The RCTs should be sufficiently powered to show clinically significant differences. Primary outcomes should be core temperature at the end of surgery and incidence of hypothermia. Patients may be stratified by anaesthesia duration and type of surgery. Adverse effects and numbers of patients with complications of hypothermia (for example, cardiac events or wound infections) should be recorded. [new 2016]\n\n# Forced-air warming compared with conductive fabric warming in laminar flow theatre\n\nWhat is the clinical and cost effectiveness of intraoperative forced-air warming compared with conductive fabric warming in laminar flow theatre?\n\n## Why this is important\n\nIt has been suggested that forced-air warming may increase the risk of surgical site infection during implantation surgery (such as joint replacement) because the air flowing through the forced-air warming device disrupts the air flow around the surgical site. Research suggests that conductive warming devices are less likely to cause surgical site infection because the disruption to air flow is less than that caused by forced-air warming. More evidence is needed on the incidence of surgical site infection in implantation surgery using different warming devices. RCTs should be carried out to compare forced-air warming with conductive warming in laminar flow theatre. The RCTs should be sufficiently powered to show clinically significant differences. Primary outcomes should be surgical site infection and core temperature at the end of surgery. Adverse effects and numbers of patients with complications of hypothermia (for example, cardiac events or increased length of hospital stay) should be recorded. [new 2016].\n\n# Temperature thresholds for preoperative warming\n\nWhat is the optimum temperature target when warming patients preoperatively?\n\n## Why this is important\n\nPreoperative warming is intended to minimise the impact of redistribution hypothermia by reducing the temperature difference between the patient's core temperature and peripheral temperature. There is a lack of evidence for the optimum preoperative temperature for preventing intraoperative hypothermia. Large RCTs (with at least 100\xa0patients in each arm) should be conducted in adults undergoing surgery to compare warming patients to 36.5°C and 37.0°C in the preoperative phase. Warming should be continued intraoperatively in all patients. All intravenous fluids given should be warmed to 37°C. Primary outcomes should be the incidence of hypothermia, and patient temperature intraoperatively (at 15, 30, 60 and 120\xa0minutes) and in recovery. The duration of warming required to achieve the target preoperative temperature should be recorded. Adverse effects (including patient discomfort) and numbers of patients with complications of hypothermia (for example, morbid cardiac events, wound infection) should be recorded. \n\n# Effects of nutritional solutions\n\nDoes the infusion of nutritional solutions such as amino acids and fructose further reduce the incidence of inadvertent perioperative hypothermia in patients receiving intraoperative warming?\n\n## Why this is important\n\nLimited evidence suggests that infusion of amino acids or fructose in the preoperative and intraoperative phases may prevent hypothermia. Such infusions may also have additional benefits in fasted patients. A large RCT (with at least 100\xa0patients in each arm) comparing infusions of amino acids, fructose and saline should be conducted in adults undergoing surgery. These infusions should be started before the induction of anaesthesia and continued throughout the intraoperative phase. All patients should receive forced-air warming intraoperatively and all intravenous fluids given should be warmed to 37°C. Primary outcomes should be the incidence of hypothermia, and patient temperature intraoperatively (at 15, 30, 60 and 120\xa0minutes) and in recovery. Adverse effects and numbers of patients with complications of hypothermia (for example, morbid cardiac events, wound infections) should be recorded. "}	https://www.nice.org.uk/guidance/cg65	This guideline covers preventing and managing inadvertent hypothermia in people aged 18 and over having surgery. It offers advice on assessing patients’ risk of hypothermia, measuring and monitoring temperature, and devices for keeping patients warm before, during and after surgery.
030a2b73f40ae121a520e4b904c38112241f1bce	nice	Epiduroscopic lumbar discectomy through the sacral hiatus for sciatica	Epiduroscopic lumbar discectomy through the sacral hiatus for sciatica Evidence-based recommendations on epiduroscopic lumbar discectomy through the sacral hiatus for sciatica in adults. This involves removing the part of the spinal disc pressing against the spinal nerve, to relieve pain. # Recommendations Current evidence on the safety and efficacy of epiduroscopic lumbar discectomy through the sacral hiatus for sciatica is limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. This procedure should only be done by surgeons with expertise in endoscopic spinal surgery and specific training in epiduroscopy through the sacral hiatus. NICE encourages further research into epiduroscopic lumbar discectomy through the sacral hiatus for sciatica and may update the guidance on publication of further evidence. Research studies should include details of patient selection, complications and long-term results.# Indications and current treatments Lumbar disc herniation occurs when the nucleus pulposus of an intervertebral disc protrudes through a weakening or a tear in the surrounding annulus fibrosus. Symptoms include pain in the back or leg, and numbness or weakness in the leg. Serious neurological sequelae including painful foot drop, bladder dysfunction, or cauda equina syndrome, may sometimes occur. Conservative treatments include analgesics, non-steroidal anti-inflammatory medication and manual therapy. Epidural corticosteroid injections can also be used to reduce nerve pain in the short term. Lumbar discectomy is considered if there is severe nerve compression or persistent symptoms that are unresponsive to conservative treatment. Surgical techniques include open discectomy or minimally invasive alternatives using percutaneous endoscopic approaches. The choice of technique may be guided by several factors, including the presenting symptoms and signs and the location and size of the disc involved.# The procedure Epiduroscopic lumbar discectomy through the sacral hiatus for sciatica is usually done with the patient under sedation and local anaesthesia. Under fluoroscopic guidance, a needle is inserted through the sacral hiatus. Over a guidewire a dilator is used to create a working channel through which a flexible endoscope can be steered into the anterior epidural space. The endoscope can reach nerve roots as high as the mid-lumbar spine bilaterally. When the appropriate disc level is reached, a laser optic fibre is introduced through the working channel of the endoscope to ablate disc tissue. The aim is to relieve pain by removing parts of the disc that press against the spinal nerve.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non-randomised comparative study of 98 patients compared treatment by endoscopic adhesiolysis, foraminoplasty and discectomy (n=78) with endoscopic adhesiolysis and foraminoplasty without discectomy (n=20). Visual analogue scale (VAS) scores (ranging from 0 to 10, with lower scores indicating less pain) for radicular pain improved from 7.6 to 3.6 with discectomy and from 8.5 to 6.1 without discectomy at final follow-up (p values not reported; mean follow-up periods were 21 and 23 months respectively). A non-randomised comparative study of 57 patients compared treatment by endoscopic adhesiolysis, foraminoplasty and discectomy (n=32) with endoscopic adhesiolysis and foraminoplasty without discectomy (n=25). The improvement in VAS score for low back pain was statistically significant with discectomy (from 8.1 to 4.4; p=0.01) but not without discectomy (from 8.5 to 6.7; p=0.12) at 24-month follow-up. The difference between the groups was statistically significant (p<0.01). In the same study, improvements in VAS scores for leg pain were not statistically significant (from 6.2 to 4.7; p=0.07 and from 6.7 to 5.2; p=0.15, respectively) at 24-month follow-up. The difference between the groups was statistically significant (p=0.05). In a case series of 154 patients, there was a statistically significant decrease in VAS score for pain from 7.5 at baseline to 3.4 at follow-up (p<0.005). In a case series of 250 patients, the mean VAS score for leg pain decreased from 7.1 at baseline to 2.6 (p<0.01) and the mean VAS score for back pain decreased from 5.9 at baseline to 2.7 (p<0.01) at 3-month follow-up. In the non-randomised comparative study of 98 patients, Roland Morris disability questionnaire scores (ranging from 0 to 24, with lower scores indicating less disability) changed from 18.8 to 10.6 with discectomy and from 11.3 to 11.4 without discectomy at final follow-up (p values not reported; mean follow-up periods were 21 and 23 months respectively). In the non-randomised comparative study of 57 patients, the change in Roland Morris disability questionnaire scores was statistically significant with discectomy (from 13.2 to 8.5; p=0.03) but not without discectomy (from 12.6 to 10.4; p=0.09) at 24-month follow-up. The difference between the groups was statistically significant (p<0.01). In the case series of 154 patients, the change in Roland Morris disability questionnaire score was statistically significant, from 18.1 at baseline to 10.3 at follow-up (p<0.005). In the case series of 250 patients, the Oswestry Disability Index score (ranging from 0 to 100) improved from 50 at baseline to 12 at 3-month follow-up (p<0.01). The specialist advisers listed key efficacy outcomes as relief of back or leg pain, improvement in patient-reported outcome measures (such as Oswestry Disability Index), reduced length of hospital stay and reduced time off work.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Transient mild motor paralysis was reported in 1 patient from the discectomy group (n=32) in a non-randomised comparative study of 57 patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. Symptoms resolved 1 month after the procedure. Foot drop was reported in 3% (2/78) of patients in the discectomy group in a non-randomised comparative study of 98 patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy (n=78) or endoscopic adhesiolysis and foraminoplasty without discectomy (n=20). Symptoms resolved within 6 months. Transient hyperaesthesia was reported in 1 patient in the non-randomised comparative study of 98 patients. The authors did not state which group this patient was in. Paraesthesia was reported in 19% (15/78) of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy in the same study; symptoms resolved within 6 months. Transient headaches were reported in 8% (8/98) and 5% (3/57) of patients in the 2 non-randomised comparative studies of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. The authors did not state which groups these patients were in. Headache was reported in 1% (3/250) of patients in a case series of 250 patients. Epidural pneumocephalus was reported in 1 patient in the case series of 250 patients (no further information given). Focal infection was reported in 2% (2/98) and 4% (2/57) of patients in the 2 non-randomised comparative studies of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. The authors did not state which groups these patients were in. Meningitis was reported in 1 patient each in the 2 non-randomised comparative studies of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. The authors of the studies did not state which treatment groups these patients were in. Symptoms resolved after bed rest and symptomatic treatment. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers reported no anecdotal adverse events. They considered that the following were theoretical adverse events: cauda equina syndrome, spinal fluid leak, and epidural haematoma.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2217-8	{'Recommendations': 'Current evidence on the safety and efficacy of epiduroscopic lumbar discectomy through the sacral hiatus for sciatica is limited in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nThis procedure should only be done by surgeons with expertise in endoscopic spinal surgery and specific training in epiduroscopy through the sacral hiatus.\n\nNICE encourages further research into epiduroscopic lumbar discectomy through the sacral hiatus for sciatica and may update the guidance on publication of further evidence. Research studies should include details of patient selection, complications and long-term results.', 'Indications and current treatments': 'Lumbar disc herniation occurs when the nucleus pulposus of an intervertebral disc protrudes through a weakening or a tear in the surrounding annulus fibrosus. Symptoms include pain in the back or leg, and numbness or weakness in the leg. Serious neurological sequelae including painful foot drop, bladder dysfunction, or cauda equina syndrome, may sometimes occur.\n\nConservative treatments include analgesics, non-steroidal anti-inflammatory medication and manual therapy. Epidural corticosteroid injections can also be used to reduce nerve pain in the short term. Lumbar discectomy is considered if there is severe nerve compression or persistent symptoms that are unresponsive to conservative treatment. Surgical techniques include open discectomy or minimally invasive alternatives using percutaneous endoscopic approaches. The choice of technique may be guided by several factors, including the presenting symptoms and signs and the location and size of the disc involved.', 'The procedure': 'Epiduroscopic lumbar discectomy through the sacral hiatus for sciatica is usually done with the patient under sedation and local anaesthesia. Under fluoroscopic guidance, a needle is inserted through the sacral hiatus. Over a guidewire a dilator is used to create a working channel through which a flexible endoscope can be steered into the anterior epidural space. The endoscope can reach nerve roots as high as the mid-lumbar spine bilaterally. When the appropriate disc level is reached, a laser optic fibre is introduced through the working channel of the endoscope to ablate disc tissue. The aim is to relieve pain by removing parts of the disc that press against the spinal nerve.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA non-randomised comparative study of 98\xa0patients compared treatment by endoscopic adhesiolysis, foraminoplasty and discectomy (n=78) with endoscopic adhesiolysis and foraminoplasty without discectomy (n=20). Visual analogue scale (VAS) scores (ranging from 0\xa0to\xa010, with lower scores indicating less pain) for radicular pain improved from 7.6 to 3.6 with discectomy and from 8.5 to 6.1 without discectomy at final follow-up (p values not reported; mean follow-up periods were 21 and 23\xa0months respectively). A non-randomised comparative study of 57\xa0patients compared treatment by endoscopic adhesiolysis, foraminoplasty and discectomy (n=32) with endoscopic adhesiolysis and foraminoplasty without discectomy (n=25). The improvement in VAS score for low back pain was statistically significant with discectomy (from 8.1 to 4.4; p=0.01) but not without discectomy (from 8.5 to 6.7; p=0.12) at 24-month follow-up. The difference between the groups was statistically significant (p<0.01). In the same study, improvements in VAS scores for leg pain were not statistically significant (from 6.2 to 4.7; p=0.07 and from 6.7 to 5.2; p=0.15, respectively) at 24-month follow-up. The difference between the groups was statistically significant (p=0.05). In a case series of 154\xa0patients, there was a statistically significant decrease in VAS score for pain from 7.5 at baseline to 3.4 at follow-up (p<0.005). In a case series of 250\xa0patients, the mean VAS score for leg pain decreased from 7.1 at baseline to 2.6 (p<0.01) and the mean VAS score for back pain decreased from 5.9 at baseline to 2.7 (p<0.01) at 3-month follow-up.\n\nIn the non-randomised comparative study of 98\xa0patients, Roland Morris disability questionnaire scores (ranging from 0\xa0to\xa024, with lower scores indicating less disability) changed from 18.8 to 10.6 with discectomy and from 11.3 to 11.4 without discectomy at final follow-up (p\xa0values not reported; mean follow-up periods were 21\xa0and 23\xa0months respectively). In the non-randomised comparative study of 57\xa0patients, the change in Roland Morris disability questionnaire scores was statistically significant with discectomy (from 13.2 to 8.5; p=0.03) but not without discectomy (from 12.6 to 10.4; p=0.09) at 24-month follow-up. The difference between the groups was statistically significant (p<0.01). In the case series of 154\xa0patients, the change in Roland Morris disability questionnaire score was statistically significant, from 18.1 at baseline to 10.3 at follow-up (p<0.005). In the case series of 250\xa0patients, the Oswestry Disability Index score (ranging from 0\xa0to\xa0100) improved from 50 at baseline to 12 at 3-month follow-up (p<0.01).\n\nThe specialist advisers listed key efficacy outcomes as relief of back or leg pain, improvement in patient-reported outcome measures (such as Oswestry Disability Index), reduced length of hospital stay and reduced time off work.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nTransient mild motor paralysis was reported in 1\xa0patient from the discectomy group (n=32) in a non-randomised comparative study of 57\xa0patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. Symptoms resolved 1\xa0month after the procedure. Foot drop was reported in 3% (2/78) of patients in the discectomy group in a non-randomised comparative study of 98\xa0patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy (n=78) or endoscopic adhesiolysis and foraminoplasty without discectomy (n=20). Symptoms resolved within 6\xa0months.\n\nTransient hyperaesthesia was reported in 1\xa0patient in the non-randomised comparative study of 98\xa0patients. The authors did not state which group this patient was in. Paraesthesia was reported in 19% (15/78) of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy in the same study; symptoms resolved within 6\xa0months.\n\nTransient headaches were reported in 8% (8/98) and 5% (3/57) of patients in the 2\xa0non-randomised comparative studies of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. The authors did not state which groups these patients were in. Headache was reported in 1% (3/250) of patients in a case series of 250\xa0patients.\n\nEpidural pneumocephalus was reported in 1\xa0patient in the case series of 250\xa0patients (no further information given).\n\nFocal infection was reported in 2% (2/98) and 4% (2/57) of patients in the 2\xa0non-randomised comparative studies of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. The authors did not state which groups these patients were in.\n\nMeningitis was reported in 1\xa0patient each in the 2\xa0non-randomised comparative studies of patients treated by endoscopic adhesiolysis, foraminoplasty and discectomy or endoscopic adhesiolysis and foraminoplasty without discectomy. The authors of the studies did not state which treatment groups these patients were in. Symptoms resolved after bed rest and symptomatic treatment.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers reported no anecdotal adverse events. They considered that the following were theoretical adverse events: cauda equina syndrome, spinal fluid leak, and epidural haematoma.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2217-8'}	https://www.nice.org.uk/guidance/ipg570	Evidence-based recommendations on epiduroscopic lumbar discectomy through the sacral hiatus for sciatica in adults. This involves removing the part of the spinal disc pressing against the spinal nerve, to relieve pain.
a9c9773fa94fbc9bc9e51cef45030c80e9a2ef50	nice	Ticagrelor for preventing atherothrombotic events after myocardial infarction	Ticagrelor for preventing atherothrombotic events after myocardial infarction Evidence-based recommendations on ticagrelor (Brilique) for preventing atherothrombotic events after myocardial infarction in adults. # Recommendations Ticagrelor, in combination with aspirin, is recommended within its marketing authorisation as an option for preventing atherothrombotic events in adults who had a myocardial infarction and who are at high risk of a further event.Treatment should be stopped when clinically indicated or at a maximum of 3 years.# The technology Description of the technology Ticagrelor (Brilique, AstraZeneca) is an oral antagonist of the P2Y12 adenosine diphosphate receptor that inhibits platelet aggregation and thrombus formation in atherosclerotic disease. Marketing authorisation Ticagrelor 60 mg twice daily, co‑administered with aspirin (acetylsalicylic acid), has a marketing authorisation for 'the prevention of atherothrombotic events in adult patients with a history of myocardial infarction of at least 1 year and a high risk of developing an atherothrombotic event'. The marketing authorisation for preventing atherothrombotic events in adults with a history of myocardial infarction and a high risk of an atherothrombotic event was granted in February 2016. NICE's technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes covers ticagrelor 90 mg and aspirin for preventing atherothrombotic events. Adverse reactions Ticagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or severe hepatic impairment. Co‑administration of ticagrelor with a strong CYP3A4 inhibitor (for example, ketoconazole, clarithromycin, nefazodone, ritonavir or atazanavir) is also contraindicated. The most commonly reported adverse effects include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, and bruising. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Ticagrelor 60 mg twice daily is the recommended dose when extended treatment is needed for patients with a history of myocardial infarction of at least 1 year and a high risk of an atherothrombotic event. Treatment may be started without interruption (continuation therapy) after the initial 1‑year treatment with ticagrelor 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in patients with acute coronary syndromes and with a high risk of an atherothrombotic event. Treatment can also be started up to 2 years from the myocardial infarction, or within 1 year after stopping previous ADP receptor inhibitor treatment. Unless contraindicated, ticagrelor should always be given with a daily low maintenance dose of aspirin 75 mg to 150 mg. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment. Price Ticagrelor costs £54.60 for a 56‑tablet pack (28 days' supply). Costs may vary in different settings because of negotiated procurement discounts.# Evidence The appraisal committee (section 6) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of extended therapy with ticagrelor 60 mg twice daily plus aspirin (hereafter referred to as ticagrelor), having considered evidence on the nature of preventing atherothrombotic events in people with a history of myocardial infarction and at high risk of atherothrombotic events, and the value placed on the benefits of ticagrelor by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Nature of the treatment and patient perspective The committee heard from the clinical expert and patient experts that a history of a myocardial infarction causes considerable anxiety, particularly about having further myocardial infarctions or other cardiovascular events such as a stroke. People also have concerns about the risk of bleeding associated with antiplatelet therapy, particularly with extended treatment. The fear of a bleed increases over time and can have a negative impact on the quality of life of the person and their family. The committee concluded that an additional antiplatelet agent to reduce the risk of further cardiovascular events would be useful, but that any additional bleeding risk associated with extended treatment should be taken into account when deciding whether to continue a person's antiplatelet treatment. # Clinical management The committee understood that ticagrelor is a therapy to prevent further atherothrombotic events after treatment of the acute coronary syndrome has stopped. It therefore briefly discussed the clinical management of acute coronary syndromes. It was aware of NICE's technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes and prasugrel with percutaneous coronary intervention for treating acute coronary syndromes, as well as the NICE guidelines on myocardial infarction with ST-segment elevation: acute management and unstable angina and NSTEMI: early management. The clinical experts explained that practice varies across the NHS and although clopidogrel plus aspirin has been the most commonly used treatment for acute coronary syndromes, the use of newer therapies such as prasugrel and ticagrelor (each as dual antiplatelet therapy with aspirin) is increasing. The committee considered how treatment with ticagrelor would fit into the clinical pathway for preventing a myocardial infarction. The committee was aware that patients enrolled into PEGASUS‑TIMI 54, the trial which formed the basis of the company submission, had a history of myocardial infarction occurring between 12 and 36 months before entry. Patients also had at least 1 additional risk factor for subsequent atherothrombotic events, listed in the summary of product characteristics as age 65 or over, diabetes mellitus needing medication, a second prior myocardial infarction, evidence of multivessel coronary artery disease, or chronic non‑end‑stage renal dysfunction. In the trial, treatment with a previous adenosine diphosphate (ADP) receptor could have been stopped any time before randomisation to the treatment arms. The committee was also aware that 84% of patients in each treatment arm received clopidogrel plus aspirin as their previous antiplatelet therapy and, therefore, had switched from clopidogrel (as their first-line therapy) to ticagrelor. The committee heard from clinical experts that switching between treatments occurs in clinical practice and is not as much of a concern as having a gap between treatments. The clinical experts clarified that when there is a gap in therapy, the risk of an atherothrombotic event increases, particularly in people at high risk. Therefore any gap in therapy should be minimised whenever possible. The committee considered whether ticagrelor would only be used as continuation therapy, but noted from consultation comments that this would not always be possible if, for example, a person had stopped their first-line therapy because of an adverse reaction within 1 year of their myocardial infarction (that is, before ticagrelor 60 mg is indicated). Based on comments from clinical experts and those received during consultation, the committee concluded that patients and clinicians would value ticagrelor either as continuation therapy after their first year of treatment, or when first-line dual antiplatelet therapy has been used but stopped for less than 1 year. # Decision problem: population The committee was aware that the population in the company's decision problem, and therefore the focus of the company's submission, was adults who had a myocardial infarction between 1 and 2 years ago who are at increased risk of an atherothrombotic event (referred to by the company as its base-case population). The committee noted that the company had defined a narrower population than that in NICE's scope, that is, adults who have had a myocardial infarction and are at increased risk of atherothrombotic events. The committee was aware that the company's rationale for the narrower population was that the marketing authorisation focuses on those patients for whom the adverse effect profile was most favourable in PEGASUS‑TIMI 54. The marketing authorisation allows ticagrelor to be started in patients 1 to 2 years after a myocardial infarction or within 1 year of stopping treatment with a previous antiplatelet therapy. Based on clinical practice in England, the company suggested that few patients would have stopped antiplatelet therapy within 1 year. However, the committee noted comments received during consultation that the full population covered by the marketing authorisation should be included in the committee's discussions; that is, not only people who had a myocardial infarction 1 to 2 years ago, but also people who had a myocardial infarction more than 2 years ago and stopped taking antiplatelet therapy no more than 1 year ago. The committee considered that because this latter group is covered by the marketing authorisation, and given comments that ticagrelor would be valued as an option for these people, it should include this group. The committee further concluded that although there may be only a minority of patients in this position, it was not appropriate to exclude these people in decision-making. # Decision problem: comparator The committee noted that the final scope specified clopidogrel plus aspirin and aspirin alone as comparators and that the company considered aspirin alone to be the appropriate comparator. The committee understood that the company did not consider clopidogrel plus aspirin to be an appropriate comparator because it does not have a marketing authorisation for use more than 12 months after a myocardial infarction and is not considered established clinical practice at that point in the treatment pathway. The committee recognised that although the company did not consider clopidogrel plus aspirin to be an appropriate comparator, it had considered doing an indirect comparison of ticagrelor with clopidogrel plus aspirin because there were no trials directly comparing the 2 treatments. But the company considered this inappropriate (as did the evidence review group; ERG) because of differences in the design of the trials and the patient populations included in the indirect comparison. The committee understood from the clinical experts that clopidogrel plus aspirin was commonly used as an initial antiplatelet agent for up to 12 months after a myocardial infarction. However it is not used in clinical practice when continued treatment is needed for patients with a history of myocardial infarction and a high risk of an atherothrombotic event, that is, at the same point in the treatment pathway where the summary of product characteristics recommends ticagrelor (see section 4.3). The committee concluded that clopidogrel plus aspirin was not an appropriate comparator and that the most appropriate comparison for its decision-making was ticagrelor compared with aspirin alone. # Clinical effectiveness ## PEGASUS‑TIMI 54 The company presented clinical effectiveness results for the PEGASUS‑TIMI 54 trial whole population who had ticagrelor compared with placebo (ticagrelor n=7,045, placebo n=7,067). The marketing authorisation for ticagrelor as an extended therapy was based on prespecified subgroup analyses. The committee noted that the company presented a prespecified subgroup analysis of patients who had a myocardial infarction 1 to 2 years previously (ticagrelor n=4,331, placebo n=4,333). The committee also noted that these results (referred to as the 'base-case' population by the company) tended to be more favourable to ticagrelor than the results from the overall ticagrelor population. The committee acknowledged that PEGASUS‑TIMI 54 was not statistically powered to detect a difference in outcomes in the company's base-case population, but agreed that because of the size of the subgroup, and the baseline characteristics being sufficiently similar to the overall ticagrelor group, it was appropriate for it to focus on this subgroup analysis in its decision-making about the clinical effectiveness of ticagrelor. The committee considered the effectiveness of ticagrelor compared with placebo in the subgroup of patients from PEGASUS‑TIMI 54 who had a myocardial infarction between 1 and 2 years ago. The committee noted that ticagrelor reduced the risk of myocardial infarction, stroke or death from cardiovascular causes by 23% compared with placebo. The committee concluded that treatment with ticagrelor is clinically effective for people with a history of myocardial infarction and a high risk of an atherothrombotic event. The committee heard contrasting views from the clinical and patient experts on the length of treatment with ticagrelor. Based on the progressive disease process that causes an atherothrombotic event, continued therapy may be justified. However, the committee was persuaded that the risk of bleeding was substantial and that prescribing should be informed by the evidence. The committee understood that the mean length of treatment in PEGASUS‑TIMI 54 was 25.3 months, and that the ticagrelor marketing authorisation states that there are limited data on its efficacy and safety beyond 3 years of treatment with ticagrelor. The committee concluded that it could only consider a maximum duration of treatment of up to 3 years, in line with the evidence presented for ticagrelor. # Cost effectiveness The committee considered the cost effectiveness of ticagrelor for preventing atherothrombotic events after myocardial infarction. It noted that the company's economic model was based on data for secondary efficacy outcomes in PEGASUS‑TIMI 54, including first and subsequent events, hospitalisations, dyspnoea, bleeds, EQ‑5D responses and treatment discontinuations. The committee considered whether PEGASUS‑TIMI 54 was underpowered to analyse these data. It was persuaded by the clinical and health economic experts that using these outcomes was acceptable because the population was large, so the numbers of patients on whom the secondary outcomes were based were likely to generate reasonable estimates. In addition, the committee understood that the model used equations to calculate the risk of an event occurring and that the company had used the intention-to-treat population for calculating these. The ERG confirmed the company's view that the risk equations were likely to be conservative and would, therefore, be unfavourable to ticagrelor. The committee concluded that the company's incremental cost-effectiveness ratios (ICERs) were likely to be overestimates because the parameters used to derive them were for the intention-to-treat population and therefore likely to underestimate the effect of ticagrelor. The committee considered the most plausible ICER on which to base its decision. It considered the company's deterministic base-case estimate of £20,636, which incorporated some minor amendments suggested by the ERG. It also considered the ERG's exploratory preferred base case of £24,711, which incorporated small changes to parameters including the cost and disutility associated with gout, adjusted health care costs, uncertainty around NHS reference costs and disutility for major bleeds. The committee was further reassured that when the ERG conducted scenario analysis, only one scenario resulted in an ICER above £30,000 per quality-adjusted life year (QALY) gained. This scenario was considered to be implausible because it held treatment efficacy constant while assuming that all patients who did not die or have a non-fatal event incurred 3‑year treatment costs, whereas the actual time on treatment for patients in the study who did not die or have a non-fatal event was less than 3 years. The committee concluded that all the estimates were within a range considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) and that it could recommend treatment with ticagrelor in line with its marketing authorisation. The committee agreed that, although the ICERs presented did not include the people at high risk who had a myocardial infarction more than 2 years ago and whose antiplatelet therapy had been stopped less than 1 year ago, the recommendation should cover this group. The committee recognised that all the cost-effectiveness evidence assumed a maximum treatment length of 3 years. It understood that some clinicians and patients may want to continue treatment indefinitely, but that the costs and clinical benefits of doing so had not been presented. The committee therefore concluded that the positive recommendation should only be for the length of time for which evidence had been presented, specifically 3 years. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA420 Appraisal title: Ticagrelor for preventing atherothrombotic events after myocardial infarction Section Key conclusion Ticagrelor, in combination with aspirin, is recommended within its marketing authorisation as an option for preventing atherothrombotic events in adults who have had a myocardial infarction and who are at high risk of a further event. Treatment should be stopped when clinically indicated or at a maximum of 3 years. Current practice Clinical need of patients, including the availability of alternative treatments The clinical experts explained that practice varies across the NHS. Although clopidogrel has been the most commonly used treatment for acute coronary syndromes, the use of newer therapies such as prasugrel and ticagrelor (each as dual antiplatelet therapy with aspirin) is increasing. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee was aware that ticagrelor has potential advantages over clopidogrel in preventing atherothrombotic events after myocardial infarction because of their faster antiplatelet action, although it is also associated with higher bleeding risk. What is the position of the treatment in the pathway of care for the condition? Ticagrelor would fit in the current treatment pathway either as continuation therapy after the first year of treatment, or when first-line dual antiplatelet therapy has been used but stopped for less than 1 year. Adverse reactions Ticagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or severe hepatic impairment. The most commonly reported adverse effects include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, and bruising. Evidence for clinical effectiveness Availability, nature and quality of evidence The company presented clinical effectiveness results for the PEGASUS‑TIMI 54 trial whole population who had ticagrelor compared with placebo (ticagrelor n=7,045, placebo n=7,067) and a prespecified subgroup analysis of patients who had a myocardial infarction 1 to 2 years previously (ticagrelor n=4,331, placebo n=4,333). The marketing authorisation for ticagrelor was based on the prespecified subgroup analysis. Relevance to general clinical practice in the NHS In the trial, treatment with a previous antiplatelet agent could have been stopped any time before randomisation to the treatment arms and 84% of patients in each treatment arm received clopidogrel plus aspirin as their previous antiplatelet therapy and, therefore, had switched from clopidogrel (as their first-line therapy) to ticagrelor. The committee heard from clinical experts that switching between treatments occurs in clinical practice and is not as much of a concern as having a gap between treatments. The clinical experts clarified that when there is a gap in therapy, the risk of an atherothrombotic event increases, particularly in people at high risk. Therefore, the gap should be minimised whenever possible. Uncertainties generated by the evidence The committee acknowledged that PEGASUS‑TIMI 54 was not statistically powered to detect a difference in outcomes in the company's base-case population, but agreed that because of the size of the subgroups, and the baseline characteristics being sufficiently similar to the overall ticagrelor group, it was appropriate for it to focus on this subgroup analysis in its decision-making about the clinical effectiveness of ticagrelor. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee was aware that the population in the company's decision problem, and therefore the focus of the company's submission, was adults who had a myocardial infarction between 1 and 2 years ago and who are at increased risk of atherothrombotic events (referred to by the company as its base-case population). The committee concluded that it was appropriate for it to focus its decision-making on this patient subgroup. Estimate of the size of the clinical effectiveness including strength of supporting evidence Data from PEGASUS‑TIMI 54 demonstrated that ticagrelor was effective in people with history of myocardial infarction between 1 and 2 years previously. The committee also understood that ticagrelor reduced the risk of myocardial infarction, stroke and death from cardiovascular causes by 23% compared with placebo. Evidence for cost effectiveness Availability and nature of evidence The committee considered cost-effectiveness modelling, which compared ticagrelor with placebo. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee discussed: the use of 3 different approaches to cost effectiveness modelling evaluate the most plausible ICER (2 deterministic approaches and 1 probabilistic approach) the application of a composite outcome measure of cardiovascular death, myocardial infarction or stroke in the PEGASUS‑TIMI 54 trial. The committee concluded that although the model did not account for all uncertainties, further refinements were unlikely to alter its decision on cost effectiveness. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee did not raise any concerns. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? The use of 3 different approaches to cost effectiveness modelling (2 deterministic approaches and 1 probabilistic approach). Most likely cost-effectiveness estimate (given as an ICER) Although it would have preferred a probabilistic estimate, it recognised that on this occasion the individual patient approach could be used as a starting point for its discussion, alongside the probabilistic analyses presented by the ERG using average-patient characteristics. Using this approach, the ICER for ticagrelor compared with placebo was £20,636 per quality‑adjusted life year (QALY) gained (incremental costs £1,432, incremental QALYs 0.069). The ERG's probabilistic ICER was £24,711. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End‑of‑life considerations Not applicable. Equalities considerations and social value judgements A consultee commented that the PEGASUS‑TIMI 54 trial excluded people with a previous stroke, gastrointestinal bleed or who needed anticoagulation therapy. The consultee further commented that this is not representative of practice and that if these people presented with a further ischaemic event they would still need treatment. The inclusion criteria of clinical trials cannot be addressed in a technology appraisal; however, the committee was aware that the ticagrelor summary of product characteristics advises caution if ticagrelor is clinically indicated in such circumstances.	{'Recommendations': 'Ticagrelor, in combination with aspirin, is recommended within its marketing authorisation as an option for preventing atherothrombotic events in adults who had a myocardial infarction and who are at high risk of a further event.Treatment should be stopped when clinically indicated or at a maximum of 3\xa0years.', 'The technology': "Description of the technology\n\nTicagrelor (Brilique, AstraZeneca) is an oral antagonist of the P2Y12 adenosine diphosphate receptor that inhibits platelet aggregation and thrombus formation in atherosclerotic disease.\n\nMarketing authorisation\n\nTicagrelor 60\xa0mg twice daily, co‑administered with aspirin (acetylsalicylic acid), has a marketing authorisation for 'the prevention of atherothrombotic events in adult patients with a history of myocardial infarction of at least 1\xa0year and a high risk of developing an atherothrombotic event'.\n\n\n\nThe marketing authorisation for preventing atherothrombotic events in adults with a history of myocardial infarction and a high risk of an atherothrombotic event was granted in February 2016.\n\n\n\nNICE's technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes covers ticagrelor 90\xa0mg and aspirin for preventing atherothrombotic events.\n\nAdverse reactions\n\nTicagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or severe hepatic impairment. Co‑administration of ticagrelor with a strong CYP3A4 inhibitor (for example, ketoconazole, clarithromycin, nefazodone, ritonavir or atazanavir) is also contraindicated. The most commonly reported adverse effects include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, and bruising. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nTicagrelor 60\xa0mg twice daily is the recommended dose when extended treatment is needed for patients with a history of myocardial infarction of at least 1\xa0year and a high risk of an atherothrombotic event. Treatment may be started without interruption (continuation therapy) after the initial 1‑year treatment with ticagrelor 90\xa0mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in patients with acute coronary syndromes and with a high risk of an atherothrombotic event. Treatment can also be started up to 2\xa0years from the myocardial infarction, or within 1\xa0year after stopping previous ADP receptor inhibitor treatment.\n\nUnless contraindicated, ticagrelor should always be given with a daily low maintenance dose of aspirin 75\xa0mg to 150\xa0mg.\n\nThere are limited data on the efficacy and safety of ticagrelor beyond 3\xa0years of extended treatment.\n\nPrice\n\nTicagrelor costs £54.60 for a 56‑tablet pack (28\xa0days' supply). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of extended therapy with ticagrelor 60\xa0mg twice daily plus aspirin (hereafter referred to as ticagrelor), having considered evidence on the nature of preventing atherothrombotic events in people with a history of myocardial infarction and at high risk of atherothrombotic events, and the value placed on the benefits of ticagrelor by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Nature of the treatment and patient perspective\n\nThe committee heard from the clinical expert and patient experts that a history of a myocardial infarction causes considerable anxiety, particularly about having further myocardial infarctions or other cardiovascular events such as a stroke. People also have concerns about the risk of bleeding associated with antiplatelet therapy, particularly with extended treatment. The fear of a bleed increases over time and can have a negative impact on the quality of life of the person and their family. The committee concluded that an additional antiplatelet agent to reduce the risk of further cardiovascular events would be useful, but that any additional bleeding risk associated with extended treatment should be taken into account when deciding whether to continue a person's antiplatelet treatment.\n\n# Clinical management\n\nThe committee understood that ticagrelor is a therapy to prevent further atherothrombotic events after treatment of the acute coronary syndrome has stopped. It therefore briefly discussed the clinical management of acute coronary syndromes. It was aware of NICE's technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes and prasugrel with percutaneous coronary intervention for treating acute coronary syndromes, as well as the NICE guidelines on myocardial infarction with ST-segment elevation: acute management and unstable angina and NSTEMI: early management. The clinical experts explained that practice varies across the NHS and although clopidogrel plus aspirin has been the most commonly used treatment for acute coronary syndromes, the use of newer therapies such as prasugrel and ticagrelor (each as dual antiplatelet therapy with aspirin) is increasing.\n\nThe committee considered how treatment with ticagrelor would fit into the clinical pathway for preventing a myocardial infarction. The committee was aware that patients enrolled into PEGASUS‑TIMI\xa054, the trial which formed the basis of the company submission, had a history of myocardial infarction occurring between 12\xa0and 36\xa0months before entry. Patients also had at least 1\xa0additional risk factor for subsequent atherothrombotic events, listed in the summary of product characteristics as age\xa065 or over, diabetes mellitus needing medication, a second prior myocardial infarction, evidence of multivessel coronary artery disease, or chronic non‑end‑stage renal dysfunction. In the trial, treatment with a previous adenosine diphosphate (ADP) receptor could have been stopped any time before randomisation to the treatment arms. The committee was also aware that 84% of patients in each treatment arm received clopidogrel plus aspirin as their previous antiplatelet therapy and, therefore, had switched from clopidogrel (as their first-line therapy) to ticagrelor. The committee heard from clinical experts that switching between treatments occurs in clinical practice and is not as much of a concern as having a gap between treatments. The clinical experts clarified that when there is a gap in therapy, the risk of an atherothrombotic event increases, particularly in people at high risk. Therefore any gap in therapy should be minimised whenever possible. The committee considered whether ticagrelor would only be used as continuation therapy, but noted from consultation comments that this would not always be possible if, for example, a person had stopped their first-line therapy because of an adverse reaction within 1\xa0year of their myocardial infarction (that is, before ticagrelor 60\xa0mg is indicated). Based on comments from clinical experts and those received during consultation, the committee concluded that patients and clinicians would value ticagrelor either as continuation therapy after their first year of treatment, or when first-line dual antiplatelet therapy has been used but stopped for less than 1\xa0year.\n\n# Decision problem: population\n\nThe committee was aware that the population in the company's decision problem, and therefore the focus of the company's submission, was adults who had a myocardial infarction between 1\xa0and 2\xa0years ago who are at increased risk of an atherothrombotic event (referred to by the company as its base-case population). The committee noted that the company had defined a narrower population than that in NICE's scope, that is, adults who have had a myocardial infarction and are at increased risk of atherothrombotic events. The committee was aware that the company's rationale for the narrower population was that the marketing authorisation focuses on those patients for whom the adverse effect profile was most favourable in PEGASUS‑TIMI\xa054. The marketing authorisation allows ticagrelor to be started in patients 1\xa0to 2\xa0years after a myocardial infarction or within 1\xa0year of stopping treatment with a previous antiplatelet therapy. Based on clinical practice in England, the company suggested that few patients would have stopped antiplatelet therapy within 1\xa0year. However, the committee noted comments received during consultation that the full population covered by the marketing authorisation should be included in the committee's discussions; that is, not only people who had a myocardial infarction 1\xa0to 2\xa0years ago, but also people who had a myocardial infarction more than 2\xa0years ago and stopped taking antiplatelet therapy no more than 1\xa0year ago. The committee considered that because this latter group is covered by the marketing authorisation, and given comments that ticagrelor would be valued as an option for these people, it should include this group. The committee further concluded that although there may be only a minority of patients in this position, it was not appropriate to exclude these people in decision-making.\n\n# Decision problem: comparator\n\nThe committee noted that the final scope specified clopidogrel plus aspirin and aspirin alone as comparators and that the company considered aspirin alone to be the appropriate comparator. The committee understood that the company did not consider clopidogrel plus aspirin to be an appropriate comparator because it does not have a marketing authorisation for use more than 12\xa0months after a myocardial infarction and is not considered established clinical practice at that point in the treatment pathway. The committee recognised that although the company did not consider clopidogrel plus aspirin to be an appropriate comparator, it had considered doing an indirect comparison of ticagrelor with clopidogrel plus aspirin because there were no trials directly comparing the 2\xa0treatments. But the company considered this inappropriate (as did the evidence review group; ERG) because of differences in the design of the trials and the patient populations included in the indirect comparison. The committee understood from the clinical experts that clopidogrel plus aspirin was commonly used as an initial antiplatelet agent for up to 12\xa0months after a myocardial infarction. However it is not used in clinical practice when continued treatment is needed for patients with a history of myocardial infarction and a high risk of an atherothrombotic event, that is, at the same point in the treatment pathway where the summary of product characteristics recommends ticagrelor (see section\xa04.3). The committee concluded that clopidogrel plus aspirin was not an appropriate comparator and that the most appropriate comparison for its decision-making was ticagrelor compared with aspirin alone.\n\n# Clinical effectiveness\n\n## PEGASUS‑TIMI\xa054\n\nThe company presented clinical effectiveness results for the PEGASUS‑TIMI\xa054 trial whole population who had ticagrelor compared with placebo (ticagrelor n=7,045, placebo n=7,067). The marketing authorisation for ticagrelor as an extended therapy was based on prespecified subgroup analyses. The committee noted that the company presented a prespecified subgroup analysis of patients who had a myocardial infarction 1\xa0to 2\xa0years previously (ticagrelor n=4,331, placebo n=4,333). The committee also noted that these results (referred to as the 'base-case' population by the company) tended to be more favourable to ticagrelor than the results from the overall ticagrelor population. The committee acknowledged that PEGASUS‑TIMI\xa054 was not statistically powered to detect a difference in outcomes in the company's base-case population, but agreed that because of the size of the subgroup, and the baseline characteristics being sufficiently similar to the overall ticagrelor group, it was appropriate for it to focus on this subgroup analysis in its decision-making about the clinical effectiveness of ticagrelor.\n\nThe committee considered the effectiveness of ticagrelor compared with placebo in the subgroup of patients from PEGASUS‑TIMI\xa054 who had a myocardial infarction between 1\xa0and 2\xa0years ago. The committee noted that ticagrelor reduced the risk of myocardial infarction, stroke or death from cardiovascular causes by 23% compared with placebo. The committee concluded that treatment with ticagrelor is clinically effective for people with a history of myocardial infarction and a high risk of an atherothrombotic event.\n\nThe committee heard contrasting views from the clinical and patient experts on the length of treatment with ticagrelor. Based on the progressive disease process that causes an atherothrombotic event, continued therapy may be justified. However, the committee was persuaded that the risk of bleeding was substantial and that prescribing should be informed by the evidence. The committee understood that the mean length of treatment in PEGASUS‑TIMI\xa054 was 25.3\xa0months, and that the ticagrelor marketing authorisation states that there are limited data on its efficacy and safety beyond 3\xa0years of treatment with ticagrelor. The committee concluded that it could only consider a maximum duration of treatment of up to 3\xa0years, in line with the evidence presented for ticagrelor.\n\n# Cost effectiveness\n\nThe committee considered the cost effectiveness of ticagrelor for preventing atherothrombotic events after myocardial infarction. It noted that the company's economic model was based on data for secondary efficacy outcomes in PEGASUS‑TIMI\xa054, including first and subsequent events, hospitalisations, dyspnoea, bleeds, EQ‑5D responses and treatment discontinuations. The committee considered whether PEGASUS‑TIMI\xa054 was underpowered to analyse these data. It was persuaded by the clinical and health economic experts that using these outcomes was acceptable because the population was large, so the numbers of patients on whom the secondary outcomes were based were likely to generate reasonable estimates. In addition, the committee understood that the model used equations to calculate the risk of an event occurring and that the company had used the intention-to-treat population for calculating these. The ERG confirmed the company's view that the risk equations were likely to be conservative and would, therefore, be unfavourable to ticagrelor. The committee concluded that the company's incremental cost-effectiveness ratios (ICERs) were likely to be overestimates because the parameters used to derive them were for the intention-to-treat population and therefore likely to underestimate the effect of ticagrelor.\n\nThe committee considered the most plausible ICER on which to base its decision. It considered the company's deterministic base-case estimate of £20,636, which incorporated some minor amendments suggested by the ERG. It also considered the ERG's exploratory preferred base case of £24,711, which incorporated small changes to parameters including the cost and disutility associated with gout, adjusted health care costs, uncertainty around NHS reference costs and disutility for major bleeds. The committee was further reassured that when the ERG conducted scenario analysis, only one scenario resulted in an ICER above £30,000 per quality-adjusted life year (QALY) gained. This scenario was considered to be implausible because it held treatment efficacy constant while assuming that all patients who did not die or have a non-fatal event incurred 3‑year treatment costs, whereas the actual time on treatment for patients in the study who did not die or have a non-fatal event was less than 3\xa0years. The committee concluded that all the estimates were within a range considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) and that it could recommend treatment with ticagrelor in line with its marketing authorisation. The committee agreed that, although the ICERs presented did not include the people at high risk who had a myocardial infarction more than 2\xa0years ago and whose antiplatelet therapy had been stopped less than 1\xa0year ago, the recommendation should cover this group.\n\nThe committee recognised that all the cost-effectiveness evidence assumed a maximum treatment length of 3\xa0years. It understood that some clinicians and patients may want to continue treatment indefinitely, but that the costs and clinical benefits of doing so had not been presented. The committee therefore concluded that the positive recommendation should only be for the length of time for which evidence had been presented, specifically 3\xa0years.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA420\n\nAppraisal title: Ticagrelor for preventing atherothrombotic events after myocardial infarction\n\nSection\n\nKey conclusion\n\nTicagrelor, in combination with aspirin, is recommended within its marketing authorisation as an option for preventing atherothrombotic events in adults who have had a myocardial infarction and who are at high risk of a further event.\n\nTreatment should be stopped when clinically indicated or at a maximum of 3\xa0years.\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe clinical experts explained that practice varies across the NHS. Although clopidogrel has been the most commonly used treatment for acute coronary syndromes, the use of newer therapies such as prasugrel and ticagrelor (each as dual antiplatelet therapy with aspirin) is increasing.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee was aware that ticagrelor has potential advantages over clopidogrel in preventing atherothrombotic events after myocardial infarction because of their faster antiplatelet action, although it is also associated with higher bleeding risk.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nTicagrelor would fit in the current treatment pathway either as continuation therapy after the first year of treatment, or when first-line dual antiplatelet therapy has been used but stopped for less than 1\xa0year.\n\n\n\nAdverse reactions\n\nTicagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or severe hepatic impairment. The most commonly reported adverse effects include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, and bruising.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe company presented clinical effectiveness results for the PEGASUS‑TIMI\xa054 trial whole population who had ticagrelor compared with placebo (ticagrelor n=7,045, placebo n=7,067) and a prespecified subgroup analysis of patients who had a myocardial infarction 1\xa0to 2\xa0years previously (ticagrelor n=4,331, placebo n=4,333). The marketing authorisation for ticagrelor was based on the prespecified subgroup analysis.\n\n\n\nRelevance to general clinical practice in the NHS\n\nIn the trial, treatment with a previous antiplatelet agent could have been stopped any time before randomisation to the treatment arms and 84% of patients in each treatment arm received clopidogrel plus aspirin as their previous antiplatelet therapy and, therefore, had switched from clopidogrel (as their first-line therapy) to ticagrelor. The committee heard from clinical experts that switching between treatments occurs in clinical practice and is not as much of a concern as having a gap between treatments. The clinical experts clarified that when there is a gap in therapy, the risk of an atherothrombotic event increases, particularly in people at high risk. Therefore, the gap should be minimised whenever possible.\n\n\n\nUncertainties generated by the evidence\n\nThe committee acknowledged that PEGASUS‑TIMI\xa054 was not statistically powered to detect a difference in outcomes in the company's base-case population, but agreed that because of the size of the subgroups, and the baseline characteristics being sufficiently similar to the overall ticagrelor group, it was appropriate for it to focus on this subgroup analysis in its decision-making about the clinical effectiveness of ticagrelor.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee was aware that the population in the company's decision problem, and therefore the focus of the company's submission, was adults who had a myocardial infarction between 1\xa0and 2\xa0years ago and who are at increased risk of atherothrombotic events (referred to by the company as its base-case population). The committee concluded that it was appropriate for it to focus its decision-making on this patient subgroup.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nData from PEGASUS‑TIMI\xa054 demonstrated that ticagrelor was effective in people with history of myocardial infarction between 1\xa0and 2\xa0years previously. The committee also understood that ticagrelor reduced the risk of myocardial infarction, stroke and death from cardiovascular causes by 23% compared with placebo.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee considered cost-effectiveness modelling, which compared ticagrelor with placebo.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee discussed:\n\nthe use of 3\xa0different approaches to cost effectiveness modelling evaluate the most plausible ICER (2\xa0deterministic approaches and 1\xa0probabilistic approach)\n\nthe application of a composite outcome measure of cardiovascular death, myocardial infarction or stroke in the PEGASUS‑TIMI\xa054 trial.\n\nThe committee concluded that although the model did not account for all uncertainties, further refinements were unlikely to alter its decision on cost effectiveness.\n\n, 4.10\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee did not raise any concerns.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe use of 3\xa0different approaches to cost effectiveness modelling (2\xa0deterministic approaches and 1\xa0probabilistic approach).\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nAlthough it would have preferred a probabilistic estimate, it recognised that on this occasion the individual patient approach could be used as a starting point for its discussion, alongside the probabilistic analyses presented by the ERG using average-patient characteristics. Using this approach, the ICER for ticagrelor compared with placebo was £20,636 per quality‑adjusted life year (QALY) gained (incremental costs £1,432, incremental QALYs 0.069). The ERG's probabilistic ICER was £24,711.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd‑of‑life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nA consultee commented that the PEGASUS‑TIMI\xa054 trial excluded people with a previous stroke, gastrointestinal bleed or who needed anticoagulation therapy. The consultee further commented that this is not representative of practice and that if these people presented with a further ischaemic event they would still need treatment. The inclusion criteria of clinical trials cannot be addressed in a technology appraisal; however, the committee was aware that the ticagrelor summary of product characteristics advises caution if ticagrelor is clinically indicated in such circumstances.\n\n–"}	https://www.nice.org.uk/guidance/ta420	Evidence-based recommendations on ticagrelor (Brilique) for preventing atherothrombotic events after myocardial infarction in adults.
72c536e870f8757fd98ff50a2002c7b9bfc754de	nice	XprESS multi sinus dilation system for treating chronic sinusitis	XprESS multi sinus dilation system for treating chronic sinusitis Evidence-based recommendations on the XprESS multi-sinus dilation system for treating chronic sinusitis after medical treatment has failed. # Recommendations The case for adopting the XprESS multi‑sinus dilation system for treating uncomplicated chronic sinusitis after medical treatment has failed is supported by the evidence. Treatment with XprESS leads to a rapid and sustained improvement in chronic symptoms, fewer acute episodes and improved quality of life which is comparable to functional endoscopic sinus surgery (FESS). XprESS should be considered in patients with uncomplicated chronic sinusitis who do not have severe nasal polyposis. In these patients, XprESS works as well as FESS, is associated with faster recovery times, and can more often be done under local anaesthesia. Cost modelling indicates that XprESS is cost saving compared with FESS when treatment is done using local anaesthetic in an outpatient setting. The estimated saving per patient is £152, assuming that 80% of treatments are done this way, FESS takes 60 minutes and the device cost for XprESS is £820. By adopting this technology, the NHS in England may save around £7.4 million a year by 2020. Estimated savings are mainly achieved through the shift of treatment from operating theatre to outpatient setting.# The technology # Description of the technology The XprESS multi‑sinus dilation system (XprESS, Entellus Medical) is a sterile, single‑use device for treating chronic sinusitis. The system comprises a balloon‑tipped device with a reshapeable end that is inserted through the nose into the maxillary, frontal or sphenoidal sinuses. XprESS also includes an inflation syringe, bending tool and 2 extension lines to provide irrigation. The balloon is manipulated into the bony sinus outflow tracts (ostia) and inflated with saline. This reshapes and opens the ostia by displacing adjacent bone and paranasal sinus structures allowing the sinuses to drain more effectively The system is available in 3 variants, XprESS Ultra, LoProfile and Pro, which differ in the dimensions of the suction tip and the balloon diameter and length. All suction tips and balloon lengths are appropriate for treating all sinuses; selection is based on clinician preference. The XprESS device, inflation syringe and bending tool are included in all variants. The Ultra and LoProfile (the version currently sold in the UK) systems also include an integrated PathAssist LED light fibre, which is available as an add‑on for the Pro. XprESS can be used under local anaesthesia, once the surgeon has had sufficient experience of using the device. According to the company's submission XprESS costs £900. The company informed the committee that a reduction to £820 is available for centres that order 50 or more units in a year. The claimed benefits of XprESS in the case for adoption presented by the company are: A minimally invasive alternative to functional endoscopic sinus surgery (FESS), offering equivalent efficacy and minimal acute inflammation while preserving more sinus tissue and mucosa. Reduction in risks associated with general anaesthetic and fewer staff resources needed, because the procedure is done while the patient is awake and under local anaesthesia. Faster recovery time with less nasal bleeding and a shorter duration of pain medication. Improved patient comfort and tolerance compared with other balloon technologies because XprESS allows more control of device placement. Easier to use than other balloon technologies, because XprESS is based on a sinus seeker and no guidewire is needed. More accurate cannulation of the maximally ostium. Reduction in theatre time compared with FESS. Reduction in length of stay in hospital. Reduction in duration of prescription pain medication. Reduction in postoperative nasal bleeding visits. Reduction in hospital readmissions. Potentially fewer patients waiting 18 weeks or longer for ear, nose and throat (ENT) surgery. # Current management Sinusitis (also known as rhinosinusitis and sinus infection) refers to inflammation (because of infection or irritation) of the mucosal lining of the sinuses. This causes an increase in mucus production and a reduction in mucus drainage if the inflamed swollen mucosa blocks the sinus ostia. Both acute and chronic sinusitis are defined by the presence of nasal blockage or nasal discharge, accompanied by facial pain or a loss of smell. Acute sinusitis refers to an episode of symptoms that resolves within 12 weeks. Recurrent acute sinusitis refers to multiple episodes of acute sinusitis, (usually considered to be 3 or more in a year) that are separated by validated, symptom‑free intervals. Chronic sinusitis refers to an episode of symptoms that lasts more than 12 weeks. Chronic sinusitis may sometimes be accompanied by nasal polyps. Sinusitis may be associated with the extension of inflammation outside the paranasal sinuses and nasal cavity and be accompanied by neurologic, ophthalmologic, or local soft tissue sequelae. Chronic sinusitis is regarded as uncomplicated if none of these are present. Current treatment options for chronic sinusitis include nasal saline irrigation, intranasal corticosteroids, systemic antibiotics or topical drops, and FESS. NICE's clinical knowledge summary on chronic sinusitis describes measures to relieve symptoms, particularly for acute exacerbations of chronic rhinosinusitis, that include analgesics for pain or fever, occasional intranasal decongestants and intranasal saline irrigation, and warm face packs. Patients should be offered advice about managing associated conditions (such as allergic rhinitis, asthma and dental infections), along with advice on smoking cessation and dental hygiene when appropriate. A short course of antibiotics may be prescribed for acute exacerbations, but longer‑term courses are not recommended without seeking specialist advice. A course of intranasal corticosteroids of up to 3 months may be considered, especially if there is a suspicion of an allergic cause (such as concomitant allergic rhinitis). A patient should be admitted to hospital if chronic sinusitis is associated with a severe systemic infection, or a serious complication such as orbital or intracranial infection or inflammation. Referral to an ENT specialist should be considered for people with frequent recurrent episodes of acute sinusitis (for example more than 3 episodes requiring antibiotics in a year), unremitting or progressive facial pain (urgent referral for suspected malignancy), or nasal polyps that are causing significant nasal obstruction. Referral to an ENT specialist should also be considered if a person has taken intranasal corticosteroids for 3 months without effect. FESS is the most common ENT surgery used to treat persistent and severe cases of chronic sinusitis. During FESS, the surgeon uses a magnifying endoscope inserted through the nostrils to identify and remove affected sinus tissue and bone. The aim is to clear the obstructed ostia and flush out infected material, but retain enough healthy tissue for normal nose and sinus function. FESS is usually done under general anaesthesia. Scarring and adhesions can occur as a result of FESS, which may need postoperative removal of tissue, blood and bone (debridement). Other more serious risks occasionally associated with FESS include intraorbital and intracranial complications. NICE interventional procedure guidance on balloon catheter dilation of paranasal sinus ostia for chronic sinusitis concluded that the current evidence on the procedure's short‑term efficacy is adequate and raised no major safety concerns# Clinical evidence # Summary of clinical evidence The key clinical outcomes presented in the decision problem were: change in sinusitis symptoms number of post‑procedure sinusitis episodes needing medication number of postoperative debridements change in ostial patency (assessed by endoscopy or CT scan) number and types of sinus treated length of hospital stay procedure time and theatre/outpatient treatment room time rate of revision surgery number of sinus‑related follow‑up appointments rate of readmission rate and severity of nasal bleeding device‑related adverse events. The company conducted a literature search for evidence on XprESS and its predecessor device FinESS, which identified 13 papers describing 9 trials, 7 published and 2 unpublished. The retrieved papers included a meta‑analysis involving 6 of the 11 published studies. The external assessment centre (EAC) judged the company's search terms to be appropriate, but could not fully reproduce them because the search strategies were not fully reported. The EAC re‑ran the company's searches and conducted its own search, which identified no further evidence. The EAC considered that 1 included study, Eloy et al. (2012), should be excluded from further assessment because the population (patients who had previously had a failed frontal sinustomy) was not consistent with the scope. The EAC therefore assessed 12 publications, which reported on 1 randomised controlled trial and 7 observational studies, 2 of which were unpublished. ## Included studies: REMODEL Three studies (Cutler et al. 2013, Bikhazi et al. 2014, Chandra at al. 2016) reported on the REMODEL trial, a prospective, multicentre, non‑inferiority, parallel, randomised clinical trial (the methodology is most comprehensively reported in Cutler et al. 2013). The REMODEL trial compared FESS with balloon dilation systems (FinESS and XprESS) in adult patients with uncomplicated chronic sinusitis or recurrent acute sinusitis associated with maxillary sinus disease with or without anterior ethmoid sinus disease. The split between XprESS and FinESS was not reported but the company has indicated it was approximately 50:50. Patients and clinicians were blinded to their allocation. Blinding could not be maintained after treatment allocation, but some post‑surgical assessments were done or audited by independent physicians. Following withdrawals after randomisation, there were 50 patients in the balloon arm and 42 in the FESS arm. A post hoc modified intention‑to‑treat analysis was done. The primary outcome measure was change in chronic sinusitis symptoms as measured by the Sino‑Nasal Outcome Test‑20 (SNOT‑20) scores at 6 months from baseline (pre‑procedure). Cutler et al. (2013) reported outcomes up to 6 months after the procedure. At 1 week, the average change in SNOT‑20 scores in the balloon arm was −1.49 (standard deviation =0.87), compared with −0.96 (SD=1.12) in the FESS arm. At 1 month, the average change was −1.70 (SD=0.98) for the balloon arm and −1.62 (SD=0.95) for FESS. At 6 months, the change was −1.67 (SD=1.10) for the balloon arm and −1.60 (SD=0.96) for FESS. The changes from baseline were significant (p<0.001) in both groups at all time points, and because the change in score exceeded 0.8, the differences were judged to be clinically meaningful. With the exception of the results at 1 week (p=0.014), there was no statistically significant difference between the SNOT‑20 scores in the balloon dilation and FESS arms. This indicated non‑inferiority of the balloon procedures in terms of symptom improvement, with a potentially significant short‑term effect (at 1 week). The authors also reported significant (p<0.0001) and clinically meaningful improvements in each of the subscales of the SNOT‑20 at 6 months, with no statistically significant differences between the 2 arms. The same results were reported at 6 months for the following subgroups: maxillary only or maxillary and anterior ethmoid; presence or absence of accessory ostia; presence or absence of septal deviation and sinusitis diagnosis (chronic or recurrent acute). In the balloon arm, 92.0% (46/50) of patients did not need a postoperative debridement compared with 26.2% (11/42) of patients in the FESS arm. There was a mean of 0.1±0.6 postoperative debridements per patient in the balloon arm compared with 1.2±1.0 in the FESS arm (p<0.0001). No statistically significant differences were found between balloon dilation and FESS in terms of post‑discharge nausea or duration of over‑the‑counter pain medication. One patient in each arm had revision surgery. Bikhazi et al. (2014) described 12‑month results for 89 of the 92 patients reported by Cutler (2013) who completed 1‑year follow‑up (48 balloon, 41 FESS). Changes in SNOT‑20 scores from baseline remained statistically significant and clinically meaningful in both groups, and confirmed non‑inferiority at 12 months between the 2 interventions on this measure (balloon arm: −1.64±1.06, FESS arm: −1.65±0.94; p<0.0001). In both arms patients reported significant reductions (p<0.0001) in sinusitis episodes at 12 months following surgery compared with the year before (4.2 in the balloon arm, 3.5 in the FESS arm), although the comparison between the 2 was not statistically significant. Overall patency (maxillary ostia) in those with an evaluable CT scan at 12 months was 96.7% in the balloon arm and 98.7% in the FESS arm but this was not statistically significant. Both treatments had positive effects in all the domains of the Work Productivity and Activity Impairment (WPAI) survey, except for FESS in the absenteeism domain (p=0.169). All eligible patients in Chandra et al. (2016) reported longer‑term outcomes at 18 months (n=66) and 24 months (n=25), and included an additional cohort who had been subsequently randomised (a total of 135 patients, 133 patients at 6 months and 130 patients at 12 months). Mean changes in SNOT‑20 scores at 6 and 12 months were statistically significantly lower than baseline and clinically meaningful in both arms in this enlarged cohort (6 months, balloon arm −1.56, FESS arm −1.60; 12 months, balloon arm −1.59, FESS arm −1.60). Mean changes in SNOT‑20 scores were also statistically significantly lower than baseline and clinically meaningful in the patients from the original cohort followed up at 24 months (balloon arm −1.65, FESS arm −1.45). There were no statistically significant differences between the 2 arms. Overall revision rates at 18 months were 2.7% in the balloon arm and 6.9% in the FESS arm (not statistically significant). ## Included studies: others The company and EAC identified a number of observational studies which compared balloon dilation (XprESS or FinESS) with baseline data. The EAC considered them to be lower quality evidence. Symptom improvement data from some of these studies were pooled in a meta‑analysis reported in Chandra et al. (2016). The XprESS Multi‑Sinus Study (Gould et al. 2016) was a single‑arm, prospective observational study which enrolled 82 adults with chronic sinusitis or acute recurrent sinusitis; the method of recruitment was not reported. Patients had to have maxillary sinus disease as a minimum, although patients with additionally affected sinuses (frontal, sphenoid or ethmoid) were also included. The study found a significant and clinically meaningful improvement in the primary outcome, change in mean SNOT‑20 score at 12 months, compared with baseline (−1.57, p<0.0001). At 12 months there were also statistically significant reductions in Rhinosinusitis Symptoms Inventory (RSI) major symptoms score, medication use, absenteeism, and acute sinus infection and sinus‑related physician visits. The authors reported that the procedure was a technical success in 307 of 313 sinuses operated on (98.1%), with only 1 patient needing revision of the procedure at 12 months (1.3%), with no serious device or procedural adverse events. The procedure appeared to be well tolerated (mean pain VAS 2.8±2.2), with a high degree of patient satisfaction (87.8%). The XprESS registry (Brodner et al. 2013) was the first full clinical study of XprESS. This was a prospective observational study that enrolled 175 patients needing treatment of the frontal recess and sphenoid sinus ostium, who had previously been scheduled for FESS. The primary outcome was safety, although effectiveness outcomes were also prespecified. Of the targeted sinuses, 96% (479/497) were successfully accessed and treated with the balloon, including 276 frontal recesses, 131 sphenoid ostia, and 72 maxillary ostia/ethmoid infundibula. In 4 the balloon did not inflate, and in 10 the ostia could not be accessed using XprESS so FESS was used instead. Over 90% (448 of 497) of sinuses were treated using a hybrid procedure of FESS and XprESS. Because these results were not disaggregated, they were not included in the Chandra (2016) meta‑analysis, and the EAC considered them to be of limited relevance. Results were similar to the other observational studies employing standalone balloon dilation only, and included statistically significant reductions at 3 and 12 months in SNOT‑20 score (−1.1), and in medication use, work or school days missed and sinus‑related physician visits in the year following surgery compared with the year before. There was no statistically significant reduction in acute sinus infections reported after the procedure, and no serious adverse events reported. The XprESS Maxillary Pilot Study (Gould et al. 2012) was a single‑arm, prospective observational study involving 21 adults with uncomplicated refractory chronic sinusitis or recurrent acute sinusitis of the maxillary or anterior ethmoid sinuses. All patients had the XprESS procedure under local anaesthesia, and the main outcome was change in SNOT‑20 score from pre‑procedure to up to 6‑months post‑procedure. The study was not peer reviewed. The RELIEF study (Levine et al. 2013) was a single‑arm, prospective observational study involving 74 adult patients with refractory chronic sinusitis or recurrent acute sinusitis of the maxillary and anterior ethmoid sinuses. The primary outcome was quality of life as measured by SNOT‑20; this and most other outcomes were reported at 12 months. All patients had the procedure with FinESS, the predecessor device to XprESS. There was a statistically significant and clinically meaningful reduction in SNOT‑20 score (−1.2) compared with baseline. Statistically significant reductions were also reported in RSI major symptoms, medication use (intranasal corticosteroids, antihistamines, antibiotics), absenteeism, sinus‑related physician visits, and acute sinus infections. The procedure was reported as a technical success in 91.9% of sinuses operated on (124 of 135) with a revision surgery rate of 5.8% (4 of 69 patients). No serious adverse events were reported The BREATHE study was published in 3 papers: Stankiewicz (2011 and 2012) and Cutler (2011). This was the first published study of an Entellus balloon product (FinESS) involving 71 patients with chronic sinusitis of the maxillary or ethmoid sinuses. The study was a single‑arm, prospective study. Follow‑up was 2 years with the primary outcome of quality of life improvement measured using SNOT‑20. There was a statistically significant and clinically meaningful improvement compared with baseline in SNOT‑20 at 1 year (−1.80) and 2 year (−1.86) follow‑up. At 1 year there was also a statistically significant reduction in WPAI survey score and on the Work Limitation Questionnaire (WLQ) compared with baseline. The technical success rate was reported as 97.7% (129 of 132 sinuses). Procedures were well tolerated with a mean pain VAS of 2.7, and 88% of patients were reported to have recovered within 2 days. Patient satisfaction rates were 89% after 1 year and 91.5% after 2 years. After 2 years, 4 of 59 patients (6.8%) needed revision surgery. One patient was reported as having suffered a serious procedure‑related adverse event following balloon dilation (subcutaneous emphysema). The protocol for the FinESS registry study was published on ClinicalTrials.gov but was only provided as an abstract, and has not been subsequently published or peer reviewed. Because the EAC could not appraise this study, and only limited outcomes were reported, it did not consider it further. Data from the FinESS registry did contribute to the meta‑analysis by Chandra et al. (2016). Soler et al. (2016) is a single‑arm, prospective observational study (n=50) expected to be published in 2016. It was provided to the EAC as an abstract that did not allow for critical appraisal, and only limited results were reported as academic in confidence. This was the only study that was reported on children. Although children were included the scope of the decision problem as a subgroup, the EAC understands through discussion with clinical experts that sinus surgery is rarely done in children in England. Because of this, the EAC did not consider the study any further. Chandra et al. (2016) undertook a meta‑analysis of the observational studies (excluding the XprESS registry) and the REMODEL trial to evaluate the clinical effectiveness of Entellus balloon dilation devices in a larger population. Results on SNOT‑20, RSI scores and short‑term outcomes were reported. The authors had access to individual patient data so the EAC could not replicate the meta‑analyses. The authors reported that there was no statistical difference in SNOT‑20 outcomes between studies (REMODEL FESS arm, REMODEL balloon dilation arm or pooled observational studies), measured at 6, 12 and 24 months. There were significant reductions (p<0.0001) from baseline to 12 months in the standalone balloon dilation studies in absenteeism (5.0 days±9.5), homebound because of nasal problems (6.3 days±11.3), number of physician/nurse visits because of nasal problems (4.5±11.5), number of infections of nose/sinuses (3.9±4.5), and number of antibiotic courses (2.9±3.1). Changes in WLQ score over 1 week, 1 month, 3 months, 6 months, 12 months, 18 months and 24 months compared with baseline were presented as a longitudinal graph. There were statistically significant and immediate reductions in several domains, which appeared maximal at 1 month before plateauing over 2 years. Revision rates at 12 months were 1.7% for the FESS arm of the REMODEL trial, 1.4% for the balloon dilation arm of the REMODEL trial and 3.2% for the pooled analysis (p=0.628). However, this analysis was based on a single patient in each of the REMODEL arms. ## Adverse events The company conducted a limited search for adverse events and identified 5 case reports of adverse events with a different balloon technology and 3 that did not specify which device was used). The EAC searched the FDA MAUDE database for Entellus and identified 12 reports, of which 8 involved XprESS. Of the reports, 6 described a cerebral spinal fluid leak in balloon‑only procedures (n=2), balloon with septoplasty (n=2), or hybrid endoscopic sinus surgery procedures (n=2). None noted any long‑term adverse health effects as a consequence. One report was a case of orbital wall damage identified by the company in its clinical evidence submission, which was reported to have had no long‑term adverse effect on the patient's vision. The eighth reported case was a death from massive intracranial bleed, shortly after successful completion of a bilateral maxillary balloon procedure. This was reported by the clinicians involved as unrelated to the device or procedure. ## EAC analysis The EAC considered that the best evidence was from the REMODEL trial. This study design was assessed as being of high methodological quality, and internal validity was generally good. However, the EAC noted concerns about the high initial attrition rates in the FESS arm immediately following randomisation, which may have introduced differences between the characteristics of the 2 arms. The EAC was satisfied that the evidence showed balloon dilation to be non‑inferior to FESS in terms of the primary outcome (SNOT‑20) for up to 2 years post‑procedure. The EAC also judged that balloon dilation was equivalent to FESS in the secondary outcomes measured, such as maintaining ostia patency, reducing future episodes of sinusitis, and improving work and productivity. However, it noted that long‑term outcomes were assessed on small patient numbers. The EAC considered that balloon dilation with XprESS offers advantages over FESS by speeding recovery, reducing postoperative pain and reducing the need for nasal debridement. The observational studies supplemented the evidence from REMODEL and were supportive of its results. However, the EAC noted a number of methodological weaknesses in all the observational studies which led it to conclude that the evidence from these studies was of limited quality to inform the decision problem. Although the studies matched the scope, the EAC was concerned about extrapolating the results from selected patient cohorts enrolled in trials in the US to the wider population of patients in the NHS. The EAC assumed equivalence between the FinESS and XprESS systems but considered there was only weak, indirect evidence to substantiate this assumption ## Committee considerations The committee considered that the evidence from REMODEL demonstrated that balloon dilation (with either XprESS or FinESS) is clinically non‑inferior to FESS in terms of alleviating symptom in patients with uncomplicated chronic sinusitis. The committee considered that although the single‑arm observational studies were of lower quality, the results were consistent with the findings of the REMODEL study. It considered that these studies provide evidence that balloon dilation is effective in improving other clinical outcomes including postoperative debridements, ostial patency, use of analgesic medication, time of recovery, and time taken to return to work. The committee heard from the company that FinESS and XprESS function in the same way once inflated within the sinus ostia. However, it was informed that the trans‑nasal approach used for XprESS allows more sinuses to be treated than the trans‑antral approach used with FinESS. The committee heard from experts that XprESS can be done using local anaesthetic and so allows patients to return to work on the same day. It further heard that balloon dilation reduces postoperative pain, preserves mucosa and bony structures, reduces scarring in the sinuses, and reduces nasal bleeding and the risk of damage to the ethmoidal artery. The committee noted that the REMODEL study excluded patients with severe nasal polyposis, and it was advised by experts that balloon dilation is not suitable in these patients.# NHS considerations # System impact The company presented a number of claimed system benefits for XprESS; see section 2.4 for details. ## Committee considerations The committee accepted expert advice that in the NHS, XprESS is easier than functional endoscopic sinus surgery (FESS) as an outpatient procedure. Its use may increase patient throughput and allow for earlier disease treatment. The committee was advised by experts that adopting XprESS involves a learning curve. Because of this, the procedure should first be done in an operating theatre using general anaesthetic before moving to an outpatient setting. The experts added that there has been resistance to switching to balloon dilatation in UK clinical practice because of the price of the technology and a lack of familiarity with the new technique.# Cost considerations # Cost evidence The company conducted a search of the health economics literature on balloon sinus dilation using XprESS or equivalent systems and functional endoscopic sinus surgery (FESS). This identified 134 papers, 6 of which were included in the company's submission. The external assessment centre (EAC) judged the company's search terms to be appropriate. However, it noted: inconsistencies in the search terms across the databases searched; that the company's submissions did not provide search terms for its searches of the Cochrane database or the NHS Economic Evaluation Database; and it considered that the company's searches would have benefited from the inclusion of a wider range of databases, such as the cost‑effectiveness registry. The EAC re‑ran the company's searches and identified no additional studies. The EAC concluded that none of the economic studies identified was relevant to the decision problem. # Economic model ## Model design The company presented a decision tree model to capture costs and outcomes in the first year following sinus surgery and a Markov model out to 5 years after sinus surgery, applying a 1‑year cycle length. Patients entered the model needing sinus surgery, and could be routed to either FESS or XprESS. The model base case used a theoretical patient with multiple sinuses treated in a single episode of care. The first phase of the decision tree captures differences in treatment costs. The next stage covers the first 3 months following surgery, during which there is sustained recovery or a need for GP visits; either scenario could need readmission to secondary care. Surgical re‑interventions and GP visits are also included from 3 months to 12 months. Irrespective of these outcomes, patients then enter the Markov model out to 5 years which consists of 2 mutually exclusive states, surgery revision or sustained recovery. Surgery revision is an absorbent state, meaning that patients cannot leave it, so it is assumed that patients could have only 1 revision surgery over the study period. Death is not included because it was expected to be very rare over the time horizon modelled. Figures for clinical parameters were obtained from published literature, expert opinion and England and Wales audit data. The company relied heavily on the audit data published by Brown et al. (2003) to determine the base values for FESS. It then used US data reported in Chandra et al. (2016) to determine the relative values for XprESS in relation to FESS. ## Model costs The cost for FESS and XprESS surgery under general anaesthesia was based on staff costs for a nurse and surgeon, bed day costs, theatre time, device and surgical consumable costs. The total cost for a FESS surgery under general anaesthesia (including equipment costs of £300) was calculated to be £2,894. The total cost for XprESS surgery (including device costs of £900) was calculated to be £1,884. The equivalent costs under local anaesthesia were calculated by applying a ratio of 0.631 to the surgical costs under general anaesthesia reported in Zilvetti et al. (2009), providing costs for FESS of £1,936 and for XprESS of £1,520. These costs were also used in the model if the patient had a revision surgery. The company reported a base‑case per‑patient cost of £2,679 for XprESS and £3,981 for FESS, representing an average saving of £1,302 per patient. ## Sensitivity and scenario analyses The company presented one‑way deterministic sensitivity analyses varying the model parameters from their base‑case level by 20%. The parameters with the biggest effect on the level of cost saving were device costs and procedure time for XprESS. The results of these analyses provided a range of cost savings, from £1,044 to £1,559. Scenario analyses were done by changing parameter values for type of anaesthetic (from general only to include local), the percentage of patients having revision surgery each year, procedure time, length of hospital stay, and unit cost of theatre time. None of these altered the direction of the cost saving for XprESS, and at worst reduced it to £367, when a unit cost for theatre time of £6.40 per minute was used. Break‑even analyses were conducted varying the procedure time with XprESS and FESS. The company reported that XprESS was cost neutral when the XprESS procedure time was 80 minutes or cost saving when the FESS procedure time was greater than 41 minutes. # EAC comments on the model The EAC noted the assumptions in the company's model and considered them to be largely appropriate. It did note some important omissions in the model tornado diagram, such as the unit cost of a FESS procedure. The EAC was also unable to replicate results in the tornado diagram for the monthly rate of GP visits beyond 3 months with FESS. The EAC considered the company's analyses of the structural uncertainties to be limited. It judged that it would have been appropriate to run the model assuming that there was no difference in GP visits and readmission in the first 3 months following surgery. ## EAC changes to the model The EAC revised the company's relative risk estimates for revision surgery, based on their limited numbers in the REMODEL study. It judged the estimates for the values up to 12 months provided in the REMODEL trial to be more appropriate than those used by the company. Based on expert opinion and Philpott et al. (2015), the EAC considered that the evidence did not show any difference in revision surgery rates between FESS and XprESS beyond 12 months. Based on expert opinion, the EAC judged the company's base‑case estimate of 0% for the proportion of XprESS procedures done under local anaesthesia to be conservative, and revised it up to 10%. It also revised the estimate for FESS procedures done under local anaesthesia to 2%, noting that this was consistent with the company's scenario analysis. The EAC determined the costs of FESS and XprESS surgery using a bottom‑up approach. In the absence of published data, the EAC consulted experts to determine the duration of surgery for FESS in the patient population eligible for XprESS. Based on their responses, the average procedure times were 42.5 minutes for FESS and 26.7 minutes for XprESS. The FESS figure was consistent with figures quoted in a national audit and a health technology assessment report. The EAC revised the cost of operating time to £13.65 per minute based on data for ENT surgery (2014/15) reported by the Information Services Division Scotland. It also revised the length of stay in hospital following FESS to under 5 hours (0.208 days), and for XprESS to 4.17 hours (0.174 days) based on expert responses. The EAC revised the cost per day in hospital to £370 using a weighted average of 2014/15 NHS reference costs for elective inpatient excess bed days for minor sinus procedures (CA29Z), intermediate sinus procedures (CA28Z), major sinus procedures (CA23Z) and complex sinus procedures (CA26Z). Based on these figures, the revised cost of FESS under general anaesthesia was £657, and the cost of XprESS under general anaesthesia was £428 (not including device cost). The EAC also revised the cost of FESS and XprESS under local anaesthesia in an operating theatre using a similar bottom‑up approach. Using averages based on expert advice, it estimated procedure lengths of 30 minutes for FESS and 31.7 minutes for XprESS, and in‑hospital stays of 3.00 hours for FESS and 2.17 hours for XprESS. Information Services Division Scotland operating theatre costs of £13.65 a minute were used to calculate operation costs. The hospital bed cost of FESS was calculated using the same methodology. The EAC revised the cost of revision surgery for FESS and XprESS by applying weightings to the cost per procedure figures. The weightings applied for FESS were 98% general anaesthetic and 2% local anaesthetic. The weightings applied for XprESS were 90% general anaesthetic and 10% local anaesthetic. This gave a cost per revision surgery for FESS of £653 and for XprESS of £432. The EAC revised the cost of a GP visit based on expert advice, the British National Formulary and data from the Personal Social Services Research Unit. It used a value of £37.00 per GP visit, and added drug prescription costs according to the clinical indication for the visit, leading to the following total costs per visit: blocked nose (£48.91), infection (£38.97 to £39.64), and blocked nose and infection (£50.00). The mean value of these figures produced an estimate of £46.00. The company did not include any training costs for XprESS because it provides training at no extra cost, but the EAC judged that the costs for the staff time spent on training should be included in the model. It concluded that this amounted to 7 hours of a surgeon time at a cost of £106 an hour, leading to a total of £742 per surgeon. Over the duration of the economic model this was estimated to add £5.50 to the cost of each procedure. The EAC used a bottom‑up approach to estimate the unit cost of XprESS done in an outpatient setting. Based on expert advice it used a length of a procedure of 31.7 minutes, and a length of stay in hospital of 2.17 hours. It used NHS reference costs of £370 for a hospital bed day, the Personal Social Services Research Unit for the costs of surgeon time and nurse time, and applied £115 for the costs of gown and a tray to produce a total estimate of £251. The analysis based on the EAC's revised parameters found that XprESS was cost incurring by £330 compared with FESS (average per‑patient costs: XprESS £1,694, FESS £1,364). The EAC conducted univariate analyses on all the model parameters, varying their value by 20%. None of these analyses changed the direction of the results, and XprESS remained cost incurring. The main factors affecting cost were the device cost of XprESS and the unit costs of a FESS and XprESS procedure under general anaesthesia. This was consistent with the company's analysis. ## EAC sensitivity and scenario analyses The EAC conducted a series of univariate sensitivity analyses on the main model parameters. Sensitivity analysis on the length of FESS procedure under general anaesthesia demonstrated that XprESS became cost saving when the duration of FESS exceeded 66.0 minutes, compared with the EAC base case of 42.5 minutes. Analysis on the length of stay in hospital after FESS found that XprESS became cost saving when hospital stay was longer than 1 day. Further analyses showed that length of XprESS procedure under general anaesthesia had to be as low as 0 before XprESS became cost saving, and that no value for length of stay in hospital after XprESS under general anaesthesia changed the direction of the result. Analysis on the unit cost of theatre time demonstrated that XprESS became cost incurring when the unit cost exceeded £34 per minute (£2,040 per hour). Varying the unit cost of hospital stay had very little effect on the results, and the cost would have to reach an unreasonably high level for XprESS to become cost saving The EAC conducted a number of scenario analyses. In the first of these, the EAC used hospital episode statistics data for length of stay, as per the company's model, of 0.97 days. In this scenario, XprESS remained cost incurring by a smaller margin of £136 per patient. The EAC considered a scenario in which XprESS was done in an outpatient setting, without theatre costs. The total procedure cost was £251. The proportion of procedures in an outpatient setting under local anaesthesia was varied between 0% and 100%, and the results showed that XprESS remained cost incurring even at 100%. The EAC also conducted scenario analyses in which: it used a cost ratio of 0.631 between general and local anaesthetic (as used in the company's submission) it used an annual revision rate of 3.5% between years 2 and 5, based on figures reported by Hopkins et al. (2009) the cost of a hospital appointment for debridement of £162 (NHS reference cost, 2014/15) was added to each FESS procedure it used a consistent proportion of 42% for patients visiting the GP in the first 90 days after the procedure for both treatments it varied the rate of revision surgery for XprESS at 2 to 5 years after surgery. In all cases, XprESS remained cost incurring. The EAC considered a scenario that included an extra appointment for debridement after FESS, and in which the rate of XprESS procedures done in an outpatient setting under local anaesthesia was varied. In this scenario, XprESS was cost saving when over 80% of procedures were done in an outpatient setting under local anaesthesia and when every FESS procedure needed a single extra hospital appointment for debridement. The EAC did additional sensitivity analyses on the price of XprESS and FESS consumables. XprESS became cost saving when the price of the device is less than £586 per patient, and the cost of FESS consumables is more than £614 per patient. The EAC did a two‑way sensitivity analysis varying the price of XprESS and the length of a FESS procedure. XprESS was only cost saving when the device cost £800 or less and the FESS procedure takes more than 60 minutes. At prices above £800, the EAC stated that the length of time the FESS procedure would need to take in order for XprESS to be cost saving was increasingly implausible. # Committee considerations The committee was advised that the price of the XprESS device was the main factor influencing the economic model, and thought that this should also be its main consideration in the case for adoption. It heard from experts that the cost of the technology was a barrier to current adoption in the NHS. It heard from the company that the price is negotiable based on the volume of products used. For example, XprESS is available at a lower price of £820 per unit for centres that order 50 or more in a year. The committee considered that the length of procedure with both XprESS and FESS was integral to the outcome of the cost modelling. Expert advice indicated that estimates of procedure length should include the time taken to administer anaesthetic. Experts indicated that the length of the FESS procedure will usually be the composite of the time taken to administer general anaesthetic as well as to undertake the surgery. For XprESS, experts indicated that this will usually be the composite of the time taken to administer and wait for local anaesthesia to take effect as well as performing the balloon dilatation. The committee heard from experts that the greater use of XprESS could change the care pathway by allowing chronic sinusitis to be treated earlier, and potentially avoiding the need for FESS. Patients who have XprESS are also able to return to work on the same day. The committee heard expert advice that these factors may result in additional cost savings that were not considered in the model. The committee carefully considered the plausibility of the EAC scenario in which XprESS is cost saving (that is, when more than 80% of procedures are done in an outpatient setting under local anaesthesia and assuming that every FESS procedure needs an extra appointment for debridement). The committee was advised by experts that patients in the NHS do not usually have a follow‑up debridement appointment after FESS, and so concluded that this scenario is unlikely to be widely applicable. The committee was advised that if XprESS were more widely adopted, many patients currently having FESS could instead have XprESS. The committee considered the cost case for XprESS to be uncertain. It concluded that any cost savings were dependent on the length of the FESS procedure, the cost of the device, and the proportion of XprESS procedures done in an outpatient setting under local anaesthesia. The committee encouraged further research on the resource consequences of using XprESS for treating chronic sinusitis.# Conclusions The committee concluded from the evidence presented that XprESS is a clinically non‑inferior, but less invasive, alternative to functional endoscopic sinus surgery (FESS) in patients with uncomplicated chronic sinusitis. Compared with FESS, it may lead to faster recovery times and carries a lower risk of some complications. The committee concluded that cost savings are plausible, but depend on the device cost of XprESS, how long a FESS procedure takes and the proportion of XprESS procedures that can be done in an outpatient setting using local anaesthetic. For example, XprESS may save £152 per patient if 80% of XprESS treatments are done in an outpatient setting using local anaesthetic, FESS takes 60 minutes and the XprESS device costs £820. The committee considered that XprESS has the potential to treat uncomplicated chronic sinusitis earlier in disease progression than is currently available in the NHS. As such, it may improve quality of life and clinical outcomes, as well as reduce surgical waiting lists.	{'Recommendations': 'The case for adopting the XprESS multi‑sinus dilation system for treating uncomplicated chronic sinusitis after medical treatment has failed is supported by the evidence. Treatment with XprESS leads to a rapid and sustained improvement in chronic symptoms, fewer acute episodes and improved quality of life which is comparable to functional endoscopic sinus surgery (FESS).\n\nXprESS should be considered in patients with uncomplicated chronic sinusitis who do not have severe nasal polyposis. In these patients, XprESS works as well as FESS, is associated with faster recovery times, and can more often be done under local anaesthesia.\n\nCost modelling indicates that XprESS is cost saving compared with FESS when treatment is done using local anaesthetic in an outpatient setting. The estimated saving per patient is £152, assuming that 80% of treatments are done this way, FESS takes 60\xa0minutes and the device cost for XprESS is £820. By adopting this technology, the NHS in England may save around £7.4\xa0million a year by 2020. Estimated savings are mainly achieved through the shift of treatment from operating theatre to outpatient setting.', 'The technology': "# Description of the technology\n\nThe XprESS multi‑sinus dilation system (XprESS, Entellus Medical) is a sterile, single‑use device for treating chronic sinusitis. The system comprises a balloon‑tipped device with a reshapeable end that is inserted through the nose into the maxillary, frontal or sphenoidal sinuses. XprESS also includes an inflation syringe, bending tool and 2\xa0extension lines to provide irrigation. The balloon is manipulated into the bony sinus outflow tracts (ostia) and inflated with saline. This reshapes and opens the ostia by displacing adjacent bone and paranasal sinus structures allowing the sinuses to drain more effectively\n\nThe system is available in 3\xa0variants, XprESS Ultra, LoProfile and Pro, which differ in the dimensions of the suction tip and the balloon diameter and length. All suction tips and balloon lengths are appropriate for treating all sinuses; selection is based on clinician preference. The XprESS device, inflation syringe and bending tool are included in all variants. The Ultra and LoProfile (the version currently sold in the UK) systems also include an integrated PathAssist LED light fibre, which is available as an add‑on for the Pro. XprESS can be used under local anaesthesia, once the surgeon has had sufficient experience of using the device.\n\nAccording to the company's submission XprESS costs £900. The company informed the committee that a reduction to £820\xa0is available for centres that order 50\xa0or more units in a year.\n\nThe claimed benefits of XprESS in the case for adoption presented by the company are:\n\nA minimally invasive alternative to functional endoscopic sinus surgery (FESS), offering equivalent efficacy and minimal acute inflammation while preserving more sinus tissue and mucosa.\n\nReduction in risks associated with general anaesthetic and fewer staff resources needed, because the procedure is done while the patient is awake and under local anaesthesia.\n\nFaster recovery time with less nasal bleeding and a shorter duration of pain medication.\n\nImproved patient comfort and tolerance compared with other balloon technologies because XprESS allows more control of device placement.\n\nEasier to use than other balloon technologies, because XprESS is based on a sinus seeker and no guidewire is needed.\n\nMore accurate cannulation of the maximally ostium.\n\nReduction in theatre time compared with FESS.\n\nReduction in length of stay in hospital.\n\nReduction in duration of prescription pain medication.\n\nReduction in postoperative nasal bleeding visits.\n\nReduction in hospital readmissions.\n\nPotentially fewer patients waiting 18\xa0weeks or longer for ear, nose and throat (ENT) surgery.\n\n# Current management\n\nSinusitis (also known as rhinosinusitis and sinus infection) refers to inflammation (because of infection or irritation) of the mucosal lining of the sinuses. This causes an increase in mucus production and a reduction in mucus drainage if the inflamed swollen mucosa blocks the sinus ostia. Both acute and chronic sinusitis are defined by the presence of nasal blockage or nasal discharge, accompanied by facial pain or a loss of smell. Acute sinusitis refers to an episode of symptoms that resolves within 12\xa0weeks. Recurrent acute sinusitis refers to multiple episodes of acute sinusitis, (usually considered to be 3\xa0or more in a year) that are separated by validated, symptom‑free intervals. Chronic sinusitis refers to an episode of symptoms that lasts more than 12\xa0weeks. Chronic sinusitis may sometimes be accompanied by nasal polyps. Sinusitis may be associated with the extension of inflammation outside the paranasal sinuses and nasal cavity and be accompanied by neurologic, ophthalmologic, or local soft tissue sequelae. Chronic sinusitis is regarded as uncomplicated if none of these are present.\n\nCurrent treatment options for chronic sinusitis include nasal saline irrigation, intranasal corticosteroids, systemic antibiotics or topical drops, and FESS.\n\nNICE's clinical knowledge summary on chronic sinusitis describes measures to relieve symptoms, particularly for acute exacerbations of chronic rhinosinusitis, that include analgesics for pain or fever, occasional intranasal decongestants and intranasal saline irrigation, and warm face packs. Patients should be offered advice about managing associated conditions (such as allergic rhinitis, asthma and dental infections), along with advice on smoking cessation and dental hygiene when appropriate. A short course of antibiotics may be prescribed for acute exacerbations, but longer‑term courses are not recommended without seeking specialist advice. A course of intranasal corticosteroids of up to 3\xa0months may be considered, especially if there is a suspicion of an allergic cause (such as concomitant allergic rhinitis).\n\nA patient should be admitted to hospital if chronic sinusitis is associated with a severe systemic infection, or a serious complication such as orbital or intracranial infection or inflammation. Referral to an ENT specialist should be considered for people with frequent recurrent episodes of acute sinusitis (for example more than 3\xa0episodes requiring antibiotics in a year), unremitting or progressive facial pain (urgent referral for suspected malignancy), or nasal polyps that are causing significant nasal obstruction. Referral to an ENT specialist should also be considered if a person has taken intranasal corticosteroids for 3\xa0months without effect.\n\nFESS is the most common ENT surgery used to treat persistent and severe cases of chronic sinusitis. During FESS, the surgeon uses a magnifying endoscope inserted through the nostrils to identify and remove affected sinus tissue and bone. The aim is to clear the obstructed ostia and flush out infected material, but retain enough healthy tissue for normal nose and sinus function. FESS is usually done under general anaesthesia. Scarring and adhesions can occur as a result of FESS, which may need postoperative removal of tissue, blood and bone (debridement). Other more serious risks occasionally associated with FESS include intraorbital and intracranial complications.\n\nNICE interventional procedure guidance on balloon catheter dilation of paranasal sinus ostia for chronic sinusitis concluded that the current evidence on the procedure's short‑term efficacy is adequate and raised no major safety concerns", 'Clinical evidence': "# Summary of clinical evidence\n\nThe key clinical outcomes presented in the decision problem were:\n\nchange in sinusitis symptoms\n\nnumber of post‑procedure sinusitis episodes needing medication\n\nnumber of postoperative debridements\n\nchange in ostial patency (assessed by endoscopy or CT scan)\n\nnumber and types of sinus treated\n\nlength of hospital stay\n\nprocedure time and theatre/outpatient treatment room time\n\nrate of revision surgery\n\nnumber of sinus‑related follow‑up appointments\n\nrate of readmission\n\nrate and severity of nasal bleeding\n\ndevice‑related adverse events.\n\nThe company conducted a literature search for evidence on XprESS and its predecessor device FinESS, which identified 13\xa0papers describing 9\xa0trials, 7\xa0published and 2\xa0unpublished. The retrieved papers included a meta‑analysis involving 6\xa0of the 11\xa0published studies.\n\nThe external assessment centre (EAC) judged the company's search terms to be appropriate, but could not fully reproduce them because the search strategies were not fully reported. The EAC re‑ran the company's searches and conducted its own search, which identified no further evidence.\n\nThe EAC considered that 1\xa0included study, Eloy et al. (2012), should be excluded from further assessment because the population (patients who had previously had a failed frontal sinustomy) was not consistent with the scope. The EAC therefore assessed 12\xa0publications, which reported on 1\xa0randomised controlled trial and 7\xa0observational studies, 2\xa0of which were unpublished.\n\n## Included studies: REMODEL\n\nThree studies (Cutler et al. 2013, Bikhazi et al. 2014, Chandra at al. 2016) reported on the REMODEL trial, a prospective, multicentre, non‑inferiority, parallel, randomised clinical trial (the methodology is most comprehensively reported in Cutler et al. 2013). The REMODEL trial compared FESS with balloon dilation systems (FinESS and XprESS) in adult patients with uncomplicated chronic sinusitis or recurrent acute sinusitis associated with maxillary sinus disease with or without anterior ethmoid sinus disease. The split between XprESS and FinESS was not reported but the company has indicated it was approximately 50:50. Patients and clinicians were blinded to their allocation. Blinding could not be maintained after treatment allocation, but some post‑surgical assessments were done or audited by independent physicians. Following withdrawals after randomisation, there were 50\xa0patients in the balloon arm and 42\xa0in the FESS arm. A post hoc modified intention‑to‑treat analysis was done. The primary outcome measure was change in chronic sinusitis symptoms as measured by the Sino‑Nasal Outcome Test‑20\xa0(SNOT‑20) scores at 6\xa0months from baseline (pre‑procedure).\n\nCutler et al. (2013) reported outcomes up to 6\xa0months after the procedure. At 1\xa0week, the average change in SNOT‑20\xa0scores in the balloon arm was −1.49\xa0(standard deviation [SD]=0.87), compared with −0.96\xa0(SD=1.12) in the FESS arm. At 1\xa0month, the average change was −1.70\xa0(SD=0.98) for the balloon arm and −1.62\xa0(SD=0.95) for FESS. At 6\xa0months, the change was −1.67\xa0(SD=1.10) for the balloon arm and −1.60\xa0(SD=0.96) for FESS. The changes from baseline were significant (p<0.001) in both groups at all time points, and because the change in score exceeded 0.8, the differences were judged to be clinically meaningful. With the exception of the results at 1\xa0week (p=0.014), there was no statistically significant difference between the SNOT‑20\xa0scores in the balloon dilation and FESS arms. This indicated non‑inferiority of the balloon procedures in terms of symptom improvement, with a potentially significant short‑term effect (at 1\xa0week). The authors also reported significant (p<0.0001) and clinically meaningful improvements in each of the subscales of the SNOT‑20\xa0at 6\xa0months, with no statistically significant differences between the 2\xa0arms. The same results were reported at 6\xa0months for the following subgroups: maxillary only or maxillary and anterior ethmoid; presence or absence of accessory ostia; presence or absence of septal deviation and sinusitis diagnosis (chronic or recurrent acute). In the balloon arm, 92.0% (46/50) of patients did not need a postoperative debridement compared with 26.2% (11/42) of patients in the FESS arm. There was a mean of 0.1±0.6\xa0postoperative debridements per patient in the balloon arm compared with 1.2±1.0\xa0in the FESS arm (p<0.0001). No statistically significant differences were found between balloon dilation and FESS in terms of post‑discharge nausea or duration of over‑the‑counter pain medication. One patient in each arm had revision surgery.\n\nBikhazi et al. (2014) described 12‑month results for 89\xa0of the 92\xa0patients reported by Cutler (2013) who completed 1‑year follow‑up (48\xa0balloon, 41\xa0FESS). Changes in SNOT‑20\xa0scores from baseline remained statistically significant and clinically meaningful in both groups, and confirmed non‑inferiority at 12\xa0months between the 2\xa0interventions on this measure (balloon arm: −1.64±1.06, FESS arm: −1.65±0.94; p<0.0001). In both arms patients reported significant reductions (p<0.0001) in sinusitis episodes at 12\xa0months following surgery compared with the year before (4.2\xa0in the balloon arm, 3.5\xa0in the FESS arm), although the comparison between the 2\xa0was not statistically significant. Overall patency (maxillary ostia) in those with an evaluable CT scan at 12\xa0months was 96.7% in the balloon arm and 98.7% in the FESS arm but this was not statistically significant. Both treatments had positive effects in all the domains of the Work Productivity and Activity Impairment (WPAI) survey, except for FESS in the absenteeism domain (p=0.169).\n\nAll eligible patients in Chandra et al. (2016) reported longer‑term outcomes at 18\xa0months (n=66) and 24\xa0months (n=25), and included an additional cohort who had been subsequently randomised (a total of 135\xa0patients, 133\xa0patients at 6\xa0months and 130\xa0patients at 12\xa0months). Mean changes in SNOT‑20\xa0scores at 6\xa0and 12\xa0months were statistically significantly lower than baseline and clinically meaningful in both arms in this enlarged cohort (6\xa0months, balloon arm −1.56, FESS arm −1.60; 12\xa0months, balloon arm −1.59, FESS arm −1.60). Mean changes in SNOT‑20\xa0scores were also statistically significantly lower than baseline and clinically meaningful in the patients from the original cohort followed up at 24\xa0months (balloon arm −1.65, FESS arm −1.45). There were no statistically significant differences between the 2\xa0arms. Overall revision rates at 18\xa0months were 2.7% in the balloon arm and 6.9% in the FESS arm (not statistically significant).\n\n## Included studies: others\n\nThe company and EAC identified a number of observational studies which compared balloon dilation (XprESS or FinESS) with baseline data. The EAC considered them to be lower quality evidence. Symptom improvement data from some of these studies were pooled in a meta‑analysis reported in Chandra et al. (2016).\n\nThe XprESS Multi‑Sinus Study (Gould et al. 2016) was a single‑arm, prospective observational study which enrolled 82\xa0adults with chronic sinusitis or acute recurrent sinusitis; the method of recruitment was not reported. Patients had to have maxillary sinus disease as a minimum, although patients with additionally affected sinuses (frontal, sphenoid or ethmoid) were also included. The study found a significant and clinically meaningful improvement in the primary outcome, change in mean SNOT‑20\xa0score at 12\xa0months, compared with baseline (−1.57, p<0.0001). At 12\xa0months there were also statistically significant reductions in Rhinosinusitis Symptoms Inventory (RSI) major symptoms score, medication use, absenteeism, and acute sinus infection and sinus‑related physician visits. The authors reported that the procedure was a technical success in 307\xa0of 313\xa0sinuses operated on (98.1%), with only 1\xa0patient needing revision of the procedure at 12\xa0months (1.3%), with no serious device or procedural adverse events. The procedure appeared to be well tolerated (mean pain VAS 2.8±2.2), with a high degree of patient satisfaction (87.8%).\n\nThe XprESS registry (Brodner et al. 2013) was the first full clinical study of XprESS. This was a prospective observational study that enrolled 175\xa0patients needing treatment of the frontal recess and sphenoid sinus ostium, who had previously been scheduled for FESS. The primary outcome was safety, although effectiveness outcomes were also prespecified. Of the targeted sinuses, 96% (479/497) were successfully accessed and treated with the balloon, including 276\xa0frontal recesses, 131\xa0sphenoid ostia, and 72\xa0maxillary ostia/ethmoid infundibula. In 4\xa0the balloon did not inflate, and in 10\xa0the ostia could not be accessed using XprESS so FESS was used instead. Over 90% (448\xa0of 497) of sinuses were treated using a hybrid procedure of FESS and XprESS. Because these results were not disaggregated, they were not included in the Chandra (2016) meta‑analysis, and the EAC considered them to be of limited relevance. Results were similar to the other observational studies employing standalone balloon dilation only, and included statistically significant reductions at 3\xa0and 12\xa0months in SNOT‑20\xa0score (−1.1), and in medication use, work or school days missed and sinus‑related physician visits in the year following surgery compared with the year before. There was no statistically significant reduction in acute sinus infections reported after the procedure, and no serious adverse events reported.\n\nThe XprESS Maxillary Pilot Study (Gould et al. 2012) was a single‑arm, prospective observational study involving 21\xa0adults with uncomplicated refractory chronic sinusitis or recurrent acute sinusitis of the maxillary or anterior ethmoid sinuses. All patients had the XprESS procedure under local anaesthesia, and the main outcome was change in SNOT‑20\xa0score from pre‑procedure to up to 6‑months post‑procedure. The study was not peer reviewed.\n\nThe RELIEF study (Levine et al. 2013) was a single‑arm, prospective observational study involving 74\xa0adult patients with refractory chronic sinusitis or recurrent acute sinusitis of the maxillary and anterior ethmoid sinuses. The primary outcome was quality of life as measured by SNOT‑20; this and most other outcomes were reported at 12\xa0months. All patients had the procedure with FinESS, the predecessor device to XprESS. There was a statistically significant and clinically meaningful reduction in SNOT‑20\xa0score (−1.2) compared with baseline. Statistically significant reductions were also reported in RSI major symptoms, medication use (intranasal corticosteroids, antihistamines, antibiotics), absenteeism, sinus‑related physician visits, and acute sinus infections. The procedure was reported as a technical success in 91.9% of sinuses operated on (124\xa0of 135) with a revision surgery rate of 5.8% (4\xa0of 69\xa0patients). No serious adverse events were reported\n\nThe BREATHE study was published in 3\xa0papers: Stankiewicz (2011\xa0and 2012) and Cutler (2011). This was the first published study of an Entellus balloon product (FinESS) involving 71\xa0patients with chronic sinusitis of the maxillary or ethmoid sinuses. The study was a single‑arm, prospective study. Follow‑up was 2\xa0years with the primary outcome of quality of life improvement measured using SNOT‑20. There was a statistically significant and clinically meaningful improvement compared with baseline in SNOT‑20\xa0at 1\xa0year (−1.80) and 2\xa0year (−1.86) follow‑up. At 1\xa0year there was also a statistically significant reduction in WPAI survey score and on the Work Limitation Questionnaire (WLQ) compared with baseline. The technical success rate was reported as 97.7% (129\xa0of 132\xa0sinuses). Procedures were well tolerated with a mean pain VAS of 2.7, and 88% of patients were reported to have recovered within 2\xa0days. Patient satisfaction rates were 89% after 1\xa0year and 91.5% after 2\xa0years. After 2\xa0years, 4\xa0of 59\xa0patients (6.8%) needed revision surgery. One patient was reported as having suffered a serious procedure‑related adverse event following balloon dilation (subcutaneous emphysema).\n\nThe protocol for the FinESS registry study was published on ClinicalTrials.gov but was only provided as an abstract, and has not been subsequently published or peer reviewed. Because the EAC could not appraise this study, and only limited outcomes were reported, it did not consider it further. Data from the FinESS registry did contribute to the meta‑analysis by Chandra et al. (2016).\n\nSoler et al. (2016) is a single‑arm, prospective observational study (n=50) expected to be published in 2016. It was provided to the EAC as an abstract that did not allow for critical appraisal, and only limited results were reported as academic in confidence. This was the only study that was reported on children. Although children were included the scope of the decision problem as a subgroup, the EAC understands through discussion with clinical experts that sinus surgery is rarely done in children in England. Because of this, the EAC did not consider the study any further.\n\nChandra et al. (2016) undertook a meta‑analysis of the observational studies (excluding the XprESS registry) and the REMODEL trial to evaluate the clinical effectiveness of Entellus balloon dilation devices in a larger population. Results on SNOT‑20, RSI scores and short‑term outcomes were reported. The authors had access to individual patient data so the EAC could not replicate the meta‑analyses. The authors reported that there was no statistical difference in SNOT‑20\xa0outcomes between studies (REMODEL FESS arm, REMODEL balloon dilation arm or pooled observational studies), measured at 6, 12\xa0and 24\xa0months. There were significant reductions (p<0.0001) from baseline to 12\xa0months in the standalone balloon dilation studies in absenteeism (5.0\xa0days±9.5), homebound because of nasal problems (6.3\xa0days±11.3), number of physician/nurse visits because of nasal problems (4.5±11.5), number of infections of nose/sinuses (3.9±4.5), and number of antibiotic courses (2.9±3.1).\n\nChanges in WLQ score over 1\xa0week, 1\xa0month, 3\xa0months, 6\xa0months, 12\xa0months, 18\xa0months and 24\xa0months compared with baseline were presented as a longitudinal graph. There were statistically significant and immediate reductions in several domains, which appeared maximal at 1\xa0month before plateauing over 2\xa0years. Revision rates at 12\xa0months were 1.7% for the FESS arm of the REMODEL trial, 1.4% for the balloon dilation arm of the REMODEL trial and 3.2% for the pooled analysis (p=0.628). However, this analysis was based on a single patient in each of the REMODEL arms.\n\n## Adverse events\n\nThe company conducted a limited search for adverse events and identified 5\xa0case reports of adverse events with a different balloon technology and 3\xa0that did not specify which device was used). The EAC searched the FDA MAUDE database for Entellus and identified 12\xa0reports, of which 8\xa0involved XprESS. Of the reports, 6\xa0described a cerebral spinal fluid leak in balloon‑only procedures (n=2), balloon with septoplasty (n=2), or hybrid endoscopic sinus surgery procedures (n=2). None noted any long‑term adverse health effects as a consequence. One report was a case of orbital wall damage identified by the company in its clinical evidence submission, which was reported to have had no long‑term adverse effect on the patient's vision. The eighth reported case was a death from massive intracranial bleed, shortly after successful completion of a bilateral maxillary balloon procedure. This was reported by the clinicians involved as unrelated to the device or procedure.\n\n## EAC analysis\n\nThe EAC considered that the best evidence was from the REMODEL trial. This study design was assessed as being of high methodological quality, and internal validity was generally good. However, the EAC noted concerns about the high initial attrition rates in the FESS arm immediately following randomisation, which may have introduced differences between the characteristics of the 2\xa0arms. The EAC was satisfied that the evidence showed balloon dilation to be non‑inferior to FESS in terms of the primary outcome (SNOT‑20) for up to 2\xa0years post‑procedure. The EAC also judged that balloon dilation was equivalent to FESS in the secondary outcomes measured, such as maintaining ostia patency, reducing future episodes of sinusitis, and improving work and productivity. However, it noted that long‑term outcomes were assessed on small patient numbers. The EAC considered that balloon dilation with XprESS offers advantages over FESS by speeding recovery, reducing postoperative pain and reducing the need for nasal debridement.\n\nThe observational studies supplemented the evidence from REMODEL and were supportive of its results. However, the EAC noted a number of methodological weaknesses in all the observational studies which led it to conclude that the evidence from these studies was of limited quality to inform the decision problem. Although the studies matched the scope, the EAC was concerned about extrapolating the results from selected patient cohorts enrolled in trials in the US to the wider population of patients in the NHS. The EAC assumed equivalence between the FinESS and XprESS systems but considered there was only weak, indirect evidence to substantiate this assumption\n\n## Committee considerations\n\nThe committee considered that the evidence from REMODEL demonstrated that balloon dilation (with either XprESS or FinESS) is clinically non‑inferior to FESS in terms of alleviating symptom in patients with uncomplicated chronic sinusitis.\n\nThe committee considered that although the single‑arm observational studies were of lower quality, the results were consistent with the findings of the REMODEL study. It considered that these studies provide evidence that balloon dilation is effective in improving other clinical outcomes including postoperative debridements, ostial patency, use of analgesic medication, time of recovery, and time taken to return to work.\n\nThe committee heard from the company that FinESS and XprESS function in the same way once inflated within the sinus ostia. However, it was informed that the trans‑nasal approach used for XprESS allows more sinuses to be treated than the trans‑antral approach used with FinESS.\n\nThe committee heard from experts that XprESS can be done using local anaesthetic and so allows patients to return to work on the same day. It further heard that balloon dilation reduces postoperative pain, preserves mucosa and bony structures, reduces scarring in the sinuses, and reduces nasal bleeding and the risk of damage to the ethmoidal artery.\n\nThe committee noted that the REMODEL study excluded patients with severe nasal polyposis, and it was advised by experts that balloon dilation is not suitable in these patients.", 'NHS considerations': '# System impact\n\nThe company presented a number of claimed system benefits for XprESS; see section 2.4\xa0for details.\n\n## Committee considerations\n\nThe committee accepted expert advice that in the NHS, XprESS is easier than functional endoscopic sinus surgery (FESS) as an outpatient procedure. Its use may increase patient throughput and allow for earlier disease treatment.\n\nThe committee was advised by experts that adopting XprESS involves a learning curve. Because of this, the procedure should first be done in an operating theatre using general anaesthetic before moving to an outpatient setting. The experts added that there has been resistance to switching to balloon dilatation in UK clinical practice because of the price of the technology and a lack of familiarity with the new technique.', 'Cost considerations': "# Cost evidence\n\nThe company conducted a search of the health economics literature on balloon sinus dilation using XprESS or equivalent systems and functional endoscopic sinus surgery (FESS). This identified 134\xa0papers, 6\xa0of which were included in the company's submission.\n\nThe external assessment centre (EAC) judged the company's search terms to be appropriate. However, it noted: inconsistencies in the search terms across the databases searched; that the company's submissions did not provide search terms for its searches of the Cochrane database or the NHS Economic Evaluation Database; and it considered that the company's searches would have benefited from the inclusion of a wider range of databases, such as the cost‑effectiveness registry. The EAC re‑ran the company's searches and identified no additional studies. The EAC concluded that none of the economic studies identified was relevant to the decision problem.\n\n# Economic model\n\n## Model design\n\nThe company presented a decision tree model to capture costs and outcomes in the first year following sinus surgery and a Markov model out to 5\xa0years after sinus surgery, applying a 1‑year cycle length.\n\nPatients entered the model needing sinus surgery, and could be routed to either FESS or XprESS. The model base case used a theoretical patient with multiple sinuses treated in a single episode of care. The first phase of the decision tree captures differences in treatment costs. The next stage covers the first 3\xa0months following surgery, during which there is sustained recovery or a need for GP visits; either scenario could need readmission to secondary care. Surgical re‑interventions and GP visits are also included from 3\xa0months to 12\xa0months. Irrespective of these outcomes, patients then enter the Markov model out to 5\xa0years which consists of 2\xa0mutually exclusive states, surgery revision or sustained recovery. Surgery revision is an absorbent state, meaning that patients cannot leave it, so it is assumed that patients could have only 1\xa0revision surgery over the study period. Death is not included because it was expected to be very rare over the time horizon modelled.\n\nFigures for clinical parameters were obtained from published literature, expert opinion and England and Wales audit data. The company relied heavily on the audit data published by Brown et al. (2003) to determine the base values for FESS. It then used US data reported in Chandra et al. (2016) to determine the relative values for XprESS in relation to FESS.\n\n## Model costs\n\nThe cost for FESS and XprESS surgery under general anaesthesia was based on staff costs for a nurse and surgeon, bed day costs, theatre time, device and surgical consumable costs. The total cost for a FESS surgery under general anaesthesia (including equipment costs of £300) was calculated to be £2,894. The total cost for XprESS surgery (including device costs of £900) was calculated to be £1,884. The equivalent costs under local anaesthesia were calculated by applying a ratio of 0.631\xa0to the surgical costs under general anaesthesia reported in Zilvetti et al. (2009), providing costs for FESS of £1,936\xa0and for XprESS of £1,520. These costs were also used in the model if the patient had a revision surgery.\n\nThe company reported a base‑case per‑patient cost of £2,679\xa0for XprESS and £3,981\xa0for FESS, representing an average saving of £1,302\xa0per patient.\n\n## Sensitivity and scenario analyses\n\nThe company presented one‑way deterministic sensitivity analyses varying the model parameters from their base‑case level by 20%. The parameters with the biggest effect on the level of cost saving were device costs and procedure time for XprESS. The results of these analyses provided a range of cost savings, from £1,044\xa0to £1,559.\n\nScenario analyses were done by changing parameter values for type of anaesthetic (from general only to include local), the percentage of patients having revision surgery each year, procedure time, length of hospital stay, and unit cost of theatre time. None of these altered the direction of the cost saving for XprESS, and at worst reduced it to £367, when a unit cost for theatre time of £6.40\xa0per minute was used.\n\nBreak‑even analyses were conducted varying the procedure time with XprESS and FESS. The company reported that XprESS was cost neutral when the XprESS procedure time was 80\xa0minutes or cost saving when the FESS procedure time was greater than 41\xa0minutes.\n\n# EAC comments on the model\n\nThe EAC noted the assumptions in the company's model and considered them to be largely appropriate. It did note some important omissions in the model tornado diagram, such as the unit cost of a FESS procedure. The EAC was also unable to replicate results in the tornado diagram for the monthly rate of GP visits beyond 3\xa0months with FESS. The EAC considered the company's analyses of the structural uncertainties to be limited. It judged that it would have been appropriate to run the model assuming that there was no difference in GP visits and readmission in the first 3\xa0months following surgery.\n\n## EAC changes to the model\n\nThe EAC revised the company's relative risk estimates for revision surgery, based on their limited numbers in the REMODEL study. It judged the estimates for the values up to 12\xa0months provided in the REMODEL trial to be more appropriate than those used by the company. Based on expert opinion and Philpott et al. (2015), the EAC considered that the evidence did not show any difference in revision surgery rates between FESS and XprESS beyond 12\xa0months.\n\nBased on expert opinion, the EAC judged the company's base‑case estimate of 0% for the proportion of XprESS procedures done under local anaesthesia to be conservative, and revised it up to 10%. It also revised the estimate for FESS procedures done under local anaesthesia to 2%, noting that this was consistent with the company's scenario analysis.\n\nThe EAC determined the costs of FESS and XprESS surgery using a bottom‑up approach. In the absence of published data, the EAC consulted experts to determine the duration of surgery for FESS in the patient population eligible for XprESS. Based on their responses, the average procedure times were 42.5\xa0minutes for FESS and 26.7\xa0minutes for XprESS. The FESS figure was consistent with figures quoted in a national audit and a health technology assessment report. The EAC revised the cost of operating time to £13.65\xa0per minute based on data for ENT surgery (2014/15) reported by the Information Services Division Scotland. It also revised the length of stay in hospital following FESS to under 5\xa0hours (0.208\xa0days), and for XprESS to 4.17\xa0hours (0.174\xa0days) based on expert responses. The EAC revised the cost per day in hospital to £370\xa0using a weighted average of 2014/15\xa0NHS reference costs for elective inpatient excess bed days for minor sinus procedures (CA29Z), intermediate sinus procedures (CA28Z), major sinus procedures (CA23Z) and complex sinus procedures (CA26Z). Based on these figures, the revised cost of FESS under general anaesthesia was £657, and the cost of XprESS under general anaesthesia was £428\xa0(not including device cost).\n\nThe EAC also revised the cost of FESS and XprESS under local anaesthesia in an operating theatre using a similar bottom‑up approach. Using averages based on expert advice, it estimated procedure lengths of 30\xa0minutes for FESS and 31.7\xa0minutes for XprESS, and in‑hospital stays of 3.00\xa0hours for FESS and 2.17\xa0hours for XprESS. Information Services Division Scotland operating theatre costs of £13.65\xa0a minute were used to calculate operation costs. The hospital bed cost of FESS was calculated using the same methodology.\n\nThe EAC revised the cost of revision surgery for FESS and XprESS by applying weightings to the cost per procedure figures. The weightings applied for FESS were 98% general anaesthetic and 2% local anaesthetic. The weightings applied for XprESS were 90% general anaesthetic and 10% local anaesthetic. This gave a cost per revision surgery for FESS of £653\xa0and for XprESS of £432.\n\nThe EAC revised the cost of a GP visit based on expert advice, the British National Formulary and data from the Personal Social Services Research Unit. It used a value of £37.00\xa0per GP visit, and added drug prescription costs according to the clinical indication for the visit, leading to the following total costs per visit: blocked nose (£48.91), infection (£38.97\xa0to £39.64), and blocked nose and infection (£50.00). The mean value of these figures produced an estimate of £46.00.\n\nThe company did not include any training costs for XprESS because it provides training at no extra cost, but the EAC judged that the costs for the staff time spent on training should be included in the model. It concluded that this amounted to 7\xa0hours of a surgeon time at a cost of £106\xa0an hour, leading to a total of £742\xa0per surgeon. Over the duration of the economic model this was estimated to add £5.50\xa0to the cost of each procedure.\n\nThe EAC used a bottom‑up approach to estimate the unit cost of XprESS done in an outpatient setting. Based on expert advice it used a length of a procedure of 31.7\xa0minutes, and a length of stay in hospital of 2.17\xa0hours. It used NHS reference costs of £370\xa0for a hospital bed day, the Personal Social Services Research Unit for the costs of surgeon time and nurse time, and applied £115\xa0for the costs of gown and a tray to produce a total estimate of £251.\n\nThe analysis based on the EAC's revised parameters found that XprESS was cost incurring by £330\xa0compared with FESS (average per‑patient costs: XprESS £1,694, FESS £1,364). The EAC conducted univariate analyses on all the model parameters, varying their value by 20%. None of these analyses changed the direction of the results, and XprESS remained cost incurring. The main factors affecting cost were the device cost of XprESS and the unit costs of a FESS and XprESS procedure under general anaesthesia. This was consistent with the company's analysis.\n\n## EAC sensitivity and scenario analyses\n\nThe EAC conducted a series of univariate sensitivity analyses on the main model parameters. Sensitivity analysis on the length of FESS procedure under general anaesthesia demonstrated that XprESS became cost saving when the duration of FESS exceeded 66.0\xa0minutes, compared with the EAC base case of 42.5\xa0minutes. Analysis on the length of stay in hospital after FESS found that XprESS became cost saving when hospital stay was longer than 1\xa0day. Further analyses showed that length of XprESS procedure under general anaesthesia had to be as low as 0\xa0before XprESS became cost saving, and that no value for length of stay in hospital after XprESS under general anaesthesia changed the direction of the result. Analysis on the unit cost of theatre time demonstrated that XprESS became cost incurring when the unit cost exceeded £34\xa0per minute (£2,040\xa0per hour). Varying the unit cost of hospital stay had very little effect on the results, and the cost would have to reach an unreasonably high level for XprESS to become cost saving\n\nThe EAC conducted a number of scenario analyses. In the first of these, the EAC used hospital episode statistics data for length of stay, as per the company's model, of 0.97\xa0days. In this scenario, XprESS remained cost incurring by a smaller margin of £136\xa0per patient. The EAC considered a scenario in which XprESS was done in an outpatient setting, without theatre costs. The total procedure cost was £251. The proportion of procedures in an outpatient setting under local anaesthesia was varied between 0% and 100%, and the results showed that XprESS remained cost incurring even at 100%. The EAC also conducted scenario analyses in which:\n\nit used a cost ratio of 0.631\xa0between general and local anaesthetic (as used in the company's submission)\n\nit used an annual revision rate of 3.5% between years 2\xa0and 5, based on figures reported by Hopkins et al. (2009)\n\nthe cost of a hospital appointment for debridement of £162\xa0(NHS reference cost, 2014/15) was added to each FESS procedure\n\nit used a consistent proportion of 42% for patients visiting the GP in the first 90\xa0days after the procedure for both treatments\n\nit varied the rate of revision surgery for XprESS at 2\xa0to 5\xa0years after surgery.\n\nIn all cases, XprESS remained cost incurring. The EAC considered a scenario that included an extra appointment for debridement after FESS, and in which the rate of XprESS procedures done in an outpatient setting under local anaesthesia was varied. In this scenario, XprESS was cost saving when over 80% of procedures were done in an outpatient setting under local anaesthesia and when every FESS procedure needed a single extra hospital appointment for debridement.\n\nThe EAC did additional sensitivity analyses on the price of XprESS and FESS consumables. XprESS became cost saving when the price of the device is less than £586\xa0per patient, and the cost of FESS consumables is more than £614\xa0per patient. The EAC did a two‑way sensitivity analysis varying the price of XprESS and the length of a FESS procedure. XprESS was only cost saving when the device cost £800\xa0or less and the FESS procedure takes more than 60\xa0minutes. At prices above £800, the EAC stated that the length of time the FESS procedure would need to take in order for XprESS to be cost saving was increasingly implausible.\n\n# Committee considerations\n\nThe committee was advised that the price of the XprESS device was the main factor influencing the economic model, and thought that this should also be its main consideration in the case for adoption. It heard from experts that the cost of the technology was a barrier to current adoption in the NHS. It heard from the company that the price is negotiable based on the volume of products used. For example, XprESS is available at a lower price of £820\xa0per unit for centres that order 50\xa0or more in a year.\n\nThe committee considered that the length of procedure with both XprESS and FESS was integral to the outcome of the cost modelling. Expert advice indicated that estimates of procedure length should include the time taken to administer anaesthetic. Experts indicated that the length of the FESS procedure will usually be the composite of the time taken to administer general anaesthetic as well as to undertake the surgery. For XprESS, experts indicated that this will usually be the composite of the time taken to administer and wait for local anaesthesia to take effect as well as performing the balloon dilatation.\n\nThe committee heard from experts that the greater use of XprESS could change the care pathway by allowing chronic sinusitis to be treated earlier, and potentially avoiding the need for FESS. Patients who have XprESS are also able to return to work on the same day. The committee heard expert advice that these factors may result in additional cost savings that were not considered in the model.\n\nThe committee carefully considered the plausibility of the EAC scenario in which XprESS is cost saving (that is, when more than 80% of procedures are done in an outpatient setting under local anaesthesia and assuming that every FESS procedure needs an extra appointment for debridement). The committee was advised by experts that patients in the NHS do not usually have a follow‑up debridement appointment after FESS, and so concluded that this scenario is unlikely to be widely applicable.\n\nThe committee was advised that if XprESS were more widely adopted, many patients currently having FESS could instead have XprESS.\n\nThe committee considered the cost case for XprESS to be uncertain. It concluded that any cost savings were dependent on the length of the FESS procedure, the cost of the device, and the proportion of XprESS procedures done in an outpatient setting under local anaesthesia. The committee encouraged further research on the resource consequences of using XprESS for treating chronic sinusitis.", 'Conclusions': 'The committee concluded from the evidence presented that XprESS is a clinically non‑inferior, but less invasive, alternative to functional endoscopic sinus surgery (FESS) in patients with uncomplicated chronic sinusitis. Compared with FESS, it may lead to faster recovery times and carries a lower risk of some complications.\n\nThe committee concluded that cost savings are plausible, but depend on the device cost of XprESS, how long a FESS procedure takes and the proportion of XprESS procedures that can be done in an outpatient setting using local anaesthetic. For example, XprESS may save £152\xa0per patient if 80% of XprESS treatments are done in an outpatient setting using local anaesthetic, FESS takes 60\xa0minutes and the XprESS device costs £820.\n\nThe committee considered that XprESS has the potential to treat uncomplicated chronic sinusitis earlier in disease progression than is currently available in the NHS. As such, it may improve quality of life and clinical outcomes, as well as reduce surgical waiting lists.'}	https://www.nice.org.uk/guidance/mtg30	Evidence-based recommendations on the XprESS multi-sinus dilation system for treating chronic sinusitis after medical treatment has failed.
9d70130811adf683815395cac980c517119af1c2	nice	HIV testing: increasing uptake among people who may have undiagnosed HIV	HIV testing: increasing uptake among people who may have undiagnosed HIV This guideline covers how to increase the uptake of HIV testing in primary and secondary care, specialist sexual health services and the community. It describes how to plan and deliver services that are tailored to the local prevalence of HIV, promote awareness of HIV testing and increase opportunities to offer testing to people who may have undiagnosed HIV. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Offering and recommending HIV testing in different settings ## Local prevalence Offer and recommend HIV testing based on local prevalence and how it affects different groups and communities. Use Public Health England's sexual and reproductive health profiles and local data to establish: local HIV prevalence, including whether an area has high prevalence or extremely high prevalence rates of HIV in different groups and communities. ## Specialist sexual health services (including genitourinary medicine) Offer and recommend an HIV test to everyone who attends for testing or treatment. Ensure both fourth-generation serological testing and point-of-care testing (POCT) are available. ## Secondary and emergency care Routinely offer and recommend an HIV test to everyone attending their first appointment (followed by repeat testing in line with recommendation 1.2.6) at drug dependency programmes, termination of pregnancy services, and services providing treatment for: hepatitis B hepatitis C lymphoma tuberculosis. Antenatal HIV testing is covered by the UK National Screening Committee and is outside the remit of this guideline. In all areas, offer and recommend HIV testing on admission to hospital, including emergency departments, to everyone who has not previously been diagnosed with HIV and who: has symptoms that may indicate HIV or HIV is part of the differential diagnosis (for example, infectious mononucleosis-like syndrome), in line with HIV in Europe's HIV in indicator conditions is known to be from a country or group with a high rate of HIV infection (see recommendation 1.1.1) if male, discloses that they have sex with men, or is known to have sex with men, and has not had an HIV test in the previous year is a trans woman who has sex with men and has not had an HIV test in the previous year reports sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV discloses high-risk sexual practices, for example the practice known as 'chemsex' is diagnosed with, or requests testing for, a sexually transmitted infection reports a history of injecting drug use discloses that they are the sexual partner of someone known to be HIV positive, or of someone at high risk of HIV (for example, female sexual contacts of men who have sex with men). In areas of high and extremely high prevalence, also offer and recommend HIV testing on admission to hospital, including emergency departments, to everyone who has not previously been diagnosed with HIV and who is undergoing blood tests for another reason. Additionally, in areas of extremely high prevalence, offer and recommend HIV testing on admission to hospital, including emergency departments, to everyone who has not previously been diagnosed with HIV. ## GP surgeries In all areas, offer and recommend HIV testing to everyone who has not previously been diagnosed with HIV and who: has symptoms that may indicate HIV or HIV is part of the differential diagnosis (for example, infectious mononucleosis-like syndrome), in line with HIV in Europe's HIV in indicator conditions is known to be from a country or group with a high rate of HIV infection (see recommendation 1.1.1) if male, discloses that they have sex with men, or is known to have sex with men, and has not had an HIV test in the previous year is a trans woman who has sex with men and has not had an HIV test in the previous year reports sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV discloses high-risk sexual practices, for example the practice known as 'chemsex' is diagnosed with, or requests testing for, a sexually transmitted infection reports a history of injecting drug use discloses that they are the sexual partner of someone known to be HIV positive, or of someone at high risk of HIV (for example, female sexual contacts of men who have sex with men). In areas of high and extremely high prevalence, also offer and recommend HIV testing to everyone who has not previously been diagnosed with HIV and who: registers with the practice or is undergoing blood tests for another reason and has not had an HIV test in the previous year. Additionally, in areas of extremely high prevalence, consider HIV testing opportunistically at each consultation (whether bloods are being taken for another reason or not), based on clinical judgement. Offer and recommend repeat testing to the people in recommendations 1.1.8 and 1.1.9 in line with recommendation 1.2.6. If a venous blood sample is declined, offer a less invasive form of specimen collection, such as a mouth swab or finger-prick. ## Prisons At reception, recommend HIV testing to everyone who has not previously been diagnosed with HIV. For more information, see NICE's guideline on physical health of people in prison. ## Community settings Providers of community testing services (including outreach and detached services) should set up testing services in: areas with a high prevalence or extremely high prevalence of HIV, using venues such as pharmacies or voluntary sector premises (for example, those of faith groups) venues where there may be high-risk sexual behaviour, for example public sex environments, or where people at high risk may gather, such as nightclubs, saunas and festivals. Recognise that not all community settings are appropriate for providing testing services, for example because tests should be undertaken in a secluded or private area (in line with British HIV Association guidelines). Ensure that people who decline or are unable to consent to a test are offered information about other local testing services, including self-sampling. See making decisions using NICE guidelines for more information about consent. Ensure that lay testers delivering tests are competent to do so and have access to clinical advice and supervision. # Increasing opportunities for HIV testing ## Point-of-care testing Offer point-of-care testing (POCT) in situations where it would be difficult to give people their results, for example if they are unwilling to leave contact details. Explain to people at the time of their test about the specificity and sensitivity of the POCT being used and that confirmatory serological testing will be needed if the test is reactive. ## Self-sampling Consider providing self-sampling kits to people in groups and communities with a high rate of HIV (see recommendation 1.1.1). Ensure that people know how to get their own self-sampling kits, for example, by providing details of websites to order them from. ## Repeat testing When giving results to people who have tested negative but who may have been exposed to HIV recently, recommend that they have another test once they are past the window period. Recommend annual testing to people in groups or communities with a high rate of HIV, and more frequently if they are at high risk of exposure (in line with Public Health England's HIV in the UK: situation report 2015). For example: men who have sex with men should have HIV and sexually transmitted infection tests at least annually, and every 3 months if they are having unprotected sex with new or casual partners black African men and women should have an HIV test and regular HIV and sexually transmitted infection tests if having unprotected sex with new or casual partners. Consider the following interventions to promote repeat testing: Call–recall methods using letters or other media, such as text messages or email, to remind people to return for annual testing. Electronic reminders in health records systems to prompt healthcare professionals to identify the need for testing during appointments and offer it if needed. ## People who decline a test If people choose not to take up the immediate offer of a test, tell them about nearby testing services and how to get self-sampling kits. ## Partners of people who test positive Partners of people who test positive should receive a prompt offer and recommendation of an HIV test through partner notification procedures. # Promoting awareness and uptake of HIV testing ## Content Materials and interventions for promoting awareness and increasing the uptake of HIV testing should be designed in line with NICE's guidelines on behaviour change: general approaches, behaviour change: individual approaches and patient experience in adult NHS services. Provide promotional material tailored to the needs of local communities. It should: provide information about HIV infection and transmission, the benefits of HIV testing and the availability of treatment emphasise that early diagnosis is not only a route into treatment and a way to avoid complications and reduce serious illness in the future, but also reduces onward transmission detail how and where to access local HIV testing services, including services offering POCT and self-sampling, and sexual health clinics dispel common misconceptions about HIV diagnosis and treatment present testing as a responsible act by focusing on trigger points, such as the beginning of a new relationship or change of sexual partner, or on the benefits of knowing one's HIV status address the needs of non-English-speaking groups, for example, through translated and culturally sensitive information. Ensure interventions to increase the uptake of HIV testing are hosted by, or advertised at, venues that encourage or facilitate sex (such as some saunas, websites, or geospatial apps that allow people to find sexual partners in their proximity). This should be in addition to general community-based HIV health promotion. Promote HIV testing when delivering sexual health promotion and HIV prevention interventions. This can be carried out in person (using printed publications such as leaflets, booklets and posters) or through electronic media. Ensure health promotion material aims to reduce the stigma associated with HIV testing and living with HIV, both among communities and among healthcare professionals. Ensure health promotion material provides up-to-date information on the different kinds of HIV tests available. It should also highlight the significantly reduced window period resulting from the introduction of newer tests such as fourth-generation serological testing. ## Methods of raising awareness Use or modify existing resources, for example TV screens in GP surgeries, to help raise awareness of where HIV testing (including self-sampling) is available (for content see recommendations 1.3.1 and 1.3.2). Consider a range of approaches to promote HIV testing, including: local media campaigns digital media, such as educational videos social media, such as online social networking, dating and geospatial apps printed materials, such as information leaflets. # Reducing barriers to HIV testing Advertise HIV testing in settings that offer it (for example, using posters in GP surgeries) and make people aware that healthcare professionals welcome the opportunity to discuss HIV testing. Staff offering HIV tests should: Emphasise that the tests are confidential. If people remain concerned about confidentiality, explain that they can visit a sexual health clinic anonymously. Be able to discuss HIV symptoms and the implications of a positive or a negative test. Be familiar with existing referral pathways so that people who test positive receive prompt and appropriate support. Provide appropriate information to people who test negative, including details of where to get free condoms and how to access local behavioural and preventive interventions. Recognise and be sensitive to the cultural issues facing different groups (for example, some groups or communities may be less used to preventive health services and advice, or may fear isolation and social exclusion if they test positive for HIV). Be able to challenge stigmas and dispel misconceptions surrounding HIV and HIV testing and be sensitive to people's needs. Be able to recognise the symptoms that may signify primary HIV infection or illnesses that often coexist with HIV. In such cases, they should be able to offer and recommend an HIV test. Ensure practitioners delivering HIV tests (including those delivering outreach POCT) have clear referral pathways available for people with both positive and negative test results, including to sexual health services, behavioural and health promotion services, HIV services and confirmatory serological testing, if needed. These pathways should ensure the following: People who test positive are seen by an HIV specialist preferably within 48 hours, certainly within 2 weeks of receiving the result (in line with UK national guidelines for HIV testing). They should also be given information about their diagnosis and local support groups. Practitioners in the voluntary or statutory sector can refer people from HIV prevention and health promotion services into services that offer HIV testing and vice versa. # Terms used in this guideline ## Chemsex This term is commonly used to describe sex between men that occurs under the influence of drugs taken immediately before and/or during the sexual session. The drugs most commonly associated with chemsex are crystal methamphetamine, GHB/GBL, mephedrone and, to a lesser extent, cocaine and ketamine. ## Extremely high prevalence Local authorities with a diagnosed HIV prevalence of 5 or more per 1,000 people aged 15 to 59 years (based on modelling of diagnosed HIV prevalence distribution in local authorities in England; see Public Health England's sexual and reproductive health profiles). ## Fourth-generation serological testing Fourth-generation tests detect HIV antibodies and p24 antigen simultaneously. This means they have the advantage of reducing the time between infection and testing HIV positive to about 1 month. ## High prevalence Local authorities with a diagnosed HIV prevalence of between 2 and 5 per 1,000 people aged 15 to 59 years (based on modelling of diagnosed HIV prevalence distribution in local authorities in England; see Public Health England's sexual and reproductive health profiles). ## Lay tester A non-clinical practitioner who has been trained to carry out HIV tests. ## Point-of-care testing Point-of-care tests (POCT) or 'rapid' tests are a common way to test for HIV. They are easy to use when an alternative to venepuncture is preferable, for example outside conventional healthcare settings and if it is important to avoid a delay in obtaining a result. However, they have reduced specificity and sensitivity compared with fourth-generation laboratory tests. This means there will be false positives, particularly in areas with lower HIV prevalence, and all positive results need to be confirmed by serological tests. ## Public sex environments Public sex environments are public areas where people go to engage in consensual sexual contact (both same sex and opposite sex). ## Self-sampling Self-sampling HIV kits allow people to collect their own sample of blood or saliva and send it by post for testing. They usually receive negative results by text message. ## Self-testing Self-testing kits allow people to perform their own HIV test in a place of their own choosing and get an immediate result (typically within 15 to 20 minutes). ## Window period The window period is the time between potential exposure to HIV infection and when a test will give an accurate result. The window period is 1 month for a fourth-generation test and 3 months for older tests.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline and are: The need to address misconceptions about HIV testing and treatment, for example: the cost of HIV treatment life expectancy following a positive diagnosis (particular emphasis is needed on the benefits of early diagnosis for outcomes including life expectancy). The need to reduce the stigma (real or perceived) associated with HIV testing and living with HIV, both among communities with a high or extremely high prevalence of HIV and among healthcare professionals. The need to take local patterns of HIV into account when planning how to deliver services. Services should be tailored to the needs of the population, including whether an area has high prevalence or extremely high prevalence of HIV.# Context In 2014, an estimated 103,700 people (69,200 men and 34,400 women) in the UK were living with HIV. The overall HIV prevalence was 1.9 per 1,000 people aged 15 and over (Public Health England's HIV in the UK). Although there are significant pockets of HIV in other populations and communities, the most significant burden of HIV continues to be borne by men who have sex with men and by black Africans. An estimated 45,000 men living with HIV in the UK in 2014 had acquired their infection through sex with other men, an increase from 43,000 in 2013. One in 20 men aged 15 to 44 who have sex with men is estimated to be living with HIV. A recent increase in HIV testing coverage among men attending sexual health clinics is likely to be the reason for an increase in new diagnoses and a decline in undiagnosed infections: about 6,500 men who have sex with men were unaware of their infection in 2014, compared with 8,500 in 2010 ('HIV in the UK'). Almost 1 in 1,000 heterosexual people aged 15 to 44 in the UK is estimated to be living with HIV. Prevalence is higher in black African heterosexual women (1 in 22) and men (1 in 56), who together form the second largest group affected by HIV. Late diagnosis remains a significant problem in heterosexual people: in 2014, 55% were newly diagnosed at a late stage of infection (just over half of whom were black African) ('HIV in the UK'). Overall, 17% of people estimated to have HIV are unaware they are infected and so are at risk of passing it on. More people living outside London are unaware of their HIV infection (24%) compared with those in London (12%) ('HIV in the UK'). In 2013, in response to the international AIDS epidemic, UNAIDS launched a new target known as '90-90-90' (UNAIDS's 90-90-90: An ambitious treatment target to help end the AIDS epidemic). By 2020: % of all people living with HIV will know their HIV status % of all people with diagnosed HIV infection will receive sustained antiretroviral therapy % of all people receiving antiretroviral therapy will have viral suppression. In 2011, NICE published guidelines PH33 and PH34, which aimed to increase the uptake of HIV testing in black Africans living in the UK and in men who have sex with men. In 2014, experts reviewed the evidence and agreed that the guidelines should be updated to reflect changes in the way HIV testing is delivered (following the legalisation of self-sampling and self-testing kits) and to reflect the normalisation of HIV testing across health services.# The committee's discussion Evidence statement numbers are given in square brackets and refer to the summaries of evidence contained within the reviews that were conducted to support the development of this guideline. For an explanation of the evidence statement numbering, see the evidence reviews section. # Background ## Updating the previous guidelines The committee discussed the recommendations and considerations in the 2 guidelines being updated (NICE guidelines PH33 and PH34), and considered the view of the experts in the review decision. The committee agreed that the previous recommendations were still pertinent but they needed some updating to better reflect current practice. The committee removed or amended parts of the recommendations that it agreed were outdated. For more information, see update information. The committee concluded that many of the recommendations from the previous guidelines were aimed at a broader population than men who have sex with men, and black Africans. For the more specific recommendations, the committee agreed it would be appropriate to broaden them to apply to any population with a high rate of HIV. The committee recognised that men who have sex with men, and black Africans are still the most high-risk groups for HIV in the UK and this is reflected in the guideline (recommendation 1.2.6). An additional benefit of broadening the recommendations to apply to everyone with undiagnosed HIV is that it should help to normalise HIV testing so that it is not seen differently from any other blood test. For more information on the relevance of this guideline for other groups, see the equality impact assessment. ## HIV testing and HIV screening The committee discussed the distinction between testing and screening. It was reminded that recommending screening programmes is outside NICE's role. It was aware that HIV screening in antenatal settings is currently recommended by the UK National Screening Committee and has a very high uptake. It also discussed the differences between opt-in and opt-out approaches to testing, that is whether people are asked if they want an HIV test or they are told they will be tested for HIV unless they specifically ask not to be. It agreed that it was important to make sure people understand that HIV testing is voluntary and to give everyone the opportunity to opt out of a test. The committee discussed that HIV testing may not always be routinely undertaken among people who have conditions that might indicate HIV infection. For this reason, it agreed that it is important for national guidelines to recommend HIV testing when diagnosing or treating conditions that may indicate HIV infection (see HIV in Europe's guidance on HIV in indicator conditions). ## Other guidelines The committee agreed that the British HIV Association's UK national guidelines for HIV testing are the most up-to-date HIV guidelines available in the UK and are also accredited by NICE, so they remain in the recommendations. The only exception relates to indicator conditions, for which more up-to-date guidance is available from HIV in Europe's guidance on HIV in indicator conditions. Although this guideline has not been accredited by NICE, the committee agreed it was a useful and authoritative source of information to give people who are offering HIV testing. ## High prevalence and extremely high prevalence of HIV The committee discussed the meaning of 'high prevalence'. NICE guidelines PH33 and PH34 used the definition given by Public Health England of 2 in 1,000 people. However, as more people are being diagnosed with HIV and treated, and because they are living longer, the background prevalence of HIV is rising and the overall UK prevalence in 2014 was 1.9 per 1,000. The committee was aware that during the development of this guideline, Public Health England carried out a new analysis of 2014 data on diagnosed HIV prevalence distribution in local authorities in England. Based on this analysis, groups and communities at high prevalence of diagnosed HIV can be defined as follows: High prevalence: local authorities with a diagnosed HIV prevalence of between 2 and 5 per 1,000 people aged 15 to 59 years. Extremely high prevalence: local authorities with a diagnosed HIV prevalence of 5 or more per 1,000 people aged 15 to 59 years. When this is applied to national late HIV diagnosis data, it shows that two-thirds of late HIV diagnoses occur in high-prevalence and extremely-high-prevalence local authorities. This means that if this guideline is successfully applied in high- and extremely-high-prevalence areas, it could potentially affect two-thirds of late diagnoses nationally. The committee agreed that the definitions of high prevalence and extremely high prevalence were useful, and it incorporated them into the recommendations. The committee also agreed it was important for areas to find out their diagnosed prevalence, as well as that of surrounding areas (recommendation 1.1.1). This allows them to adapt their strategy for HIV testing using the recommendations in this guideline. These data are available from Public Health England's sexual and reproductive health profiles. Additionally, the committee was aware that local data are often available to supplement national data from Public Health England, and that local data may be more up to date and provide more granular detail about local groups and populations with a high rate of HIV. ## Evidence statements not used to make recommendations The committee did not make recommendations for all of the evidence statements. This was mainly because it did not believe, based on the evidence, that an intervention was effective; or it agreed that the intervention may not be applicable in the UK. For details of the evidence statements not used to make recommendations, see the evidence reviews section. # Sections 1.1 and 1.2 The discussion below explains how we made recommendations in: section 1.1 on offering and recommending HIV testing in different settings section 1.2 on increasing opportunities for HIV testing. ## Current practice The committee discussed the appropriateness of different settings for offering HIV testing. It noted the role the voluntary sector plays in HIV testing, particularly in terms of increasing its acceptability among some subpopulations. In terms of healthcare settings, it acknowledged that previous evidence for PH33 and PH34 had shown that both primary and secondary care were suitable settings to offer and recommend HIV tests. The committee did not feel it was appropriate to recommend promoting HIV testing in any particular setting more than others, so it made recommendations for all settings, using HIV prevalence to determine the intensity of interventions. The committee noted that there is pressure on healthcare professionals' time during appointments. Some kinds of HIV tests might take too long – for example, a GP would not be able to perform point-of-care testing (POCT) during a 10-minute appointment in addition to the main consultation. However, another healthcare practitioner in the practice, for example a practice nurse, might be able to offer this test. The committee considered that the uptake of HIV testing was generally high when testing was offered but that staff are often reluctant to offer and recommend a test. The committee felt it was particularly important that practitioners who are reluctant to offer tests more widely should know about this. ## Evidence for effectiveness The committee discussed criteria for offering testing in secondary care, emergency care and GP surgeries based on the identified HIV prevalence of the area (recommendations 1.1.5 to 1.1.10). It agreed that further opportunities to maximise HIV testing should be pursued in areas with a high prevalence of HIV. This could include testing someone who has not previously been diagnosed with HIV when they are having blood tests on admission to hospital, or when they register with a GP practice (recommendations 1.1.6 and 1.1.9). In high- and extremely-high-prevalence areas, having a blood test for another reason provides an opportunity for an HIV test with little resource impact (just the cost of the test). The committee also agreed that when new patients register with a GP surgery their overall health is assessed and this is an efficient opportunity to promote HIV testing. The committee felt it was important not to miss opportunities to offer testing opportunistically in areas of extremely high prevalence (recommendations 1.1.7 and 1.1.10). This could include offering testing to everyone who has not previously been diagnosed with HIV, when they are admitted to hospital, or to people attending GP appointments. However, the committee also noted the importance of using clinical judgement before offering an opportunistic test in general practice (recommendation 1.1.10). For example, a GP might decide not to offer a test during a consultation if the person is distressed or upset or has recently been tested. On balance, recognising the practical implications of introducing opportunistic testing in GP practices as well as the potential resource impact, the committee made a weaker 'consider' recommendation for GP surgeries (recommendation 1.1.10). This means that the recommendations place a stronger onus on hospitals to deliver testing in extremely-high-prevalence areas, compared with GP surgeries. The committee agreed this was justifiable because testing in acute settings is likely to be cheaper than in GP surgeries, and most people being admitted to hospital have blood taken for other reasons (recommendations 1.1.6 and 1.1.7). The committee also discussed the effectiveness of offering testing to people who present to health services with conditions that might indicate HIV. The effectiveness of this depends to some extent on the accuracy of the list of indicator conditions used. The committee agreed that defining a list of indicator conditions was outside the scope of this guideline. However, it agreed that HIV in Europe's guidance on HIV in indicator conditions from was sufficiently evidence-based to inform recommendations 1.1.5 and 1.1.8 and to be a useful supplement to the guideline. The committee noted stakeholder comments about the importance of testing in prisons. Little evidence was identified on the effectiveness of interventions to provide HIV testing in custodial settings, although 2 studies looked at the timing of HIV tests in prisons . Despite the lack of evidence, the committee agreed that prisons were a high-prevalence environment for HIV and other blood-borne viruses and that health services in prisons would be expected to recommend testing to people in line with the approach used in GP surgeries. It was also clear that the committee had a duty to promote equality through its guidelines, and a recommendation for people in prison would support this. The committee saw evidence to suggest that uptake of HIV testing was higher if tests were offered within 24 hours of reception into prison . It was aware of the national guidance in Public Health England's improving testing rates for blood-borne viruses in prisons and other secure settings, which indicates that testing should happen within 72 hours of reception, and inferred that, if combined with other tests for blood-borne viruses, HIV testing would have a lower cost impact. It was mindful that there is a NICE guideline on physical health of people in prison. On balance, it felt that the evidence was strong enough to recommend that HIV testing should be recommended at prison reception. The committee discussed the range of settings where HIV testing could be offered, especially less invasive tests. It noted the importance of offering testing to people in places they would normally go, but was also aware that there could be a potential stigma associated with this (for example, because they might not want to be seen by other members of their community). The committee discussed faith settings as an example of a setting where HIV testing could be offered. However, it acknowledged that not all faith settings would be appropriate or faith groups willing to participate. The committee discussed the distinction between self-sampling and self-testing. No evidence was found on self-testing so it did not include this in the recommendations. The committee discussed self-sampling and agreed that although there was limited evidence currently, it showed great promise, especially as a way to engage people who are less likely to present at services. However, given the paucity of the evidence, the committee decided that it was only able to make a 'consider' recommendation (making decisions using NICE guidelines explains how we use words to show the strength, or certainty, of our recommendations). The committee recognised that not all community settings are appropriate for providing self-sampling kits and agreed it was important to consult stakeholders when setting up self-sampling services. The committee agreed there were likely to be economies of scale and that some local authorities might get better value for money by commissioning online self-sampling services such as the one currently provided by Public Health England . The committee noted the importance of timely partner tracing and notification, not only for the purposes of offering an HIV test, but if the sexual contact was recent then providing post-exposure prophylaxis promptly could reduce the risk of infection. The committee discussed the frequency of HIV testing and agreed that repeat testing should be promoted to people in higher-risk groups. It discussed evidence for the effectiveness of different systems to promote repeat testing, such as call–recall methods and electronic reminders. The committee agreed that systems like these should be implemented wherever possible. It noted that the evidence suggested that electronic reminders that cannot be dismissed without completing a query box were more effective than reminders that could be clicked off. However the evidence was not sufficient to support this as a recommendation and overall the committee agreed it would be too onerous . ## Evidence for cost effectiveness The committee noted that late diagnosis of HIV is substantially more costly than early diagnosis, because of the costs of inpatient admission and treatment. The committee was aware that prompt diagnosis of HIV would be cost saving per person, and there could be further cost savings through averting transmission (recommendation 1.2.9). The committee agreed that HIV testing is most cost effective when the cost per positive test is lowest. The committee noted that the cost of an HIV test is incurred for each person tested and therefore the cost per positive test result decreases when either the cost of the HIV test decreases, or the HIV prevalence in a population increases. The committee noted that the review of cost effectiveness identified mixed evidence as to whether it is more cost effective to test everyone for HIV, or to target certain groups. The studies identified considered the general population in the UK or the US and compared various strategies for testing everyone or only those who disclosed risk factors that identified them as a higher-risk group. Differences in populations, strategies, inputs, cost perspectives and model structure presented difficulties in comparing and interpreting the results. The committee was limited in how it could use this evidence in making recommendations. The committee discussed that the additional cost of testing for HIV for a person already undergoing blood tests was likely to be low. The committee felt that in an areas of high and extremely high prevalence, offering HIV testing to everyone undergoing blood tests for another reason would be cost effective, because of the low incremental cost and high HIV prevalence (recommendations 1.1.6, 1.1.9). The committee discussed that HIV testing for everyone admitted to hospital would incur an additional cost, but that this would be cost effective in areas of extremely high prevalence (recommendation 1.1.7) given the likelihood of bloods being taken for other reasons. The committee discussed that HIV testing for everyone attending a GP surgery would incur an additional cost, but that opportunistic testing would be cost effective in areas of extremely high prevalence (recommendation 1.1.10). In other settings or areas of lower prevalence, the committee felt that targeting specific groups was more likely to be cost effective: that is, it would result in the lowest cost per positive test (recommendations 1.1.5, 1.1.8, 1.2.6). The committee noted an analysis of pilot projects for HIV testing in hospitals, primary care and community settings and for self-sampling, which found variation in cost per positive test. It concluded that no single setting was likely to offer the greatest value for money. The committee recommended setting up community testing in high- and extremely high-prevalence areas in addition to testing in hospitals and primary care (recommendation 1.1.14). The same analysis found that the cost per test of self-sampling was comparable to the cost per test in other settings, and so could represent a cost-effective method of diagnosing HIV (recommendations 1.1.16, 1.2.3, 1.2.4, 1.2.8). ## Resource impact and implementation issues When discussing testing in GP surgeries and emergency departments (section 1.1), the committee discussed the resource impact of the recommendations. It felt that making testing routine for all attendees in GP surgeries and emergency settings could have a substantial resource impact and could only be justified in areas of extremely high prevalence. However, the committee agreed that opportunistic testing for everyone having a blood test in these settings in extremely-high- and high-prevalence areas represents best practice, although it was mindful of the resource implications. The committee also considered the potential resource impact of self-sampling. An expert told the committee that self-sampling was likely to cost the same as traditional testing approaches involving healthcare professionals. It may also be an effective approach in harder to reach subgroups at risk, and could have potential to reduce late diagnosis in these groups. This could reduce the health and social care costs associated with late diagnosis . The committee discussed further the role that primary care professionals (particularly GPs) could have in opportunistically offering and recommending HIV testing to a subpopulation of people at risk who are difficult to reach through methods described in recommendations 1.1.8 and 1.1.9. It discussed promoting opportunistic testing at every consultation in extremely-high-prevalence areas as a way of promoting testing to this subpopulation. The committee agreed that HIV testing for everyone attending a GP surgery would incur an additional cost. The proportion of HIV tests conducted in GP surgeries was estimated to be 3.8%. The committee reasoned that if 3.8% of all people aged 15 to 59 in areas of extremely high prevalence who do not have an HIV diagnosis had an HIV test in their GP surgery, the estimated cost would be between £2 million and £4 million depending on the cost used for GP time and laboratory costs. The committee noted that, given current HIV testing practice, this was a highly unlikely scenario and therefore the resource impact of the recommendation is likely to be much smaller. Notwithstanding, given the annual treatment costs for HIV, the life expectancy of somebody living with HIV and the potential reduction in transmission due to treatment, the committee agreed that opportunistic GP testing was good value. # Sections 1.3 and 1.4 The discussion below explains how we made recommendations in: section 1.3 on promoting awareness and uptake of HIV testing section 1.4 on reducing barriers to HIV testing. ## Evidence for effectiveness There was some evidence of effectiveness for media campaigns, educational videos, online social networking and information leaflets in raising awareness of HIV testing. The committee agreed that different methods of awareness raising are effective for different groups and that a range of methods should be recommended . The committee discussed the evidence from 1 study on the effectiveness of motivational interviewing for increasing uptake of HIV testing . The committee felt that there was not enough evidence from the study to recommend this as an intervention but that referring to NICE's guidelines on behaviour change would cover this type of approach (recommendation 1.3.1). The committee noted that evidence suggested computerised interviews and risk assessments were unlikely to be effective at increasing uptake of HIV testing in people who may have undiagnosed HIV. However, it did not think the evidence was strong enough to recommend that they should not be used. . There was evidence suggesting that financial incentives are effective at increasing uptake of HIV testing . However, the committee noted a lack of evidence from UK healthcare settings. Without stronger evidence of effectiveness in the UK, the potentially significant resource impact of the intervention could not be justified. ## Evidence for cost effectiveness and resource impact The committee noted that awareness raising was a core element of any health promotion and it deemed the resource impact of the new recommendations to be minimal. The intention behind the new recommendations was to bring the principles in line with current technologies and modes of delivery of messages. # Evidence reviews Details of the evidence discussed are in evidence reviews, reports and papers from experts in the area. The evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from. ## Evidence statements from 2011 guidelines Evidence statement number E1.1 indicates that the linked statement is numbered 1.1 in review 1 for PH33, 'Review of effectiveness and cost effectiveness: increasing the uptake of HIV testing to reduce undiagnosed infection and prevent transmission among black African communities living in England'. Q1 indicates that the linked statement is numbered 1 in review 2 for PH33, 'Increasing the uptake of HIV testing to reduce undiagnosed infection and prevent transmission among black African communities living in England – barriers to HIV testing'. ES1 indicates that the linked statement is numbered 1 in the review for PH34 'Preventing and reducing HIV transmission among men who have sex with men'. The expert report 'Time to test for HIV: expanded healthcare and community HIV testing in England. Interim report' was also used to inform the original recommendations in PH33 and PH34. ## Evidence statements from 2016 reviews ES1a.1 indicates that the linked statement is numbered 1 in review 1a for this guideline. ES1b.1 indicates that the linked statement is numbered 1 in review 1b for this guideline. ES1c.1 indicates that the linked statement is numbered 1 in review 1c for this guideline. ES2.1 indicates that the linked statement is numbered 1 in review 2 for this guideline. EP1 indicates that expert paper 'Targeted testing based on indicator conditions' is linked to a recommendation. EP2 indicates that expert paper 'HIV testing in the UK and summary of current UK practice' is linked to a recommendation. If a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). : EP2; IDE : E3.5b, ES4 2016: ES1b.14, ES2.3 : E3.5c 2016: ES1b.12; ES1c.1; IDE : E3.5b, ES4 2016: ES1b.13, ES1c.7, ES2.1; EP1 : ES4, Q6.1 2016: ES1c.4, ES1c.5; IDE : ES4, Q6.1 2016: ES1c.4, ES1c.5; IDE : ES4, Q6.1 2016: ES1c.4, ES1c.5; IDE : Q6.2, Q6.3 2016: ES1c.5, ES2.1; IDE : Q6.2, Q6.3 2016: ES1c.5, ES2.1; IDE : Q6.2, Q6.3 2016: ES1c.5, ES2.1; IDE : ES4; IDE : ES15 2016: ES1b.15; IDE : ES1b14; IDE : Q6.2, ES1, ES14, ES15, ES2.3; IDE : ES14, ES15; IDE : Q1.3, ES18, ES2.2; EP2 IDE : E3.5c, Q6.3 2016: ES1b.16, ES1c.1; IDE IDE : Q5.3, ES1 2016: ES1b.17, ES2.4; EP2; IDE : IDE : E3.5b, ES4, ES7 2016: ES1c.6; IDE : ES4; IDE : ES1b.18; IDE : EP2; IDE : IDE : ES13; IDE : E3.3, E3.4, Q1.2, Q1.3, Q4.2, Q4.3, Q5.1, ES3, ES13; IDE : ES3, ES13; IDE : ES13 2016: ES1a.6; IDE : Q.3, ES10, ES13, ES18, ES2.2; IDE : ES10, ES13; IDE : E3.2, ES3, ES13 2016: ES1a.1, ES1a.2, ES1a.6, ES1a.7, ES1a.8, ES1a.9, ES1a.10 : E3.2, ES3, ES13 2016: ES1a.1, ES1a.2, ES1a.6, ES1a.7, ES1a.8, ES1a.9, ES1a.10 : ES1a.6; IDE : E3.5c, E3.6, E3.7a, E3.7b, Q1.3, Q5.4, Q7.4, ES18 2016: ES1b.20, ES2.2 : Q5.1; IDE The following new 2016 evidence statements were not used to make recommendations: ES1a.3, ES1a.4, ES1a.5, ES1b.13, ES1b.19, ES1b.20, ES1b.21, ES1b.22, ES1c.2, ES1c.3, ES1c.7 # Gaps in the evidence The committee's assessment of the evidence on HIV testing identified a number of gaps. These gaps are set out below. . Interventions to increase awareness of the benefits of HIV testing and details of local testing services among people who have not been diagnosed with HIV, particularly: -ne-to-one and group-based information provision -pportunistic information provision use of social media mass media campaigns. (Source ER1) . Interventions to increase awareness of the indicators for, and the benefits of, HIV testing among practitioners who should offer testing or refer people for testing. (Source ER1) . Increasing the range of settings where tests can be carried out, particularly in community and outreach settings. (Source ER1) . Changes in service delivery to increase the uptake of HIV testing, for example, increasing the number of tests offered; changing opening times and appointment systems; and changing confidentiality policies. (Source ER1) . The impact of lay testers recommending or offering an HIV test. (Source ER1) . The effectiveness of self-testing for HIV and self-sampling for an HIV test. (Source ER1) . Interventions to assess whether indicator condition-targeted testing is effective compared with routine testing. (Source ER1) . Interventions to increase uptake of HIV testing among people who have an illness that may indicate HIV infection. (Source ER1) . Attitudes towards HIV testing among people who may have undiagnosed HIV, and service providers (that is, whether or not there is any stigma associated with HIV tests). (Source ER2) . Barriers to HIV testing for people who may have undiagnosed HIV (for example, people who do not speak English as a first language) and service providers. (Source ER2) . Appropriate settings for delivering HIV testing, for example custodial settings or faith settings. (Source ER1) . Appropriate definition of 'high prevalence' in the UK context, especially in terms of cost effectiveness. (Source committee discussion)# Recommendations for research The guideline committee has made the following recommendations for research. # Interventions to improve the acceptability and uptake of HIV testing among people at higher risk What interventions would be effective and cost effective among people at higher risk in the UK to increase uptake of HIV testing among people who may have undiagnosed HIV? ## Why this is important Improving the acceptability of HIV testing and increasing the uptake of HIV testing will reduce the pool of undiagnosed infection, improve outcomes for those affected (because of earlier diagnosis) and reduce onward transmission, particularly in some high-risk populations. There is a lack of evidence among some groups in the UK, such as people in prison, trans women and people accessing services through community and outreach settings. # Supporting healthcare professionals to offer HIV tests What interventions are effective and cost effective to increase the likelihood of healthcare professionals offering and recommending an HIV test and of its subsequent uptake? ## Why this is important Evidence suggests that the uptake of HIV testing is high among people who are offered and recommended a test. However, healthcare professionals often do not offer or recommend HIV tests in situations in which guidelines suggest it would be appropriate to do so. Research exploring interventions to promote the offer of HIV testing among a variety of test providers would inform future iterations of the guideline. Most of the evidence on increasing the uptake of HIV testing came from the USA, often from settings that do not exist in the UK, for example veterans' health clinics. Given the lack of UK-based evidence, it is also important to ascertain how applicable this research is to cultural and healthcare contexts in the UK. # Self-sampling and self-testing How effective are self-sampling and self-testing in terms of accuracy of sampling, ability to reach different groups, test completion, receipt of results and subsequent care-seeking behaviour? ## Why this is important Self-sampling and self-testing are relatively new modalities in the UK and limited evidence exists about their effectiveness and cost effectiveness. # Indicator conditions What is the UK prevalence of HIV in various indicator conditions, and how effective are interventions using indicator condition-targeted testing compared with other testing strategies? ## Why this is important There is a lack of evidence on the effectiveness of using indicator conditions to target HIV testing, an approach that may improve detection rates. Also, because it is targeted, there may be economies of scale, for example, HIV testing could be commissioned in clinics that treat people with indicator conditions. # Cost utility What is the cost utility of increasing the offer or uptake of HIV testing in different settings, for different types of tests, using different strategies (for example opt-in or opt-out approaches) and in areas and groups with different background prevalence? ## Why this is important There is no UK evidence to enable commissioners and service providers to plan the most cost-effective services for their local communities.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Offering and recommending HIV testing in different settings\n\n## Local prevalence\n\nOffer and recommend HIV testing based on local prevalence and how it affects different groups and communities. Use Public Health England's sexual and reproductive health profiles and local data to establish:\n\nlocal HIV prevalence, including whether an area has high prevalence or extremely high prevalence\n\nrates of HIV in different groups and communities. [new 2016]\n\n## Specialist sexual health services (including genitourinary medicine)\n\nOffer and recommend an HIV test to everyone who attends for testing or treatment. [2011, amended 2016]\n\nEnsure both fourth-generation serological testing and point-of-care testing (POCT) are available. [2011, amended 2016]\n\n## Secondary and emergency care\n\nRoutinely offer and recommend an HIV test to everyone attending their first appointment (followed by repeat testing in line with recommendation 1.2.6) at drug dependency programmes, termination of pregnancy services, and services providing treatment for:\n\nhepatitis B\n\nhepatitis C\n\nlymphoma\n\ntuberculosis. Antenatal HIV testing is covered by the UK National Screening Committee and is outside the remit of this guideline. [2011, amended 2016]\n\nIn all areas, offer and recommend HIV testing on admission to hospital, including emergency departments, to everyone who has not previously been diagnosed with HIV and who:\n\nhas symptoms that may indicate HIV or HIV is part of the differential diagnosis (for example, infectious mononucleosis-like syndrome), in line with HIV in Europe's HIV in indicator conditions\n\nis known to be from a country or group with a high rate of HIV infection (see recommendation 1.1.1)\n\nif male, discloses that they have sex with men, or is known to have sex with men, and has not had an HIV test in the previous year\n\nis a trans woman who has sex with men and has not had an HIV test in the previous year\n\nreports sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV\n\ndiscloses high-risk sexual practices, for example the practice known as 'chemsex'\n\nis diagnosed with, or requests testing for, a sexually transmitted infection\n\nreports a history of injecting drug use\n\ndiscloses that they are the sexual partner of someone known to be HIV positive, or of someone at high risk of HIV (for example, female sexual contacts of men who have sex with men). [2011, amended 2016]\n\nIn areas of high and extremely high prevalence, also offer and recommend HIV testing on admission to hospital, including emergency departments, to everyone who has not previously been diagnosed with HIV and who is undergoing blood tests for another reason. [new 2016]\n\nAdditionally, in areas of extremely high prevalence, offer and recommend HIV testing on admission to hospital, including emergency departments, to everyone who has not previously been diagnosed with HIV. [new 2016]\n\n## GP surgeries\n\nIn all areas, offer and recommend HIV testing to everyone who has not previously been diagnosed with HIV and who:\n\nhas symptoms that may indicate HIV or HIV is part of the differential diagnosis (for example, infectious mononucleosis-like syndrome), in line with HIV in Europe's HIV in indicator conditions\n\nis known to be from a country or group with a high rate of HIV infection (see recommendation 1.1.1)\n\nif male, discloses that they have sex with men, or is known to have sex with men, and has not had an HIV test in the previous year\n\nis a trans woman who has sex with men and has not had an HIV test in the previous year\n\nreports sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV\n\ndiscloses high-risk sexual practices, for example the practice known as 'chemsex'\n\nis diagnosed with, or requests testing for, a sexually transmitted infection\n\nreports a history of injecting drug use\n\ndiscloses that they are the sexual partner of someone known to be HIV positive, or of someone at high risk of HIV (for example, female sexual contacts of men who have sex with men). [2011, amended 2016]\n\nIn areas of high and extremely high prevalence, also offer and recommend HIV testing to everyone who has not previously been diagnosed with HIV and who:\n\nregisters with the practice or\n\nis undergoing blood tests for another reason and has not had an HIV test in the previous year. [new 2016]\n\nAdditionally, in areas of extremely high prevalence, consider HIV testing opportunistically at each consultation (whether bloods are being taken for another reason or not), based on clinical judgement. [new 2016]\n\nOffer and recommend repeat testing to the people in recommendations 1.1.8 and 1.1.9 in line with recommendation 1.2.6. [new 2016]\n\nIf a venous blood sample is declined, offer a less invasive form of specimen collection, such as a mouth swab or finger-prick. [2011, amended 2016]\n\n## Prisons\n\nAt reception, recommend HIV testing to everyone who has not previously been diagnosed with HIV. For more information, see NICE's guideline on physical health of people in prison. [new 2016]\n\n## Community settings\n\nProviders of community testing services (including outreach and detached services) should set up testing services in:\n\nareas with a high prevalence or extremely high prevalence of HIV, using venues such as pharmacies or voluntary sector premises (for example, those of faith groups)\n\nvenues where there may be high-risk sexual behaviour, for example public sex environments, or where people at high risk may gather, such as nightclubs, saunas and festivals. [2011, amended 2016]\n\nRecognise that not all community settings are appropriate for providing testing services, for example because tests should be undertaken in a secluded or private area (in line with British HIV Association guidelines). [2011, amended 2016]\n\nEnsure that people who decline or are unable to consent to a test are offered information about other local testing services, including self-sampling. See making decisions using NICE guidelines for more information about consent. [2011, amended 2016]\n\nEnsure that lay testers delivering tests are competent to do so and have access to clinical advice and supervision. [2011, amended 2016]\n\n# Increasing opportunities for HIV testing\n\n## Point-of-care testing\n\nOffer point-of-care testing (POCT) in situations where it would be difficult to give people their results, for example if they are unwilling to leave contact details. [new 2016]\n\nExplain to people at the time of their test about the specificity and sensitivity of the POCT being used and that confirmatory serological testing will be needed if the test is reactive. [2011, amended 2016]\n\n## Self-sampling\n\nConsider providing self-sampling kits to people in groups and communities with a high rate of HIV (see recommendation 1.1.1). [new 2016]\n\nEnsure that people know how to get their own self-sampling kits, for example, by providing details of websites to order them from. [new 2016]\n\n## Repeat testing\n\nWhen giving results to people who have tested negative but who may have been exposed to HIV recently, recommend that they have another test once they are past the window period. [2011, amended 2016]\n\nRecommend annual testing to people in groups or communities with a high rate of HIV, and more frequently if they are at high risk of exposure (in line with Public Health England's HIV in the UK: situation report 2015). For example:\n\nmen who have sex with men should have HIV and sexually transmitted infection tests at least annually, and every 3\xa0months if they are having unprotected sex with new or casual partners\n\nblack African men and women should have an HIV test and regular HIV and sexually transmitted infection tests if having unprotected sex with new or casual partners. [2011, amended 2016]\n\nConsider the following interventions to promote repeat testing:\n\nCall–recall methods using letters or other media, such as text messages or email, to remind people to return for annual testing.\n\nElectronic reminders in health records systems to prompt healthcare professionals to identify the need for testing during appointments and offer it if needed. [new 2016]\n\n## People who decline a test\n\nIf people choose not to take up the immediate offer of a test, tell them about nearby testing services and how to get self-sampling kits. [2011, amended 2016]\n\n## Partners of people who test positive\n\nPartners of people who test positive should receive a prompt offer and recommendation of an HIV test through partner notification procedures. [new 2016]\n\n# Promoting awareness and uptake of HIV testing\n\n## Content\n\nMaterials and interventions for promoting awareness and increasing the uptake of HIV testing should be designed in line with NICE's guidelines on behaviour change: general approaches, behaviour change: individual approaches and patient experience in adult NHS services. [new 2016]\n\nProvide promotional material tailored to the needs of local communities. It should:\n\nprovide information about HIV infection and transmission, the benefits of HIV testing and the availability of treatment\n\nemphasise that early diagnosis is not only a route into treatment and a way to avoid complications and reduce serious illness in the future, but also reduces onward transmission\n\ndetail how and where to access local HIV testing services, including services offering POCT and self-sampling, and sexual health clinics\n\ndispel common misconceptions about HIV diagnosis and treatment\n\npresent testing as a responsible act by focusing on trigger points, such as the beginning of a new relationship or change of sexual partner, or on the benefits of knowing one's HIV status\n\naddress the needs of non-English-speaking groups, for example, through translated and culturally sensitive information. [2011, amended 2016]\n\nEnsure interventions to increase the uptake of HIV testing are hosted by, or advertised at, venues that encourage or facilitate sex (such as some saunas, websites, or geospatial apps that allow people to find sexual partners in their proximity). This should be in addition to general community-based HIV health promotion. [2011, amended 2016]\n\nPromote HIV testing when delivering sexual health promotion and HIV prevention interventions. This can be carried out in person (using printed publications such as leaflets, booklets and posters) or through electronic media. \n\nEnsure health promotion material aims to reduce the stigma associated with HIV testing and living with HIV, both among communities and among healthcare professionals. [2011, amended 2016]\n\nEnsure health promotion material provides up-to-date information on the different kinds of HIV tests available. It should also highlight the significantly reduced window period resulting from the introduction of newer tests such as fourth-generation serological testing. [2011, amended 2016]\n\n## Methods of raising awareness\n\nUse or modify existing resources, for example TV screens in GP surgeries, to help raise awareness of where HIV testing (including self-sampling) is available (for content see recommendations 1.3.1 and 1.3.2). [new 2016]\n\nConsider a range of approaches to promote HIV testing, including:\n\nlocal media campaigns\n\ndigital media, such as educational videos\n\nsocial media, such as online social networking, dating and geospatial apps\n\nprinted materials, such as information leaflets. [new 2016]\n\n# Reducing barriers to HIV testing\n\nAdvertise HIV testing in settings that offer it (for example, using posters in GP surgeries) and make people aware that healthcare professionals welcome the opportunity to discuss HIV testing. [new 2016]\n\nStaff offering HIV tests should:\n\nEmphasise that the tests are confidential. If people remain concerned about confidentiality, explain that they can visit a sexual health clinic anonymously.\n\nBe able to discuss HIV symptoms and the implications of a positive or a negative test.\n\nBe familiar with existing referral pathways so that people who test positive receive prompt and appropriate support.\n\nProvide appropriate information to people who test negative, including details of where to get free condoms and how to access local behavioural and preventive interventions.\n\nRecognise and be sensitive to the cultural issues facing different groups (for example, some groups or communities may be less used to preventive health services and advice, or may fear isolation and social exclusion if they test positive for HIV).\n\nBe able to challenge stigmas and dispel misconceptions surrounding HIV and HIV testing and be sensitive to people's needs.\n\nBe able to recognise the symptoms that may signify primary HIV infection or illnesses that often coexist with HIV. In such cases, they should be able to offer and recommend an HIV test. [2011, amended 2016]\n\nEnsure practitioners delivering HIV tests (including those delivering outreach POCT) have clear referral pathways available for people with both positive and negative test results, including to sexual health services, behavioural and health promotion services, HIV services and confirmatory serological testing, if needed. These pathways should ensure the following:\n\nPeople who test positive are seen by an HIV specialist preferably within 48\xa0hours, certainly within 2\xa0weeks of receiving the result (in line with UK national guidelines for HIV testing). They should also be given information about their diagnosis and local support groups.\n\nPractitioners in the voluntary or statutory sector can refer people from HIV prevention and health promotion services into services that offer HIV testing and vice versa. [2011, amended 2016]\n\n# Terms used in this guideline\n\n## Chemsex\n\nThis term is commonly used to describe sex between men that occurs under the influence of drugs taken immediately before and/or during the sexual session. The drugs most commonly associated with chemsex are crystal methamphetamine, GHB/GBL, mephedrone and, to a lesser extent, cocaine and ketamine.\n\n## Extremely high prevalence\n\nLocal authorities with a diagnosed HIV prevalence of 5 or more per 1,000 people aged 15 to 59\xa0years (based on modelling of diagnosed HIV prevalence distribution in local authorities in England; see Public Health England's sexual and reproductive health profiles).\n\n## Fourth-generation serological testing\n\nFourth-generation tests detect HIV antibodies and p24 antigen simultaneously. This means they have the advantage of reducing the time between infection and testing HIV positive to about 1\xa0month.\n\n## High prevalence\n\nLocal authorities with a diagnosed HIV prevalence of between 2 and 5 per 1,000 people aged 15 to 59\xa0years (based on modelling of diagnosed HIV prevalence distribution in local authorities in England; see Public Health England's sexual and reproductive health profiles).\n\n## Lay tester\n\nA non-clinical practitioner who has been trained to carry out HIV tests.\n\n## Point-of-care testing\n\nPoint-of-care tests (POCT) or 'rapid' tests are a common way to test for HIV. They are easy to use when an alternative to venepuncture is preferable, for example outside conventional healthcare settings and if it is important to avoid a delay in obtaining a result. However, they have reduced specificity and sensitivity compared with fourth-generation laboratory tests. This means there will be false positives, particularly in areas with lower HIV prevalence, and all positive results need to be confirmed by serological tests.\n\n## Public sex environments\n\nPublic sex environments are public areas where people go to engage in consensual sexual contact (both same sex and opposite sex).\n\n## Self-sampling\n\nSelf-sampling HIV kits allow people to collect their own sample of blood or saliva and send it by post for testing. They usually receive negative results by text message.\n\n## Self-testing\n\nSelf-testing kits allow people to perform their own HIV test in a place of their own choosing and get an immediate result (typically within 15\xa0to\xa020\xa0minutes).\n\n## Window period\n\nThe window period is the time between potential exposure to HIV infection and when a test will give an accurate result. The window period is 1\xa0month for a fourth-generation test and 3\xa0months for older tests.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline and are:\n\nThe need to address misconceptions about HIV testing and treatment, for example:\n\n\n\nthe cost of HIV treatment\n\nlife expectancy following a positive diagnosis (particular emphasis is needed on the benefits of early diagnosis for outcomes including life expectancy).\n\n\n\nThe need to reduce the stigma (real or perceived) associated with HIV testing and living with HIV, both among communities with a high or extremely high prevalence of HIV and among healthcare professionals.\n\nThe need to take local patterns of HIV into account when planning how to deliver services. Services should be tailored to the needs of the population, including whether an area has high prevalence or extremely high prevalence of HIV.', 'Context': "In 2014, an estimated 103,700 people (69,200 men and 34,400 women) in the UK were living with HIV. The overall HIV prevalence was 1.9 per 1,000 people aged 15 and over (Public Health England's HIV in the UK).\n\nAlthough there are significant pockets of HIV in other populations and communities, the most significant burden of HIV continues to be borne by men who have sex with men and by black Africans. An estimated 45,000 men living with HIV in the UK in 2014 had acquired their infection through sex with other men, an increase from 43,000 in 2013. One in 20 men aged 15 to 44 who have sex with men is estimated to be living with HIV.\n\nA recent increase in HIV testing coverage among men attending sexual health clinics is likely to be the reason for an increase in new diagnoses and a decline in undiagnosed infections: about 6,500 men who have sex with men were unaware of their infection in 2014, compared with 8,500 in 2010 ('HIV in the UK').\n\nAlmost 1 in 1,000 heterosexual people aged 15 to 44 in the UK is estimated to be living with HIV. Prevalence is higher in black African heterosexual women (1\xa0in\xa022) and men (1\xa0in\xa056), who together form the second largest group affected by HIV. Late diagnosis remains a significant problem in heterosexual people: in 2014, 55% were newly diagnosed at a late stage of infection (just over half of whom were black African) ('HIV in the UK').\n\nOverall, 17% of people estimated to have HIV are unaware they are infected and so are at risk of passing it on. More people living outside London are unaware of their HIV infection (24%) compared with those in London (12%) ('HIV in the UK').\n\nIn 2013, in response to the international AIDS epidemic, UNAIDS launched a new target known as '90-90-90' (UNAIDS's 90-90-90: An ambitious treatment target to help end the AIDS epidemic). By 2020:\n\n% of all people living with HIV will know their HIV status\n\n% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy\n\n% of all people receiving antiretroviral therapy will have viral suppression.\n\nIn 2011, NICE published guidelines PH33 and PH34, which aimed to increase the uptake of HIV testing in black Africans living in the UK and in men who have sex with men. In 2014, experts reviewed the evidence and agreed that the guidelines should be updated to reflect changes in the way HIV testing is delivered (following the legalisation of self-sampling and self-testing kits) and to reflect the normalisation of HIV testing across health services.", "The committee's discussion ": "Evidence statement numbers are given in square brackets and refer to the summaries of evidence contained within the reviews that were conducted to support the development of this guideline. For an explanation of the evidence statement numbering, see the evidence reviews section.\n\n# Background\n\n## Updating the previous guidelines\n\nThe committee discussed the recommendations and considerations in the 2 guidelines being updated (NICE guidelines PH33 and PH34), and considered the view of the experts in the review decision. The committee agreed that the previous recommendations were still pertinent but they needed some updating to better reflect current practice. The committee removed or amended parts of the recommendations that it agreed were outdated. For more information, see update information.\n\nThe committee concluded that many of the recommendations from the previous guidelines were aimed at a broader population than men who have sex with men, and black Africans. For the more specific recommendations, the committee agreed it would be appropriate to broaden them to apply to any population with a high rate of HIV. The committee recognised that men who have sex with men, and black Africans are still the most high-risk groups for HIV in the UK and this is reflected in the guideline (recommendation 1.2.6). An additional benefit of broadening the recommendations to apply to everyone with undiagnosed HIV is that it should help to normalise HIV testing so that it is not seen differently from any other blood test. For more information on the relevance of this guideline for other groups, see the equality impact assessment.\n\n## HIV testing and HIV screening\n\nThe committee discussed the distinction between testing and screening. It was reminded that recommending screening programmes is outside NICE's role. It was aware that HIV screening in antenatal settings is currently recommended by the UK National Screening Committee and has a very high uptake. It also discussed the differences between opt-in and opt-out approaches to testing, that is whether people are asked if they want an HIV test or they are told they will be tested for HIV unless they specifically ask not to be. It agreed that it was important to make sure people understand that HIV testing is voluntary and to give everyone the opportunity to opt out of a test.\n\nThe committee discussed that HIV testing may not always be routinely undertaken among people who have conditions that might indicate HIV infection. For this reason, it agreed that it is important for national guidelines to recommend HIV testing when diagnosing or treating conditions that may indicate HIV infection (see HIV in Europe's guidance on HIV in indicator conditions).\n\n## Other guidelines\n\nThe committee agreed that the British HIV Association's UK national guidelines for HIV testing are the most up-to-date HIV guidelines available in the UK and are also accredited by NICE, so they remain in the recommendations. The only exception relates to indicator conditions, for which more up-to-date guidance is available from HIV in Europe's guidance on HIV in indicator conditions. Although this guideline has not been accredited by NICE, the committee agreed it was a useful and authoritative source of information to give people who are offering HIV testing.\n\n## High prevalence and extremely high prevalence of HIV\n\nThe committee discussed the meaning of 'high prevalence'. NICE guidelines PH33 and PH34 used the definition given by Public Health England of 2 in 1,000 people. However, as more people are being diagnosed with HIV and treated, and because they are living longer, the background prevalence of HIV is rising and the overall UK prevalence in 2014 was 1.9 per 1,000.\n\nThe committee was aware that during the development of this guideline, Public Health England carried out a new analysis of 2014 data on diagnosed HIV prevalence distribution in local authorities in England. Based on this analysis, groups and communities at high prevalence of diagnosed HIV can be defined as follows:\n\nHigh prevalence: local authorities with a diagnosed HIV prevalence of between 2 and 5 per 1,000 people aged 15 to 59\xa0years.\n\nExtremely high prevalence: local authorities with a diagnosed HIV prevalence of 5 or more per 1,000 people aged 15 to 59\xa0years.\n\nWhen this is applied to national late HIV diagnosis data, it shows that two-thirds of late HIV diagnoses occur in high-prevalence and extremely-high-prevalence local authorities. This means that if this guideline is successfully applied in high- and extremely-high-prevalence areas, it could potentially affect two-thirds of late diagnoses nationally.\n\nThe committee agreed that the definitions of high prevalence and extremely high prevalence were useful, and it incorporated them into the recommendations. The committee also agreed it was important for areas to find out their diagnosed prevalence, as well as that of surrounding areas (recommendation 1.1.1). This allows them to adapt their strategy for HIV testing using the recommendations in this guideline. These data are available from Public Health England's sexual and reproductive health profiles. Additionally, the committee was aware that local data are often available to supplement national data from Public Health England, and that local data may be more up to date and provide more granular detail about local groups and populations with a high rate of HIV.\n\n## Evidence statements not used to make recommendations\n\nThe committee did not make recommendations for all of the evidence statements. This was mainly because it did not believe, based on the evidence, that an intervention was effective; or it agreed that the intervention may not be applicable in the UK. For details of the evidence statements not used to make recommendations, see the evidence reviews section.\n\n# Sections 1.1 and 1.2\n\nThe discussion below explains how we made [new 2016] recommendations in:\n\nsection 1.1 on offering and recommending HIV testing in different settings\n\nsection 1.2 on increasing opportunities for HIV testing.\n\n## Current practice\n\nThe committee discussed the appropriateness of different settings for offering HIV testing. It noted the role the voluntary sector plays in HIV testing, particularly in terms of increasing its acceptability among some subpopulations. In terms of healthcare settings, it acknowledged that previous evidence for PH33 and PH34 had shown that both primary and secondary care were suitable settings to offer and recommend HIV tests. The committee did not feel it was appropriate to recommend promoting HIV testing in any particular setting more than others, so it made recommendations for all settings, using HIV prevalence to determine the intensity of interventions.\n\nThe committee noted that there is pressure on healthcare professionals' time during appointments. Some kinds of HIV tests might take too long – for example, a GP would not be able to perform point-of-care testing (POCT) during a 10-minute appointment in addition to the main consultation. However, another healthcare practitioner in the practice, for example a practice nurse, might be able to offer this test.\n\nThe committee considered that the uptake of HIV testing was generally high when testing was offered but that staff are often reluctant to offer and recommend a test. The committee felt it was particularly important that practitioners who are reluctant to offer tests more widely should know about this.\n\n## Evidence for effectiveness\n\nThe committee discussed criteria for offering testing in secondary care, emergency care and GP surgeries based on the identified HIV prevalence of the area (recommendations 1.1.5 to 1.1.10). It agreed that further opportunities to maximise HIV testing should be pursued in areas with a high prevalence of HIV. This could include testing someone who has not previously been diagnosed with HIV when they are having blood tests on admission to hospital, or when they register with a GP practice (recommendations 1.1.6 and 1.1.9). In high- and extremely-high-prevalence areas, having a blood test for another reason provides an opportunity for an HIV test with little resource impact (just the cost of the test). The committee also agreed that when new patients register with a GP surgery their overall health is assessed and this is an efficient opportunity to promote HIV testing.\n\nThe committee felt it was important not to miss opportunities to offer testing opportunistically in areas of extremely high prevalence (recommendations 1.1.7 and 1.1.10). This could include offering testing to everyone who has not previously been diagnosed with HIV, when they are admitted to hospital, or to people attending GP appointments. However, the committee also noted the importance of using clinical judgement before offering an opportunistic test in general practice (recommendation 1.1.10). For example, a GP might decide not to offer a test during a consultation if the person is distressed or upset or has recently been tested.\n\nOn balance, recognising the practical implications of introducing opportunistic testing in GP practices as well as the potential resource impact, the committee made a weaker 'consider' recommendation for GP surgeries (recommendation 1.1.10). This means that the recommendations place a stronger onus on hospitals to deliver testing in extremely-high-prevalence areas, compared with GP surgeries. The committee agreed this was justifiable because testing in acute settings is likely to be cheaper than in GP surgeries, and most people being admitted to hospital have blood taken for other reasons (recommendations 1.1.6 and 1.1.7).\n\nThe committee also discussed the effectiveness of offering testing to people who present to health services with conditions that might indicate HIV. The effectiveness of this depends to some extent on the accuracy of the list of indicator conditions used. The committee agreed that defining a list of indicator conditions was outside the scope of this guideline. However, it agreed that HIV in Europe's guidance on HIV in indicator conditions from was sufficiently evidence-based to inform recommendations 1.1.5 and 1.1.8 and to be a useful supplement to the guideline.\n\nThe committee noted stakeholder comments about the importance of testing in prisons. Little evidence was identified on the effectiveness of interventions to provide HIV testing in custodial settings, although 2 studies looked at the timing of HIV tests in prisons [ES14]. Despite the lack of evidence, the committee agreed that prisons were a high-prevalence environment for HIV and other blood-borne viruses and that health services in prisons would be expected to recommend testing to people in line with the approach used in GP surgeries. It was also clear that the committee had a duty to promote equality through its guidelines, and a recommendation for people in prison would support this.\n\nThe committee saw evidence to suggest that uptake of HIV testing was higher if tests were offered within 24\xa0hours of reception into prison [ES14]. It was aware of the national guidance in Public Health England's improving testing rates for blood-borne viruses in prisons and other secure settings, which indicates that testing should happen within 72\xa0hours of reception, and inferred that, if combined with other tests for blood-borne viruses, HIV testing would have a lower cost impact. It was mindful that there is a NICE guideline on physical health of people in prison. On balance, it felt that the evidence was strong enough to recommend that HIV testing should be recommended at prison reception.\n\nThe committee discussed the range of settings where HIV testing could be offered, especially less invasive tests. It noted the importance of offering testing to people in places they would normally go, but was also aware that there could be a potential stigma associated with this (for example, because they might not want to be seen by other members of their community). The committee discussed faith settings as an example of a setting where HIV testing could be offered. However, it acknowledged that not all faith settings would be appropriate or faith groups willing to participate.\n\nThe committee discussed the distinction between self-sampling and self-testing. No evidence was found on self-testing so it did not include this in the recommendations.\n\nThe committee discussed self-sampling and agreed that although there was limited evidence currently, it showed great promise, especially as a way to engage people who are less likely to present at services. However, given the paucity of the evidence, the committee decided that it was only able to make a 'consider' recommendation (making decisions using NICE guidelines explains how we use words to show the strength, or certainty, of our recommendations).\n\nThe committee recognised that not all community settings are appropriate for providing self-sampling kits and agreed it was important to consult stakeholders when setting up self-sampling services. The committee agreed there were likely to be economies of scale and that some local authorities might get better value for money by commissioning online self-sampling services such as the one currently provided by Public Health England [ES17].\n\nThe committee noted the importance of timely partner tracing and notification, not only for the purposes of offering an HIV test, but if the sexual contact was recent then providing post-exposure prophylaxis promptly could reduce the risk of infection.\n\nThe committee discussed the frequency of HIV testing and agreed that repeat testing should be promoted to people in higher-risk groups. It discussed evidence for the effectiveness of different systems to promote repeat testing, such as call–recall methods and electronic reminders. The committee agreed that systems like these should be implemented wherever possible. It noted that the evidence suggested that electronic reminders that cannot be dismissed without completing a query box were more effective than reminders that could be clicked off. However the evidence was not sufficient to support this as a recommendation and overall the committee agreed it would be too onerous [ES18].\n\n## Evidence for cost effectiveness\n\nThe committee noted that late diagnosis of HIV is substantially more costly than early diagnosis, because of the costs of inpatient admission and treatment. The committee was aware that prompt diagnosis of HIV would be cost saving per person, and there could be further cost savings through averting transmission (recommendation 1.2.9). The committee agreed that HIV testing is most cost effective when the cost per positive test is lowest. The committee noted that the cost of an HIV test is incurred for each person tested and therefore the cost per positive test result decreases when either the cost of the HIV test decreases, or the HIV prevalence in a population increases.\n\nThe committee noted that the review of cost effectiveness identified mixed evidence as to whether it is more cost effective to test everyone for HIV, or to target certain groups. The studies identified considered the general population in the UK or the US and compared various strategies for testing everyone or only those who disclosed risk factors that identified them as a higher-risk group. Differences in populations, strategies, inputs, cost perspectives and model structure presented difficulties in comparing and interpreting the results. The committee was limited in how it could use this evidence in making recommendations.\n\nThe committee discussed that the additional cost of testing for HIV for a person already undergoing blood tests was likely to be low. The committee felt that in an areas of high and extremely high prevalence, offering HIV testing to everyone undergoing blood tests for another reason would be cost effective, because of the low incremental cost and high HIV prevalence (recommendations 1.1.6, 1.1.9).\n\nThe committee discussed that HIV testing for everyone admitted to hospital would incur an additional cost, but that this would be cost effective in areas of extremely high prevalence (recommendation 1.1.7) given the likelihood of bloods being taken for other reasons.\n\nThe committee discussed that HIV testing for everyone attending a GP surgery would incur an additional cost, but that opportunistic testing would be cost effective in areas of extremely high prevalence (recommendation 1.1.10).\n\nIn other settings or areas of lower prevalence, the committee felt that targeting specific groups was more likely to be cost effective: that is, it would result in the lowest cost per positive test (recommendations 1.1.5, 1.1.8, 1.2.6).\n\nThe committee noted an analysis of pilot projects for HIV testing in hospitals, primary care and community settings and for self-sampling, which found variation in cost per positive test. It concluded that no single setting was likely to offer the greatest value for money. The committee recommended setting up community testing in high- and extremely high-prevalence areas in addition to testing in hospitals and primary care (recommendation 1.1.14). The same analysis found that the cost per test of self-sampling was comparable to the cost per test in other settings, and so could represent a cost-effective method of diagnosing HIV (recommendations 1.1.16, 1.2.3, 1.2.4, 1.2.8).\n\n## Resource impact and implementation issues\n\nWhen discussing testing in GP surgeries and emergency departments (section 1.1), the committee discussed the resource impact of the recommendations. It felt that making testing routine for all attendees in GP surgeries and emergency settings could have a substantial resource impact and could only be justified in areas of extremely high prevalence. However, the committee agreed that opportunistic testing for everyone having a blood test in these settings in extremely-high- and high-prevalence areas represents best practice, although it was mindful of the resource implications. The committee also considered the potential resource impact of self-sampling. An expert told the committee that self-sampling was likely to cost the same as traditional testing approaches involving healthcare professionals. It may also be an effective approach in harder to reach subgroups at risk, and could have potential to reduce late diagnosis in these groups. This could reduce the health and social care costs associated with late diagnosis [EP2].\n\nThe committee discussed further the role that primary care professionals (particularly GPs) could have in opportunistically offering and recommending HIV testing to a subpopulation of people at risk who are difficult to reach through methods described in recommendations 1.1.8 and 1.1.9. It discussed promoting opportunistic testing at every consultation in extremely-high-prevalence areas as a way of promoting testing to this subpopulation. The committee agreed that HIV testing for everyone attending a GP surgery would incur an additional cost. The proportion of HIV tests conducted in GP surgeries was estimated to be 3.8%. The committee reasoned that if 3.8% of all people aged 15 to 59 in areas of extremely high prevalence who do not have an HIV diagnosis had an HIV test in their GP surgery, the estimated cost would be between £2\xa0million and £4\xa0million depending on the cost used for GP time and laboratory costs. The committee noted that, given current HIV testing practice, this was a highly unlikely scenario and therefore the resource impact of the recommendation is likely to be much smaller. Notwithstanding, given the annual treatment costs for HIV, the life expectancy of somebody living with HIV and the potential reduction in transmission due to treatment, the committee agreed that opportunistic GP testing was good value.\n\n# Sections 1.3 and 1.4\n\nThe discussion below explains how we made [new 2016] recommendations in:\n\nsection 1.3 on promoting awareness and uptake of HIV testing\n\nsection 1.4 on reducing barriers to HIV testing.\n\n## Evidence for effectiveness\n\nThere was some evidence of effectiveness for media campaigns, educational videos, online social networking and information leaflets in raising awareness of HIV testing. The committee agreed that different methods of awareness raising are effective for different groups and that a range of methods should be recommended [ES1, ES2, ES6, ES7, ES8, ES9, ES10].\n\nThe committee discussed the evidence from 1 study on the effectiveness of motivational interviewing for increasing uptake of HIV testing [ES4]. The committee felt that there was not enough evidence from the study to recommend this as an intervention but that referring to NICE's guidelines on behaviour change would cover this type of approach (recommendation 1.3.1).\n\nThe committee noted that evidence suggested computerised interviews and risk assessments were unlikely to be effective at increasing uptake of HIV testing in people who may have undiagnosed HIV. However, it did not think the evidence was strong enough to recommend that they should not be used. [ES3].\n\nThere was evidence suggesting that financial incentives are effective at increasing uptake of HIV testing [ES21]. However, the committee noted a lack of evidence from UK healthcare settings. Without stronger evidence of effectiveness in the UK, the potentially significant resource impact of the intervention could not be justified.\n\n## Evidence for cost effectiveness and resource impact\n\nThe committee noted that awareness raising was a core element of any health promotion and it deemed the resource impact of the new recommendations to be minimal. The intention behind the new recommendations was to bring the principles in line with current technologies and modes of delivery of messages.\n\n# Evidence reviews\n\nDetails of the evidence discussed are in evidence reviews, reports and papers from experts in the area.\n\nThe evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from.\n\n## Evidence statements from 2011 guidelines\n\nEvidence statement number E1.1 indicates that the linked statement is numbered 1.1 in review 1 for PH33, 'Review of effectiveness and cost effectiveness: increasing the uptake of HIV testing to reduce undiagnosed infection and prevent transmission among black African communities living in England'. Q1 indicates that the linked statement is numbered 1 in review 2 for PH33, 'Increasing the uptake of HIV testing to reduce undiagnosed infection and prevent transmission among black African communities living in England – barriers to HIV testing'. ES1 indicates that the linked statement is numbered 1 in the review for PH34 'Preventing and reducing HIV transmission among men who have sex with men'.\n\nThe expert report 'Time to test for HIV: expanded healthcare and community HIV testing in England. Interim report' was also used to inform the original recommendations in PH33 and PH34.\n\n## Evidence statements from 2016 reviews\n\nES1a.1 indicates that the linked statement is numbered 1 in review 1a for this guideline. ES1b.1 indicates that the linked statement is numbered 1 in review 1b for this guideline. ES1c.1 indicates that the linked statement is numbered 1 in review 1c for this guideline. ES2.1 indicates that the linked statement is numbered 1 in review 2 for this guideline. EP1 indicates that expert paper 'Targeted testing based on indicator conditions' is linked to a recommendation. EP2 indicates that expert paper 'HIV testing in the UK and summary of current UK practice' is linked to a recommendation.\n\nIf a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\n: EP2; IDE\n\n: E3.5b, ES4 2016: ES1b.14, ES2.3\n\n: E3.5c 2016: ES1b.12; ES1c.1; IDE\n\n: E3.5b, ES4 2016: ES1b.13, ES1c.7, ES2.1; EP1\n\n: ES4, Q6.1 2016: ES1c.4, ES1c.5; IDE\n\n: ES4, Q6.1 2016: ES1c.4, ES1c.5; IDE\n\n: ES4, Q6.1 2016: ES1c.4, ES1c.5; IDE\n\n: Q6.2, Q6.3 2016: ES1c.5, ES2.1; IDE\n\n: Q6.2, Q6.3 2016: ES1c.5, ES2.1; IDE\n\n: Q6.2, Q6.3 2016: ES1c.5, ES2.1; IDE\n\n: ES4; IDE\n\n: ES15 2016: ES1b.15; IDE\n\n: ES1b14; IDE\n\n: Q6.2, ES1, ES14, ES15, ES2.3; IDE\n\n: ES14, ES15; IDE\n\n: Q1.3, ES18, ES2.2; EP2\n\nIDE\n\n: E3.5c, Q6.3 2016: ES1b.16, ES1c.1; IDE\n\nIDE\n\n: Q5.3, ES1 2016: ES1b.17, ES2.4; EP2; IDE\n\n: IDE\n\n: E3.5b, ES4, ES7 2016: ES1c.6; IDE\n\n: ES4; IDE\n\n: ES1b.18; IDE\n\n: EP2; IDE\n\n: IDE\n\n: ES13; IDE\n\n: E3.3, E3.4, Q1.2, Q1.3, Q4.2, Q4.3, Q5.1, ES3, ES13; IDE\n\n: ES3, ES13; IDE\n\n: ES13 2016: ES1a.6; IDE\n\n: Q.3, ES10, ES13, ES18, ES2.2; IDE\n\n: ES10, ES13; IDE\n\n: E3.2, ES3, ES13 2016: ES1a.1, ES1a.2, ES1a.6, ES1a.7, ES1a.8, ES1a.9, ES1a.10\n\n: E3.2, ES3, ES13 2016: ES1a.1, ES1a.2, ES1a.6, ES1a.7, ES1a.8, ES1a.9, ES1a.10\n\n: ES1a.6; IDE\n\n: E3.5c, E3.6, E3.7a, E3.7b, Q1.3, Q5.4, Q7.4, ES18 2016: ES1b.20, ES2.2\n\n: Q5.1; IDE\n\nThe following new 2016 evidence statements were not used to make recommendations: ES1a.3, ES1a.4, ES1a.5, ES1b.13, ES1b.19, ES1b.20, ES1b.21, ES1b.22, ES1c.2, ES1c.3, ES1c.7\n\n# Gaps in the evidence\n\nThe committee's assessment of the evidence on HIV testing identified a number of gaps. These gaps are set out below.\n\n. Interventions to increase awareness of the benefits of HIV testing and details of local testing services among people who have not been diagnosed with HIV, particularly:\n\none-to-one and group-based information provision\n\nopportunistic information provision\n\nuse of social media\n\nmass media campaigns.\n\n(Source ER1)\n\n. Interventions to increase awareness of the indicators for, and the benefits of, HIV testing among practitioners who should offer testing or refer people for testing.\n\n(Source ER1)\n\n. Increasing the range of settings where tests can be carried out, particularly in community and outreach settings.\n\n(Source ER1)\n\n. Changes in service delivery to increase the uptake of HIV testing, for example, increasing the number of tests offered; changing opening times and appointment systems; and changing confidentiality policies.\n\n(Source ER1)\n\n. The impact of lay testers recommending or offering an HIV test.\n\n(Source ER1)\n\n. The effectiveness of self-testing for HIV and self-sampling for an HIV test.\n\n(Source ER1)\n\n. Interventions to assess whether indicator condition-targeted testing is effective compared with routine testing.\n\n(Source ER1)\n\n. Interventions to increase uptake of HIV testing among people who have an illness that may indicate HIV infection.\n\n(Source ER1)\n\n. Attitudes towards HIV testing among people who may have undiagnosed HIV, and service providers (that is, whether or not there is any stigma associated with HIV tests).\n\n(Source ER2)\n\n. Barriers to HIV testing for people who may have undiagnosed HIV (for example, people who do not speak English as a first language) and service providers.\n\n(Source ER2)\n\n. Appropriate settings for delivering HIV testing, for example custodial settings or faith settings.\n\n(Source ER1)\n\n. Appropriate definition of 'high prevalence' in the UK context, especially in terms of cost effectiveness.\n\n(Source committee discussion)", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Interventions to improve the acceptability and uptake of HIV testing among people at higher risk\n\nWhat interventions would be effective and cost effective among people at higher risk in the UK to increase uptake of HIV testing among people who may have undiagnosed HIV?\n\n## Why this is important\n\nImproving the acceptability of HIV testing and increasing the uptake of HIV testing will reduce the pool of undiagnosed infection, improve outcomes for those affected (because of earlier diagnosis) and reduce onward transmission, particularly in some high-risk populations. There is a lack of evidence among some groups in the UK, such as people in prison, trans women and people accessing services through community and outreach settings.\n\n# Supporting healthcare professionals to offer HIV tests\n\nWhat interventions are effective and cost effective to increase the likelihood of healthcare professionals offering and recommending an HIV test and of its subsequent uptake?\n\n## Why this is important\n\nEvidence suggests that the uptake of HIV testing is high among people who are offered and recommended a test. However, healthcare professionals often do not offer or recommend HIV tests in situations in which guidelines suggest it would be appropriate to do so. Research exploring interventions to promote the offer of HIV testing among a variety of test providers would inform future iterations of the guideline.\n\nMost of the evidence on increasing the uptake of HIV testing came from the USA, often from settings that do not exist in the UK, for example veterans' health clinics. Given the lack of UK-based evidence, it is also important to ascertain how applicable this research is to cultural and healthcare contexts in the UK.\n\n# Self-sampling and self-testing\n\nHow effective are self-sampling and self-testing in terms of accuracy of sampling, ability to reach different groups, test completion, receipt of results and subsequent care-seeking behaviour?\n\n## Why this is important\n\nSelf-sampling and self-testing are relatively new modalities in the UK and limited evidence exists about their effectiveness and cost effectiveness.\n\n# Indicator conditions\n\nWhat is the UK prevalence of HIV in various indicator conditions, and how effective are interventions using indicator condition-targeted testing compared with other testing strategies?\n\n## Why this is important\n\nThere is a lack of evidence on the effectiveness of using indicator conditions to target HIV testing, an approach that may improve detection rates. Also, because it is targeted, there may be economies of scale, for example, HIV testing could be commissioned in clinics that treat people with indicator conditions.\n\n# Cost utility\n\nWhat is the cost utility of increasing the offer or uptake of HIV testing in different settings, for different types of tests, using different strategies (for example opt-in or opt-out approaches) and in areas and groups with different background prevalence?\n\n## Why this is important\n\nThere is no UK evidence to enable commissioners and service providers to plan the most cost-effective services for their local communities."}	https://www.nice.org.uk/guidance/ng60	This guideline covers how to increase the uptake of HIV testing in primary and secondary care, specialist sexual health services and the community. It describes how to plan and deliver services that are tailored to the local prevalence of HIV, promote awareness of HIV testing and increase opportunities to offer testing to people who may have undiagnosed HIV.
b028ab13a13823c57f01a789dbe499ff1423a4e1	nice	Coexisting severe mental illness and substance misuse: community health and social care services	Coexisting severe mental illness and substance misuse: community health and social care services This guideline covers how to improve services for people aged 14 and above who have been diagnosed as having coexisting severe mental illness and substance misuse. The aim is to provide a range of coordinated services that address people’s wider health and social care needs, as well as other issues such as employment and housing. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read in conjunction with NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings. This covers the assessment of, and support for, adults and young people (aged 14 and older) who have a suspected or known clinical diagnosis of psychosis with coexisting substance misuse. The following should ensure service specifications take into account the recommendations in this guideline: commissioners of mental health, substance misuse and primary care local authorities when commissioning support services, including housing and other services provided by the public, community and voluntary sectors. # First contact with services These recommendations are for all staff who may be the first point of contact with young people and adults with coexisting severe mental illness and substance misuse working in: health (including urgent care and liaison services) social care public health voluntary and community sector organisations housing (for example, homeless shelters or temporary accommodation) criminal justice system. Identify and provide support to people with coexisting severe mental illness and substance misuse. Aim to meet their immediate needs, wherever they present. This includes: looking out for multiple needs (including physical health problems, homelessness or unstable housing) remembering they may find it difficult to access services because they face stigma. Be aware that the person may have a range of chronic physical health conditions including: cardiovascular, respiratory, hepatic or related complications communicable diseases cancer -ral health problems diabetes. Be aware that people's unmet needs may lead them to have a relapse or may affect their physical health. This could include: social isolation, homelessness, poor or lack of stable housing, or problems obtaining benefits. Provide direct help, or get help from other services, for any urgent physical health, social care, housing or other needs. Ensure the safeguarding needs of all people with coexisting severe mental illness and substance misuse, and their carers and wider family, are met. (See also the section on safeguarding issues in the NICE guideline on coexisting severe mental illness and substance misuse: assessment and management in healthcare settings.) Ensure the person is referred to and followed up within secondary care, and that mental health services take the lead for assessment and care planning (see sections 1.2 and 1.3). # Referral to secondary care mental health services Ensure secondary care mental health services: Do not exclude people with severe mental illness because of their substance misuse. Do not exclude people from physical health, social care, housing or other support services because of their coexisting severe mental illness and substance misuse. Adopt a person-centred approach to reduce stigma and address any inequity to access to services people may face (see NICE's guidelines on coexisting severe mental illness and substance misuse: assessment and management in healthcare settings and service user experience in adult mental health for the principles of using a person-centred approach). Undertake a comprehensive assessment of the person's mental health and substance misuse needs (see also NICE's guideline on coexisting severe mental illness and substance misuse – the section recognition of psychosis with coexisting substance misuse and the recommendations on assessment in secondary care mental health services). ## On acceptance to secondary care mental health services Provide a care coordinator working in mental health services in the community to: act as a contact for the person identify and contact their family or carers help develop a care plan with the person (in line with the Department of Health's Care Programme Approach guidance) and coordinate it (see the section on the care plan).The Care Programme Approach is a way that services are assessed, planned, coordinated and reviewed for someone with mental health problems or a range of related complex needs. Ensure the care coordinator works with other services to address the person's social care, housing, physical and mental health needs, as well as their substance misuse problems, and provide any other support they may need. ## Involving people with coexisting severe mental illness and substance misuse in care planning Involve the person (and their family or carers if the person wants them involved) in developing and reviewing the care plan (as needed) to ensure it is tailored to meet their needs. This includes offering the person information about the services available so they can decide which ones would best meet their jointly identified needs and goals. Also involve practitioners from: adult or child and adolescent mental health teams and substance misuse services -ther health and social care disciplines such as medicine, pharmacy, nursing, social work, occupational therapy and housing. Ensure the care plan: Is based on a discussion with the person about how their abilities (such as the extent to which they can take part in the activities of daily living) can help them to engage with services and recover. Takes into account the person's past experiences (such as their coping strategies to deal with crises). Lists how the person will be supported to meet their identified needs and goals. This includes listing any carers they have identified to help them, and the type of support the carer can provide. (Also see the recommendation on ensuring interventions meet individual needs in the NICE guideline on behaviour change: individual approaches). Takes into account the concerns of the person's family or carers. Recognises and, if possible, reconciles any goals the person may have decided for themselves if they differ from those identified by their service provider. Is optimistic about the prospects of recovery. Is reviewed at every contact. Share a copy of the care plan with the person's family or carers (if the person agrees). In line with local information sharing agreements, share copies with other services as needed (see the section on information sharing). ## Carers Ensure carers (including young carers) who are providing support are aware they are entitled to, and are offered, an assessment of their own needs (see NICE's guideline on supporting adult carers). If the carer wishes, make a referral to their local authority for a carer's assessment (in line with the Care Act 2014). When undertaking an assessment, consider: carers have needs in their own right the effect that caring has on their mental health carers may be unaware of, or excluded from, any plans or decisions being taken by the person any assumptions the person with coexisting severe mental illness and substance misuse has made about the support and check that they agree the level of support their carer will provide. Based on the carer's assessment: Advise the carer that they may be entitled to their own support. For example, using a personal budget to buy care or to have a break from their caring responsibilities. Give information and advice on how to access services in the community, for example respite or recreational activities or other support to improve their wellbeing.See NICE's guideline on supporting adult carers. # The care plan: multi-agency approach to address physical health, social care, housing and other support needs The person's care coordinator should adopt a collaborative approach with other organisations (involving shared responsibilities and regular communication) when developing or reviewing the person's care plan. This includes substance misuse services, primary and secondary care health, social care, local authorities and organisations such as housing and employment services. Ensure the care plan includes an assessment of the person's physical health, social care and other support needs, and make provision to meet those needs. This could include: personal care and hygiene family and personal relationships housing learning new skills for future employment or while in employment (including those administering social security benefits) education pregnancy and childcare responsibilities. Consider covering behaviours in the care plan that may affect the person's physical or mental health, in addition to their substance misuse (see the NICE topic pages on drug misuse and alcohol). Pay particular attention to: diet (see the NICE topic page on diet, nutrition and obesity) physical activity (see the NICE topic page on physical activity) smoking (see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence) consequences of drug or alcohol misuse practices (see the NICE topic page on hepatitis and the NICE guideline on needle and syringe programmes) sexual practices (see the NICE topic page on sexual health). Explore any barriers to self-care to help the person look after their own physical health. Address these barriers in the care plan. Consider incorporating activities in the care plan that can help to improve wellbeing and create a sense of belonging or purpose. For example, encourage sport or recreation activities, or attendance at community groups that support their physical health or social needs. Ensure activities take account of a range of different abilities. Consider, for example: the gym education opportunities volunteering use of personal budgets (if applicable) for learning new skills, such as those that might support a return to employment. Consider the following approaches to keep people involved in their care plan: Practical one-to-one support, for example in relation to housing, education, training or employment. Support to develop self-care skills, for example, to help them develop their budgeting skills so they know how to allocate enough money to buy food. Or support to help them develop their cooking skills. Practical help with tasks that are important to the person, for example, housework or occupational support. Support at appointments, for example: arranging or travelling with them to hospital outpatient appointments or attendance at support groups arranging for an advocate to accompany them at their appointments and provide independent advocacy (see the section on maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them in the NICE guideline on coexisting severe mental illness and substance misuse). Consider the suitability of the type of housing (for example, high to low support or independent tenancies), employment, detox, rehabilitation services or other support identified for the person, in collaboration with relevant providers. Take the person's preferences into account. Ensure agencies and staff communicate with each other so the person is not automatically discharged from the care plan because they missed an appointment. All practitioners involved in the person's care should discuss a non-attendance. ## Review Hold multi-agency and multidisciplinary case review meetings annually, as set out in the Department of Health's Care Programme Approach guidance or more frequently, based on the person's circumstances. (A care coordinator in the secondary care mental health team should usually arrange this.) Use this to check the person's physical health needs (including any adverse effects from medications), social care, housing or other support needs. Involve practitioners from a range of disciplines, including: secondary care mental health substance misuse primary care emergency care (if applicable) voluntary sector housing adult and young people's social care. Ensure the care plan is updated in response to changing needs or circumstances. ## Discharge or transition Before discharging the person from their care plan (the Department of Health's Care Programme Approach guidance) or before they move between services, settings or agencies (for example, from inpatient care to the community, or from child and adolescent mental health services to adult mental health services) ensure: All practitioners who have been, or who will be, involved are invited to the multi-agency and multidisciplinary meetings (see recommendation 1.3.9) and the discharge or transfer meeting. There is support to meet the person's housing needs. The discharge plan includes strategies for ongoing safety or risk management and details of how they can get back in contact with services. There are crisis and contingency plans in place if the person's mental or physical health deteriorates (including for risk of suicide or unintentional overdose). Providers share information on how to manage challenging or risky situations (see also NICE's guideline on violence and aggression: short-term management in mental health, health and community settings). Reassess the person's needs to ensure there is continuity of care when they are at a transition point in their life. Particular groups who may need additional support include: young people who move from child and adolescent mental health services to adult health or social care services (see also NICE's guideline on transition from children's to adults' services and the section on specific issues for young people with psychosis and coexisting substance misuse in NICE's guideline on coexisting severe mental illness and substance misuse) looked after children people who move from adult to older adult mental health or social care services.Also see NICE's guideline on transition between inpatient mental health settings and community and care home settings. # Partnership working between specialist services, health, social care and other support services and commissioners Work together to encourage people with coexisting severe mental illness and substance misuse to use services. Consider: using an agreed set of local policies and procedures that is regularly reviewed by key strategic partners working across traditional institutional boundaries being responsive to requests for advice and joint-working arrangements sharing the response to risk management. Ensure joint strategic working arrangements are in place so that: services can offer continuity of care and service provision (for example, when commissioning contracts are due to expire) services are based on a local needs or a joint strategic needs assessment service quality is monitored and data sharing protocols are in place (see also recommendations 1.4.6 and 1.4.7). Consider including the needs of people with coexisting severe mental illness and substance misuse in other local needs assessment strategies, for example, on housing, employment projects, alcohol, drug services or crime prevention. Agree joint care pathways to: Meet the health, social care or other support needs and preferences of people with coexisting severe mental illness and substance misuse, wherever they may present. Give people access to a range of primary healthcare and social care providers including GP practices, pharmacies, podiatrists, dentists, social workers, housing, housing support or benefit advisers. Ensure people have prompt access to local services (including direct referrals if possible). Ensure staff follow people up to make sure their needs are being met. Ensure continuity of care to support people at different transition points in their lives. Ensure referral processes and care pathways within and across agencies are consistent and that governance arrangements are in place. This includes local care pathways to meet the physical health, social care, housing and support needs of people with coexisting severe mental illness and substance misuse. ## Information sharing Agree a protocol for information sharing between secondary care mental health services and substance misuse, health, social care, education, housing, voluntary and community services (see the Caldicott Guardian Manual). Adopt a consistent approach to getting people with coexisting severe mental illness and substance misuse help from the most relevant service by: sharing information on support services between agencies ensuring all providers know about and can provide information on the services taking responsibility, as agreed in referral processes, providing timely feedback and communicating regularly about progress. # Improving service delivery ## Making health, social care and other support services more inclusive Ensure existing health and social care services (including substance misuse services) are adapted to engage with and meet the needs of people with coexisting severe mental illness and substance misuse. Involve people with coexisting severe mental illness and substance misuse, their family or carers in improving the design and delivery of existing services (see the section on referral to secondary care mental health services in NICE's guideline on coexisting severe mental illness and substance misuse). This may include them providing training, developing interventions to help people or taking part in steering committees. Provide local services in places that are easily accessible, safe and discreet. Bear in mind any perceived stigma involved in being seen to use the service. Consider flexible opening times, drop-in sessions, or meeting people in their preferred locations. Ensure people with coexisting severe mental illness and substance misuse, their family or carers are given accurate information about relevant local services (including, for example, community or family support groups). Also ensure they are given help to make initial contact with services. This could include information on how to access services, ways to contact the service, opening hours and how long the waiting list may be. Raise staff awareness of the needs of people with coexisting severe mental illness and substance misuse, including the fact that they may be traumatised. Ensure staff can meet their needs. ## Adapting existing secondary care mental health services Adapt existing specialist services to meet both a person's coexisting severe mental illness and substance misuse needs and their wider health and social care needs. Do not create a specialist 'dual diagnosis' service. Offer interventions that aim to improve engagement with all services, support harm reduction, change behaviour and prevent relapse. Take advice from substance misuse services (if applicable) about these interventions. (See the NICE guidelines on coexisting severe mental illness and substance misuse, psychosis and schizophrenia in children and young people, psychosis and schizophrenia in adults, bipolar disorder, self-harm, alcohol-use disorders, and drug misuse in over 16s: psychosocial interventions.) Offer individual, face-to-face or phone appointment sessions to encourage people with coexisting severe mental illness and substance misuse to use services. Offer phone sessions to their family or carers. Sessions could cover: how the person is coping with their current mental health and substance use and its impact on their physical health and social care needs progress on current goals or changes to future goals ways to help the person stay safe monitoring symptoms getting support from (and for) their family, carers or providers.Determine how often the sessions take place based on the person's needs. Consider the following: Crisis and contingency plans for the person with coexisting severe mental illness and substance misuse and their family or carers. Ensure these are updated to reflect changing circumstances. Support to sustain change and prevent relapse. Discharge planning, including planning for potential relapses, so the person with coexisting severe mental illness and substance misuse knows which service to contact and the service can provide the right ongoing support. (See also NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.) ## Support for staff Ensure the care coordinator in secondary care mental health services is supervised and receives professional development to provide or coordinate flexible, personalised care. Recognise that different attitudes towards, or knowledge of, mental health and drug- or alcohol-related problems may exist between agencies and that this may present a barrier to delivering services. To overcome this: challenge negative attitudes or preconceptions about working with people with coexisting severe mental illness and substance misuse develop leadership skills so staff can challenge attitudes and preconceptions (for an example, see the study by Hughes Closing the gap: a capability framework for working effectively with people with combined mental health and substance use problems). Ensure practitioners have the resilience and tolerance to help people with coexisting severe mental illness and substance misuse through a relapse or crisis, so they are not discharged before they are fully equipped to cope or excluded from services (see the section on maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them). # Maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them Recognise that even though building a relationship with the person and seeing even small improvements may take a long time, it is worth persevering. It involves: showing empathy and using a non-judgemental approach to listen, identify and be responsive to the person's needs and goals providing consistent services, for example, if possible keeping the same staff member as their point of contact and the same lead for organising care staying in contact by using the person's chosen method of communication (for example, by letter, phone, text, emails or outreach work, if possible). Explore with the person why they may stop using services that can help them. This may include: fragmented care or services inflexible services (for example, not taking into account that the side effects the person may experience from medication may affect their attendance at appointments) inability to attend because, for example, services are not local, transport links are poor, or services do not provide childcare not being allowed to attend, for example because they have started misusing substances again fear of stigma, prejudice or being labelled as having both mental health and substance misuse problems feeling coerced into using treatments or services that do not reflect their preferences or their readiness to change previous poor relationships with practitioners -ther personal, cultural, social, environmental or economic reasons. Help those who may find it difficult to engage with services to get into and stay connected with services. Start and maintain contact using proactive, flexible approaches (see recommendation 1.3.6 on approaches to keep people involved in their care plan). Recognise that people with coexisting severe mental illness and substance misuse are at higher risk of not using, or losing contact with, services. There are specific populations who are more at risk. These include men, young people, older people and women who are pregnant or have recently given birth. It also includes: people who are homeless people who have experienced or witnessed abuse or violence people with language difficulties people who are parents or carers who may fear the consequences of contact with statutory services. Ensure any loss of contact or non-attendance at any appointment or activity is viewed by all practitioners involved in the person's care as a matter of concern. Follow-up actions could include: contacting the person to rearrange an appointment visiting the person at home contacting any other practitioners involved in their care, or family or carers identified in the person's care plan (see recommendation 1.2.4 on involving the person in developing and reviewing the care plan) contacting the person's care coordinator within mental health services in the community immediately if there is a risk of self-harm or suicide, or at least within 24 hours if there are existing concerns. # Terms used in this guideline This section defines terms that have been used in a specific way for this guideline. ## Contingency management Contingency management is a set of techniques that focus on changing specific behaviours. For example, in drug misuse, it involves offering incentives for positive behaviours such as abstinence or a reduction in illicit drug use, and participation in health-promoting interventions. ## Dual diagnosis Dual diagnosis usually refers to mental illness combined with substance misuse. But it may also be used to describe a number of other conditions, including physical health problems. In the UK social care sector, the term is sometimes used for people who have both a learning disability and a mental illness. ## Relapse A recurrence or exacerbation of a person's mental health problems, a return to substance misuse, or both. ## Severe mental illness Severe mental illness includes a clinical diagnosis of: schizophrenia, schizotypal and delusional disorders, or bipolar affective disorder, or severe depressive episodes with or without psychotic episodes. ## Specialist services Specialist services refers to secondary care mental health services and dual diagnosis services. ## Substance misuse Substance misuse refers to the use of legal or illicit drugs, including alcohol and medicine, in a way that causes mental or physical damage. This may include low levels of substance use that would not usually be considered harmful or problematic, but may have a significant effect on the mental health of people with a mental illness such as psychosis.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during development of this guideline. They are: Lower caseloads are needed to provide consistent, coordinated and optimum services, but this has cost implications. Joint training could lead to a more consistent approach across mental health and substance misuse services. Leadership is needed from commissioners across health and social care services. Putting a guideline fully into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may need to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Adults and young people with coexisting severe mental illness and substance misuse have some of the worst health, wellbeing and social outcomes (see the Social Care Institute for Excellence's briefing on the relationship between dual diagnosis: substance misuse and dealing with mental health issues). It is not clear how many people in the UK have a coexisting severe mental illness and misuse substances, partly because some people in this group do not use services or get relevant care or treatment. The Department of Health's Refocusing the Care Programme Approach identifies people with coexisting severe mental illness and substance misuse as one of the groups in need of an enhanced Care Programme Approach. That is because they are not being identified consistently and services are sometimes failing to provide the support they need. The policy highlights the need for a whole systems approach to their care, involving a range of services and organisations working together. This guideline aims to address this need. Groups covered in this guideline include: young people (aged 14 to 25) and adults who have been diagnosed as having a severe mental illness and who misuse substances and who live in the community. The age cut-off for young people has been set at 14 to reflect the small numbers affected below this age – and the fact that many early intervention services usually start at age 14. In this guideline, severe mental illness includes a clinical diagnosis of: schizophrenia, schizotypal and delusional disorders or bipolar affective disorder or severe depressive episodes with or without psychotic episodes. Substance misuse refers to the use of legal or illicit drugs, including alcohol and medicine, in a way that causes mental or physical damage.# The committee's discussion Evidence statement numbers are given in square brackets. For an explanation of the evidence statement numbering, see the evidence reviews section. # Section 1.1 First contact with services ## Recommendations 1.1.1 to 1.1.6 The discussion below explains how we made recommendations 1.1.1 to 1.1.6. Committee members were aware from their experience that people with coexisting severe mental illness and substance misuse may present in crisis (for example, at A&E). But they may be also be found opportunistically in other settings (for example, homeless shelters) and identified as needing immediate assistance with a range of needs. This includes their mental or physical health, substance misuse or social care needs. They noted that the physical health and social care needs of this group are often overlooked because of the challenging nature of dealing with both mental health and substance misuse issues. They also noted that this group is often excluded from services because no one wants to take responsibility for them and they need help to access a wide range of services. In addition, members noted that a policy guide in 2002 (Department of Health's Dual diagnosis good practice guide) has advised that care for people with coexisting severe mental illness and substance misuse should be delivered within mental health services. The committee noted from the evidence and members' experience that people with coexisting severe mental illness and substance misuse are a vulnerable group, who often have poor physical health, are unemployed, homeless or are at risk of other people taking advantage of them. The latter includes being subjected to sexual exploitation or being taken advantage of in relation to their housing or financial situation. It noted there was strong evidence from a meta-analysis of 3 cohort and case–control UK studies (2 high quality and 1 low quality ) that people with coexisting severe mental illness and substance misuse (compared with those with severe mental illness only) were more likely to have a history of homelessness or housing problems. There was also evidence from 1 high-quality UK case–control study that this group of people are more likely to live in the most deprived areas. There was moderate evidence from 3 high-quality UK cohort studies that showed a greater number of people with coexisting severe mental illness and substance misuse are unemployed than those with severe mental illness only . The committee noted that a meta-analysis of 2 UK case–control studies (1 high and 1 moderate quality ) showed no difference in social functioning between this group and people with a severe mental illness only. However, 1 high-quality UK cohort study showed poorer social functioning in people with coexisting severe mental illness and substance misuse than in those with substance misuse . The committee also noted that this evidence was mainly from people in contact with secondary care mental health services and may not reflect the needs of the wider population of people with coexisting severe mental illness and substance misuse . The committee noted inconsistent evidence for educational outcomes . But members also noted from their experience that the point at which a person is diagnosed would have an effect on their educational attainment. The committee was aware, from the evidence and its experience, that this group is often stigmatised by staff or because of the type of services they are using. For example, this may be a negative attitude towards substance misuse within mental health settings or vice versa. This is based on evidence from 7 qualitative studies (2 high, 3 moderate and 2 low quality) reporting on barriers related to stigma and attitudes towards this group . Six qualitative studies showed that people with coexisting severe mental illness and substance misuse face a number of barriers or facilitators when accessing social care services, particularly housing support. Of the 4 studies that identified barriers to accessing housing support, 1 high-quality qualitative study reported that people with coexisting severe mental illness and substance misuse often feel there is a social stigma associated with seeking help . Also, services are often not easy to access. The committee felt that it is important for all services to address these issues from an inequalities perspective and to prevent further deterioration in the person's mental and physical health, social care and substance misuse needs. It was also aware from 7 qualitative studies (2 high, 3 moderate and 2 low quality) reporting on fragmented care, that a consequence of fragmented care is a negative impact on a person's experience of care and willingness to engage with services . So it made a strong recommendation that all staff coming into contact with this group should be able to understand their needs and help them access services. Committee members were aware from their practice and the evidence from 1 high-, 3 moderate- and 2 low-quality qualitative studies (3 set in the UK) that mental health and substance misuse services often fail to take responsibility for people with coexisting severe mental illness and substance misuse . The committee also noted the evidence from 1 low-quality UK qualitative study that highlighted commissioners' views that the health and wellbeing of this group need to be addressed . The committee noted that wherever people with coexisting severe mental illness and substance misuse present, a similar approach to helping them access care is needed. The committee advised that secondary care mental health services need to be the lead organisation responsible for delivery of services and therefore made a recommendation to refer people with coexisting severe mental illness and substance misuse to secondary care mental health services. The committee heard from an expert about the physical health issues that can affect people with coexisting severe mental illness and substance misuse . It noted that although the expertise was from a perspective of primary care services for homeless people, the range of health needs identified could be transferable to the wider population of people with coexisting severe mental illness and substance misuse. So the committee made a weak recommendation on the range of physical health conditions (for example, cardiovascular, cancer or communicable diseases) that staff need to be aware of. However, it noted that this is not an exhaustive list. It also reflected on the lack of evidence on the prevalence of coexisting physical health problems and agreed further research is needed (see the recommendation for research on needs assessment). The committee noted that because of the complexity of their needs, people with coexisting severe mental illness and substance misuse are at increased risk of poor self-care, losing contact with family and friends, social isolation or living in poor housing or having their homes abused by others as venues for substance misuse or drug dealing. Based on moderate to strong evidence from 4 cohort and 6 case–control studies, committee members were aware of the range of social care needs of people with coexisting severe mental illness and substance misuse in the UK . They were also aware from expert testimony , and their own experience of working with this group, of the detrimental effects that unmet needs (such as social isolation or poor housing) can have on a person's health and recovery, which could lead to relapse . This was based on 2 high-quality and 1 moderate-quality qualitative studies reporting on barriers when seeking housing support. The committee was aware that these unmet needs may lead to physical health problems, offending behaviour or disengagement from services. It was also aware that a person may have issues with both poor housing and physical health and that this may not always be a 'cause–effect' relationship. There was no evidence for cost effectiveness for this set of recommendations. Committee members agreed that recommendation 1.1.1 is for staff working in all general services. But they also noted that it would be applicable to other services, such as criminal justice system and urgent care. Committee members were aware that the criminal justice system was not included in the scope and that the evidence reviews did not specifically search for studies on the transition between criminal justice systems and healthcare services. They were also aware that NICE is developing guidance on the mental health of adults in contact with the criminal justice system. However, they felt it was important to include because it is a potential route for people with coexisting severe mental illness and substance misuse to come into contact with healthcare services. This was also reflected in the expert testimony on primary care services for homeless people . The committee was aware from its experience of the importance of highlighting safeguarding issues for this vulnerable population. It felt that this point needs to be for general services. The committee acknowledged that safeguarding has been made a statutory duty under the Care Act 2014. It was also aware of statutory safeguarding arrangements specific to children (see the Department of Education's guidance on working together to safeguard children) and statutory guidance to the 1989 and 2004 Children Acts (see Ofsted's report What about the children? ). The committee was also aware of the safeguarding needs of dependents and carers. # Section 1.2 Referral to secondary care mental health services ## Recommendation 1.2.1 The discussion below explains how we made recommendation 1.2.1. The committee was advised by the topic experts that secondary care mental health services are usually the lead agency that supports people with coexisting severe mental illness and substance misuse. Although this guideline focuses on people with diagnosed coexisting severe mental illness and substance misuse, the committee felt it was important to address the general issue of ensuring people are properly assessed so they can be offered an effective care plan. The committee noted from 1 moderate-quality study, 1 low-quality UK study and members' experience that timely assessments can help people to access services and stay involved with their care plan . The committee agreed with the recommendations on the principles of recognition and assessment in NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings, even though it has a narrower focus than this guideline. The committee also agreed that the recommendations on identification and diagnosis were useful (identification and diagnosis was outside the scope of this guideline). Although the psychosis with substance misuse guideline was specific to psychosis and not the range of severe mental illnesses covered in this guideline, members agreed it would be useful for readers to refer to both recommendations. The committee agreed to develop a recommendation on what needs to happen once a person is referred to and accepted into secondary care mental health services based on the evidence, expert testimony and members' own experience. There was no evidence for cost effectiveness for this recommendation. The committee agreed that substance misuse should not be a reason to exclude people from secondary care mental health services. Based on the evidence and from members' experience this is a common problem . The committee also noted from members' experience that the person's wider needs are often not recognised, or they are not given a routine assessment of their mental health or substance misuse needs to develop a care plan. From their experience, committee members were aware of the importance of a person-centred approach. This was reinforced by review 2. The committee was also aware of NICE's guidelines on coexisting severe mental illness (psychosis) and substance misuse and service user experience in adult mental health. Both outline the need for a non‑judgemental and empathetic approach built on trust and respect. The committee felt it was important to take a person-centred approach when developing and reviewing the care plan and made a strong recommendation on involving people in their care planning. This was based on evidence from: qualitative studies (2 high, 2 moderate and 1 low quality) reporting on facilitators related to the relationship between people who use services and practitioners. 1 of these studies was conducted in the UK qualitative studies, of these 2 qualitative studies (1 moderate and 1 low quality) reporting on benefits of consistent care. 1 of the studies reporting on facilitators was conducted in the UK qualitative studies (2 high, 3 moderate and 3 low quality) reporting on barriers and facilitators to engagement with healthcare and support services. 3 of these studies were conducted in the UK . ## On acceptance to secondary care mental health services The discussion below explains how we made recommendations 1.2.2 and 1.2.3. The committee agreed that secondary care mental health services take the lead in coordinating services and developing a care plan. The committee noted that care planning is usually led by a care coordinator because this is part of the Department of Health's Care Programme Approach. The committee was aware of the importance of continuing care. It was also aware that the continuity provided by a key contact encourages people to keep in touch with services (evidence review 2). This was based on the evidence from: qualitative studies (1 moderate- and 4 low-quality) reporting on barriers or facilitators associated with organisation and continuity of care, 3 based in the UK qualitative studies (2 high, 3 moderate and 2 low quality) reporting on barriers or facilitators associated with the impact of fragment care provision on continuity of care . There was no evidence for cost effectiveness for this set of recommendations. Based on their expertise and the responsibilities outlined in the Care Programme Approach, committee members made a strong recommendation that a care coordinator from community mental health services is assigned once a person has been referred to secondary care mental health services. They agreed that the care coordinator should take the lead in developing and reviewing the care plan and should take responsibility for organising delivery of a range of services, with the support of a wider team. Committee members advised that the role of care coordinator already exists within secondary care mental health services. They noted that care coordinators are part of a multidisciplinary team. But they also noted that overall responsibility (for example, for discharging a person) would lie with a consultant psychiatrist. ## Involving people with coexisting severe mental illness and substance misuse in care planning The discussion below explains how we made recommendations 1.2.4 to 1.2.6. The committee agreed that it is important to take a person-centred approach, by focusing on actions that are agreed with the person and by offering, not imposing, services on them. So it developed a set of recommendations on 'involving people' in care planning. These recommendations are deliberately separate from the recommendations on the actual content of the care plan (see the section on the care plan: multi-agency approach to address physical health, social care, housing and other support needs). The committee took into account qualitative evidence from 3 studies reporting on the barriers or facilitators that face people with severe mental illness and substance misuse face when trying to make decisions about their care : low-quality UK study about encouraging the person to be involved in their care plan decisions moderate-quality qualitative studies about respecting their preferences. It felt that these factors can help a person adhere to their care plan. The committee was also aware from the evidence (5 qualitative studies: 2 high quality, 2 moderate quality and 1 low quality) and their experience that a good relationship between the health or social care professional and the person with coexisting severe mental illness and substance misuse is key to effective delivery of health and social care services . Members noted that a good relationship can affect a person's willingness to engage with and respond to care, and can also affect their recovery. Bearing in mind all these factors, it made a strong recommendation on the need to take them all into account when developing a care plan. The committee noted from members' experience that providers need to understand what is having an effect on the person each time they see them, so that they can provide the right level of support, including information, each time. It noted that the frequency of contact can vary depending on the person's circumstances. It also noted the importance of sharing the care plan between services. The committee noted that people can recover. But it also noted that for this group of people, 'recovery' may not necessarily only be about reducing their substance use but about leading a productive life. The members felt that although recovery may take time, providers need to always convey a sense of optimism whenever possible. The committee was aware that changing behaviour may be a lengthy process and that NICE's guideline on behaviour change: individual approaches may provide useful strategies on personalising messages. There was no evidence for cost effectiveness for this set of recommendations. ## Carers The discussion below explains how we made recommendations 1.2.7 and 1.2.8. The committee was aware of current legislation that entitled carers to an assessment of their needs (Care Act 2014). The committee was aware from the evidence and members' experience, that a carers assessment may be particularly important if the carers are children . Members' experience highlighted that a point of contention for carers is that they may not be privy to the person's plans and wishes. Evidence from 2 qualitative studies (1 moderate quality and 1 UK study of low quality) highlighted the barriers faced by families and carers in relation to receiving support for themselves . So the committee developed a recommendation based on the evidence, expert testimony and their expert knowledge to highlight young people and adult carers' needs and ways to support them . There was no evidence on cost effectiveness for this set of recommendations. The committee was aware, from its own experience, that carers may not be offered the opportunity to decline caring responsibilities that are beyond their capacity when they are being assessed. That is why it is important to highlight that carers may be entitled to further support, even though this is specified in the Care Act. # Section 1.3 The care plan: multi-agency approach to address physical health, social care, housing or support needs ## Recommendations 1.3.1 to 1.3.8 The discussion below explains how we made recommendations 1.3.1 to 1.3.8. Social care needs should be assessed in line with the Care Act 2014. Provision of an advocate is in line with this legislation. The committee noted from the evidence from 1 high-, 4 moderate- and 3 low-quality qualitative studies (including 4 studies in the UK) that the lack of a shared approach between services could act as a barrier to providing health and social care services . The committee heard from an expert on local partnership working and experts working with people with coexisting severe mental illness and substance misuse who are homeless . The experts highlighted factors that could help with a coordinated approach. Based on the evidence, expert testimonies and their own experience, members agreed that important factors in providing a coordinated approach included a shared vision, joint responsibilities and regular communication . The committee highlighted the range of agencies or providers the care coordinator in secondary mental health services would need to work with to ensure people receive care for their wider health or social care, housing or support needs. The committee highlighted the physical health, social care, housing and other support needs that need to be considered when developing and reviewing a care plan. Members reflected on the evidence, expert testimony and their own experience to inform their recommendations on social care, housing and other support needs . The committee referred to evidence previously noted in the discussion for section 1.1 . It also considered the evidence from 2 qualitative studies (1 high quality and 1 moderate) which described the barriers faced by this group in relation to employment support . Members reflected on expert testimony and existing NICE guidelines on a range of health behaviours . Based on this and their knowledge and experience they made a weak recommendation to decide on how a person's physical health could be improved and provided examples of how this may be achieved. This included addressing health behaviours (such as improving diet, quitting smoking or increasing physical activity) and minimising risky behaviours (such as unprotected sex, sharing needles). They realised this is not an exhaustive list and that the care plan may need to address other behaviours. The committee also noted that care coordinators may need to help people with practical tasks so that the person can look after their own physical health. The examples were based on the committee's expertise on the type of tasks undertaken by care coordinators. So the committee made a weak recommendation on approaches to keep people involved in their care plan. In addition, the committee noted the importance of encouraging activities to improve physical wellbeing (for example football or walking groups). But it was aware of the risk of widening inequalities if this only reaches people who already use services. The committee agreed that potential inequalities could be addressed by recommending providing inclusive services and strategies to improve engagement. The committee made a weak recommendation on practical strategies that may help improve uptake of services and prevent relapse. This was based on evidence, expert testimony and the committee's expertise . The committee was aware from 1 moderate and 1 low-quality study (set in the UK) of barriers or facilitators associated with providing information or training . One moderate-quality study showed supporting people to develop self-care skills helped with daily living. The committee used this evidence combined with their experience to give other examples of practical skills to include in the recommendation. Recommendations on how to encourage use of services and the suitability of different types of support were based on evidence review 2, expert testimony and the committee's expertise. The committee noted that people with coexisting severe mental illness and substance misuse are particularly at risk of being taken advantage of, so it is important to ensure the type of support they are offered is suitable for them . The committee was aware from members' experience and expert testimony that communication between services is often poor . The committee was also aware, from members' experience, that people are often discharged early or denied access to services because of missed appointments. There is often a good reason why the appointment was missed – for example, because the person was having side effects from their medication – but this has not been shared among the agencies involved. This was also highlighted in 2 qualitative studies (1 high, 1 moderate quality) in review 2. Members made a strong recommendation, noting that this can be addressed by making sure practitioners communicate and share information with each other, particularly in relation to non-attendance, so that it does not lead to an automatic discharge. There was no evidence for cost effectiveness for this set of recommendations. ## Review The discussion below explains how we made recommendations 1.3.9 and 1.3.10. Committee members were aware from their experience and from the evidence of the barriers or facilitators associated with an integrated approach to care from 1 high-quality, 6 moderate- quality, and 2 low-quality qualitative studies (2 set in the UK) . They noted from members' experience, expert testimony and the evidence that this could increase engagement and result in positive improvements in health, functioning and wellbeing. Although the UK studies were low quality, the committee felt the findings were relevant because they reflected the views of providers and users in voluntary sector services. They also noted the importance of different disciplines working collaboratively, and taking part in case review meetings. This was based on the evidence from 8 qualitative studies reporting on barriers or facilitators associated with the management of cases with members of the same team and across different health and social care agencies . The committee noted that the frequency of case review meetings would vary and would involve multidisciplinary team members and several different agencies. This is important to make sure a person's care plan is up to date and relevant. The strong recommendation to review the plan annually was based on the Care Programme Approach. But the committee recognised that this would depend on the person's level of need and circumstances and so recommended review meetings could be more frequent, if needed. The committee noted the importance of regular monitoring of physical health, including for adverse effects of medications . It was aware of strong evidence from 3 UK studies (2 case control and 1 cohort) that people with coexisting severe mental illness and substance misuse are less likely to adhere to medications than those with severe mental illness only . The committee heard expert testimony about the side effects of medication and was aware from members' experience that this includes weight gain and other adverse effects . Members felt this could be a barrier to adhering to treatment and could have a negative impact on a person's mental or physical health. Committee members acknowledged that the evidence on working collaboratively and the views expressed in the expert testimony reflected their own experiences of working with people with coexisting severe mental illness and substance misuse . They noted that changes in circumstances need to be taken into account in a person's care plan and physical health or social care, support or housing needs revised accordingly. There was no evidence for cost effectiveness for this recommendation. ## Discharge or transition The discussion below explains how we made recommendations 1.3.11 and 1.3.12. Committee members noted from their experience that transfer between services and discharge from the Care Programme Approach are key points when a person can lose touch with services. The committee felt that a robust relapse prevention plan and re-entry into the system would help to mitigate the risk of suicide or death from unintentional overdose. The committee agreed that housing needs are a priority before discharge and referred to evidence previously noted in the discussion for section 1.1 and discussion for section 1.3 . The committee noted that the discharge plan should also include information on managing risky situations because of the challenging nature of working with people who may be intoxicated or in withdrawal. This was based on members' experience and evidence from 2 moderate-quality and 1 low-quality studies . The committee was aware of NICE's guideline on violence and aggression and agreed it was a useful source for providers. Members noted the evidence on challenges people can face when moving between services and felt this was applicable to other key points in a person's life . The committee acknowledged the need to take a 'life course' approach. So it strongly recommended that provision for continuity of care needs to be in place when transition between services occurs and at key points in a person's life. This was based on members' experience and evidence from 4 qualitative studies (2 high and 2 moderate quality) . The members highlighted particular groups who may need additional support based on their expertise and existing NICE guidelines. There was no evidence for cost effectiveness for this set of recommendations. The committee heard expert testimony on the importance of making sure the guideline included the referral of young people to adult services . It also reflected on members' experience and noted that groups such as looked after children and older people may need additional help. So handover of care on discharge, or when a person transfers to another service (in consultation with other providers), was included in the recommendation. The committee agreed that encouraging practitioners to meet at multidisciplinary and multi-agency meetings is likely to improve physical health, social care and support outcomes and potentially reduce admissions for crisis care. But it also noted that this may be a new approach for the non-mental health sectors and that releasing staff for these meetings could be problematic without additional resources. # Section 1.4 Partnership working between specialist services, health, social care and support services and commissioners ## Recommendations 1.4.1 to 1.4.5 The discussion below explains how we made recommendations 1.4.1 to 1.4.5. The committee noted that although a policy guide in 2002 (the Department of Health's dual diagnosis good practice guide) had set out the vision for how services and care could be delivered, it was not being implemented. The committee was aware of Public Health England's guidance on co-existing alcohol and drug misuse with mental health issues: guidance to support local commissioning and delivery of care which sets out the importance of joint working. The committee discussed the fact that since April 2013 there have been separate funding streams for mental health and substance misuse services, with mental health services funded by clinical commissioning groups and substance misuse services by local authorities. The committee felt this exacerbated a longstanding division between the mental health and substance misuse sectors. It has also led to 2 different sets of organising paradigms for commissioners, which does not serve people with coexisting severe mental illness and substance misuse. Members also noted that funding for addiction services comes from local authority budgets and is subject to commissioning contracts (which may exclude provision of mental health assessment or prescribing) and competitive tendering. The committee decided to recommend partnership working because there is a lack of provision of health and social care services for people with coexisting severe mental illness and substance misuse. Where it exists, it is often fragmented and inconsistent and this can affect continuity of care. This was based on members' experience and the evidence previously noted in the discussion for section 1.2 . The committee noted from the qualitative evidence previously described in the discussion for section 1.3 that different disciplines working together to support people with coexisting severe mental illness and substance misuse could help with coordinating care. If they work together and share responsibility for this group, the evidence showed it could improve the quality of health and social care services offered . The evidence showed this could be done by joint management of cases and regular communication. The committee also heard from an expert in local partnership working who described a framework designed to help local areas design and deliver flexible and coordinated services for people with multiple needs . The committee noted that there needs to be a strategic framework for services that work with people with coexisting severe mental illness and substance misuse. And that commitment from providers and commissioners is essential for services to collaborate locally. Based on the evidence, the expert testimony and their own experience, committee members agreed that a cross-sector partnership, with a shared understanding of the problem (based on assessment of local needs) and a shared vision for the future were important factors . Based on their expertise and expert testimony, they developed a recommendation on how services need to work together. They also noted the lack of evidence from review question 1.2 on existing care pathways and agreed further research is needed (see the recommendation for research on care pathway). The committee was aware of evidence from review 2 that a lack of policy on referrals has an effect on the organisation and continuity of care. Evidence from 4 qualitative studies conducted in different settings (including 1 UK study set in the voluntary sector) noted that uncertainty on who should make referrals can also have an impact . Committee members noted that the evidence from qualitative studies (previously noted in sections 1.1 and 1.2) was consistent with their experience . This showed that pathways were inadequately planned and supported and that movement across a care pathway was often restricted because none of the specialist services took responsibility for this group. They also noted that continuity of care can be interrupted because of changes in the commissioning process or cycle. For example, re-tendering for services can lead to disruption and the need to build new care pathways. One UK low-quality qualitative study exploring the views of commissioners provided evidence of a facilitator associated with organisation and continuity of care. The study noted that good links between the statutory and voluntary sectors improved outcomes, such as reduced waiting times and delivery of care . This could also help with organisation and continuity of care. The same study also highlighted that existing resources were stretched and that investment in the non-statutory sector could lead to provision of services not available in the statutory sector . But the committee noted that this study was published in 2006. It also noted that commissioning and service provision for addiction services, the demography of people who use the services, treatment and the types of substances used have all changed markedly since 2002. The committee noted from the evidence that there is no national service configuration in place (review question 1.2). Members acknowledged the importance of including the needs of people with coexisting severe mental illness and substance misuse in the joint strategic needs assessment. They agreed the needs of this group could be included in local strategies (for example, housing, alcohol or drug services and crime prevention). The committee noted that referral processes and pathways need to be in place to ensure this happens – and that a joined-up approach would help because this group often falls through the gaps in services. Committee members also highlighted the importance of prompt access to services, based on their own experience and evidence. This was based on 1 high-, 2 moderate- and 3 low- quality qualitative studies (3 set in the UK) reporting on barriers and facilitators when seeking access to health advice. Barriers included long waiting lists, and 1 low-quality UK study indicated that direct referrals by alcohol and addictions teams could act as a facilitator . Members agreed that direct referrals may be useful. They noted that direct access to services may be beneficial (compared with, for example, open access drop-in clinics) because this would give the person a sense of continuity of care. In turn, this may also enhance feelings of trust . There was no evidence for cost effectiveness for this recommendation. ## Information sharing The discussion below explains how we made recommendations 1.4.6 and 1.4.7. The committee made recommendations to highlight the importance of information sharing. The committee noted an expert testimony that highlighted that confidentiality is a barrier often faced by voluntary sector as an excuse not to share information . The committee also noted the importance of services knowing about other local services and being able to tell people with coexisting severe mental illness and substance misuse or their families or carers about them . For example, 1 UK low-quality study set in the voluntary sector noted that GPs were unaware of local community groups that people with coexisting severe mental illness and substance misuse could use . There was no evidence for cost effectiveness for this recommendation. # Section 1.5 Improving service delivery ## Making health, social care and other support services more inclusive The discussion below explains how we made recommendations 1.5.1 to 1.5.5. The committee observed what appears to be an inequity in the way that people with coexisting severe mental illness and substance misuse are treated by services compared with other groups. It noted that the needs of this group are often not taken into account and they risk being excluded from mainstream services. Therefore the committee made a strong recommendation on improving delivery of existing services to make them more inclusive. Committee members were aware, from their own experience, the evidence and expert testimonies of the benefits of supporting people to participate in improving services . The committee also noted from the evidence (previously described in the discussion for section 1.2) the importance of involving people with coexisting severe mental illness and substance misuse (and their family or carers), and providing them with information and support . The ways in which people with coexisting severe mental illness and substance misuse, and their family or carers, could be involved in design and delivery of services were based on the findings from the review on epidemiology and current configuration . The committee noted from its expertise and evidence (previously noted in the discussion for section 1.1) that people are often passed between services without being provided with appropriate care and support and that this may be because of negative attitudes or stereotyping by staff or services . The committee also noted from its experience and the evidence that these factors can lead to a mistrust of professionals, resulting in poor engagement with services . This was based on evidence from 3 (1 high and 2 moderate quality) of the 9 qualitative studies (1 high, 4 moderate and 4 low quality) reporting on barriers associated with access to effective care by trusted professionals. In addition, members agreed that a pessimistic attitude among professionals, about the likelihood of the person staying in the service may also be a contributing factor to the poor service. The committee was aware from the evidence review on epidemiology that the prevalence of coexisting severe mental illness and substance misuse varied across regions. The evidence showed that semi-rural areas seem to have the highest need . This was based on moderate evidence from 9 cohort studies (4 high, 1 moderate and 4 low quality) and 7 case–control studies (2 high, 2 moderate and 3 low quality) reporting on the prevalence of coexisting severe mental illness and substance misuse among those in contact with secondary mental health services. Expert testimony suggested there is a high incidence of early psychosis in rural areas, but the committee noted from the evidence that specialist services are mostly in urban areas . The committee agreed not to make a recommendation specifying content or configuration of service delivery by geographical settings. Instead it felt that the most important message was to ensure that any services needed (as identified by the joint strategic needs assessment) are delivered locally. The committee made a strong recommendation on locating services in places that are safe and where there is minimal stigma attached to attending. It acknowledged the evidence (1 moderate- and 1 low-quality study) on co‑location of services (for example, services based in the same facility) was mixed but recognised that there may be stigma in accessing certain services . Committee members were aware from their experience and from expert testimony that people with coexisting severe mental illness and substance misuse are particularly vulnerable. They may be at risk of exploitation (for example, being forced to become sex workers or being taken advantage of in relation to their housing or financial situation). Or they may have experienced trauma (for example, women may have experienced rape) . It agreed that a 'trauma-informed' approach would provide the best support for this group. Members were also aware from the evidence that even if people knew about services, barriers to access included difficulty in contacting or gaining admission to services outside hours, long waiting lists and services not being local . The committee considered the evidence review (review question 1.2) on current configuration of services and developed a recommendation highlighting the importance of safety of location, low stigma and flexibility in opening times as factors that can help make services more accessible. See the end of this section for details on cost effectiveness. ## Adapting existing secondary care mental health services The discussion below explains how we made recommendations 1.5.6 to 1.5.9. The committee was aware of moderate evidence from 13 UK studies (2 high, 9 moderate and 2 low quality) that there were inconsistencies in the current configuration of 'dual diagnosis' services in NHS trusts across the UK . These inconsistencies lie in several areas, including sources of funding, structure of services, type of staff members, services delivered and coordination of care. The committee considered the evidence on configuration of services and observed there were few specialist services for adults . The committee agreed that the recommendations for specialist services (secondary care mental health services and 'dual diagnosis' services) need to focus on improving existing services using the expertise that is available instead of creating a specialist 'dual diagnosis' service. It felt that the standard care delivered in the UK could be improved by increasing the level of engagement people with severe mental illness and substance misuse have with existing services and that existing capacity and resources could be used to deliver this. The committee made recommendations about the design, delivery and content of the service model, based on the evidence, economic model, expert testimony and members' expertise. The committee considered the evidence for the effectiveness and efficiency of service delivery models, which included randomised controlled trials (RCTs) and observational studies . The evidence covered a range of service delivery interventions, showing some positive outcomes and that there was value in what the models were aiming to achieve. However, the members agreed that there was no overwhelming evidence of benefit to indicate a particular model should be recommended. The committee agreed that there was limited evidence of effect for assertive community treatment and integrated treatment interventions in relation to mental health and substance misuse outcomes . The committee noted that fidelity to delivery of interventions (whether the intervention was delivered as designed) in the service models was reported for only 5 studies. Where reported, the fidelity was considered to be good. There was weak evidence for assertive community treatment based on 5 US RCTs . The committee noted that the assertive community treatment intervention model is no longer used in the US and is rare in the UK. There was moderate evidence from 6 RCTs and 1 observational study (3 studies based in the UK) for integrated treatment interventions compared with treatment as usual . There was weak evidence from 1 RCT for integrated treatment intervention compared with enhanced assessment and monitoring. The RCTs did not all show a clear evidence of benefit . There was some improvement in service use outcomes (increase in physical and telephone contact) but members noted that it was debatable whether this was necessarily an evidence of benefit, because the reasons for contacts were not reported . There was some evidence of effect on social care outcomes such as housing, employment and social functioning . The committee felt that although the follow-up in the studies ranged from 24 weeks to 3 years, the length of time needed to observe small improvements can sometimes be 5 to 10 years . There was moderate to weak evidence from 8 RCTs and 1 non-randomised controlled trial evaluating a range of interventions. The intervention included: brokerage case management contingency management time-limited care coordination shelter-based psychiatric clinic staff training supportive housing supportive text messaging. The comparator arms were no intervention, treatment as usual or an active comparator. The committee noted that there was mainly weak evidence from small studies, with short follow-up (ranging from 16 to 78 weeks). Three studies were based in UK and Ireland but most of the evidence was from US. It noted that fidelity to delivery of the intervention was reported in only 2 studies (1 reported as low and 1 as high fidelity). Members discussed the potential value of service models incorporating contingency management, peer support (delivered as part of a care coordination intervention in 1 US study) or text messaging, and considered these further under research recommendations (see the recommendation for research on what works). The committee agreed that there was weak evidence for a staff training intervention considered in the review of effectiveness of service delivery models . It noted that the 2 UK studies were of low quality, the evidence was inconsistent and did not appear to show an overall benefit. In addition, a committee member reflected on their own involvement in delivery of the intervention in 1 of the studies. The committee member noted that there were a number of challenges: staff often moved between services, there was a high turnover of staff, and low fidelity to delivery of the intervention. The committee agreed not make a recommendation on training because the evidence did not show an overall benefit. The committee agreed there were several gaps in the evidence from review 3 including: population (limited evidence on young people and vulnerable groups) interventions or measures – for example, measures looking at improving accessibility and availability of services -utcomes (no evidence on physical health outcomes) efficiency of service delivery models – for example outcomes on accessibility of services (waiting times). See the end of this section for details on cost effectiveness. The committee was aware of evidence from 4 qualitative studies (1 moderate- and 3 low-quality studies) of barriers or facilitators associated with integrated services. One low-quality UK study, for example, described mixed views among staff in a specialist 'dual diagnosis' service on whether services should be separate or integrated with mental health or substance misuse services . It noted that there was evidence from the same study indicating that most commissioners felt that integrating services is essential for the effective and efficient delivery of care for people with complex needs. Some commissioners also noted that relationships between different services could be expected to improve if they were required to share budgets and resources. Committee members felt this finding (published in 2006) should be treated with caution because the funding landscape has changed considerably since 2002. Based on their experience they noted that: a third tier of provision may not necessarily meet the needs of people with coexisting severe mental illness and substance misuse, and 'integration' in this context should be about joint working and coordinated care rather than developing a specialist service. The committee noted that there was limited description of the comparator arms (often described as 'treatment as usual') in the studies included in review 3 and that most of the studies were conducted in the US. The committee's view was that 'usual care' in the US is likely to differ from that in the UK and the level of 'usual care' in the UK was considered to be of a better standard. The committee used members' expert knowledge and the evidence to develop a recommendation on aspects that could be included in a service. This includes interventions that have shown to be effective in NICE guidelines for either severe mental illness or substance misuse. The committee was aware of the study by Wenze (2015; adjunctive psychosocial intervention following Hospital discharge for Patients with bipolar disorder and comorbid substance use: a pilot randomized controlled trial) included in the economic model. It reflected on the components of the 'treatment–engagement' sessions in the Wenze (2015) study as well as members' own experience to develop a recommendation on ways to improve engagement. The committee noted that any recommendation on improving service delivery needs to take into account the needs of those who reach crisis and those who experience a relapse after discharge. This recommendation was based on members' expertise. Members were aware from the evidence and their experience that people's care is often fragmented and that plans need to be in place to allow people to return for additional support after being discharged or losing touch with the system. They noted the evidence on facilitators for consistent care, including from 1 low-quality UK study that highlighted that good aftercare is an important means of preventing relapse . They also noted that the Department of Health's Mental Health Crisis Care Concordat has information on developing an action plan for people in a crisis. ## Support for staff The discussion below explains how we made recommendations 1.5.10 to 1.5.12. ## Current practice It is good practice for care coordinators working with people with severe mental illness who misuse substances to be offered support and supervision in secondary care mental health services. But practice may vary. ## Evidence The committee noted the importance of support and supervision from their experience and the evidence from 2 high-, 1 moderate- and 2 low-quality qualitative studies (3 set in the UK) . Because of the complexity of the care coordinator's role, the committee felt it was important to highlight in the recommendation the importance of a support structure for this role. Committee members were also aware from the evidence that lack of training may act as a barrier to the effective delivery of care . This was based on 10 qualitative studies (2 high, 3 moderate and 5 low quality), with 5 studies set in the UK. They also noted from the evidence and their experience that addressing gaps in practitioners' knowledge on substance misuse and mental health can encourage them to establish links with other services and help improve delivery of services. Evidence from 1 high-, 3 moderate-, and 1 low-quality qualitative studies (2 set in the UK) found that staff having different perceptions of people with drug and alcohol problems, depending on the focus of the service they work in, is a barrier to service delivery and partnerships. This view was consistent among providers and commissioners across various settings . Providers' views across 6 qualitative studies highlighted services not taking responsibility for people with coexisting severe mental illness and substance misuse, and the potential impact of this on meeting people's wider health, social care or support needs . Three of the studies were set in the UK, 1 was of moderate quality and 2 were low quality. The committee noted that although 1 of the UK studies was of low quality it was recent and reflected voluntary sector providers' views. Members drew on the evidence and their own expertise and noted that helping overcome negative attitudes in staff will help make sure people with coexisting severe mental illness and substance misuse are not excluded from services. Committee members were aware from the evidence from 5 qualitative studies (2 high-, 2 moderate- and 1 low-quality studies) of the importance of establishing good relationships between practitioners and people with coexisting severe mental illness and substance misuse and its impact on delivery of care . They also noted there was high-quality UK evidence from 1 study to show that practitioners perceived that behaviours such as misusing drugs could affect relationships and act as a barrier to delivering care . Based on the evidence and their experience, the committee made a strong recommendation on the need to build services that are tolerant and resilient. It agreed that services need to be able to help people work through relapse, poor attendance or a crisis to ensure they are not discharged too soon. The committee heard from an expert on a service delivery model in early intervention services . It noted that these services offer a more consistent and coordinated approach. That is because the staff working in them have lower caseloads, so can have more contact with the people they work with and provide stability. The committee noted a similar approach needs to be considered for staff who work with people with severe mental illness and substance misuse. Taking into account the evidence, members' experience and expert testimony, the committee made strong recommendations on providing the right kind of support for staff. The committee discussed the evidence from the cost effectiveness studies and the economic model when developing the recommendations on improving service delivery. An economic analysis was undertaken. This comprised a review of existing cost effectiveness studies and a bespoke economic model. The findings from the review of evidence (from 1 UK and 7 US studies) were inconsistent . The US studies found that integrated treatment leads to minor cost savings but the UK study found that the intervention resulted in an increase in public sector costs. In all studies, integrated treatment appears to result in improvement in some outcomes. But economic analyses used different outcome measures, reported as changes on various scales, making comparisons challenging. Three studies adopted before-and-after design, studies used different perspectives and time horizons, only 1 included economic study was judged to be directly applicable, 3 studies were judged to be characterised by minor limitations , 4 by potentially serious limitations , and 1 by very serious limitations . Overall, there is little evidence to support one service delivery model over another, based on existing economic evidence. The model was based on 3 studies. The first study, conducted in the US, comprised a treatment–engagement intervention (using resources more intensively than in standard care) for people with bipolar disorder and substance misuse. It was a small study whose health outcome was inconclusive, but yielded resource use data. The remaining 2 studies, both from the UK, were used to estimate baseline admissions rates for people with dual diagnosis. The model's time-horizon was 1 year only. So increases in life expectancy that might have occurred as a result of an intervention were not included as benefits in the model. Because of the lack of data, a further conservative assumption was that wider costs, particularly those falling on the criminal justice system, were not included. Further, the model's measured outcome might not have measured all of the health outcome benefits. The model showed that an intervention that combined enhanced engagement with standard care would need to reduce relapses by about 12% for the intervention to become cost saving. The committee members had differing views about whether UK standard care is better than that reported in the US studies. It was felt that standard care in the UK may be more similar to the enhanced intervention modelled. Assuming standard care in the UK is equivalent to the enhanced intervention modelled, it would be offering better outcomes at the same cost. By definition, that would be a cost-effective approach. However, assuming standard care in the UK would need to be enhanced and therefore need additional resources, at a cost of £226 per person and assuming an effect size of 10% the intervention would need to result in a small quality-adjusted life year (QALY) gain of 0.002 (equivalent to 0.73 days in full health) to be considered cost effective at an incremental cost effectiveness ratio threshold of £20,000 per QALY . Given the results that were obtained even though a number of potential benefits were not considered because of the lack of data (for example on a person's life expectancy, improvement in the substance misuse problem, improvement in the mental health of service users the reduction in health and social care and the criminal justice system costs) the treatment–engagement intervention is very likely to be a cost-effective option. # Section 1.6 Maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them The discussion below outlines how we made recommendations 1.6.1 to 1.6.5. Committee members decided to make recommendations on encouraging people to stay in contact with services and making services accessible. That is because they were aware, from the evidence and their own experience, that this group may find it hard to start or maintain contact with services . Also, their physical health, social care, housing or support needs are not being met. ## Evidence The committee noted from its experience that it is important to take a long-term, realistic view in relation to involving the person in their care plan and coordinating their care. It noted from experience and evidence (previously noted in the discussion for section 1.3) that this is particularly true in light of the challenging nature of working with this group . Committee members were aware – from the evidence, expert testimony and their own experience – of the importance of providing continuity and adopting a flexible approach. The committee heard from experts working with people who are homeless about a range of methods that could be used to engage and stay in touch with this group . The committee also considered evidence from 4 qualitative studies (1 high, 1 moderate, 2 low quality), of which 2 were UK studies . This highlighted that a lack of continuity of care, along with changes in staff, can result in a lack of trust or reluctance to engage with services. It also highlighted that good aftercare was an important aspect of preventing relapse. Committee members reflected on their experience and the evidence from 8 qualitative studies of mixed quality (2 high, 3 moderate and 3 low). Three of the studies (low quality) were set in the UK. The studies showed that a non-judgemental empathetic approach was needed when encouraging a person to stay in contact . The committee noted barriers to access or uptake of social care or physical health services as highlighted in review 2 . These included: fragmented care lack of support during a transition period (for those who had criminal convictions) failure to recognise cultural differences mistrust of healthcare professionals poor links to services negative connotations of being labelled as having problems with both mental health and substance misuse negative attitudes stereotyping or stigma about mental health diagnoses in substance misuse settings or about substance misuse in mental health settings. The committee was aware from evidence review 2 and members' experience that having continuity of contact encourages people to keep in touch with services. The committee made a weak recommendation on a range of approaches based on members' experience and expert testimony . The committee recognised that everyone with coexisting severe mental illness and substance misuse faces difficulties in receiving care, but it wanted to highlight that some groups are particularly vulnerable. It acknowledged that factors contributing to this include not being able get to, or stay in contact with, the services they need . The committee noted moderate to strong evidence from 11 cohort studies and 7 case–control studies on the characteristics of the coexisting severe mental illness and substance misuse population . It noted that it is more common in younger people and men . It also noted that homelessness is a frequent outcome for this group . Members also acknowledged that pregnant women or women who have recently given birth are particularly vulnerable. This was based on their experience and evidence review 2. The committee noted from its experience that people with coexisting severe mental illness and substance misuse frequently have a history of trauma and that this can lead to disruptive attachments and challenging behaviour. It also noted that, from a 'life course' perspective, older people may be a particularly vulnerable group. The committee noted that the evidence linking ethnicity with coexisting severe mental illness and substance misuse was inconsistent . Apart from age, gender and ethnicity, there was a lack of evidence to show that groups identified in the equality impact assessment are more likely to have a coexisting severe mental illness and substance misuse. This includes, for example: people with a learning disability; teenage parents; Gypsies and Travellers; asylum seekers or refugees; lesbian, gay, bisexual, transsexual or transgender people; and sex workers . The committee was aware from its experience that everyone has a range of social care needs, but noted that the evidence did not identify particular social care needs for groups identified in the equality impact assessment. That includes, for example, those who are socially isolated, on low income, have a history of being 'looked after' or are adopted or have a history of experiencing or witnessing domestic violence and abuse . Although no evidence was identified, the committee was aware from its experience that some groups may be reluctant to engage with, or may encounter difficulties when engaging with, services for people with coexisting severe mental illness and substance misuse. This includes people who are recent migrants, have language difficulties or are from specific religious communities. From an equality perspective, committee members recommended including people with language difficulties. Although it is not an exhaustive list, the committee highlighted the groups identified in recommendation 1.6.4 based on the evidence, their expertise and expert testimony . The committee noted that, although the evidence from review 2 provided insight into barriers and facilitators to delivery of care, it agreed that research was needed to understand the experience of people at different stages of recovery (see the recommendation for research on barriers and facilitators). Committee members were aware, from the evidence and their experience, that lack of emotional support and empathy can be a contributing factor to non-attendance at appointments or loss of contact . They were also aware that non-attendance can often lead to discharge . Based on the evidence, their expertise and expert testimony, they made a strong recommendation on actions services can take to ensure that non-attendance or loss of contact is treated as a matter of concern . Committee members reflected on their experience and expert testimony and noted the importance of maintaining contact and reaching out to people to help them remain engaged with services . Based on their experience, they made a weak recommendation on the follow-up actions to address non-attendance. The committee noted that maintaining engagement can lead to improved outcomes and may place less burden on crisis care or inpatient admissions. # Other points the committee discussed The committee discussed the exclusion criteria in the scope and noted that exclusion of mental health disorders such as eating disorders was a major gap. The committee noted that criminal justice system settings were excluded from the scope, but was aware of NICE guidelines currently in development on the mental health of adults in contact with criminal justice system and the physical health of people in prison. It also recognised that young people and adults with coexisting severe mental illness and substance misuse who need a safe place to stay may come into contact with people within this setting, for example, the police. The committee noted that resources for helping the police to support people with vulnerabilities are available in the Home Office's Crisis Care Concordat. The committee considered a range of expertise that would be helpful to inform the development of the guideline and invited expert testimony in early intervention services, primary care, homeless, and local partnership working. The committee also acknowledged other groups (refugees, veterans) but recognised that there is a general set of needs that would subsume the specific needs of particular populations. The committee considered all the evidence available in developing this guideline. However, some evidence statements provided background information and could not be explicitly linked to recommendations . The committee heard from an expert in early intervention services who described a study on contingency management (see the CIRCLE study) that provided background information and was not linked to a specific recommendation . The committee discussed the various forms of support groups or mechanisms for peer support. It was aware of mutual aid organisations including Alcoholics Anonymous (AA), Narcotics Anonymous (NA), Dual Recovery Anonymous (DRA) and SMART recovery and discussed the merit of adding a reference to such forms of support as examples in the guideline recommendations. It was also aware of Public Health England's briefing on the evidence-based drug and alcohol treatment guidance recommendations on mutual aid but noted it was not aware of evidence establishing use of mutual aid in people with coexisting severe mental illness and substance misuse. In addition, because peer support and mutual aid were areas identified for a research recommendation, the committee did not recommend specifying examples of mutual aid groups in the guideline recommendations. The committee also noted that there is a stigma attached to the term substance 'misuse' but recognised that this term is used in other NICE guidelines. # Evidence reviews Details of the evidence discussed are in evidence reviews, reports and papers from experts in the area. Studies reported in evidence review 1 were all based in the UK. For evidence statements derived from evidence reviews 2, 3 and 4 we have noted the number of studies based in the UK in the committee's discussion section. Please refer to the full evidence statements in the evidence reviews on the applicability of the evidence base to the UK. The evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from. Evidence statement (ES) number 1.1.1 indicates that the linked statement is numbered 1 in review question 1.1 of review 1. ES1.2.1 indicates that the linked statement is numbered 1 in review question 1.2 of review 1. ES2.1.1 indicates that the linked statement is numbered 1 in review question 2.1 of review 2. ES3.1 indicates the linked statement is numbered 1 in review 3 and ES4.1 indicates the linked statement is numbered 1 in review 4. EP1 indicates that expert paper 1: 'Local partnership working: examples drawn from the work of the Making Every Adult Matter coalition' is linked to a recommendation. EP2 indicates that expert paper 2: 'St Mungo's: people who have a dual diagnosis and are homeless' is linked. EP3 indicates that expert paper 3: 'Early Intervention in psychosis services' is linked. EP4 indicates that expert paper 4: 'Dual diagnosis among homeless people: primary care perspective' is linked. If a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Section 1.1: ES1.1.8, ES1.1.9, ES2.1.2, ES2.1.3, ES2.1.10, ES2.2.1, ES2.2.4; EP2, EP4; IDE Section 1.2: ES2.1.1, ES2.1.4, ES2.1.9, ES2.1.11, ES2.2.4, ES2.2.7, ES2.2.9, ES2.2.10; EP2; IDE Section 1.3: ES1.1.8, ES1.1.9, ES2.1.7, ES2.1.8, ES2.2.1, ES2.2.2, ES2.2.3, ES2.2.4, ES2.2.6; EP1, EP2, EP3, EP4; IDE Section 1.4: ES2.1.5, ES2.1.6, ES2.1.7, ES2.1.10, ES2.1.11, ES2.2.3, ES2.2.4, ES2.2.8, ES2.2.10; EP1, EP2; IDE Section 1.5: ES1.1.2, ES1.2.1, ES2.1.3, ES2.1.4, ES2.1.10, ES2.1.12, ES2.1.13, ES2.1.14, ES2.1.15, ES2.1.16, ES2.2.4, ES2.2.5, ES2.2.9, ES2.2.10, ES3.1, ES3.2, ES3.3, ES3.4, ES3.5, ES3.6, ES3.7, ES3.8, ES3.9. ES3.10, ES4.1, ES4.2. ES4.3, ES4.4, ES4.5, ES4.6; EP1, EP2, EP3; IDE Section 1.6: ES1.1.5, ES1.1.9, ES2.1.3, ES2.1.8, ES2.1.10, ES2.1.12, ES2.2.1, ES2.2.2, ES2.2.4, ES2.2.5, ES2.2.7; EP2, EP4; IDE # Gaps in the evidence The committee's assessment of the evidence on coexisting severe mental illness and substance misuse identified a number of gaps. These gaps are set out below. . Evidence on the characteristics of people with coexisting severe mental illness and substance misuse in the groups identified in the equity impact assessment. This includes: people with a learning disability; teenage parents; Gypsies and Travellers; asylum seekers or refugees; lesbian, gay, bisexual, transsexual or transgender people; and sex workers. (Source review 1) . Social care needs of people identified in the equity impact assessment. This includes those who are socially isolated, are on a low income, have a history of being 'looked after' or are adopted, or have a history of experiencing or witnessing domestic violence and abuse. (Source review 1) . Views and experiences of: a) commissioners b) primary care practitioners who work with vulnerable groups c) groups identified in the equity impact assessment (with the exception of young people and ex-offenders). (Source review 2) . Interventions or measures assessing efficiency of services (for example, measures looking at improving accessibility and availability of services). (Source review 3) . Different models of service delivery (for example, a comparison of specialist, integrated or separate services) and efficiency of service delivery models. (Source review 3)# Recommendations for research The guideline committee has made the following recommendations for research. # Needs assessment In the UK, how prevalent is coexisting severe mental illness with substance misuse and what are the physical health, social care, housing or other support needs of people with this diagnosis? ## Why this is important There is limited evidence on the physical health, social care, housing or other support needs of people with coexisting severe mental illness and substance misuse. This includes prevalence of coexisting physical conditions such as cardiovascular, respiratory or infectious diseases and social care needs such as social isolation or poor housing. Evidence on the differential impact on physical health of the type of substance used and the mental health condition would also be useful. Longitudinal evidence is needed. This will help design coordinated evidence-based services to meet the wider health and social care needs of this group of people and provide a good standard of care. People with coexisting severe mental illness and substance misuse may present in a variety of settings. Research on the needs that this group present with in specific settings (for example, primary care) would be beneficial. So would research evaluating the needs of particularly vulnerable groups (for example, those identified in the equality impact assessment). # What works? In the UK, how effective and cost effective are service delivery interventions such as peer support, contingency management or text messaging delivered alone or in combination (in conjunction with standard care) compared with standard care alone for young people and adults with coexisting severe mental illness and substance misuse? ## Why this is important There is limited evidence on the optimal service delivery model for young people and adults with coexisting severe mental illness and substance misuse. There is increasing use of contingency management, peer support (including mutual aid) or text messaging as part of a service delivery model to help people access services. More research is needed to assess the use, benefit and whether these methods improve this group's engagement with services. There is limited evidence on the cost effectiveness of interventions and services with this group. Further research is also needed on whether particular services or elements of standard care for this group give better value for money. A mixed methods approach could identify which of the different elements delivered in a service model are optimal for the person. Research in particularly vulnerable groups (for example those identified in the equality impact assessment) is needed. # Costing tool Which elements of health, social care or other support services work best at a local level and provide the best 'value for money' to address the needs of young people and adults with coexisting severe mental illness and substance misuse? ## Why this is important There is a lack of agreed service models that address the range of health, social care and other support needs of people with coexisting severe mental illness and substance misuse. Information on the value these may provide are also limited. A costing tool will help decision makers 'mix and match' interventions and services to see which package provides the best outcome. It will also help identify cost savings and determine whether the additional benefits (in terms of health, social care or criminal justice outcomes) are worth the extra costs. It may also help to demonstrate whether better functioning mainstream services are effective and provide value for money. # Barriers and facilitators What are the barriers and facilitators for young people and adults with coexisting severe mental illness and substance misuse to obtain an optimal service (including optimal time frame for delivering interventions) to meet their needs and enable their recovery? ## Why this is important There is limited evidence that identifies the triggers for deterioration and the turning points for recovery for people with coexisting severe mental illness and substance misuse. Although review 2 contains evidence on the views and experiences of this group, their family or carers, it is not always clear which point in the care pathway the views and experiences expressed relate to. As such, it is difficult to fully break down the experience of care received at various intervals along the care pathway. Understanding the experience of people who are at different stages of recovery and how they have maintained their progress and success (1 year, 3 years, 5 years, 10 years+) will help with designing more effective services and planning services that deliver interventions at the right time. # Care pathway In the UK, what is the optimal care pathway for young people and adults with coexisting severe mental illness and substance misuse? ## Why this is important There is a lack of published evidence on care pathways on treatment, management and follow-up of people with coexisting severe mental illness and substance misuse. In the UK, service configurations, treatment philosophies and funding streams act as barriers to providing coordinated care. Separate mental health and substance misuse services are usually provided by different organisations, have different organisational and managerial structures, and staff within each service often lack the knowledge and skills needed to work effectively with people from another organisation. A review of what has worked or not in areas that have implemented changes to practice will help services develop optimal care pathways.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read in conjunction with NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings. This covers the assessment of, and support for, adults and young people (aged 14 and older) who have a suspected or known clinical diagnosis of psychosis with coexisting substance misuse.\n\nThe following should ensure service specifications take into account the recommendations in this guideline:\n\ncommissioners of mental health, substance misuse and primary care\n\nlocal authorities when commissioning support services, including housing and other services provided by the public, community and voluntary sectors.\n\n# First contact with services\n\nThese recommendations are for all staff who may be the first point of contact with young people and adults with coexisting severe mental illness and substance misuse working in:\n\nhealth (including urgent care and liaison services)\n\nsocial care\n\npublic health\n\nvoluntary and community sector organisations\n\nhousing (for example, homeless shelters or temporary accommodation)\n\ncriminal justice system.\n\nIdentify and provide support to people with coexisting severe mental illness and substance misuse. Aim to meet their immediate needs, wherever they present. This includes:\n\nlooking out for multiple needs (including physical health problems, homelessness or unstable housing)\n\nremembering they may find it difficult to access services because they face stigma.\n\nBe aware that the person may have a range of chronic physical health conditions including:\n\ncardiovascular, respiratory, hepatic or related complications\n\ncommunicable diseases\n\ncancer\n\noral health problems\n\ndiabetes.\n\nBe aware that people's unmet needs may lead them to have a relapse or may affect their physical health. This could include: social isolation, homelessness, poor or lack of stable housing, or problems obtaining benefits.\n\nProvide direct help, or get help from other services, for any urgent physical health, social care, housing or other needs.\n\nEnsure the safeguarding needs of all people with coexisting severe mental illness and substance misuse, and their carers and wider family, are met. (See also the section on safeguarding issues in the NICE guideline on coexisting severe mental illness [psychosis] and substance misuse: assessment and management in healthcare settings.)\n\nEnsure the person is referred to and followed up within secondary care, and that mental health services take the lead for assessment and care planning (see sections 1.2 and 1.3).\n\n# Referral to secondary care mental health services\n\nEnsure secondary care mental health services:\n\nDo not exclude people with severe mental illness because of their substance misuse.\n\nDo not exclude people from physical health, social care, housing or other support services because of their coexisting severe mental illness and substance misuse.\n\nAdopt a person-centred approach to reduce stigma and address any inequity to access to services people may face (see NICE's guidelines on coexisting severe mental illness [psychosis] and substance misuse: assessment and management in healthcare settings and service user experience in adult mental health for the principles of using a person-centred approach).\n\nUndertake a comprehensive assessment of the person's mental health and substance misuse needs (see also NICE's guideline on coexisting severe mental illness [psychosis] and substance misuse – the section recognition of psychosis with coexisting substance misuse and the recommendations on assessment in secondary care mental health services).\n\n## On acceptance to secondary care mental health services\n\nProvide a care coordinator working in mental health services in the community to:\n\nact as a contact for the person\n\nidentify and contact their family or carers\n\nhelp develop a care plan with the person (in line with the Department of Health's Care Programme Approach guidance) and coordinate it (see the section on the care plan).The Care Programme Approach is a way that services are assessed, planned, coordinated and reviewed for someone with mental health problems or a range of related complex needs.\n\nEnsure the care coordinator works with other services to address the person's social care, housing, physical and mental health needs, as well as their substance misuse problems, and provide any other support they may need.\n\n## Involving people with coexisting severe mental illness and substance misuse in care planning\n\nInvolve the person (and their family or carers if the person wants them involved) in developing and reviewing the care plan (as needed) to ensure it is tailored to meet their needs. This includes offering the person information about the services available so they can decide which ones would best meet their jointly identified needs and goals. Also involve practitioners from:\n\nadult or child and adolescent mental health teams and substance misuse services\n\nother health and social care disciplines such as medicine, pharmacy, nursing, social work, occupational therapy and housing.\n\nEnsure the care plan:\n\nIs based on a discussion with the person about how their abilities (such as the extent to which they can take part in the activities of daily living) can help them to engage with services and recover.\n\nTakes into account the person's past experiences (such as their coping strategies to deal with crises).\n\nLists how the person will be supported to meet their identified needs and goals. This includes listing any carers they have identified to help them, and the type of support the carer can provide. (Also see the recommendation on ensuring interventions meet individual needs in the NICE guideline on behaviour change: individual approaches).\n\nTakes into account the concerns of the person's family or carers.\n\nRecognises and, if possible, reconciles any goals the person may have decided for themselves if they differ from those identified by their service provider.\n\nIs optimistic about the prospects of recovery.\n\nIs reviewed at every contact.\n\nShare a copy of the care plan with the person's family or carers (if the person agrees). In line with local information sharing agreements, share copies with other services as needed (see the section on information sharing).\n\n## Carers\n\nEnsure carers (including young carers) who are providing support are aware they are entitled to, and are offered, an assessment of their own needs (see NICE's guideline on supporting adult carers). If the carer wishes, make a referral to their local authority for a carer's assessment (in line with the Care Act 2014). When undertaking an assessment, consider:\n\ncarers have needs in their own right\n\nthe effect that caring has on their mental health\n\ncarers may be unaware of, or excluded from, any plans or decisions being taken by the person\n\nany assumptions the person with coexisting severe mental illness and substance misuse has made about the support and check that they agree the level of support their carer will provide.\n\nBased on the carer's assessment:\n\nAdvise the carer that they may be entitled to their own support. For example, using a personal budget to buy care or to have a break from their caring responsibilities.\n\nGive information and advice on how to access services in the community, for example respite or recreational activities or other support to improve their wellbeing.See NICE's guideline on supporting adult carers.\n\n# The care plan: multi-agency approach to address physical health, social care, housing and other support needs\n\nThe person's care coordinator should adopt a collaborative approach with other organisations (involving shared responsibilities and regular communication) when developing or reviewing the person's care plan. This includes substance misuse services, primary and secondary care health, social care, local authorities and organisations such as housing and employment services.\n\nEnsure the care plan includes an assessment of the person's physical health, social care and other support needs, and make provision to meet those needs. This could include:\n\npersonal care and hygiene\n\nfamily and personal relationships\n\nhousing\n\nlearning new skills for future employment or while in employment (including those administering social security benefits)\n\neducation\n\npregnancy and childcare responsibilities.\n\nConsider covering behaviours in the care plan that may affect the person's physical or mental health, in addition to their substance misuse (see the NICE topic pages on drug misuse and alcohol). Pay particular attention to:\n\ndiet (see the NICE topic page on diet, nutrition and obesity)\n\nphysical activity (see the NICE topic page on physical activity)\n\nsmoking (see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence)\n\nconsequences of drug or alcohol misuse practices (see the NICE topic page on hepatitis and the NICE guideline on needle and syringe programmes)\n\nsexual practices (see the NICE topic page on sexual health).\n\nExplore any barriers to self-care to help the person look after their own physical health. Address these barriers in the care plan.\n\nConsider incorporating activities in the care plan that can help to improve wellbeing and create a sense of belonging or purpose. For example, encourage sport or recreation activities, or attendance at community groups that support their physical health or social needs. Ensure activities take account of a range of different abilities. Consider, for example:\n\nthe gym\n\neducation opportunities\n\nvolunteering\n\nuse of personal budgets (if applicable) for learning new skills, such as those that might support a return to employment.\n\nConsider the following approaches to keep people involved in their care plan:\n\nPractical one-to-one support, for example in relation to housing, education, training or employment.\n\nSupport to develop self-care skills, for example, to help them develop their budgeting skills so they know how to allocate enough money to buy food. Or support to help them develop their cooking skills.\n\nPractical help with tasks that are important to the person, for example, housework or occupational support.\n\nSupport at appointments, for example:\n\n\n\narranging or travelling with them to hospital outpatient appointments or attendance at support groups\n\narranging for an advocate to accompany them at their appointments and provide independent advocacy (see the section on maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them in the NICE guideline on coexisting severe mental illness and substance misuse).\n\n\n\nConsider the suitability of the type of housing (for example, high to low support or independent tenancies), employment, detox, rehabilitation services or other support identified for the person, in collaboration with relevant providers. Take the person's preferences into account.\n\nEnsure agencies and staff communicate with each other so the person is not automatically discharged from the care plan because they missed an appointment. All practitioners involved in the person's care should discuss a non-attendance.\n\n## Review\n\nHold multi-agency and multidisciplinary case review meetings annually, as set out in the Department of Health's Care Programme Approach guidance or more frequently, based on the person's circumstances. (A care coordinator in the secondary care mental health team should usually arrange this.) Use this to check the person's physical health needs (including any adverse effects from medications), social care, housing or other support needs. Involve practitioners from a range of disciplines, including:\n\nsecondary care mental health\n\nsubstance misuse\n\nprimary care\n\nemergency care (if applicable)\n\nvoluntary sector\n\nhousing\n\nadult and young people's social care.\n\nEnsure the care plan is updated in response to changing needs or circumstances.\n\n## Discharge or transition\n\nBefore discharging the person from their care plan (the Department of Health's Care Programme Approach guidance) or before they move between services, settings or agencies (for example, from inpatient care to the community, or from child and adolescent mental health services to adult mental health services) ensure:\n\nAll practitioners who have been, or who will be, involved are invited to the multi-agency and multidisciplinary meetings (see recommendation 1.3.9) and the discharge or transfer meeting.\n\nThere is support to meet the person's housing needs.\n\nThe discharge plan includes strategies for ongoing safety or risk management and details of how they can get back in contact with services.\n\nThere are crisis and contingency plans in place if the person's mental or physical health deteriorates (including for risk of suicide or unintentional overdose).\n\nProviders share information on how to manage challenging or risky situations (see also NICE's guideline on violence and aggression: short-term management in mental health, health and community settings).\n\nReassess the person's needs to ensure there is continuity of care when they are at a transition point in their life. Particular groups who may need additional support include:\n\nyoung people who move from child and adolescent mental health services to adult health or social care services (see also NICE's guideline on transition from children's to adults' services and the section on specific issues for young people with psychosis and coexisting substance misuse in NICE's guideline on coexisting severe mental illness [psychosis] and substance misuse)\n\nlooked after children\n\npeople who move from adult to older adult mental health or social care services.Also see NICE's guideline on transition between inpatient mental health settings and community and care home settings.\n\n# Partnership working between specialist services, health, social care and other support services and commissioners\n\nWork together to encourage people with coexisting severe mental illness and substance misuse to use services. Consider:\n\nusing an agreed set of local policies and procedures that is regularly reviewed by key strategic partners\n\nworking across traditional institutional boundaries\n\nbeing responsive to requests for advice and joint-working arrangements\n\nsharing the response to risk management.\n\nEnsure joint strategic working arrangements are in place so that:\n\nservices can offer continuity of care and service provision (for example, when commissioning contracts are due to expire)\n\nservices are based on a local needs or a joint strategic needs assessment\n\nservice quality is monitored and data sharing protocols are in place (see also recommendations 1.4.6 and 1.4.7).\n\nConsider including the needs of people with coexisting severe mental illness and substance misuse in other local needs assessment strategies, for example, on housing, employment projects, alcohol, drug services or crime prevention.\n\nAgree joint care pathways to:\n\nMeet the health, social care or other support needs and preferences of people with coexisting severe mental illness and substance misuse, wherever they may present.\n\nGive people access to a range of primary healthcare and social care providers including GP practices, pharmacies, podiatrists, dentists, social workers, housing, housing support or benefit advisers.\n\nEnsure people have prompt access to local services (including direct referrals if possible).\n\nEnsure staff follow people up to make sure their needs are being met.\n\nEnsure continuity of care to support people at different transition points in their lives.\n\nEnsure referral processes and care pathways within and across agencies are consistent and that governance arrangements are in place. This includes local care pathways to meet the physical health, social care, housing and support needs of people with coexisting severe mental illness and substance misuse.\n\n## Information sharing\n\nAgree a protocol for information sharing between secondary care mental health services and substance misuse, health, social care, education, housing, voluntary and community services (see the Caldicott Guardian Manual).\n\nAdopt a consistent approach to getting people with coexisting severe mental illness and substance misuse help from the most relevant service by:\n\nsharing information on support services between agencies\n\nensuring all providers know about and can provide information on the services\n\ntaking responsibility, as agreed in referral processes, providing timely feedback and communicating regularly about progress.\n\n# Improving service delivery\n\n## Making health, social care and other support services more inclusive\n\nEnsure existing health and social care services (including substance misuse services) are adapted to engage with and meet the needs of people with coexisting severe mental illness and substance misuse.\n\nInvolve people with coexisting severe mental illness and substance misuse, their family or carers in improving the design and delivery of existing services (see the section on referral to secondary care mental health services in NICE's guideline on coexisting severe mental illness and substance misuse). This may include them providing training, developing interventions to help people or taking part in steering committees.\n\nProvide local services in places that are easily accessible, safe and discreet. Bear in mind any perceived stigma involved in being seen to use the service. Consider flexible opening times, drop-in sessions, or meeting people in their preferred locations.\n\nEnsure people with coexisting severe mental illness and substance misuse, their family or carers are given accurate information about relevant local services (including, for example, community or family support groups). Also ensure they are given help to make initial contact with services. This could include information on how to access services, ways to contact the service, opening hours and how long the waiting list may be.\n\nRaise staff awareness of the needs of people with coexisting severe mental illness and substance misuse, including the fact that they may be traumatised. Ensure staff can meet their needs.\n\n## Adapting existing secondary care mental health services\n\nAdapt existing specialist services to meet both a person's coexisting severe mental illness and substance misuse needs and their wider health and social care needs. Do not create a specialist 'dual diagnosis' service.\n\nOffer interventions that aim to improve engagement with all services, support harm reduction, change behaviour and prevent relapse. Take advice from substance misuse services (if applicable) about these interventions. (See the NICE guidelines on coexisting severe mental illness [psychosis] and substance misuse, psychosis and schizophrenia in children and young people, psychosis and schizophrenia in adults, bipolar disorder, self-harm, alcohol-use disorders, and drug misuse in over\xa016s: psychosocial interventions.)\n\nOffer individual, face-to-face or phone appointment sessions to encourage people with coexisting severe mental illness and substance misuse to use services. Offer phone sessions to their family or carers. Sessions could cover:\n\nhow the person is coping with their current mental health and substance use and its impact on their physical health and social care needs\n\nprogress on current goals or changes to future goals\n\nways to help the person stay safe\n\nmonitoring symptoms\n\ngetting support from (and for) their family, carers or providers.Determine how often the sessions take place based on the person's needs.\n\nConsider the following:\n\nCrisis and contingency plans for the person with coexisting severe mental illness and substance misuse and their family or carers. Ensure these are updated to reflect changing circumstances.\n\nSupport to sustain change and prevent relapse.\n\nDischarge planning, including planning for potential relapses, so the person with coexisting severe mental illness and substance misuse knows which service to contact and the service can provide the right ongoing support. (See also NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.)\n\n## Support for staff\n\nEnsure the care coordinator in secondary care mental health services is supervised and receives professional development to provide or coordinate flexible, personalised care.\n\nRecognise that different attitudes towards, or knowledge of, mental health and drug- or alcohol-related problems may exist between agencies and that this may present a barrier to delivering services. To overcome this:\n\nchallenge negative attitudes or preconceptions about working with people with coexisting severe mental illness and substance misuse\n\ndevelop leadership skills so staff can challenge attitudes and preconceptions (for an example, see the study by Hughes Closing the gap: a capability framework for working effectively with people with combined mental health and substance use problems).\n\nEnsure practitioners have the resilience and tolerance to help people with coexisting severe mental illness and substance misuse through a relapse or crisis, so they are not discharged before they are fully equipped to cope or excluded from services (see the section on maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them).\n\n# Maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them\n\nRecognise that even though building a relationship with the person and seeing even small improvements may take a long time, it is worth persevering. It involves:\n\nshowing empathy and using a non-judgemental approach to listen, identify and be responsive to the person's needs and goals\n\nproviding consistent services, for example, if possible keeping the same staff member as their point of contact and the same lead for organising care\n\nstaying in contact by using the person's chosen method of communication (for example, by letter, phone, text, emails or outreach work, if possible).\n\nExplore with the person why they may stop using services that can help them. This may include:\n\nfragmented care or services\n\ninflexible services (for example, not taking into account that the side effects the person may experience from medication may affect their attendance at appointments)\n\ninability to attend because, for example, services are not local, transport links are poor, or services do not provide childcare\n\nnot being allowed to attend, for example because they have started misusing substances again\n\nfear of stigma, prejudice or being labelled as having both mental health and substance misuse problems\n\nfeeling coerced into using treatments or services that do not reflect their preferences or their readiness to change\n\nprevious poor relationships with practitioners\n\nother personal, cultural, social, environmental or economic reasons.\n\nHelp those who may find it difficult to engage with services to get into and stay connected with services. Start and maintain contact using proactive, flexible approaches (see recommendation 1.3.6 on approaches to keep people involved in their care plan).\n\nRecognise that people with coexisting severe mental illness and substance misuse are at higher risk of not using, or losing contact with, services. There are specific populations who are more at risk. These include men, young people, older people and women who are pregnant or have recently given birth. It also includes:\n\npeople who are homeless\n\npeople who have experienced or witnessed abuse or violence\n\npeople with language difficulties\n\npeople who are parents or carers who may fear the consequences of contact with statutory services.\n\nEnsure any loss of contact or non-attendance at any appointment or activity is viewed by all practitioners involved in the person's care as a matter of concern. Follow-up actions could include:\n\ncontacting the person to rearrange an appointment\n\nvisiting the person at home\n\ncontacting any other practitioners involved in their care, or family or carers identified in the person's care plan (see recommendation 1.2.4 on involving the person in developing and reviewing the care plan)\n\ncontacting the person's care coordinator within mental health services in the community immediately if there is a risk of self-harm or suicide, or at least within 24\xa0hours if there are existing concerns.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline.\n\n## Contingency management\n\nContingency management is a set of techniques that focus on changing specific behaviours. For example, in drug misuse, it involves offering incentives for positive behaviours such as abstinence or a reduction in illicit drug use, and participation in health-promoting interventions.\n\n## Dual diagnosis\n\nDual diagnosis usually refers to mental illness combined with substance misuse. But it may also be used to describe a number of other conditions, including physical health problems. In the UK social care sector, the term is sometimes used for people who have both a learning disability and a mental illness.\n\n## Relapse\n\nA recurrence or exacerbation of a person's mental health problems, a return to substance misuse, or both.\n\n## Severe mental illness\n\nSevere mental illness includes a clinical diagnosis of: schizophrenia, schizotypal and delusional disorders, or bipolar affective disorder, or severe depressive episodes with or without psychotic episodes.\n\n## Specialist services\n\nSpecialist services refers to secondary care mental health services and dual diagnosis services.\n\n## Substance misuse\n\nSubstance misuse refers to the use of legal or illicit drugs, including alcohol and medicine, in a way that causes mental or physical damage. This may include low levels of substance use that would not usually be considered harmful or problematic, but may have a significant effect on the mental health of people with a mental illness such as psychosis.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during development of this guideline. They are:\n\nLower caseloads are needed to provide consistent, coordinated and optimum services, but this has cost implications.\n\nJoint training could lead to a more consistent approach across mental health and substance misuse services.\n\nLeadership is needed from commissioners across health and social care services.\n\nPutting a guideline fully into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may need to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': "Adults and young people with coexisting severe mental illness and substance misuse have some of the worst health, wellbeing and social outcomes (see the Social Care Institute for Excellence's briefing on the relationship between dual diagnosis: substance misuse and dealing with mental health issues).\n\nIt is not clear how many people in the UK have a coexisting severe mental illness and misuse substances, partly because some people in this group do not use services or get relevant care or treatment.\n\nThe Department of Health's Refocusing the Care Programme Approach identifies people with coexisting severe mental illness and substance misuse as one of the groups in need of an enhanced Care Programme Approach. That is because they are not being identified consistently and services are sometimes failing to provide the support they need. The policy highlights the need for a whole systems approach to their care, involving a range of services and organisations working together. This guideline aims to address this need.\n\nGroups covered in this guideline include: young people (aged 14\xa0to\xa025) and adults who have been diagnosed as having a severe mental illness and who misuse substances and who live in the community. The age cut-off for young people has been set at 14 to reflect the small numbers affected below this age – and the fact that many early intervention services usually start at age\xa014.\n\nIn this guideline, severe mental illness includes a clinical diagnosis of:\n\nschizophrenia, schizotypal and delusional disorders or\n\nbipolar affective disorder or\n\nsevere depressive episodes with or without psychotic episodes.\n\nSubstance misuse refers to the use of legal or illicit drugs, including alcohol and medicine, in a way that causes mental or physical damage.", "The committee's discussion": "Evidence statement numbers are given in square brackets. For an explanation of the evidence statement numbering, see the evidence reviews section.\n\n# Section 1.1 First contact with services\n\n## Recommendations 1.1.1 to 1.1.6\n\nThe discussion below explains how we made recommendations 1.1.1 to 1.1.6.\n\nCommittee members were aware from their experience that people with coexisting severe mental illness and substance misuse may present in crisis (for example, at A&E). But they may be also be found opportunistically in other settings (for example, homeless shelters) and identified as needing immediate assistance with a range of needs. This includes their mental or physical health, substance misuse or social care needs.\n\nThey noted that the physical health and social care needs of this group are often overlooked because of the challenging nature of dealing with both mental health and substance misuse issues. They also noted that this group is often excluded from services because no one wants to take responsibility for them and they need help to access a wide range of services.\n\nIn addition, members noted that a policy guide in 2002 (Department of Health's Dual diagnosis good practice guide) has advised that care for people with coexisting severe mental illness and substance misuse should be delivered within mental health services.\n\nThe committee noted from the evidence and members' experience that people with coexisting severe mental illness and substance misuse are a vulnerable group, who often have poor physical health, are unemployed, homeless or are at risk of other people taking advantage of them. The latter includes being subjected to sexual exploitation or being taken advantage of in relation to their housing or financial situation.\n\nIt noted there was strong evidence from a meta-analysis of 3 cohort and case–control UK studies (2 high quality [++] and 1 low quality [−]) that people with coexisting severe mental illness and substance misuse (compared with those with severe mental illness only) were more likely to have a history of homelessness or housing problems. There was also evidence from 1 high-quality UK case–control study that this group of people are more likely to live in the most deprived areas. There was moderate evidence from 3 high-quality UK cohort studies that showed a greater number of people with coexisting severe mental illness and substance misuse are unemployed than those with severe mental illness only [ES1.1.9].\n\nThe committee noted that a meta-analysis of 2 UK case–control studies (1 high and 1 moderate quality [+]) showed no difference in social functioning between this group and people with a severe mental illness only. However, 1 high-quality UK cohort study showed poorer social functioning in people with coexisting severe mental illness and substance misuse than in those with substance misuse [ES1.1.9].\n\nThe committee also noted that this evidence was mainly from people in contact with secondary care mental health services and may not reflect the needs of the wider population of people with coexisting severe mental illness and substance misuse [ES1.1.9].\n\nThe committee noted inconsistent evidence for educational outcomes [ES1.1.9]. But members also noted from their experience that the point at which a person is diagnosed would have an effect on their educational attainment.\n\nThe committee was aware, from the evidence and its experience, that this group is often stigmatised by staff or because of the type of services they are using. For example, this may be a negative attitude towards substance misuse within mental health settings or vice versa. This is based on evidence from 7 qualitative studies (2 high, 3 moderate and 2 low quality) reporting on barriers related to stigma and attitudes towards this group [ES2.1.3].\n\nSix qualitative studies showed that people with coexisting severe mental illness and substance misuse face a number of barriers or facilitators when accessing social care services, particularly housing support. Of the 4 studies that identified barriers to accessing housing support, 1 high-quality qualitative study reported that people with coexisting severe mental illness and substance misuse often feel there is a social stigma associated with seeking help [ES2.2.1]. Also, services are often not easy to access.\n\nThe committee felt that it is important for all services to address these issues from an inequalities perspective and to prevent further deterioration in the person's mental and physical health, social care and substance misuse needs. It was also aware from 7 qualitative studies (2 high, 3 moderate and 2 low quality) reporting on fragmented care, that a consequence of fragmented care is a negative impact on a person's experience of care and willingness to engage with services [ES2.2.4].\n\nSo it made a strong recommendation that all staff coming into contact with this group should be able to understand their needs and help them access services.\n\nCommittee members were aware from their practice and the evidence from 1 high-, 3 moderate- and 2 low-quality qualitative studies (3 set in the UK) that mental health and substance misuse services often fail to take responsibility for people with coexisting severe mental illness and substance misuse [ES2.1.10].\n\nThe committee also noted the evidence from 1 low-quality UK qualitative study that highlighted commissioners' views that the health and wellbeing of this group need to be addressed [ES2.1.2]. The committee noted that wherever people with coexisting severe mental illness and substance misuse present, a similar approach to helping them access care is needed.\n\nThe committee advised that secondary care mental health services need to be the lead organisation responsible for delivery of services and therefore made a recommendation to refer people with coexisting severe mental illness and substance misuse to secondary care mental health services.\n\nThe committee heard from an expert about the physical health issues that can affect people with coexisting severe mental illness and substance misuse [EP4]. It noted that although the expertise was from a perspective of primary care services for homeless people, the range of health needs identified could be transferable to the wider population of people with coexisting severe mental illness and substance misuse. So the committee made a weak recommendation on the range of physical health conditions (for example, cardiovascular, cancer or communicable diseases) that staff need to be aware of. However, it noted that this is not an exhaustive list.\n\nIt also reflected on the lack of evidence on the prevalence of coexisting physical health problems [ES1.1.8] and agreed further research is needed (see the recommendation for research on needs assessment).\n\nThe committee noted that because of the complexity of their needs, people with coexisting severe mental illness and substance misuse are at increased risk of poor self-care, losing contact with family and friends, social isolation or living in poor housing or having their homes abused by others as venues for substance misuse or drug dealing.\n\nBased on moderate to strong evidence from 4 cohort and 6 case–control studies, committee members were aware of the range of social care needs of people with coexisting severe mental illness and substance misuse in the UK [ES1.1.9]. They were also aware from expert testimony [EP2], and their own experience of working with this group, of the detrimental effects that unmet needs (such as social isolation or poor housing) can have on a person's health and recovery, which could lead to relapse [ES2.2.1, EP2]. This was based on 2 high-quality and 1 moderate-quality qualitative studies reporting on barriers when seeking housing support.\n\nThe committee was aware that these unmet needs may lead to physical health problems, offending behaviour or disengagement from services. It was also aware that a person may have issues with both poor housing and physical health and that this may not always be a 'cause–effect' relationship.\n\nThere was no evidence for cost effectiveness for this set of recommendations.\n\nCommittee members agreed that recommendation 1.1.1 is for staff working in all general services. But they also noted that it would be applicable to other services, such as criminal justice system and urgent care.\n\nCommittee members were aware that the criminal justice system was not included in the scope and that the evidence reviews did not specifically search for studies on the transition between criminal justice systems and healthcare services. They were also aware that NICE is developing guidance on the mental health of adults in contact with the criminal justice system. However, they felt it was important to include because it is a potential route for people with coexisting severe mental illness and substance misuse to come into contact with healthcare services. This was also reflected in the expert testimony on primary care services for homeless people [EP4].\n\nThe committee was aware from its experience of the importance of highlighting safeguarding issues for this vulnerable population. It felt that this point needs to be for general services. The committee acknowledged that safeguarding has been made a statutory duty under the Care Act 2014. It was also aware of statutory safeguarding arrangements specific to children (see the Department of Education's guidance on working together to safeguard children) and statutory guidance to the 1989 and 2004 Children Acts (see Ofsted's report What about the children? ). The committee was also aware of the safeguarding needs of dependents and carers.\n\n# Section 1.2 Referral to secondary care mental health services\n\n## Recommendation 1.2.1\n\nThe discussion below explains how we made recommendation 1.2.1.\n\nThe committee was advised by the topic experts that secondary care mental health services are usually the lead agency that supports people with coexisting severe mental illness and substance misuse.\n\nAlthough this guideline focuses on people with diagnosed coexisting severe mental illness and substance misuse, the committee felt it was important to address the general issue of ensuring people are properly assessed so they can be offered an effective care plan.\n\nThe committee noted from 1 moderate-quality study, 1 low-quality UK study and members' experience that timely assessments can help people to access services and stay involved with their care plan [ES2.1.1].\n\nThe committee agreed with the recommendations on the principles of recognition and assessment in NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings, even though it has a narrower focus than this guideline. The committee also agreed that the recommendations on identification and diagnosis were useful (identification and diagnosis was outside the scope of this guideline). Although the psychosis with substance misuse guideline was specific to psychosis and not the range of severe mental illnesses covered in this guideline, members agreed it would be useful for readers to refer to both recommendations.\n\nThe committee agreed to develop a recommendation on what needs to happen once a person is referred to and accepted into secondary care mental health services based on the evidence, expert testimony and members' own experience.\n\nThere was no evidence for cost effectiveness for this recommendation.\n\nThe committee agreed that substance misuse should not be a reason to exclude people from secondary care mental health services. Based on the evidence and from members' experience this is a common problem [EP2]. The committee also noted from members' experience that the person's wider needs are often not recognised, or they are not given a routine assessment of their mental health or substance misuse needs to develop a care plan.\n\nFrom their experience, committee members were aware of the importance of a person-centred approach. This was reinforced by review 2. The committee was also aware of NICE's guidelines on coexisting severe mental illness (psychosis) and substance misuse and service user experience in adult mental health. Both outline the need for a non‑judgemental and empathetic approach built on trust and respect. The committee felt it was important to take a person-centred approach when developing and reviewing the care plan and made a strong recommendation on involving people in their care planning. This was based on evidence from:\n\nqualitative studies (2 high, 2 moderate and 1 low quality) reporting on facilitators related to the relationship between people who use services and practitioners. 1 of these studies was conducted in the UK [ES2.1.4]\n\nqualitative studies, of these 2 qualitative studies (1 moderate and 1 low quality) reporting on benefits of consistent care. 1 of the studies reporting on facilitators was conducted in the UK [ES2.2.4]\n\nqualitative studies (2 high, 3 moderate and 3 low quality) reporting on barriers and facilitators to engagement with healthcare and support services. 3 of these studies were conducted in the UK [ES2.2.7].\n\n## On acceptance to secondary care mental health services\n\nThe discussion below explains how we made recommendations 1.2.2 and 1.2.3.\n\nThe committee agreed that secondary care mental health services take the lead in coordinating services and developing a care plan. The committee noted that care planning is usually led by a care coordinator because this is part of the Department of Health's Care Programme Approach.\n\nThe committee was aware of the importance of continuing care. It was also aware that the continuity provided by a key contact encourages people to keep in touch with services (evidence review 2). This was based on the evidence from:\n\nqualitative studies (1 moderate- and 4 low-quality) reporting on barriers or facilitators associated with organisation and continuity of care, 3 based in the UK [ES2.1.11]\n\nqualitative studies (2 high, 3 moderate and 2 low quality) reporting on barriers or facilitators associated with the impact of fragment care provision on continuity of care [ES2.2.4].\n\nThere was no evidence for cost effectiveness for this set of recommendations.\n\nBased on their expertise and the responsibilities outlined in the Care Programme Approach, committee members made a strong recommendation that a care coordinator from community mental health services is assigned once a person has been referred to secondary care mental health services.\n\nThey agreed that the care coordinator should take the lead in developing and reviewing the care plan and should take responsibility for organising delivery of a range of services, with the support of a wider team.\n\nCommittee members advised that the role of care coordinator already exists within secondary care mental health services. They noted that care coordinators are part of a multidisciplinary team. But they also noted that overall responsibility (for example, for discharging a person) would lie with a consultant psychiatrist.\n\n## Involving people with coexisting severe mental illness and substance misuse in care planning\n\nThe discussion below explains how we made recommendations 1.2.4 to 1.2.6.\n\nThe committee agreed that it is important to take a person-centred approach, by focusing on actions that are agreed with the person and by offering, not imposing, services on them. So it developed a set of recommendations on 'involving people' in care planning. These recommendations are deliberately separate from the recommendations on the actual content of the care plan (see the section on the care plan: multi-agency approach to address physical health, social care, housing and other support needs).\n\nThe committee took into account qualitative evidence from 3 studies reporting on the barriers or facilitators that face people with severe mental illness and substance misuse face when trying to make decisions about their care [ES2.2.9]:\n\nlow-quality UK study about encouraging the person to be involved in their care plan decisions\n\nmoderate-quality qualitative studies about respecting their preferences.\n\nIt felt that these factors can help a person adhere to their care plan.\n\nThe committee was also aware from the evidence (5 qualitative studies: 2 high quality, 2 moderate quality and 1 low quality) and their experience that a good relationship between the health or social care professional and the person with coexisting severe mental illness and substance misuse is key to effective delivery of health and social care services [ES2.1.4]. Members noted that a good relationship can affect a person's willingness to engage with and respond to care, and can also affect their recovery.\n\nBearing in mind all these factors, it made a strong recommendation on the need to take them all into account when developing a care plan.\n\nThe committee noted from members' experience that providers need to understand what is having an effect on the person each time they see them, so that they can provide the right level of support, including information, each time. It noted that the frequency of contact can vary depending on the person's circumstances. It also noted the importance of sharing the care plan between services.\n\nThe committee noted that people can recover. But it also noted that for this group of people, 'recovery' may not necessarily only be about reducing their substance use but about leading a productive life. The members felt that although recovery may take time, providers need to always convey a sense of optimism whenever possible.\n\nThe committee was aware that changing behaviour may be a lengthy process and that NICE's guideline on behaviour change: individual approaches may provide useful strategies on personalising messages.\n\nThere was no evidence for cost effectiveness for this set of recommendations.\n\n## Carers\n\nThe discussion below explains how we made recommendations 1.2.7 and 1.2.8.\n\nThe committee was aware of current legislation that entitled carers to an assessment of their needs (Care Act 2014).\n\nThe committee was aware from the evidence and members' experience, that a carers assessment may be particularly important if the carers are children [ES2.1.9; 1 UK study of low quality]. Members' experience highlighted that a point of contention for carers is that they may not be privy to the person's plans and wishes. Evidence from 2 qualitative studies (1 moderate quality and 1 UK study of low quality) highlighted the barriers faced by families and carers in relation to receiving support for themselves [ES2.2.10]. So the committee developed a recommendation based on the evidence, expert testimony and their expert knowledge to highlight young people and adult carers' needs and ways to support them [review 2, EP2].\n\nThere was no evidence on cost effectiveness for this set of recommendations.\n\nThe committee was aware, from its own experience, that carers may not be offered the opportunity to decline caring responsibilities that are beyond their capacity when they are being assessed. That is why it is important to highlight that carers may be entitled to further support, even though this is specified in the Care Act.\n\n# Section 1.3 The care plan: multi-agency approach to address physical health, social care, housing or support needs\n\n## Recommendations 1.3.1 to 1.3.8\n\nThe discussion below explains how we made recommendations 1.3.1 to 1.3.8.\n\nSocial care needs should be assessed in line with the Care Act 2014. Provision of an advocate is in line with this legislation.\n\nThe committee noted from the evidence from 1 high-, 4 moderate- and 3 low-quality qualitative studies (including 4 studies in the UK) that the lack of a shared approach between services could act as a barrier to providing health and social care services [ES2.1.7]. The committee heard from an expert on local partnership working and experts working with people with coexisting severe mental illness and substance misuse who are homeless [EP1, EP2]. The experts highlighted factors that could help with a coordinated approach.\n\nBased on the evidence, expert testimonies and their own experience, members agreed that important factors in providing a coordinated approach included a shared vision, joint responsibilities and regular communication [ES2.1.7, EP1, EP2].\n\nThe committee highlighted the range of agencies or providers the care coordinator in secondary mental health services would need to work with to ensure people receive care for their wider health or social care, housing or support needs. The committee highlighted the physical health, social care, housing and other support needs that need to be considered when developing and reviewing a care plan.\n\nMembers reflected on the evidence, expert testimony and their own experience to inform their recommendations on social care, housing and other support needs [ES1.1.9, ES2.2.1, ES2.2.2, EP2]. The committee referred to evidence previously noted in the discussion for section 1.1 [ES1.1.9, ES2.2.1]. It also considered the evidence from 2 qualitative studies (1 high quality and 1 moderate) which described the barriers faced by this group in relation to employment support [ES2.2.2].\n\nMembers reflected on expert testimony and existing NICE guidelines on a range of health behaviours [EP4]. Based on this and their knowledge and experience they made a weak recommendation to decide on how a person's physical health could be improved and provided examples of how this may be achieved. This included addressing health behaviours (such as improving diet, quitting smoking or increasing physical activity) and minimising risky behaviours (such as unprotected sex, sharing needles). They realised this is not an exhaustive list and that the care plan may need to address other behaviours.\n\nThe committee also noted that care coordinators may need to help people with practical tasks so that the person can look after their own physical health. The examples were based on the committee's expertise on the type of tasks undertaken by care coordinators. So the committee made a weak recommendation on approaches to keep people involved in their care plan.\n\nIn addition, the committee noted the importance of encouraging activities to improve physical wellbeing (for example football or walking groups). But it was aware of the risk of widening inequalities if this only reaches people who already use services. The committee agreed that potential inequalities could be addressed by recommending providing inclusive services and strategies to improve engagement.\n\nThe committee made a weak recommendation on practical strategies that may help improve uptake of services and prevent relapse. This was based on evidence, expert testimony and the committee's expertise [ES2.2.3, EP2]. The committee was aware from 1 moderate and 1 low-quality study (set in the UK) of barriers or facilitators associated with providing information or training [ES2.2.3]. One moderate-quality study showed supporting people to develop self-care skills helped with daily living. The committee used this evidence combined with their experience to give other examples of practical skills to include in the recommendation.\n\nRecommendations on how to encourage use of services and the suitability of different types of support were based on evidence review 2, expert testimony and the committee's expertise. The committee noted that people with coexisting severe mental illness and substance misuse are particularly at risk of being taken advantage of, so it is important to ensure the type of support they are offered is suitable for them [EP2].\n\nThe committee was aware from members' experience and expert testimony that communication between services is often poor [EP2]. The committee was also aware, from members' experience, that people are often discharged early or denied access to services because of missed appointments. There is often a good reason why the appointment was missed – for example, because the person was having side effects from their medication – but this has not been shared among the agencies involved. This was also highlighted in 2 qualitative studies (1 high, 1 moderate quality) in review 2. Members made a strong recommendation, noting that this can be addressed by making sure practitioners communicate and share information with each other, particularly in relation to non-attendance, so that it does not lead to an automatic discharge.\n\nThere was no evidence for cost effectiveness for this set of recommendations.\n\n## Review\n\nThe discussion below explains how we made recommendations 1.3.9 and 1.3.10.\n\nCommittee members were aware from their experience and from the evidence of the barriers or facilitators associated with an integrated approach to care from 1 high-quality, 6 moderate- quality, and 2 low-quality qualitative studies (2 set in the UK) [ES2.2.6]. They noted from members' experience, expert testimony and the evidence that this could increase engagement and result in positive improvements in health, functioning and wellbeing. Although the UK studies were low quality, the committee felt the findings were relevant because they reflected the views of providers and users in voluntary sector services.\n\nThey also noted the importance of different disciplines working collaboratively, and taking part in case review meetings. This was based on the evidence from 8 qualitative studies reporting on barriers or facilitators associated with the management of cases with members of the same team and across different health and social care agencies [ES2.1.7].\n\nThe committee noted that the frequency of case review meetings would vary and would involve multidisciplinary team members and several different agencies. This is important to make sure a person's care plan is up to date and relevant. The strong recommendation to review the plan annually was based on the Care Programme Approach. But the committee recognised that this would depend on the person's level of need and circumstances and so recommended review meetings could be more frequent, if needed.\n\nThe committee noted the importance of regular monitoring of physical health, including for adverse effects of medications [EP4]. It was aware of strong evidence from 3 UK studies (2 case control and 1 cohort) that people with coexisting severe mental illness and substance misuse are less likely to adhere to medications than those with severe mental illness only [ES1.1.8].\n\nThe committee heard expert testimony about the side effects of medication and was aware from members' experience that this includes weight gain and other adverse effects [EP4]. Members felt this could be a barrier to adhering to treatment and could have a negative impact on a person's mental or physical health.\n\nCommittee members acknowledged that the evidence on working collaboratively and the views expressed in the expert testimony reflected their own experiences of working with people with coexisting severe mental illness and substance misuse [ES2.1.7, EP4]. They noted that changes in circumstances need to be taken into account in a person's care plan and physical health or social care, support or housing needs revised accordingly.\n\nThere was no evidence for cost effectiveness for this recommendation.\n\n## Discharge or transition\n\nThe discussion below explains how we made recommendations 1.3.11 and 1.3.12.\n\nCommittee members noted from their experience that transfer between services and discharge from the Care Programme Approach are key points when a person can lose touch with services.\n\nThe committee felt that a robust relapse prevention plan and re-entry into the system would help to mitigate the risk of suicide or death from unintentional overdose. The committee agreed that housing needs are a priority before discharge and referred to evidence previously noted in the discussion for section 1.1 and discussion for section 1.3 [ES1.1.9, ES2.2.1].\n\nThe committee noted that the discharge plan should also include information on managing risky situations because of the challenging nature of working with people who may be intoxicated or in withdrawal. This was based on members' experience and evidence from 2 moderate-quality and 1 low-quality studies [ES2.1.8]. The committee was aware of NICE's guideline on violence and aggression and agreed it was a useful source for providers.\n\nMembers noted the evidence on challenges people can face when moving between services and felt this was applicable to other key points in a person's life [ES2.2.1]. The committee acknowledged the need to take a 'life course' approach. So it strongly recommended that provision for continuity of care needs to be in place when transition between services occurs and at key points in a person's life. This was based on members' experience and evidence from 4 qualitative studies (2 high and 2 moderate quality) [ES2.2.4]. The members highlighted particular groups who may need additional support based on their expertise and existing NICE guidelines.\n\nThere was no evidence for cost effectiveness for this set of recommendations.\n\nThe committee heard expert testimony on the importance of making sure the guideline included the referral of young people to adult services [EP3]. It also reflected on members' experience and noted that groups such as looked after children and older people may need additional help. So handover of care on discharge, or when a person transfers to another service (in consultation with other providers), was included in the recommendation.\n\nThe committee agreed that encouraging practitioners to meet at multidisciplinary and multi-agency meetings is likely to improve physical health, social care and support outcomes and potentially reduce admissions for crisis care. But it also noted that this may be a new approach for the non-mental health sectors and that releasing staff for these meetings could be problematic without additional resources.\n\n# Section 1.4 Partnership working between specialist services, health, social care and support services and commissioners\n\n## Recommendations 1.4.1 to 1.4.5\n\nThe discussion below explains how we made recommendations 1.4.1 to 1.4.5.\n\nThe committee noted that although a policy guide in 2002 (the Department of Health's dual diagnosis good practice guide) had set out the vision for how services and care could be delivered, it was not being implemented. The committee was aware of Public Health England's guidance on co-existing alcohol and drug misuse with mental health issues: guidance to support local commissioning and delivery of care [to be published December 2016] which sets out the importance of joint working.\n\nThe committee discussed the fact that since April 2013 there have been separate funding streams for mental health and substance misuse services, with mental health services funded by clinical commissioning groups and substance misuse services by local authorities. The committee felt this exacerbated a longstanding division between the mental health and substance misuse sectors. It has also led to 2 different sets of organising paradigms for commissioners, which does not serve people with coexisting severe mental illness and substance misuse.\n\nMembers also noted that funding for addiction services comes from local authority budgets and is subject to commissioning contracts (which may exclude provision of mental health assessment or prescribing) and competitive tendering.\n\nThe committee decided to recommend partnership working because there is a lack of provision of health and social care services for people with coexisting severe mental illness and substance misuse. Where it exists, it is often fragmented and inconsistent and this can affect continuity of care. This was based on members' experience and the evidence previously noted in the discussion for section 1.2 [ES2.2.4].\n\nThe committee noted from the qualitative evidence previously described in the discussion for section 1.3 that different disciplines working together to support people with coexisting severe mental illness and substance misuse could help with coordinating care. If they work together and share responsibility for this group, the evidence showed it could improve the quality of health and social care services offered [ES2.1.7]. The evidence showed this could be done by joint management of cases and regular communication.\n\nThe committee also heard from an expert in local partnership working who described a framework designed to help local areas design and deliver flexible and coordinated services for people with multiple needs [EP1].\n\nThe committee noted that there needs to be a strategic framework for services that work with people with coexisting severe mental illness and substance misuse. And that commitment from providers and commissioners is essential for services to collaborate locally.\n\nBased on the evidence, the expert testimony and their own experience, committee members agreed that a cross-sector partnership, with a shared understanding of the problem (based on assessment of local needs) and a shared vision for the future were important factors [ES2.1.7, EP1]. Based on their expertise and expert testimony, they developed a recommendation on how services need to work together. They also noted the lack of evidence from review question 1.2 on existing care pathways and agreed further research is needed (see the recommendation for research on care pathway).\n\nThe committee was aware of evidence from review 2 that a lack of policy on referrals has an effect on the organisation and continuity of care. Evidence from 4 qualitative studies conducted in different settings (including 1 UK study set in the voluntary sector) noted that uncertainty on who should make referrals can also have an impact [ES2.1.11].\n\nCommittee members noted that the evidence from qualitative studies (previously noted in sections 1.1 and 1.2) was consistent with their experience [ES2.1.10, ES2.1.11]. This showed that pathways were inadequately planned and supported and that movement across a care pathway was often restricted because none of the specialist services took responsibility for this group. They also noted that continuity of care can be interrupted because of changes in the commissioning process or cycle. For example, re-tendering for services can lead to disruption and the need to build new care pathways.\n\nOne UK low-quality qualitative study exploring the views of commissioners provided evidence of a facilitator associated with organisation and continuity of care. The study noted that good links between the statutory and voluntary sectors improved outcomes, such as reduced waiting times and delivery of care [ES2.1.11]. This could also help with organisation and continuity of care.\n\nThe same study also highlighted that existing resources were stretched and that investment in the non-statutory sector could lead to provision of services not available in the statutory sector [ES2.1.5; ES2.1.6]. But the committee noted that this study was published in 2006. It also noted that commissioning and service provision for addiction services, the demography of people who use the services, treatment and the types of substances used have all changed markedly since 2002.\n\nThe committee noted from the evidence that there is no national service configuration in place (review question 1.2). Members acknowledged the importance of including the needs of people with coexisting severe mental illness and substance misuse in the joint strategic needs assessment. They agreed the needs of this group could be included in local strategies (for example, housing, alcohol or drug services and crime prevention). The committee noted that referral processes and pathways need to be in place to ensure this happens – and that a joined-up approach would help because this group often falls through the gaps in services.\n\nCommittee members also highlighted the importance of prompt access to services, based on their own experience and evidence. This was based on 1 high-, 2 moderate- and 3 low- quality qualitative studies (3 set in the UK) reporting on barriers and facilitators when seeking access to health advice. Barriers included long waiting lists, and 1 low-quality UK study indicated that direct referrals by alcohol and addictions teams could act as a facilitator [ES2.2.8]. Members agreed that direct referrals may be useful. They noted that direct access to services may be beneficial (compared with, for example, open access drop-in clinics) because this would give the person a sense of continuity of care. In turn, this may also enhance feelings of trust [ES2.2.4].\n\nThere was no evidence for cost effectiveness for this recommendation.\n\n## Information sharing\n\nThe discussion below explains how we made recommendations 1.4.6 and 1.4.7.\n\nThe committee made recommendations to highlight the importance of information sharing. The committee noted an expert testimony that highlighted that confidentiality is a barrier often faced by voluntary sector as an excuse not to share information [EP2]. The committee also noted the importance of services knowing about other local services and being able to tell people with coexisting severe mental illness and substance misuse or their families or carers about them [ES2.2.3, ES2.2.10]. For example, 1 UK low-quality study set in the voluntary sector noted that GPs were unaware of local community groups that people with coexisting severe mental illness and substance misuse could use [ES2.2.3].\n\nThere was no evidence for cost effectiveness for this recommendation.\n\n# Section 1.5 Improving service delivery\n\n## Making health, social care and other support services more inclusive\n\nThe discussion below explains how we made recommendations 1.5.1 to 1.5.5.\n\nThe committee observed what appears to be an inequity in the way that people with coexisting severe mental illness and substance misuse are treated by services compared with other groups. It noted that the needs of this group are often not taken into account and they risk being excluded from mainstream services. Therefore the committee made a strong recommendation on improving delivery of existing services to make them more inclusive.\n\nCommittee members were aware, from their own experience, the evidence and expert testimonies of the benefits of supporting people to participate in improving services [review 1, EP1, EP2]. The committee also noted from the evidence (previously described in the discussion for section 1.2) the importance of involving people with coexisting severe mental illness and substance misuse (and their family or carers), and providing them with information and support [ES2.2.9, ES2.2.10]. The ways in which people with coexisting severe mental illness and substance misuse, and their family or carers, could be involved in design and delivery of services were based on the findings from the review on epidemiology and current configuration [review 1].\n\nThe committee noted from its expertise and evidence (previously noted in the discussion for section 1.1) that people are often passed between services without being provided with appropriate care and support and that this may be because of negative attitudes or stereotyping by staff or services [ES2.1.3, ES2.2.5].\n\nThe committee also noted from its experience and the evidence that these factors can lead to a mistrust of professionals, resulting in poor engagement with services [ES2.2.5]. This was based on evidence from 3 (1 high and 2 moderate quality) of the 9 qualitative studies (1 high, 4 moderate and 4 low quality) reporting on barriers associated with access to effective care by trusted professionals. In addition, members agreed that a pessimistic attitude among professionals, about the likelihood of the person staying in the service may also be a contributing factor to the poor service.\n\nThe committee was aware from the evidence review on epidemiology that the prevalence of coexisting severe mental illness and substance misuse varied across regions. The evidence showed that semi-rural areas seem to have the highest need [ES1.1.2]. This was based on moderate evidence from 9 cohort studies (4 high, 1 moderate and 4 low quality) and 7 case–control studies (2 high, 2 moderate and 3 low quality) reporting on the prevalence of coexisting severe mental illness and substance misuse among those in contact with secondary mental health services.\n\nExpert testimony suggested there is a high incidence of early psychosis in rural areas, but the committee noted from the evidence that specialist services are mostly in urban areas [review 1, EP3]. The committee agreed not to make a recommendation specifying content or configuration of service delivery by geographical settings. Instead it felt that the most important message was to ensure that any services needed (as identified by the joint strategic needs assessment) are delivered locally.\n\nThe committee made a strong recommendation on locating services in places that are safe and where there is minimal stigma attached to attending. It acknowledged the evidence (1 moderate- and 1 low-quality study) on co‑location of services (for example, services based in the same facility) was mixed but recognised that there may be stigma in accessing certain services [ES2.1.12]. Committee members were aware from their experience and from expert testimony that people with coexisting severe mental illness and substance misuse are particularly vulnerable. They may be at risk of exploitation (for example, being forced to become sex workers or being taken advantage of in relation to their housing or financial situation). Or they may have experienced trauma (for example, women may have experienced rape) [EP1, EP2]. It agreed that a 'trauma-informed' approach would provide the best support for this group.\n\nMembers were also aware from the evidence that even if people knew about services, barriers to access included difficulty in contacting or gaining admission to services outside hours, long waiting lists and services not being local [review 2]. The committee considered the evidence review (review question 1.2) on current configuration of services and developed a recommendation highlighting the importance of safety of location, low stigma and flexibility in opening times as factors that can help make services more accessible.\n\nSee the end of this section for details on cost effectiveness.\n\n## Adapting existing secondary care mental health services\n\nThe discussion below explains how we made recommendations 1.5.6 to 1.5.9.\n\nThe committee was aware of moderate evidence from 13 UK studies (2 high, 9 moderate and 2 low quality) that there were inconsistencies in the current configuration of 'dual diagnosis' services in NHS trusts across the UK [ES1.2.1]. These inconsistencies lie in several areas, including sources of funding, structure of services, type of staff members, services delivered and coordination of care. The committee considered the evidence on configuration of services and observed there were few specialist services for adults [ES1.2.1].\n\nThe committee agreed that the recommendations for specialist services (secondary care mental health services and 'dual diagnosis' services) need to focus on improving existing services using the expertise that is available instead of creating a specialist 'dual diagnosis' service. It felt that the standard care delivered in the UK could be improved by increasing the level of engagement people with severe mental illness and substance misuse have with existing services and that existing capacity and resources could be used to deliver this.\n\nThe committee made recommendations about the design, delivery and content of the service model, based on the evidence, economic model, expert testimony and members' expertise.\n\nThe committee considered the evidence for the effectiveness and efficiency of service delivery models, which included randomised controlled trials (RCTs) and observational studies [ES3.1, ES3.2, ES3.3, ES3.4, ES3.5, ES3.6, ES3.7, ES3.8, ES3.9, ES3.10]. The evidence covered a range of service delivery interventions, showing some positive outcomes and that there was value in what the models were aiming to achieve. However, the members agreed that there was no overwhelming evidence of benefit to indicate a particular model should be recommended.\n\nThe committee agreed that there was limited evidence of effect for assertive community treatment and integrated treatment interventions in relation to mental health and substance misuse outcomes [ES3.1, ES3.2, ES3.3]. The committee noted that fidelity to delivery of interventions (whether the intervention was delivered as designed) in the service models was reported for only 5 studies. Where reported, the fidelity was considered to be good.\n\nThere was weak evidence for assertive community treatment based on 5 US RCTs [ES3.1]. The committee noted that the assertive community treatment intervention model is no longer used in the US and is rare in the UK. There was moderate evidence from 6 RCTs and 1 observational study (3 studies based in the UK) for integrated treatment interventions compared with treatment as usual [ES3.2]. There was weak evidence from 1 RCT for integrated treatment intervention compared with enhanced assessment and monitoring. The RCTs did not all show a clear evidence of benefit [ES3.3].\n\nThere was some improvement in service use outcomes (increase in physical and telephone contact) but members noted that it was debatable whether this was necessarily an evidence of benefit, because the reasons for contacts were not reported [ES3.1]. There was some evidence of effect on social care outcomes such as housing, employment and social functioning [ES3.1].\n\nThe committee felt that although the follow-up in the studies ranged from 24\xa0weeks to 3\xa0years, the length of time needed to observe small improvements can sometimes be 5\xa0to 10\xa0years [ES3.1, ES3.2].\n\nThere was moderate to weak evidence from 8\xa0RCTs and 1\xa0non-randomised controlled trial evaluating a range of interventions. The intervention included:\n\nbrokerage case management [ES3.4]\n\ncontingency management [ES3.5]\n\ntime-limited care coordination [ES3.6]\n\nshelter-based psychiatric clinic [ES3.7]\n\nstaff training [ES3.8]\n\nsupportive housing [ES3.9]\n\nsupportive text messaging. [ES3.10]\n\nThe comparator arms were no intervention, treatment as usual or an active comparator.\n\nThe committee noted that there was mainly weak evidence from small studies, with short follow-up (ranging from 16 to 78\xa0weeks). Three studies were based in UK and Ireland but most of the evidence was from US. It noted that fidelity to delivery of the intervention was reported in only 2 studies (1 reported as low and 1 as high fidelity). Members discussed the potential value of service models incorporating contingency management, peer support (delivered as part of a care coordination intervention in 1 US study) or text messaging, and considered these further under research recommendations [ES3.5, ES3.6, ES3.10] (see the recommendation for research on what works).\n\nThe committee agreed that there was weak evidence for a staff training intervention considered in the review of effectiveness of service delivery models [ES3.8]. It noted that the 2 UK studies were of low quality, the evidence was inconsistent and did not appear to show an overall benefit. In addition, a committee member reflected on their own involvement in delivery of the intervention in 1 of the studies. The committee member noted that there were a number of challenges: staff often moved between services, there was a high turnover of staff, and low fidelity to delivery of the intervention.\n\nThe committee agreed not make a recommendation on training because the evidence did not show an overall benefit.\n\nThe committee agreed there were several gaps in the evidence from review\xa03 including:\n\npopulation (limited evidence on young people and vulnerable groups)\n\ninterventions or measures – for example, measures looking at improving accessibility and availability of services\n\noutcomes (no evidence on physical health outcomes)\n\nefficiency of service delivery models – for example outcomes on accessibility of services (waiting times).\n\nSee the end of this section for details on cost effectiveness.\n\nThe committee was aware of evidence from 4 qualitative studies (1 moderate- and 3 low-quality studies) of barriers or facilitators associated with integrated services. One low-quality UK study, for example, described mixed views among staff in a specialist 'dual diagnosis' service on whether services should be separate or integrated with mental health or substance misuse services [ES2.1.13]. It noted that there was evidence from the same study indicating that most commissioners felt that integrating services is essential for the effective and efficient delivery of care for people with complex needs. Some commissioners also noted that relationships between different services could be expected to improve if they were required to share budgets and resources.\n\nCommittee members felt this finding (published in 2006) should be treated with caution because the funding landscape has changed considerably since 2002. Based on their experience they noted that:\n\na third tier of provision may not necessarily meet the needs of people with coexisting severe mental illness and substance misuse, and\n\n'integration' in this context should be about joint working and coordinated care rather than developing a specialist service.\n\nThe committee noted that there was limited description of the comparator arms (often described as 'treatment as usual') in the studies included in review 3 and that most of the studies were conducted in the US. The committee's view was that 'usual care' in the US is likely to differ from that in the UK and the level of 'usual care' in the UK was considered to be of a better standard.\n\nThe committee used members' expert knowledge and the evidence to develop a recommendation on aspects that could be included in a service. This includes interventions that have shown to be effective in NICE guidelines for either severe mental illness or substance misuse. The committee was aware of the study by Wenze (2015; adjunctive psychosocial intervention following Hospital discharge for Patients with bipolar disorder and comorbid substance use: a pilot randomized controlled trial) included in the economic model. It reflected on the components of the 'treatment–engagement' sessions in the Wenze (2015) study as well as members' own experience to develop a recommendation on ways to improve engagement.\n\nThe committee noted that any recommendation on improving service delivery needs to take into account the needs of those who reach crisis and those who experience a relapse after discharge. This recommendation was based on members' expertise. Members were aware from the evidence and their experience that people's care is often fragmented and that plans need to be in place to allow people to return for additional support after being discharged or losing touch with the system. They noted the evidence on facilitators for consistent care, including from 1 low-quality UK study that highlighted that good aftercare is an important means of preventing relapse [ES2.2.4]. They also noted that the Department of Health's Mental Health Crisis Care Concordat has information on developing an action plan for people in a crisis.\n\n## Support for staff\n\nThe discussion below explains how we made recommendations 1.5.10 to 1.5.12.\n\n## Current practice\n\nIt is good practice for care coordinators working with people with severe mental illness who misuse substances to be offered support and supervision in secondary care mental health services. But practice may vary.\n\n## Evidence\n\nThe committee noted the importance of support and supervision from their experience and the evidence from 2 high-, 1 moderate- and 2 low-quality qualitative studies (3 set in the UK) [ES2.1.15]. Because of the complexity of the care coordinator's role, the committee felt it was important to highlight in the recommendation the importance of a support structure for this role.\n\nCommittee members were also aware from the evidence that lack of training may act as a barrier to the effective delivery of care [ES2.1.16]. This was based on 10\xa0qualitative studies (2 high, 3 moderate and 5 low quality), with 5 studies set in the UK. They also noted from the evidence and their experience that addressing gaps in practitioners' knowledge on substance misuse and mental health can encourage them to establish links with other services and help improve delivery of services.\n\nEvidence from 1 high-, 3 moderate-, and 1 low-quality qualitative studies (2 set in the UK) found that staff having different perceptions of people with drug and alcohol problems, depending on the focus of the service they work in, is a barrier to service delivery and partnerships. This view was consistent among providers and commissioners across various settings [ES2.1.14].\n\nProviders' views across 6 qualitative studies highlighted services not taking responsibility for people with coexisting severe mental illness and substance misuse, and the potential impact of this on meeting people's wider health, social care or support needs [ES2.1.10]. Three of the studies were set in the UK, 1 was of moderate quality and 2 were low quality. The committee noted that although 1 of the UK studies was of low quality it was recent and reflected voluntary sector providers' views. Members drew on the evidence and their own expertise and noted that helping overcome negative attitudes in staff will help make sure people with coexisting severe mental illness and substance misuse are not excluded from services.\n\nCommittee members were aware from the evidence from 5 qualitative studies (2 high-, 2 moderate- and 1 low-quality studies) of the importance of establishing good relationships between practitioners and people with coexisting severe mental illness and substance misuse and its impact on delivery of care [ES2.1.4]. They also noted there was high-quality UK evidence from 1 study to show that practitioners perceived that behaviours such as misusing drugs could affect relationships and act as a barrier to delivering care [ES2.1.4].\n\nBased on the evidence and their experience, the committee made a strong recommendation on the need to build services that are tolerant and resilient. It agreed that services need to be able to help people work through relapse, poor attendance or a crisis to ensure they are not discharged too soon.\n\nThe committee heard from an expert on a service delivery model in early intervention services [EP3]. It noted that these services offer a more consistent and coordinated approach. That is because the staff working in them have lower caseloads, so can have more contact with the people they work with and provide stability. The committee noted a similar approach needs to be considered for staff who work with people with severe mental illness and substance misuse.\n\nTaking into account the evidence, members' experience and expert testimony, the committee made strong recommendations on providing the right kind of support for staff.\n\nThe committee discussed the evidence from the cost effectiveness studies and the economic model when developing the recommendations on improving service delivery.\n\nAn economic analysis was undertaken. This comprised a review of existing cost effectiveness studies and a bespoke economic model.\n\nThe findings from the review of evidence (from 1 UK and 7 US studies) were inconsistent [ES4.1, ES4.2, ES4.3, ES4.4, ES4.5]. The US studies found that integrated treatment leads to minor cost savings but the UK study found that the intervention resulted in an increase in public sector costs.\n\nIn all studies, integrated treatment appears to result in improvement in some outcomes. But economic analyses used different outcome measures, reported as changes on various scales, making comparisons challenging. Three studies adopted before-and-after design, studies used different perspectives and time horizons, only 1 included economic study was judged to be directly applicable, 3 studies were judged to be characterised by minor limitations [++], 4 by potentially serious limitations [+], and 1 by very serious limitations [−]. Overall, there is little evidence to support one service delivery model over another, based on existing economic evidence.\n\nThe model was based on 3 studies. The first study, conducted in the US, comprised a treatment–engagement intervention (using resources more intensively than in standard care) for people with bipolar disorder and substance misuse. It was a small study whose health outcome was inconclusive, but yielded resource use data. The remaining 2 studies, both from the UK, were used to estimate baseline admissions rates for people with dual diagnosis.\n\nThe model's time-horizon was 1\xa0year only. So increases in life expectancy that might have occurred as a result of an intervention were not included as benefits in the model. Because of the lack of data, a further conservative assumption was that wider costs, particularly those falling on the criminal justice system, were not included. Further, the model's measured outcome might not have measured all of the health outcome benefits.\n\nThe model showed that an intervention that combined enhanced engagement with standard care would need to reduce relapses by about 12% for the intervention to become cost saving.\n\nThe committee members had differing views about whether UK standard care is better than that reported in the US studies. It was felt that standard care in the UK may be more similar to the enhanced intervention modelled.\n\nAssuming standard care in the UK is equivalent to the enhanced intervention modelled, it would be offering better outcomes at the same cost. By definition, that would be a cost-effective approach. However, assuming standard care in the UK would need to be enhanced and therefore need additional resources, at a cost of £226 per person and assuming an effect size of 10% the intervention would need to result in a small quality-adjusted life year (QALY) gain of 0.002 (equivalent to 0.73\xa0days in full health) to be considered cost effective at an incremental cost effectiveness ratio threshold of £20,000 per QALY [ES4.6].\n\nGiven the results that were obtained even though a number of potential benefits were not considered because of the lack of data (for example on a person's life expectancy, improvement in the substance misuse problem, improvement in the mental health of service users the reduction in health and social care and the criminal justice system costs) the treatment–engagement intervention is very likely to be a cost-effective option.\n\n# Section 1.6 Maintaining contact between services and people with coexisting severe mental illness and substance misuse who use them\n\nThe discussion below outlines how we made recommendations 1.6.1 to 1.6.5.\n\nCommittee members decided to make recommendations on encouraging people to stay in contact with services and making services accessible. That is because they were aware, from the evidence and their own experience, that this group may find it hard to start or maintain contact with services [evidence review 2, EP2]. Also, their physical health, social care, housing or support needs are not being met.\n\n## Evidence\n\nThe committee noted from its experience that it is important to take a long-term, realistic view in relation to involving the person in their care plan and coordinating their care. It noted from experience and evidence (previously noted in the discussion for section 1.3) that this is particularly true in light of the challenging nature of working with this group [ES2.1.8].\n\nCommittee members were aware – from the evidence, expert testimony and their own experience – of the importance of providing continuity and adopting a flexible approach. The committee heard from experts working with people who are homeless about a range of methods that could be used to engage and stay in touch with this group [EP2]. The committee also considered evidence from 4 qualitative studies (1 high, 1 moderate, 2 low quality), of which 2 were UK studies [ES2.2.4]. This highlighted that a lack of continuity of care, along with changes in staff, can result in a lack of trust or reluctance to engage with services. It also highlighted that good aftercare was an important aspect of preventing relapse.\n\nCommittee members reflected on their experience and the evidence from 8 qualitative studies of mixed quality (2 high, 3 moderate and 3 low). Three of the studies (low quality) were set in the UK. The studies showed that a non-judgemental empathetic approach was needed when encouraging a person to stay in contact [ES2.2.7].\n\nThe committee noted barriers to access or uptake of social care or physical health services as highlighted in review 2 [ES2.1.3, ES2.2.1, ES2.2.2, ES2.2.4, ES2.2.5, ES2.1.12]. These included:\n\nfragmented care\n\nlack of support during a transition period (for those who had criminal convictions)\n\nfailure to recognise cultural differences\n\nmistrust of healthcare professionals\n\npoor links to services\n\nnegative connotations of being labelled as having problems with both mental health and substance misuse\n\nnegative attitudes\n\nstereotyping or stigma about mental health diagnoses in substance misuse settings or about substance misuse in mental health settings.\n\nThe committee was aware from evidence review 2 and members' experience that having continuity of contact encourages people to keep in touch with services. The committee made a weak recommendation on a range of approaches based on members' experience and expert testimony [EP2, EP4].\n\nThe committee recognised that everyone with coexisting severe mental illness and substance misuse faces difficulties in receiving care, but it wanted to highlight that some groups are particularly vulnerable. It acknowledged that factors contributing to this include not being able get to, or stay in contact with, the services they need [ES2.1.10].\n\nThe committee noted moderate to strong evidence from 11 cohort studies and 7 case–control studies on the characteristics of the coexisting severe mental illness and substance misuse population [ES1.1.5]. It noted that it is more common in younger people and men [ES1.1.5]. It also noted that homelessness is a frequent outcome for this group [ES1.1.9]. Members also acknowledged that pregnant women or women who have recently given birth are particularly vulnerable. This was based on their experience and evidence review\xa02. The committee noted from its experience that people with coexisting severe mental illness and substance misuse frequently have a history of trauma and that this can lead to disruptive attachments and challenging behaviour. It also noted that, from a 'life course' perspective, older people may be a particularly vulnerable group.\n\nThe committee noted that the evidence linking ethnicity with coexisting severe mental illness and substance misuse was inconsistent [ES1.1.5]. Apart from age, gender and ethnicity, there was a lack of evidence to show that groups identified in the equality impact assessment are more likely to have a coexisting severe mental illness and substance misuse. This includes, for example: people with a learning disability; teenage parents; Gypsies and Travellers; asylum seekers or refugees; lesbian, gay, bisexual, transsexual or transgender people; and sex workers [ES1.1.5].\n\nThe committee was aware from its experience that everyone has a range of social care needs, but noted that the evidence did not identify particular social care needs for groups identified in the equality impact assessment. That includes, for example, those who are socially isolated, on low income, have a history of being 'looked after' or are adopted or have a history of experiencing or witnessing domestic violence and abuse [ES1.1.9].\n\nAlthough no evidence was identified, the committee was aware from its experience that some groups may be reluctant to engage with, or may encounter difficulties when engaging with, services for people with coexisting severe mental illness and substance misuse. This includes people who are recent migrants, have language difficulties or are from specific religious communities. From an equality perspective, committee members recommended including people with language difficulties.\n\nAlthough it is not an exhaustive list, the committee highlighted the groups identified in recommendation 1.6.4 based on the evidence, their expertise and expert testimony [ES1.1.5, ES1.1.9, review 2, EP2].\n\nThe committee noted that, although the evidence from review 2 provided insight into barriers and facilitators to delivery of care, it agreed that research was needed to understand the experience of people at different stages of recovery (see the recommendation for research on barriers and facilitators).\n\nCommittee members were aware, from the evidence and their experience, that lack of emotional support and empathy can be a contributing factor to non-attendance at appointments or loss of contact [ES2.2.7]. They were also aware that non-attendance can often lead to discharge [review 2]. Based on the evidence, their expertise and expert testimony, they made a strong recommendation on actions services can take to ensure that non-attendance or loss of contact is treated as a matter of concern [review 2, EP2].\n\nCommittee members reflected on their experience and expert testimony and noted the importance of maintaining contact and reaching out to people to help them remain engaged with services [EP2]. Based on their experience, they made a weak recommendation on the follow-up actions to address non-attendance.\n\nThe committee noted that maintaining engagement can lead to improved outcomes and may place less burden on crisis care or inpatient admissions.\n\n# Other points the committee discussed\n\nThe committee discussed the exclusion criteria in the scope and noted that exclusion of mental health disorders such as eating disorders was a major gap.\n\nThe committee noted that criminal justice system settings were excluded from the scope, but was aware of NICE guidelines currently in development on the mental health of adults in contact with criminal justice system and the physical health of people in prison. It also recognised that young people and adults with coexisting severe mental illness and substance misuse who need a safe place to stay may come into contact with people within this setting, for example, the police. The committee noted that resources for helping the police to support people with vulnerabilities are available in the Home Office's Crisis Care Concordat.\n\nThe committee considered a range of expertise that would be helpful to inform the development of the guideline and invited expert testimony in early intervention services, primary care, homeless, and local partnership working. The committee also acknowledged other groups (refugees, veterans) but recognised that there is a general set of needs that would subsume the specific needs of particular populations.\n\nThe committee considered all the evidence available in developing this guideline. However, some evidence statements provided background information and could not be explicitly linked to recommendations [ES1.1.1, ES1.1.3, ES1.1.4, ES1.1.6, ES1.1.7]. The committee heard from an expert in early intervention services who described a study on contingency management (see the CIRCLE study) that provided background information and was not linked to a specific recommendation [EP5].\n\nThe committee discussed the various forms of support groups or mechanisms for peer support. It was aware of mutual aid organisations including Alcoholics Anonymous (AA), Narcotics Anonymous (NA), Dual Recovery Anonymous (DRA) and SMART recovery and discussed the merit of adding a reference to such forms of support as examples in the guideline recommendations.\n\nIt was also aware of Public Health England's briefing on the evidence-based drug and alcohol treatment guidance recommendations on mutual aid but noted it was not aware of evidence establishing use of mutual aid in people with coexisting severe mental illness and substance misuse. In addition, because peer support and mutual aid were areas identified for a research recommendation, the committee did not recommend specifying examples of mutual aid groups in the guideline recommendations.\n\nThe committee also noted that there is a stigma attached to the term substance 'misuse' but recognised that this term is used in other NICE guidelines.\n\n# Evidence reviews\n\nDetails of the evidence discussed are in evidence reviews, reports and papers from experts in the area.\n\nStudies reported in evidence review 1 were all based in the UK. For evidence statements derived from evidence reviews 2, 3 and 4 we have noted the number of studies based in the UK in the committee's discussion section. Please refer to the full evidence statements in the evidence reviews on the applicability of the evidence base to the UK.\n\nThe evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement (ES) number 1.1.1 indicates that the linked statement is numbered 1 in review question 1.1 of review 1. ES1.2.1 indicates that the linked statement is numbered 1 in review question 1.2 of review 1. ES2.1.1 indicates that the linked statement is numbered 1 in review question 2.1 of review 2. ES3.1 indicates the linked statement is numbered 1 in review 3 and ES4.1 indicates the linked statement is numbered 1 in review 4. EP1 indicates that expert paper 1: 'Local partnership working: examples drawn from the work of the Making Every Adult Matter coalition' is linked to a recommendation. EP2 indicates that expert paper 2: 'St Mungo's: people who have a dual diagnosis and are homeless' is linked. EP3 indicates that expert paper 3: 'Early Intervention in psychosis services' is linked. EP4 indicates that expert paper 4: 'Dual diagnosis among homeless people: primary care perspective' is linked.\n\nIf a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nSection 1.1: ES1.1.8, ES1.1.9, ES2.1.2, ES2.1.3, ES2.1.10, ES2.2.1, ES2.2.4; EP2, EP4; IDE\n\nSection 1.2: ES2.1.1, ES2.1.4, ES2.1.9, ES2.1.11, ES2.2.4, ES2.2.7, ES2.2.9, ES2.2.10; EP2; IDE\n\nSection 1.3: ES1.1.8, ES1.1.9, ES2.1.7, ES2.1.8, ES2.2.1, ES2.2.2, ES2.2.3, ES2.2.4, ES2.2.6; EP1, EP2, EP3, EP4; IDE\n\nSection 1.4: ES2.1.5, ES2.1.6, ES2.1.7, ES2.1.10, ES2.1.11, ES2.2.3, ES2.2.4, ES2.2.8, ES2.2.10; EP1, EP2; IDE\n\nSection 1.5: ES1.1.2, ES1.2.1, ES2.1.3, ES2.1.4, ES2.1.10, ES2.1.12, ES2.1.13, ES2.1.14, ES2.1.15, ES2.1.16, ES2.2.4, ES2.2.5, ES2.2.9, ES2.2.10, ES3.1, ES3.2, ES3.3, ES3.4, ES3.5, ES3.6, ES3.7, ES3.8, ES3.9. ES3.10, ES4.1, ES4.2. ES4.3, ES4.4, ES4.5, ES4.6; EP1, EP2, EP3; IDE\n\nSection 1.6: ES1.1.5, ES1.1.9, ES2.1.3, ES2.1.8, ES2.1.10, ES2.1.12, ES2.2.1, ES2.2.2, ES2.2.4, ES2.2.5, ES2.2.7; EP2, EP4; IDE\n\n# Gaps in the evidence\n\nThe committee's assessment of the evidence on coexisting severe mental illness and substance misuse identified a number of gaps. These gaps are set out below.\n\n. Evidence on the characteristics of people with coexisting severe mental illness and substance misuse in the groups identified in the equity impact assessment. This includes: people with a learning disability; teenage parents; Gypsies and Travellers; asylum seekers or refugees; lesbian, gay, bisexual, transsexual or transgender people; and sex workers.\n\n(Source review 1)\n\n. Social care needs of people identified in the equity impact assessment. This includes those who are socially isolated, are on a low income, have a history of being 'looked after' or are adopted, or have a history of experiencing or witnessing domestic violence and abuse.\n\n(Source review 1)\n\n. Views and experiences of:\n\na) commissioners\n\nb) primary care practitioners who work with vulnerable groups\n\nc) groups identified in the equity impact assessment (with the exception of young people and ex-offenders).\n\n(Source review 2)\n\n. Interventions or measures assessing efficiency of services (for example, measures looking at improving accessibility and availability of services).\n\n(Source review 3)\n\n. Different models of service delivery (for example, a comparison of specialist, integrated or separate services) and efficiency of service delivery models.\n\n(Source review 3)", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Needs assessment\n\nIn the UK, how prevalent is coexisting severe mental illness with substance misuse and what are the physical health, social care, housing or other support needs of people with this diagnosis?\n\n## Why this is important\n\nThere is limited evidence on the physical health, social care, housing or other support needs of people with coexisting severe mental illness and substance misuse. This includes prevalence of coexisting physical conditions such as cardiovascular, respiratory or infectious diseases and social care needs such as social isolation or poor housing.\n\nEvidence on the differential impact on physical health of the type of substance used and the mental health condition would also be useful. Longitudinal evidence is needed.\n\nThis will help design coordinated evidence-based services to meet the wider health and social care needs of this group of people and provide a good standard of care.\n\nPeople with coexisting severe mental illness and substance misuse may present in a variety of settings. Research on the needs that this group present with in specific settings (for example, primary care) would be beneficial. So would research evaluating the needs of particularly vulnerable groups (for example, those identified in the equality impact assessment).\n\n# What works?\n\nIn the UK, how effective and cost effective are service delivery interventions such as peer support, contingency management or text messaging delivered alone or in combination (in conjunction with standard care) compared with standard care alone for young people and adults with coexisting severe mental illness and substance misuse?\n\n## Why this is important\n\nThere is limited evidence on the optimal service delivery model for young people and adults with coexisting severe mental illness and substance misuse. There is increasing use of contingency management, peer support (including mutual aid) or text messaging as part of a service delivery model to help people access services.\n\nMore research is needed to assess the use, benefit and whether these methods improve this group's engagement with services.\n\nThere is limited evidence on the cost effectiveness of interventions and services with this group. Further research is also needed on whether particular services or elements of standard care for this group give better value for money. A mixed methods approach could identify which of the different elements delivered in a service model are optimal for the person.\n\nResearch in particularly vulnerable groups (for example those identified in the equality impact assessment) is needed.\n\n# Costing tool\n\nWhich elements of health, social care or other support services work best at a local level and provide the best 'value for money' to address the needs of young people and adults with coexisting severe mental illness and substance misuse?\n\n## Why this is important\n\nThere is a lack of agreed service models that address the range of health, social care and other support needs of people with coexisting severe mental illness and substance misuse. Information on the value these may provide are also limited.\n\nA costing tool will help decision makers 'mix and match' interventions and services to see which package provides the best outcome. It will also help identify cost savings and determine whether the additional benefits (in terms of health, social care or criminal justice outcomes) are worth the extra costs. It may also help to demonstrate whether better functioning mainstream services are effective and provide value for money.\n\n# Barriers and facilitators\n\nWhat are the barriers and facilitators for young people and adults with coexisting severe mental illness and substance misuse to obtain an optimal service (including optimal time frame for delivering interventions) to meet their needs and enable their recovery?\n\n## Why this is important\n\nThere is limited evidence that identifies the triggers for deterioration and the turning points for recovery for people with coexisting severe mental illness and substance misuse.\n\nAlthough review 2 contains evidence on the views and experiences of this group, their family or carers, it is not always clear which point in the care pathway the views and experiences expressed relate to. As such, it is difficult to fully break down the experience of care received at various intervals along the care pathway. Understanding the experience of people who are at different stages of recovery and how they have maintained their progress and success (1\xa0year, 3\xa0years, 5\xa0years, 10\xa0years+) will help with designing more effective services and planning services that deliver interventions at the right time.\n\n# Care pathway\n\nIn the UK, what is the optimal care pathway for young people and adults with coexisting severe mental illness and substance misuse?\n\n## Why this is important\n\nThere is a lack of published evidence on care pathways on treatment, management and follow-up of people with coexisting severe mental illness and substance misuse. In the UK, service configurations, treatment philosophies and funding streams act as barriers to providing coordinated care. Separate mental health and substance misuse services are usually provided by different organisations, have different organisational and managerial structures, and staff within each service often lack the knowledge and skills needed to work effectively with people from another organisation.\n\nA review of what has worked or not in areas that have implemented changes to practice will help services develop optimal care pathways."}	https://www.nice.org.uk/guidance/ng58	This guideline covers how to improve services for people aged 14 and above who have been diagnosed as having coexisting severe mental illness and substance misuse. The aim is to provide a range of coordinated services that address people’s wider health and social care needs, as well as other issues such as employment and housing.
33804a8292cb95f1f379d407b90382c05d422019	nice	Recent-onset chest pain of suspected cardiac origin: assessment and diagnosis	Recent-onset chest pain of suspected cardiac origin: assessment and diagnosis This guideline covers assessing and diagnosing recent chest pain in people aged 18 and over and managing symptoms while a diagnosis is being made. It aims to improve outcomes by providing advice on tests (ECG, high-sensitivity troponin tests, multislice CT angiography, functional testing) that support healthcare professionals to make a speedy and accurate diagnosis. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Providing information for people with chest pain Discuss any concerns people (and where appropriate their family or carer/advocate) may have, including anxiety when the cause of the chest pain is unknown. Correct any misinformation. Offer people a clear explanation of the possible causes of their symptoms and the uncertainties. Clearly explain the options to people at every stage of investigation. Make joint decisions with them and take account of their preferences: Encourage people to ask questions. Provide repeated opportunities for discussion. Explain test results and the need for any further investigations. Provide information about any proposed investigations using everyday, jargon-free language. Include: their purpose, benefits and any limitations of their diagnostic accuracy duration level of discomfort and invasiveness risk of adverse events. Offer information about the risks of diagnostic testing, including any radiation exposure. Address any physical or learning difficulties, sight or hearing problems and difficulties with speaking or reading English, which may affect people's understanding of the information offered. Offer information after diagnosis as recommended in the relevant disease management guidelines: NICE guideline on acute coronary syndromes NICE guideline on stable angina NICE guideline on generalised anxiety disorder and panic disorder in adults NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults. Explain if the chest pain is non-cardiac and refer people for further investigation if appropriate. Provide individual advice to people about seeking medical help if they have further chest pain. # People presenting with acute chest pain This section of the guideline covers the assessment and diagnosis of people with recent acute chest pain or discomfort, suspected to be caused by an acute coronary syndrome (ACS). The term ACS covers a range of conditions including unstable angina, ST‑segment-elevation myocardial infarction (STEMI) and non‑ST‑segment-elevation myocardial infarction (NSTEMI). The guideline addresses assessment and diagnosis irrespective of setting, because people present in different ways. For early management of these conditions, follow the NICE guideline on acute coronary syndromes. ## Initial assessment and referral to hospital Check immediately whether people currently have chest pain. If they are pain free, check when their last episode of pain was, particularly if they have had pain in the last 12 hours. Determine whether the chest pain may be cardiac and therefore whether this guideline is relevant, by considering: the history of the chest pain the presence of cardiovascular risk factors history of ischaemic heart disease and any previous treatment previous investigations for chest pain. Initially assess people for any of the following symptoms, which may indicate an ACS: pain in the chest and/or other areas (for example, the arms, back or jaw) lasting longer than 15 minutes chest pain associated with nausea and vomiting, marked sweating, breathlessness, or particularly a combination of these chest pain associated with haemodynamic instability new onset chest pain, or abrupt deterioration in previously stable angina, with recurrent chest pain occurring frequently and with little or no exertion, and with episodes often lasting longer than 15 minutes. Do not use people's response to glyceryl trinitrate (GTN) to make a diagnosis. Do not assess symptoms of an ACS differently in men and women. Not all people with an ACS present with central chest pain as the predominant feature. Do not assess symptoms of an ACS differently in ethnic groups. There are no major differences in symptoms of an ACS among different ethnic groups. Refer people to hospital as an emergency if an ACS is suspected (see recommendation 1.2.1.3) and: they currently have chest pain or they are currently pain free, but had chest pain in the last 12 hours, and a resting 12‑lead ECG is abnormal or not available. If an ACS is suspected (see recommendation 1.2.1.3) and there are no reasons for emergency referral, refer people for urgent same-day assessment if: they had chest pain in the last 12 hours, but are now pain free with a normal resting 12‑lead ECG or the last episode of pain was 12 to 72 hours ago. Refer people for assessment in hospital if an ACS is suspected (see recommendation 1.2.1.3) and: the pain has resolved and there are signs of complications such as pulmonary oedema.Use clinical judgement to decide whether referral should be as an emergency or urgent same-day assessment. If a recent ACS is suspected in people whose last episode of chest pain was more than 72 hours ago and who have no complications such as pulmonary oedema: carry out a detailed clinical assessment (see recommendations 1.2.4.2 and 1.2.4.3) confirm the diagnosis by resting 12‑lead ECG and blood troponin level take into account the length of time since the suspected ACS when interpreting the troponin level.Use clinical judgement to decide whether referral is necessary and how urgent this should be. Refer people to hospital as an emergency if they have a recent (confirmed or suspected) ACS and develop further chest pain. When an ACS is suspected, start management immediately in the order appropriate to the circumstances (see the section on immediate management of a suspected acute coronary syndrome) and take a resting 12‑lead ECG (see the section on resting 12-lead ECG). Take the ECG as soon as possible, but do not delay transfer to hospital. If an ACS is not suspected, consider other causes of the chest pain, some of which may be life-threatening (see recommendations 1.2.6.5, 1.2.6.7 and 1.2.6.8). ## Resting 12-lead ECG Take a resting 12‑lead ECG as soon as possible. When people are referred, send the results to hospital before they arrive if possible. Recording and sending the ECG should not delay transfer to hospital. Follow local protocols for people with a resting 12‑lead ECG showing regional ST‑segment elevation or presumed new left bundle branch block (LBBB) consistent with an acute STEMI until a firm diagnosis is made. Continue to monitor (see recommendation 1.2.3.4). Follow the NICE guideline on acute coronary syndromes for people with a resting 12‑lead ECG showing regional ST‑segment depression or deep T wave inversion suggestive of a NSTEMI or unstable angina until a firm diagnosis is made. Continue to monitor (see recommendation 1.2.3.4). Even in the absence of ST‑segment changes, have an increased suspicion of an ACS if there are other changes in the resting 12‑lead ECG, specifically Q waves and T wave changes. Consider following the NICE guideline on acute coronary syndromes if these conditions are likely. Continue to monitor (see recommendation 1.2.3.4). Do not exclude an ACS when people have a normal resting 12‑lead ECG. If a diagnosis of ACS is in doubt, consider: taking serial resting 12‑lead ECGs reviewing previous resting 12‑lead ECGs recording additional ECG leads.Use clinical judgement to decide how often this should be done. Note that the results may not be conclusive. Obtain a review of resting 12‑lead ECGs by a healthcare professional qualified to interpret them as well as taking into account automated interpretation. If clinical assessment (as described in recommendation 1.2.1.10) and a resting 12‑lead ECG make a diagnosis of ACS less likely, consider other acute conditions. First consider those that are life-threatening such as pulmonary embolism, aortic dissection or pneumonia. Continue to monitor (see recommendation 1.2.3.4). ## Immediate management of a suspected acute coronary syndrome Management of ACS should start as soon as it is suspected, but should not delay transfer to hospital. The recommendations in this section should be carried out in the order appropriate to the circumstances. Offer pain relief as soon as possible. This may be achieved with GTN (sublingual or buccal), but offer intravenous opioids such as morphine, particularly if an acute myocardial infarction (MI) is suspected. Offer people a single loading dose of 300 mg aspirin as soon as possible unless there is clear evidence that they are allergic to it. If aspirin is given before arrival at hospital, send a written record that it has been given with the person.Only offer other antiplatelet agents in hospital. Follow the NICE guideline on acute coronary syndromes. Do not routinely administer oxygen, but monitor oxygen saturation using pulse oximetry as soon as possible, ideally before hospital admission. Only offer supplemental oxygen to: people with oxygen saturation (SpO2) of less than 94% who are not at risk of hypercapnic respiratory failure, aiming for SpO2 of 94% to 98% people with chronic obstructive pulmonary disease who are at risk of hypercapnic respiratory failure, to achieve a target SpO2 of 88% to 92% until blood gas analysis is available. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. Monitor people with acute chest pain, using clinical judgement to decide how often this should be done, until a firm diagnosis is made. This should include: exacerbations of pain and/or other symptoms pulse and blood pressure heart rhythm -xygen saturation by pulse oximetry repeated resting 12‑lead ECGs and checking pain relief is effective. Manage other therapeutic interventions using the NICE guideline on acute coronary syndromes. ## Assessment in hospital for people with a suspected acute coronary syndrome Take a resting 12‑lead ECG and a blood sample for high-sensitivity troponin I or T measurement (see the section on use of biochemical markers for diagnosis of an acute coronary syndrome) on arrival in hospital. Carry out a physical examination to determine: haemodynamic status signs of complications, for example, pulmonary oedema, cardiogenic shock and signs of non-coronary causes of acute chest pain, such as aortic dissection. Take a detailed clinical history unless a STEMI is confirmed from the resting 12‑lead ECG (that is, regional ST‑segment elevation or presumed new LBBB). Record: the characteristics of the pain -ther associated symptoms any history of cardiovascular disease any cardiovascular risk factors and details of previous investigations or treatments for similar symptoms of chest pain. ## Use of biochemical markers for diagnosis of an acute coronary syndrome Do not use high-sensitivity troponin tests for people in whom ACS is not suspected. For people at high or moderate risk of MI (as indicated by a validated tool), perform high-sensitivity troponin tests as recommended in the NICE diagnostics guidance on myocardial infarction. For people at low risk of MI (as indicated by a validated tool): perform a second high-sensitivity troponin test as recommended in the NICE diagnostics guidance on myocardial infarction if the first troponin test at presentation is positive. consider performing a single high-sensitivity troponin test only at presentation to rule out NSTEMI if the first troponin test is below the lower limit of detection (negative). Ensure that patients understand that a detectable troponin on the first high-sensitivity test does not necessarily indicate that they have had an MI. Do not use biochemical markers such as natriuretic peptides and high-sensitivity C-reactive protein to diagnose an ACS. Do not use biochemical markers of myocardial ischaemia (such as ischaemia-modified albumin) as opposed to markers of necrosis when assessing people with acute chest pain. When interpreting high-sensitivity troponin measurements, take into account: the clinical presentation the time from onset of symptoms the resting 12‑lead ECG findings the pre-test probability of NSTEMI the length of time since the suspected ACS the probability of chronically elevated troponin levels in some people that 99th percentile thresholds for troponin I and T may differ between sexes. ## Making a diagnosis When diagnosing MI, use the universal definition of myocardial infarction. This is the detection of rise and/or fall of cardiac biomarkers values with at least one value above the 99th percentile of the upper reference limit and at least one of the following: symptoms of ischaemia new or presumed new significant ST‑segment‑T wave (ST‑T) changes or new LBBB development of pathological Q waves in the ECG imaging evidence of new loss of viable myocardium or new regional wall motion abnormality identification of an intracoronary thrombus by angiography. When a raised troponin level is detected in people with a suspected ACS, reassess to exclude other causes for raised troponin (for example, myocarditis, aortic dissection or pulmonary embolism) before confirming the diagnosis of ACS. When a raised troponin level is detected in people with a suspected ACS, follow the NICE guideline on acute coronary syndromes until a firm diagnosis is made. Continue to monitor (see recommendation 1.2.3.4). When a diagnosis of ACS is confirmed, follow the NICE guideline on acute coronary syndromes. Reassess people with chest pain without raised troponin levels and no acute resting 12‑lead ECG changes to determine whether their chest pain is likely to be cardiac.If myocardial ischaemia is suspected, follow the recommendations on stable chest pain in this guideline (see the section on people presenting with stable chest pain). Use clinical judgement to decide on the timing of any further diagnostic investigations. Do not routinely offer non-invasive imaging or exercise ECG in the initial assessment of acute cardiac chest pain. Only consider early chest computed tomography (CT) to rule out other diagnoses such as pulmonary embolism or aortic dissection, not to diagnose ACS. Consider a chest X‑ray to help exclude complications of ACS such as pulmonary oedema, or other diagnoses such as pneumothorax or pneumonia. If an ACS has been excluded at any point in the care pathway, but people have risk factors for cardiovascular disease, follow the appropriate guidance, for example, the NICE guideline on cardiovascular disease and the NICE guideline on hypertension in adults. # People presenting with stable chest pain This section of the guideline addresses the assessment and diagnosis of intermittent stable chest pain in people with suspected stable angina. Exclude a diagnosis of stable angina if clinical assessment indicates non-anginal chest pain (see recommendation 1.3.3.1) and there are no other aspects of the history or risk factors raising clinical suspicion. If clinical assessment indicates typical or atypical angina (see recommendation 1.3.3.1), offer diagnostic testing (see the sections on diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone, additional diagnostic investigations and use of non-invasive functional testing for myocardial ischaemia). ## Clinical assessment Take a detailed clinical history documenting: the age and sex of the person the characteristics of the pain, including its location, radiation, severity, duration and frequency, and factors that provoke and relieve the pain any associated symptoms, such as breathlessness any history of angina, MI, coronary revascularisation or other cardiovascular disease and any cardiovascular risk factors. Carry out a physical examination to: identify risk factors for cardiovascular disease identify signs of other cardiovascular disease identify non-coronary causes of angina (for example, severe aortic stenosis, cardiomyopathy) and exclude other causes of chest pain. ## Making a diagnosis based on clinical assessment Assess the typicality of chest pain as follows: Presence of three of the features below is defined as typical angina. Presence of two of the three features below is defined as atypical angina. Presence of one or none of the features below is defined as non-anginal chest pain.Anginal pain is: constricting discomfort in the front of the chest, or in the neck, shoulders, jaw or arms precipitated by physical exertion relieved by rest or GTN within about 5 minutes. Do not define typical and atypical features of anginal chest pain and non-anginal chest pain differently in men and women. Do not define typical and atypical features of anginal chest pain and non-anginal chest pain differently in ethnic groups. Take the following factors, which make a diagnosis of stable angina more likely, into account when estimating people's likelihood of angina: age whether the person is male cardiovascular risk factors including: a history of smoking diabetes hypertension dyslipidaemia family history of premature coronary artery disease (CAD) -ther cardiovascular disease history of established CAD, for example, previous MI, coronary revascularisation. Unless clinical suspicion is raised based on other aspects of the history and risk factors, exclude a diagnosis of stable angina if the pain is non-anginal (see recommendation 1.3.3.1). Features which make a diagnosis of stable angina unlikely are when the chest pain is: continuous or very prolonged and/or unrelated to activity and/or brought on by breathing in and/or associated with symptoms such as dizziness, palpitations, tingling or difficulty swallowing.Consider causes of chest pain other than angina (such as gastrointestinal or musculoskeletal pain). Consider investigating other causes of angina, such as hypertrophic cardiomyopathy, in people with typical angina-like chest pain and a low likelihood of CAD. Arrange blood tests to identify conditions which exacerbate angina, such as anaemia, for all people being investigated for stable angina. Only consider chest X‑ray if other diagnoses, such as a lung tumour, are suspected. If a diagnosis of stable angina has been excluded at any point in the care pathway, but people have risk factors for cardiovascular disease, follow the appropriate guidance, for example, the NICE guideline on cardiovascular disease and the NICE guideline on hypertension in adults. For people in whom stable angina cannot be excluded on the basis of the clinical assessment alone, take a resting 12‑lead ECG as soon as possible after presentation. Do not rule out a diagnosis of stable angina on the basis of a normal resting 12‑lead ECG. Do not offer diagnostic testing to people with non-anginal chest pain on clinical assessment (see recommendation 1.3.3.1) unless there are resting ECG ST‑T changes or Q waves. A number of changes on a resting 12‑lead ECG are consistent with CAD and may indicate ischaemia or previous infarction. These include: pathological Q waves in particular LBBB ST‑segment and T wave abnormalities (for example, flattening or inversion).Note that the results may not be conclusive.Consider any resting 12‑lead ECG changes together with people's clinical history and risk factors. For people with confirmed CAD (for example, previous MI, revascularisation, previous angiography) in whom stable angina cannot be excluded based on clinical assessment alone, see recommendation 1.3.4.4 about functional testing. Consider aspirin only if the person's chest pain is likely to be stable angina, until a diagnosis is made. Do not offer additional aspirin if there is clear evidence that people are already taking aspirin regularly or are allergic to it. Follow the NICE guideline on stable angina while waiting for the results of investigations if symptoms are typical of stable angina. ## Diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone The Guideline Development Group emphasised that the recommendations in this guideline are to make a diagnosis of chest pain, not to screen for CAD. Most people diagnosed with non-anginal chest pain after clinical assessment need no further diagnostic testing. However in a very small number of people, there are remaining concerns that the pain could be ischaemic. Include the typicality of anginal pain features (see recommendation 1.3.3.1) in all requests for diagnostic investigations and in the person's notes. Use clinical judgement and take into account people's preferences and comorbidities when considering diagnostic testing. Offer 64‑slice (or above) CT coronary angiography if: clinical assessment (see recommendation 1.3.3.1) indicates typical or atypical angina or clinical assessment indicates non-anginal chest pain but 12‑lead resting ECG has been done and indicates ST‑T changes or Q waves. For people with confirmed CAD (for example, previous MI, revascularisation, previous angiography), offer non-invasive functional testing when there is uncertainty about whether chest pain is caused by myocardial ischaemia. See the section on use of non-invasive functional testing for myocardial ischaemia for further guidance on non-invasive functional testing. An exercise ECG may be used instead of functional imaging. See also NICE's medical technologies guidance on HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography. Using HeartFlow FFRCT may avoid the need for invasive coronary angiography and revascularisation for some patients ## Additional diagnostic investigations Offer non-invasive functional imaging (see the section on use of non-invasive functional testing for myocardial ischaemia) for myocardial ischaemia if 64‑slice (or above) CT coronary angiography has shown CAD of uncertain functional significance or is non-diagnostic. Offer invasive coronary angiography as a third-line investigation when the results of non-invasive functional imaging are inconclusive. ## Use of non-invasive functional testing for myocardial ischaemia When offering non-invasive functional imaging for myocardial ischaemia use: myocardial perfusion scintigraphy with single photon emission computed tomography (MPS with SPECT) or stress echocardiography or first-pass contrast-enhanced magnetic resonance (MR) perfusion or MR imaging for stress-induced wall motion abnormalities.Take account of locally available technology and expertise, the person and their preferences, and any contraindications (for example, disabilities, frailty, limited ability to exercise) when deciding on the imaging method. . Use adenosine, dipyridamole or dobutamine as stress agents for MPS with SPECT and adenosine or dipyridamole for first-pass contrast-enhanced MR perfusion. Use exercise or dobutamine for stress echocardiography or MR imaging for stress-induced wall motion abnormalities. Do not use MR coronary angiography for diagnosing stable angina. Do not use exercise ECG to diagnose or exclude stable angina for people without known CAD. ## Making a diagnosis following investigations Significant coronary artery disease (CAD) found during CT coronary angiography is ≥ 70% diameter stenosis of at least one major epicardial artery segment or ≥ 50% diameter stenosis in the left main coronary artery: Such factors allow less severe lesions (for example, ≥ 50%) to produce angina: reduced oxygen delivery: anaemia, coronary spasm increased oxygen demand: tachycardia, left ventricular hypertrophy large mass of ischaemic myocardium: proximally located lesions longer lesion length. Well-developed collateral supply. Small mass of ischaemic myocardium: distally located lesions, old infarction in the territory of coronary supply. Confirm a diagnosis of stable angina and follow the NICE guideline on stable angina when: significant CAD (see box 1) is found during invasive or 64‑slice (or above) CT coronary angiography or reversible myocardial ischaemia is found during non-invasive functional imaging. Investigate other causes of chest pain when: significant CAD (see box 1) is not found during invasive coronary angiography or 64‑slice (or above) CT coronary angiography or reversible myocardial ischaemia is not found during non-invasive functional imaging. Consider investigating other causes of angina, such as hypertrophic cardiomyopathy or syndrome X, in people with typical angina-like chest pain if investigation excludes flow-limiting disease in the epicardial coronary arteries. # Terms used in this guideline ## Chest pain The term 'chest pain' is used throughout the guideline to mean chest pain or discomfort.# Recommendations for research In 2010, the guideline committee made the following recommendations for research. The committee's full set of recommendations for research is detailed in the full guideline. # Cost-effectiveness of multislice CT coronary angiography for ruling out obstructive coronary artery disease in people with troponin-negative acute coronary syndromes Is multislice CT coronary angiography a cost-effective first-line test for ruling out obstructive coronary artery disease (CAD) in people with suspected troponin-negative acute coronary syndromes? ## Why this is important Current European Society of Cardiology guidelines state that in troponin-negative ACS with no ST‑segment change on the ECG, 'a stress test is recommended… in patients with significant ischaemia during the stress test, coronary angiography and subsequent revascularisation should be considered'. Yet stress testing has relatively low sensitivity and specificity for diagnosing CAD in this group of people. Therefore a significant proportion of at-risk people are missed while others with normal coronary arteries are subjected to an unnecessary invasive coronary angiogram. Multislice CT coronary angiography is highly sensitive and provides a potentially useful means for early rule-out of CAD in troponin-negative acute coronary disease. We need to know whether it is cost effective compared with exercise ECG as a first test in the diagnostic work-up of this group. # Refining the use of telephone advice in people with chest pain In what circumstances should telephone advice be given to people calling with chest pain? Is the appropriateness influenced by age, sex or symptoms? ## Why this is important The telephone is a common method of first contact with healthcare services, and produces a near uniform emergency response to chest pain symptoms. Such a response has considerable economic, social and human costs. Research should be conducted to clarify if an emergency response in all circumstances is appropriate, or if there are identifiable factors such as age, sex or associated symptoms that would allow a modified response and a more appropriate use of resources. # Establishing a national registry for people who are undergoing initial assessment for stable angina Can a national registry of people presenting with suspected angina be established to allow cohort analysis of treatments, investigations and outcomes in this group? Such a registry would provide a vital resource for a range of important research projects, including: development and validation of a new score for assessing the pre-test probability of disease, addressing outstanding uncertainties in the estimation of the pre-test probability of CAD based on simple measures made at initial assessment (history, examination, routine bloods, resting 12‑lead ECG) assessment of the extent to which new circulating biomarkers add additional information to measures made at initial assessment provision of a framework for trial recruitment without significant work-up bias allowing evaluation of the diagnostic and prognostic test performance of CT‑based, MR, echocardiography and radionuclide technologies. ## Why this is important A national prospective registry of consecutive people with suspected stable angina before initial diagnostic testing does not currently exist in the UK or in any other country. Establishing such a registry would offer the following methodological strengths: statistical size, representative patients without work-up bias, contemporary data. This would overcome key problems in much of the existing evidence base. Accurate assessment of pre-test likelihood of coronary disease is needed to inform the cost-effective choice of investigative technologies such as CT coronary calcium scoring for people with chest pain that may be caused by myocardial ischaemia. The data on which pre-test likelihood is based date from 1979 in a US population and may not be applicable to contemporary UK populations. There remain continuing uncertainties about the initial assessment of people with suspected stable angina. For example, the possible contributions of simple clinical measures such as body mass index, routine blood markers (for example, haemoglobin) or novel circulating biomarkers to estimates of the pre-test likelihood of CAD are not known and require further assessment in the whole population and in predefined subgroups including ethnic minorities. # Information about presenting and explaining tests All people presenting with chest pain will need to decide whether to accept the diagnostic and care pathways offered. How should information about the diagnostic pathway and the likely outcomes, risks and benefits, with and without treatment, be most effectively presented to particular groups of people, defined by age, ethnicity and sex? ## Why this is important Methods of communication (both the content and delivery) will be guided by current evidence-based best practice. Controlled trials should be conducted based on well-constructed randomised controlled clinical trials comparing the effects of different methods of communication on the understanding of the person with chest pain. Such studies might consider a number of delivery mechanisms, including advice and discussion with a clinician or a specialist nurse, as well as specific information leaflets or visual data. Any trials should also investigate the feasibility of introducing a suggested guideline protocol to be used with all people presenting with chest pain when faced with options concerning their clinical pathway. Only by clearly explaining and then discussing the proposed diagnostic and care pathways can the healthcare professional be reasonably certain that informed consent has been obtained and that a patient's moral, ethical and spiritual beliefs, expectations, and any misconceptions about their condition, have been taken into account. Consideration should be given to any communication problems the person may have.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Conditions causing chest pain or discomfort, such as an acute coronary syndrome or angina, have a potentially poor prognosis, emphasising the importance of prompt and accurate diagnosis. Treatments are available to improve symptoms and prolong life, hence the need for this guideline. This guideline covers the assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin. In deciding whether chest pain may be cardiac and therefore whether this guideline is relevant, a number of factors should be taken into account. These include the person's history of chest pain, their cardiovascular risk factors, history of ischaemic heart disease and any previous treatment, and previous investigations for chest pain. For pain that is suspected to be cardiac, there are two separate diagnostic pathways presented in the guideline. The first is for people with acute chest pain and a suspected acute coronary syndrome, and the second is for people with intermittent stable chest pain in whom stable angina is suspected. The guideline includes how to determine whether myocardial ischaemia is the cause of the chest pain and how to manage the chest pain while people are being assessed and investigated. As far as possible, the recommendations in this guideline have been listed in the order in which they will be carried out and follow the diagnostic pathways. But, as there are many permutations at each decision point, it has been necessary to include frequent cross-referencing to avoid repeating recommendations several times. The algorithms presented in full guideline show the two diagnostic pathways. This guideline does not cover the diagnosis and management of chest pain that is unrelated to the heart (for example, traumatic chest wall injury, herpes zoster infection) when myocardial ischaemia has been excluded. The guideline also recognises that in people with a prior diagnosis of coronary artery disease, chest pain or discomfort is not necessarily cardiac. The term 'chest pain' is used throughout the guideline to mean chest pain or discomfort. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Providing information for people with chest pain\n\nDiscuss any concerns people (and where appropriate their family or carer/advocate) may have, including anxiety when the cause of the chest pain is unknown. Correct any misinformation. \n\nOffer people a clear explanation of the possible causes of their symptoms and the uncertainties. \n\nClearly explain the options to people at every stage of investigation. Make joint decisions with them and take account of their preferences:\n\nEncourage people to ask questions.\n\nProvide repeated opportunities for discussion.\n\nExplain test results and the need for any further investigations. \n\nProvide information about any proposed investigations using everyday, jargon-free language. Include:\n\ntheir purpose, benefits and any limitations of their diagnostic accuracy\n\nduration\n\nlevel of discomfort and invasiveness\n\nrisk of adverse events. \n\nOffer information about the risks of diagnostic testing, including any radiation exposure. \n\nAddress any physical or learning difficulties, sight or hearing problems and difficulties with speaking or reading English, which may affect people's understanding of the information offered. \n\nOffer information after diagnosis as recommended in the relevant disease management guidelines:\n\nNICE guideline on acute coronary syndromes\n\nNICE guideline on stable angina\n\nNICE guideline on generalised anxiety disorder and panic disorder in adults\n\nNICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults. \n\nExplain if the chest pain is non-cardiac and refer people for further investigation if appropriate. \n\nProvide individual advice to people about seeking medical help if they have further chest pain. \n\n# People presenting with acute chest pain\n\nThis section of the guideline covers the assessment and diagnosis of people with recent acute chest pain or discomfort, suspected to be caused by an acute coronary syndrome (ACS). The term ACS covers a range of conditions including unstable angina, ST‑segment-elevation myocardial infarction (STEMI) and non‑ST‑segment-elevation myocardial infarction (NSTEMI).\n\nThe guideline addresses assessment and diagnosis irrespective of setting, because people present in different ways. For early management of these conditions, follow the NICE guideline on acute coronary syndromes.\n\n## Initial assessment and referral to hospital\n\nCheck immediately whether people currently have chest pain. If they are pain free, check when their last episode of pain was, particularly if they have had pain in the last 12\xa0hours. \n\nDetermine whether the chest pain may be cardiac and therefore whether this guideline is relevant, by considering:\n\nthe history of the chest pain\n\nthe presence of cardiovascular risk factors\n\nhistory of ischaemic heart disease and any previous treatment\n\nprevious investigations for chest pain. \n\nInitially assess people for any of the following symptoms, which may indicate an ACS:\n\npain in the chest and/or other areas (for example, the arms, back or jaw) lasting longer than 15\xa0minutes\n\nchest pain associated with nausea and vomiting, marked sweating, breathlessness, or particularly a combination of these\n\nchest pain associated with haemodynamic instability\n\nnew onset chest pain, or abrupt deterioration in previously stable angina, with recurrent chest pain occurring frequently and with little or no exertion, and with episodes often lasting longer than 15\xa0minutes. \n\nDo not use people's response to glyceryl trinitrate (GTN) to make a diagnosis. \n\nDo not assess symptoms of an ACS differently in men and women. Not all people with an ACS present with central chest pain as the predominant feature. \n\nDo not assess symptoms of an ACS differently in ethnic groups. There are no major differences in symptoms of an ACS among different ethnic groups. \n\nRefer people to hospital as an emergency if an ACS is suspected (see recommendation 1.2.1.3) and:\n\nthey currently have chest pain or\n\nthey are currently pain free, but had chest pain in the last 12\xa0hours, and a resting 12‑lead ECG is abnormal or not available. \n\nIf an ACS is suspected (see recommendation 1.2.1.3) and there are no reasons for emergency referral, refer people for urgent same-day assessment if:\n\nthey had chest pain in the last 12\xa0hours, but are now pain free with a normal resting 12‑lead ECG or\n\nthe last episode of pain was 12 to 72\xa0hours ago. \n\nRefer people for assessment in hospital if an ACS is suspected (see recommendation 1.2.1.3) and:\n\nthe pain has resolved and\n\nthere are signs of complications such as pulmonary oedema.Use clinical judgement to decide whether referral should be as an emergency or urgent same-day assessment. \n\nIf a recent ACS is suspected in people whose last episode of chest pain was more than 72\xa0hours ago and who have no complications such as pulmonary oedema:\n\ncarry out a detailed clinical assessment (see recommendations 1.2.4.2 and 1.2.4.3)\n\nconfirm the diagnosis by resting 12‑lead ECG and blood troponin level\n\ntake into account the length of time since the suspected ACS when interpreting the troponin level.Use clinical judgement to decide whether referral is necessary and how urgent this should be. \n\nRefer people to hospital as an emergency if they have a recent (confirmed or suspected) ACS and develop further chest pain. \n\nWhen an ACS is suspected, start management immediately in the order appropriate to the circumstances (see the section on immediate management of a suspected acute coronary syndrome) and take a resting 12‑lead ECG (see the section on resting 12-lead ECG). Take the ECG as soon as possible, but do not delay transfer to hospital. \n\nIf an ACS is not suspected, consider other causes of the chest pain, some of which may be life-threatening (see recommendations 1.2.6.5, 1.2.6.7 and 1.2.6.8). \n\n## Resting 12-lead ECG\n\nTake a resting 12‑lead ECG as soon as possible. When people are referred, send the results to hospital before they arrive if possible. Recording and sending the ECG should not delay transfer to hospital. \n\nFollow local protocols for people with a resting 12‑lead ECG showing regional ST‑segment elevation or presumed new left bundle branch block (LBBB) consistent with an acute STEMI until a firm diagnosis is made. Continue to monitor (see recommendation 1.2.3.4). \n\nFollow the NICE guideline on acute coronary syndromes for people with a resting 12‑lead ECG showing regional ST‑segment depression or deep T\xa0wave inversion suggestive of a NSTEMI or unstable angina until a firm diagnosis is made. Continue to monitor (see recommendation 1.2.3.4). \n\nEven in the absence of ST‑segment changes, have an increased suspicion of an ACS if there are other changes in the resting 12‑lead ECG, specifically Q\xa0waves and T\xa0wave changes. Consider following the NICE guideline on acute coronary syndromes if these conditions are likely. Continue to monitor (see recommendation 1.2.3.4). \n\nDo not exclude an ACS when people have a normal resting 12‑lead ECG. \n\nIf a diagnosis of ACS is in doubt, consider:\n\ntaking serial resting 12‑lead ECGs\n\nreviewing previous resting 12‑lead ECGs\n\nrecording additional ECG leads.Use clinical judgement to decide how often this should be done. Note that the results may not be conclusive. \n\nObtain a review of resting 12‑lead ECGs by a healthcare professional qualified to interpret them as well as taking into account automated interpretation. \n\nIf clinical assessment (as described in recommendation 1.2.1.10) and a resting 12‑lead ECG make a diagnosis of ACS less likely, consider other acute conditions. First consider those that are life-threatening such as pulmonary embolism, aortic dissection or pneumonia. Continue to monitor (see recommendation 1.2.3.4). \n\n## Immediate management of a suspected acute coronary syndrome\n\nManagement of ACS should start as soon as it is suspected, but should not delay transfer to hospital. The recommendations in this section should be carried out in the order appropriate to the circumstances.\n\nOffer pain relief as soon as possible. This may be achieved with GTN (sublingual or buccal), but offer intravenous opioids such as morphine, particularly if an acute myocardial infarction (MI) is suspected. \n\nOffer people a single loading dose of 300\xa0mg aspirin as soon as possible unless there is clear evidence that they are allergic to it. If aspirin is given before arrival at hospital, send a written record that it has been given with the person.Only offer other antiplatelet agents in hospital. Follow the NICE guideline on acute coronary syndromes. \n\nDo not routinely administer oxygen, but monitor oxygen saturation using pulse oximetry as soon as possible, ideally before hospital admission. Only offer supplemental oxygen to:\n\npeople with oxygen saturation (SpO2) of less than 94% who are not at risk of hypercapnic respiratory failure, aiming for SpO2 of 94% to 98%\n\npeople with chronic obstructive pulmonary disease who are at risk of hypercapnic respiratory failure, to achieve a target SpO2 of 88% to 92% until blood gas analysis is available. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nMonitor people with acute chest pain, using clinical judgement to decide how often this should be done, until a firm diagnosis is made. This should include:\n\nexacerbations of pain and/or other symptoms\n\npulse and blood pressure\n\nheart rhythm\n\noxygen saturation by pulse oximetry\n\nrepeated resting 12‑lead ECGs and\n\nchecking pain relief is effective. \n\nManage other therapeutic interventions using the NICE guideline on acute coronary syndromes. \n\n## Assessment in hospital for people with a suspected acute coronary syndrome\n\nTake a resting 12‑lead ECG and a blood sample for high-sensitivity troponin\xa0I or T\xa0measurement (see the section on use of biochemical markers for diagnosis of an acute coronary syndrome) on arrival in hospital. [2010, amended 2016]\n\nCarry out a physical examination to determine:\n\nhaemodynamic status\n\nsigns of complications, for example, pulmonary oedema, cardiogenic shock and\n\nsigns of non-coronary causes of acute chest pain, such as aortic dissection. \n\nTake a detailed clinical history unless a STEMI is confirmed from the resting 12‑lead ECG (that is, regional ST‑segment elevation or presumed new LBBB). Record:\n\nthe characteristics of the pain\n\nother associated symptoms\n\nany history of cardiovascular disease\n\nany cardiovascular risk factors and\n\ndetails of previous investigations or treatments for similar symptoms of chest pain. \n\n## Use of biochemical markers for diagnosis of an acute coronary syndrome\n\nDo not use high-sensitivity troponin tests for people in whom ACS is not suspected. \n\nFor people at high or moderate risk of MI (as indicated by a validated tool), perform high-sensitivity troponin tests as recommended in the NICE diagnostics guidance on myocardial infarction. \n\nFor people at low risk of MI (as indicated by a validated tool):\n\nperform a second high-sensitivity troponin test as recommended in the NICE diagnostics guidance on myocardial infarction if the first troponin test at presentation is positive.\n\nconsider performing a single high-sensitivity troponin test only at presentation to rule out NSTEMI if the first troponin test is below the lower limit of detection (negative). \n\nEnsure that patients understand that a detectable troponin on the first high-sensitivity test does not necessarily indicate that they have had an MI. \n\nDo not use biochemical markers such as natriuretic peptides and high-sensitivity C-reactive protein to diagnose an ACS. \n\nDo not use biochemical markers of myocardial ischaemia (such as ischaemia-modified albumin) as opposed to markers of necrosis when assessing people with acute chest pain. \n\nWhen interpreting high-sensitivity troponin measurements, take into account:\n\nthe clinical presentation\n\nthe time from onset of symptoms\n\nthe resting 12‑lead ECG findings\n\nthe pre-test probability of NSTEMI\n\nthe length of time since the suspected ACS\n\nthe probability of chronically elevated troponin levels in some people\n\nthat 99th percentile thresholds for troponin\xa0I and\xa0T may differ between sexes. [2010, amended 2016]\n\n## Making a diagnosis\n\nWhen diagnosing MI, use the universal definition of myocardial infarction. This is the detection of rise and/or fall of cardiac biomarkers values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile of the upper reference limit and at least one of the following:\n\nsymptoms of ischaemia\n\nnew or presumed new significant ST‑segment‑T\xa0wave (ST‑T) changes or new LBBB\n\ndevelopment of pathological Q\xa0waves in the ECG\n\nimaging evidence of new loss of viable myocardium or new regional wall motion abnormality\n\nidentification of an intracoronary thrombus by angiography. [2010, amended 2016]\n\nWhen a raised troponin level is detected in people with a suspected ACS, reassess to exclude other causes for raised troponin (for example, myocarditis, aortic dissection or pulmonary embolism) before confirming the diagnosis of ACS. \n\nWhen a raised troponin level is detected in people with a suspected ACS, follow the NICE guideline on acute coronary syndromes until a firm diagnosis is made. Continue to monitor (see recommendation 1.2.3.4). \n\nWhen a diagnosis of ACS is confirmed, follow the NICE guideline on acute coronary syndromes. \n\nReassess people with chest pain without raised troponin levels and no acute resting 12‑lead ECG changes to determine whether their chest pain is likely to be cardiac.If myocardial ischaemia is suspected, follow the recommendations on stable chest pain in this guideline (see the section on people presenting with stable chest pain). Use clinical judgement to decide on the timing of any further diagnostic investigations. [2010, amended 2016]\n\nDo not routinely offer non-invasive imaging or exercise ECG in the initial assessment of acute cardiac chest pain. [new 2016]\n\nOnly consider early chest computed tomography (CT) to rule out other diagnoses such as pulmonary embolism or aortic dissection, not to diagnose ACS. \n\nConsider a chest X‑ray to help exclude complications of ACS such as pulmonary oedema, or other diagnoses such as pneumothorax or pneumonia. \n\nIf an ACS has been excluded at any point in the care pathway, but people have risk factors for cardiovascular disease, follow the appropriate guidance, for example, the NICE guideline on cardiovascular disease and the NICE guideline on hypertension in adults. \n\n# People presenting with stable chest pain\n\nThis section of the guideline addresses the assessment and diagnosis of intermittent stable chest pain in people with suspected stable angina.\n\nExclude a diagnosis of stable angina if clinical assessment indicates non-anginal chest pain (see recommendation 1.3.3.1) and there are no other aspects of the history or risk factors raising clinical suspicion. \n\nIf clinical assessment indicates typical or atypical angina (see recommendation 1.3.3.1), offer diagnostic testing (see the sections on diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone, additional diagnostic investigations and use of non-invasive functional testing for myocardial ischaemia). \n\n## Clinical assessment\n\nTake a detailed clinical history documenting:\n\nthe age and sex of the person\n\nthe characteristics of the pain, including its location, radiation, severity, duration and frequency, and factors that provoke and relieve the pain\n\nany associated symptoms, such as breathlessness\n\nany history of angina, MI, coronary revascularisation or other cardiovascular disease and\n\nany cardiovascular risk factors. \n\nCarry out a physical examination to:\n\nidentify risk factors for cardiovascular disease\n\nidentify signs of other cardiovascular disease\n\nidentify non-coronary causes of angina (for example, severe aortic stenosis, cardiomyopathy) and\n\nexclude other causes of chest pain. \n\n## Making a diagnosis based on clinical assessment\n\nAssess the typicality of chest pain as follows:\n\nPresence of three of the features below is defined as typical angina.\n\nPresence of two of the three features below is defined as atypical angina.\n\nPresence of one or none of the features below is defined as non-anginal chest pain.Anginal pain is:\n\nconstricting discomfort in the front of the chest, or in the neck, shoulders, jaw or arms\n\nprecipitated by physical exertion\n\nrelieved by rest or GTN within about 5\xa0minutes. [2010, amended 2016]\n\nDo not define typical and atypical features of anginal chest pain and non-anginal chest pain differently in men and women. \n\nDo not define typical and atypical features of anginal chest pain and non-anginal chest pain differently in ethnic groups. \n\nTake the following factors, which make a diagnosis of stable angina more likely, into account when estimating people's likelihood of angina:\n\nage\n\nwhether the person is male\n\ncardiovascular risk factors including:\n\n\n\na history of smoking\n\ndiabetes\n\nhypertension\n\ndyslipidaemia\n\nfamily history of premature coronary artery disease (CAD)\n\n\n\nother cardiovascular disease\n\nhistory of established CAD, for example, previous MI, coronary revascularisation. \n\nUnless clinical suspicion is raised based on other aspects of the history and risk factors, exclude a diagnosis of stable angina if the pain is non-anginal (see recommendation 1.3.3.1). Features which make a diagnosis of stable angina unlikely are when the chest pain is:\n\ncontinuous or very prolonged and/or\n\nunrelated to activity and/or\n\nbrought on by breathing in and/or\n\nassociated with symptoms such as dizziness, palpitations, tingling or difficulty swallowing.Consider causes of chest pain other than angina (such as gastrointestinal or musculoskeletal pain). \n\nConsider investigating other causes of angina, such as hypertrophic cardiomyopathy, in people with typical angina-like chest pain and a low likelihood of CAD. [2010, amended 2016]\n\nArrange blood tests to identify conditions which exacerbate angina, such as anaemia, for all people being investigated for stable angina. \n\nOnly consider chest X‑ray if other diagnoses, such as a lung tumour, are suspected. \n\nIf a diagnosis of stable angina has been excluded at any point in the care pathway, but people have risk factors for cardiovascular disease, follow the appropriate guidance, for example, the NICE guideline on cardiovascular disease and the NICE guideline on hypertension in adults. \n\nFor people in whom stable angina cannot be excluded on the basis of the clinical assessment alone, take a resting 12‑lead ECG as soon as possible after presentation. [2010, amended 2016]\n\nDo not rule out a diagnosis of stable angina on the basis of a normal resting 12‑lead ECG. \n\nDo not offer diagnostic testing to people with non-anginal chest pain on clinical assessment (see recommendation 1.3.3.1) unless there are resting ECG ST‑T changes or Q\xa0waves. \n\nA number of changes on a resting 12‑lead ECG are consistent with CAD and may indicate ischaemia or previous infarction. These include:\n\npathological Q\xa0waves in particular\n\nLBBB\n\nST‑segment and T\xa0wave abnormalities (for example, flattening or inversion).Note that the results may not be conclusive.Consider any resting 12‑lead ECG changes together with people's clinical history and risk factors. \n\nFor people with confirmed CAD (for example, previous MI, revascularisation, previous angiography) in whom stable angina cannot be excluded based on clinical assessment alone, see recommendation 1.3.4.4 about functional testing. [2010, amended 2016]\n\nConsider aspirin only if the person's chest pain is likely to be stable angina, until a diagnosis is made. Do not offer additional aspirin if there is clear evidence that people are already taking aspirin regularly or are allergic to it. \n\nFollow the NICE guideline on stable angina while waiting for the results of investigations if symptoms are typical of stable angina. \n\n## Diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone\n\nThe Guideline Development Group emphasised that the recommendations in this guideline are to make a diagnosis of chest pain, not to screen for CAD. Most people diagnosed with non-anginal chest pain after clinical assessment need no further diagnostic testing. However in a very small number of people, there are remaining concerns that the pain could be ischaemic.\n\nInclude the typicality of anginal pain features (see recommendation 1.3.3.1) in all requests for diagnostic investigations and in the person's notes. [2010, amended 2016]\n\nUse clinical judgement and take into account people's preferences and comorbidities when considering diagnostic testing. \n\nOffer 64‑slice (or above) CT coronary angiography if:\n\nclinical assessment (see recommendation 1.3.3.1) indicates typical or atypical angina or\n\nclinical assessment indicates non-anginal chest pain but 12‑lead resting ECG has been done and indicates ST‑T changes or Q\xa0waves. \n\nFor people with confirmed CAD (for example, previous MI, revascularisation, previous angiography), offer non-invasive functional testing when there is uncertainty about whether chest pain is caused by myocardial ischaemia. See the section on use of non-invasive functional testing for myocardial ischaemia for further guidance on non-invasive functional testing. An exercise ECG may be used instead of functional imaging. See also NICE's medical technologies guidance on HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography. Using HeartFlow\xa0FFRCT\xa0may avoid the need for invasive coronary angiography and revascularisation for some patients\n\n## Additional diagnostic investigations\n\nOffer non-invasive functional imaging (see the section on use of non-invasive functional testing for myocardial ischaemia) for myocardial ischaemia if 64‑slice (or above) CT coronary angiography has shown CAD of uncertain functional significance or is non-diagnostic. \n\nOffer invasive coronary angiography as a third-line investigation when the results of non-invasive functional imaging are inconclusive. \n\n## Use of non-invasive functional testing for myocardial ischaemia\n\nWhen offering non-invasive functional imaging for myocardial ischaemia use:\n\nmyocardial perfusion scintigraphy with single photon emission computed tomography (MPS with SPECT) or\n\nstress echocardiography or\n\nfirst-pass contrast-enhanced magnetic resonance (MR) perfusion or\n\nMR imaging for stress-induced wall motion abnormalities.Take account of locally available technology and expertise, the person and their preferences, and any contraindications (for example, disabilities, frailty, limited ability to exercise) when deciding on the imaging method. [This recommendation updates and replaces recommendation 1.1 of NICE's technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction]. \n\nUse adenosine, dipyridamole or dobutamine as stress agents for MPS with SPECT and adenosine or dipyridamole for first-pass contrast-enhanced MR perfusion. \n\nUse exercise or dobutamine for stress echocardiography or MR imaging for stress-induced wall motion abnormalities. \n\nDo not use MR coronary angiography for diagnosing stable angina. \n\nDo not use exercise ECG to diagnose or exclude stable angina for people without known CAD. \n\n## Making a diagnosis following investigations\n\nSignificant coronary artery disease (CAD) found during CT coronary angiography is ≥ 70% diameter stenosis of at least one major epicardial artery segment or ≥ 50% diameter stenosis in the left main coronary artery:\n\nSuch factors allow less severe lesions (for example, ≥ 50%) to produce angina:\n\nreduced oxygen delivery: anaemia, coronary spasm\n\nincreased oxygen demand: tachycardia, left ventricular hypertrophy\n\nlarge mass of ischaemic myocardium: proximally located lesions\n\nlonger lesion length.\n\nWell-developed collateral supply.\n\nSmall mass of ischaemic myocardium: distally located lesions, old infarction in the territory of coronary supply. \n\nConfirm a diagnosis of stable angina and follow the NICE guideline on stable angina when:\n\nsignificant CAD (see box\xa01) is found during invasive or 64‑slice (or above) CT coronary angiography or\n\nreversible myocardial ischaemia is found during non-invasive functional imaging. \n\nInvestigate other causes of chest pain when:\n\nsignificant CAD (see box\xa01) is not found during invasive coronary angiography or 64‑slice (or above) CT coronary angiography or\n\nreversible myocardial ischaemia is not found during non-invasive functional imaging. \n\nConsider investigating other causes of angina, such as hypertrophic cardiomyopathy or syndrome\xa0X, in people with typical angina-like chest pain if investigation excludes flow-limiting disease in the epicardial coronary arteries. \n\n# Terms used in this guideline\n\n## Chest pain\n\nThe term 'chest pain' is used throughout the guideline to mean chest pain or discomfort.", 'Recommendations for research': "In 2010, the guideline committee made the following recommendations for research. The committee's full set of recommendations for research is detailed in the full guideline.\n\n# Cost-effectiveness of multislice CT coronary angiography for ruling out obstructive coronary artery disease in people with troponin-negative acute coronary syndromes\n\nIs multislice CT coronary angiography a cost-effective first-line test for ruling out obstructive coronary artery disease (CAD) in people with suspected troponin-negative acute coronary syndromes?\n\n## Why this is important\n\nCurrent European Society of Cardiology guidelines state that in troponin-negative ACS with no ST‑segment change on the ECG, 'a stress test is recommended… in patients with significant ischaemia during the stress test, coronary angiography and subsequent revascularisation should be considered'. Yet stress testing has relatively low sensitivity and specificity for diagnosing CAD in this group of people. Therefore a significant proportion of at-risk people are missed while others with normal coronary arteries are subjected to an unnecessary invasive coronary angiogram. Multislice CT coronary angiography is highly sensitive and provides a potentially useful means for early rule-out of CAD in troponin-negative acute coronary disease. We need to know whether it is cost effective compared with exercise ECG as a first test in the diagnostic work-up of this group.\n\n# Refining the use of telephone advice in people with chest pain\n\nIn what circumstances should telephone advice be given to people calling with chest pain? Is the appropriateness influenced by age, sex or symptoms?\n\n## Why this is important\n\nThe telephone is a common method of first contact with healthcare services, and produces a near uniform emergency response to chest pain symptoms. Such a response has considerable economic, social and human costs. Research should be conducted to clarify if an emergency response in all circumstances is appropriate, or if there are identifiable factors such as age, sex or associated symptoms that would allow a modified response and a more appropriate use of resources.\n\n# Establishing a national registry for people who are undergoing initial assessment for stable angina\n\nCan a national registry of people presenting with suspected angina be established to allow cohort analysis of treatments, investigations and outcomes in this group? Such a registry would provide a vital resource for a range of important research projects, including:\n\ndevelopment and validation of a new score for assessing the pre-test probability of disease, addressing outstanding uncertainties in the estimation of the pre-test probability of CAD based on simple measures made at initial assessment (history, examination, routine bloods, resting 12‑lead ECG)\n\nassessment of the extent to which new circulating biomarkers add additional information to measures made at initial assessment\n\nprovision of a framework for trial recruitment without significant work-up bias allowing evaluation of the diagnostic and prognostic test performance of CT‑based, MR, echocardiography and radionuclide technologies.\n\n## Why this is important\n\nA national prospective registry of consecutive people with suspected stable angina before initial diagnostic testing does not currently exist in the UK or in any other country. Establishing such a registry would offer the following methodological strengths: statistical size, representative patients without work-up bias, contemporary data. This would overcome key problems in much of the existing evidence base.\n\nAccurate assessment of pre-test likelihood of coronary disease is needed to inform the cost-effective choice of investigative technologies such as CT coronary calcium scoring for people with chest pain that may be caused by myocardial ischaemia. The data on which pre-test likelihood is based date from 1979 in a US population and may not be applicable to contemporary UK populations. There remain continuing uncertainties about the initial assessment of people with suspected stable angina. For example, the possible contributions of simple clinical measures such as body mass index, routine blood markers (for example, haemoglobin) or novel circulating biomarkers to estimates of the pre-test likelihood of CAD are not known and require further assessment in the whole population and in predefined subgroups including ethnic minorities.\n\n# Information about presenting and explaining tests\n\nAll people presenting with chest pain will need to decide whether to accept the diagnostic and care pathways offered. How should information about the diagnostic pathway and the likely outcomes, risks and benefits, with and without treatment, be most effectively presented to particular groups of people, defined by age, ethnicity and sex?\n\n## Why this is important\n\nMethods of communication (both the content and delivery) will be guided by current evidence-based best practice. Controlled trials should be conducted based on well-constructed randomised controlled clinical trials comparing the effects of different methods of communication on the understanding of the person with chest pain. Such studies might consider a number of delivery mechanisms, including advice and discussion with a clinician or a specialist nurse, as well as specific information leaflets or visual data.\n\nAny trials should also investigate the feasibility of introducing a suggested guideline protocol to be used with all people presenting with chest pain when faced with options concerning their clinical pathway.\n\nOnly by clearly explaining and then discussing the proposed diagnostic and care pathways can the healthcare professional be reasonably certain that informed consent has been obtained and that a patient's moral, ethical and spiritual beliefs, expectations, and any misconceptions about their condition, have been taken into account. Consideration should be given to any communication problems the person may have.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "Conditions causing chest pain or discomfort, such as an acute coronary syndrome or angina, have a potentially poor prognosis, emphasising the importance of prompt and accurate diagnosis. Treatments are available to improve symptoms and prolong life, hence the need for this guideline.\n\nThis guideline covers the assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin. In deciding whether chest pain may be cardiac and therefore whether this guideline is relevant, a number of factors should be taken into account. These include the person's history of chest pain, their cardiovascular risk factors, history of ischaemic heart disease and any previous treatment, and previous investigations for chest pain.\n\nFor pain that is suspected to be cardiac, there are two separate diagnostic pathways presented in the guideline. The first is for people with acute chest pain and a suspected acute coronary syndrome, and the second is for people with intermittent stable chest pain in whom stable angina is suspected. The guideline includes how to determine whether myocardial ischaemia is the cause of the chest pain and how to manage the chest pain while people are being assessed and investigated.\n\nAs far as possible, the recommendations in this guideline have been listed in the order in which they will be carried out and follow the diagnostic pathways. But, as there are many permutations at each decision point, it has been necessary to include frequent cross-referencing to avoid repeating recommendations several times.\n\nThe algorithms presented in full guideline show the two diagnostic pathways.\n\nThis guideline does not cover the diagnosis and management of chest pain that is unrelated to the heart (for example, traumatic chest wall injury, herpes zoster infection) when myocardial ischaemia has been excluded. The guideline also recognises that in people with a prior diagnosis of coronary artery disease, chest pain or discomfort is not necessarily cardiac.\n\nThe term 'chest pain' is used throughout the guideline to mean chest pain or discomfort.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients."}	https://www.nice.org.uk/guidance/cg95	This guideline covers assessing and diagnosing recent chest pain in people aged 18 and over and managing symptoms while a diagnosis is being made. It aims to improve outcomes by providing advice on tests (ECG, high-sensitivity troponin tests, multislice CT angiography, functional testing) that support healthcare professionals to make a speedy and accurate diagnosis.
d4c05b064aafd0e705f92a98e699fafe7c886df6	nice	Spasticity in under 19s: management	Spasticity in under 19s: management This guideline covers managing spasticity and co-existing motor disorders and their early musculoskeletal complications in children and young people (from birth up to their 19th birthday) with non-progressive brain disorders. It aims to reduce variation in practice and help healthcare professionals to select and use appropriate treatments. # Introduction This guideline covers the management of spasticity and co-existing motor disorders and their early musculoskeletal complications in children and young people (from birth up to their 19th birthday) with non-progressive brain disorders. Cerebral palsy is the most common condition associated with spasticity in children and young people. The incidence of cerebral palsy is not known, but its prevalence in the UK is 186 per 100,000 population, with a total of 110,000 people affected. The guideline covers the management of spasticity associated with cerebral palsy, but not all aspects of the management of cerebral palsy. The impact of spasticity and co-existing motor disorders and their early musculoskeletal complications on the child or young person varies. Common problems include impaired motor function affecting the person's ability to participate in society, pain from muscle spasms, motor developmental delay and difficulties with daily care due to the onset of secondary complications of spasticity. Management should be tailored to meet the problems faced by the individual child or young person and their individual goals. There is considerable variation in practice in managing spasticity, including variation in the availability of treatments and the intensity of their use. This guideline will help healthcare professionals to select and use appropriate treatments for individual children and young people. The guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) to inform decisions made with individual patients. This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Principles of care ## Delivering care Children and young people with spasticity should have access to a network of care that uses agreed care pathways supported by effective communication and integrated team working. The network of care should provide access to a team of healthcare professionals experienced in the care of children and young people with spasticity. The network team should provide local expertise in paediatrics, nursing, physiotherapy and occupational therapy. Access to other expertise, including orthotics, orthopaedic surgery and/or neurosurgery and paediatric neurology, may be provided locally or regionally. If a child or young person receives treatment for spasticity from healthcare professionals outside the network team, this should be planned and undertaken in discussion with the network team to ensure integrated care and effective subsequent management. ## Management programmes Following diagnosis, ensure that all children and young people with spasticity are referred without delay to an appropriate member of the network team. Offer a management programme that is: developed and implemented in partnership with the child or young person and their parents or carers individualised goal focused. When formulating a management programme take into account its possible impact on the individual child or young person and their family. Carefully assess the impact of spasticity in children and young people with cognitive impairments: be aware that the possible benefit of treatments may be more difficult to assess in a child or young person with limited communication ensure that the child or young person has access to all appropriate services. Identify and agree with children and young people and their parents or carers assessments and goals that: are age and developmentally appropriate focus on the following domains of the World Health Organization's International Classification of Functioning, Disability and Health: body functions body structures activities and participation environmental factors. Record the child or young person's individualised goals and share these goals with healthcare professionals in the network team and, where appropriate, other people involved in their care. Help children and young people and their parents or carers to be partners in developing and implementing the management programme by offering: relevant, and age and developmentally appropriate, information and educational materials regular opportunities for discussion and advice on their developmental potential and how different treatment options may affect this. ## Supporting the child or young person and their parents or carers Offer contact details of patient organisations that can provide support, befriending, counselling, information and advocacy. Ensure that children and young people have timely access to equipment necessary for their management programme (for example, postural management equipment such as sleeping, sitting or standing systems). The network team should have a central role in transition to prepare young people and their parents or carers for the young person's transfer to adult services. ## Monitoring Monitor the child or young person's condition for: the response to treatments worsening of spasticity developing secondary consequences of spasticity, for example pain or contractures the need to change their individualised goals. The network of care should have a pathway for monitoring children and young people at increased risk of hip displacement. Recognise the following clinical findings as possible indicators of hip displacement (hip migration greater than 30%): pain arising from the hip clinically important leg length difference deterioration in hip abduction or range of hip movement increasing hip muscle tone deterioration in sitting or standing increasing difficulty with perineal care or hygiene. Offer a hip X-ray to assess for hip displacement: if there are clinical concerns about possible hip displacement at 24 months in children with bilateral cerebral palsy. Consider repeating the hip X-ray annually in children or young people who are at Gross Motor Function Classification System (GMFCS) level III, IV or V. Consider repeating the hip X-ray after 6 months in children and young people where the initial hip migration is greater than 30%, and then consider repeating the hip X-ray every 6 months after this if the hip migration is increasing by more than 10 percentage points per year. # Physical therapy (physiotherapy and/or occupational therapy) ## General principles All children and young people with spasticity referred to the network team should be promptly assessed by a physiotherapist and, where necessary, an occupational therapist. Offer a physical therapy (physiotherapy and/or occupational therapy) programme tailored to the child or young person's individual needs and aimed at specific goals, such as: enhancing skill development, function and ability to participate in everyday activities preventing consequences such as pain or contractures. Give children and young people and their parents or carers verbal and written (or appropriate formats) information about the physical therapy interventions needed to achieve the intended goals. This information should emphasise the balance between possible benefits and difficulties (for example, time commitment or discomfort), to enable them to participate in choosing a suitable physical therapy programme. When formulating a physical therapy programme for children and young people take into account: the views of the child or young person and their parents or carers the likelihood of achieving the treatment goals possible difficulties in implementing the programme implications for the individual child or young person and their parents or carers, including the time and effort involved and potential individual barriers. When deciding who should deliver physical therapy, take into account: whether the child or young person and their parents or carers are able to deliver the specific therapy what training the child or young person or their parents or carers might need the wishes of the child or young person and their parents or carers. Ensure that any equipment or techniques used in the physical therapy programme are safe and appropriate, in particular for children or young people with any of the following: poorly controlled epilepsy respiratory compromise increased risk of pulmonary aspiration increased risk of bone fracture due to osteoporosis (for example, those who are unable to walk, malnourished or taking anti-epileptic therapy). Encourage children and young people and their parents or carers to incorporate physical therapy into daily activities (for example, standing at the sink while brushing teeth in order to stretch leg muscles). ## Specific strategies Consider including in the physical therapy programme 24-hour postural management strategies to: prevent or delay the development of contractures or skeletal deformities in children and young people at risk of developing these enable the child or young person to take part in activities appropriate to their stage of development. When using 24-hour postural management strategies consider on an individual basis low-load active stretching or low-load passive stretching. Offer training to parents and carers involved in delivering postural management strategies. Consider task-focused active-use therapy such as constraint-induced movement therapy (temporary restraint of an unaffected arm to encourage use of the other arm) followed by bimanual therapy (unrestrained use of both arms) to enhance manual skills. When undertaking task-focused active-use therapy consider an intensive programme over a short time period (for example, 4 to 8 weeks). Consider muscle-strengthening therapy where the assessment indicates that muscle weakness is contributing to loss of function or postural difficulties. Direct muscle-strengthening therapy towards specific goals using progressive repetitive exercises performed against resistance. Following treatment with botulinum toxin type A, continuous pump-administered intrathecal baclofen, orthopaedic surgery or selective dorsal rhizotomy, provide an adapted physical therapy programme as an essential component of management. Ensure that children and young people and their parents or carers understand that an adapted physical therapy programme will be an essential component of management following treatment with botulinum toxin type A, continuous pump-administered intrathecal baclofen, orthopaedic surgery or selective dorsal rhizotomy. ## Continuing assessment Reassess the physical therapy programme at regular intervals to ensure that: the goals are being achieved the programme remains appropriate to the child or young person's needs. # Orthoses ## General principles Consider orthoses for children and young people with spasticity based on their individual needs and aimed at specific goals, such as: improving posture improving upper limb function improving walking efficiency preventing or slowing development of contractures preventing or slowing hip migration relieving discomfort or pain preventing or treating tissue injury, for example by relieving pressure points. When considering an orthosis, discuss with the child or young person and their parents or carers the balance of possible benefits against risks. For example, discuss its cosmetic appearance, the possibility of discomfort or pressure sores or of muscle wasting through lack of muscle use. Assess whether an orthosis might: cause difficulties with self-care or care by others cause difficulties in relation to hygiene be unacceptable to the child or young person because of its appearance. Ensure that orthoses are appropriately designed for the individual child or young person and are sized and fitted correctly. If necessary seek expert advice from an orthotist within the network team. Be aware when considering a rigid orthosis that it may cause discomfort or pressure injuries in a child or young person with marked dyskinesia. They should be monitored closely to ensure that the orthosis is not causing such difficulties. The network of care should have a pathway that aims to minimise delay in: supplying an orthosis once measurements for fit have been performed and repairing a damaged orthosis. Inform children and young people who are about to start using an orthosis, and their parents or carers: how to apply and wear it when to wear it and for how long: an orthosis designed to maintain stretch to prevent contractures is more likely to be effective if worn for longer periods of time, for example at least 6 hours a day an orthosis designed to support a specific function should be worn only when needed when and where to seek advice. Advise children and young people and their parents or carers that they may remove an orthosis if it is causing pain that is not relieved despite their repositioning the limb in the orthosis or adjusting the strapping. ## Specific uses Consider the following orthoses for children and young people with upper limb spasticity: elbow gaiters to maintain extension and improve function rigid wrist orthoses to prevent contractures and limit wrist and hand flexion deformity dynamic orthoses to improve hand function (for example, a non-rigid thumb abduction splint allowing some movement for a child or young person with a 'thumb in palm' deformity). Consider ankle–foot orthoses for children and young people with serious functional limitations (GMFCS level IV or V) to improve foot position for sitting, transfers between sitting and standing, and assisted standing. Be aware that in children and young people with secondary complications of spasticity, for example contractures and abnormal torsion, ankle–foot orthoses may not be beneficial. For children and young people with equinus deformities that impair their gait consider: a solid ankle–foot orthosis if they have poor control of knee or hip extension a hinged ankle–foot orthosis if they have good control of knee or hip extension. Consider ground reaction force ankle–foot orthoses to assist with walking if the child or young person has a crouch gait and good passive range of movement at the hip and knee. Consider body trunk orthoses for children and young people with co-existing scoliosis or kyphosis if this will help with sitting. Consider the overnight use of orthoses to: improve posture prevent or delay hip migration prevent or delay contractures. Consider the overnight use of orthoses for muscles that control two joints. Immobilising the two adjacent joints provides better stretch and night-time use avoids causing functional difficulties. If an orthosis is used overnight, check that it: is acceptable to the child or young person and does not cause injury does not disturb sleep. ## Continuing assessment The network team should review the use of orthoses at every contact with the child or young person. Ensure that the orthosis: is still acceptable to the child or young person and their parents or carers remains appropriate to treatment goals is being used as advised remains well fitting and in good repair is not causing adverse effects such as discomfort, pain, sleep disturbance, injury or excessive muscle wasting. # Oral drugs Consider oral diazepam in children and young people if spasticity is contributing to one or more of the following: discomfort or pain muscle spasms (for example, night-time muscle spasms) functional disability. Diazepam is particularly useful if a rapid effect is desirable (for example, in a pain crisis). Consider oral baclofen if spasticity is contributing to one or more of the following: discomfort or pain muscle spasms (for example, night-time muscle spasms) functional disability. Baclofen is particularly useful if a sustained long-term effect is desired (for example, to relieve continuous discomfort or to improve motor function). If oral diazepam is initially used because of its rapid onset of action, consider changing to oral baclofen if long-term treatment is indicated. Give oral diazepam treatment as a bedtime dose. If the response is unsatisfactory consider: increasing the dose or adding a daytime dose. Start oral baclofen treatment with a low dose and increase the dose stepwise over about 4 weeks to achieve the optimum therapeutic effect. Continue using oral diazepam or oral baclofen if they have a clinical benefit and are well tolerated, but think about stopping the treatment whenever the child or young person's management programme is reviewed and at least every 6 months. If adverse effects (such as drowsiness) occur with oral diazepam or oral baclofen, think about reducing the dose or stopping treatment. If the response to oral diazepam and oral baclofen used individually for 4 to 6 weeks is unsatisfactory, consider a trial of combined treatment using both drugs. If a child or young person has been receiving oral diazepam and/or baclofen for several weeks, ensure that when stopping these drugs the dose is reduced in stages to avoid withdrawal symptoms. In children and young people with spasticity in whom dystonia is considered to contribute significantly to problems with posture, function and pain, consider a trial of oral drug treatment, for example with trihexyphenidyl, levodopa or baclofen.At the time of publication (July 2012), trihexyphenidyl, levodopa (which is always marketed in combination with an extra-cerebral dopa-decarboxylase inhibitor) and baclofen did not have UK marketing authorisation for use in the treatment of dystonia associated with spasticity, and their use is not recommended in children. However, they are used in the UK for the treatment of dystonia in children and young people with spasticity. Informed consent should be obtained and documented. # Botulinum toxin type A ## General principles At the time of publication (July 2012), some botulinum toxin type A products had UK marketing authorisation for use in the treatment of focal spasticity in children, young people and adults, including the treatment of dynamic equinus foot deformity due to spasticity in ambulant paediatric cerebral palsy patients, 2 years of age or older. Other products had UK marketing authorisation only for use on the face in adults or for post-stroke spasticity of the upper limb in adults. Botulinum toxin units are not interchangeable from one product to another. Details of licensed indications and doses for individual products are available at the electronic Medicines Compendium. Where appropriate, informed consent should be obtained and documented. Consider botulinum toxin type A treatment in children and young people in whom focal spasticity of the upper limb is: impeding fine motor function compromising care and hygiene causing pain impeding tolerance of other treatments, such as orthoses causing cosmetic concerns to the child or young person. Consider botulinum toxin type A treatment where focal spasticity of the lower limb is: impeding gross motor function compromising care and hygiene causing pain disturbing sleep impeding tolerance of other treatments, such as orthoses and use of equipment to support posture causing cosmetic concerns to the child or young person. Consider botulinum toxin type A treatment after an acquired non-progressive brain injury if rapid-onset spasticity is causing postural or functional difficulties. Consider a trial of botulinum toxin type A treatment in children and young people with spasticity in whom focal dystonia is causing serious problems, such as postural or functional difficulties or pain. Do not offer botulinum toxin type A treatment if the child or young person: has severe muscle weakness had a previous adverse reaction or allergy to botulinum toxin type A is receiving aminoglycoside treatment. Be cautious when considering botulinum toxin type A treatment if: the child or young person has any of the following: a bleeding disorder, for example due to anti-coagulant therapy generalised spasticity fixed muscle contractures marked bony deformity or there are concerns about the child or young person's likelihood of engaging with the post-treatment adapted physical therapy programme (see recommendation 1.2.15). When considering botulinum toxin type A treatment, perform a careful assessment of muscle tone, range of movement and motor function to: inform the decision as to whether the treatment is appropriate provide a baseline against which the response to treatment can be measured.A physiotherapist or an occupational therapist should be involved in the assessment. When considering botulinum toxin type A treatment, give the child or young person and their parents or carers information about: the possible benefits and the likelihood of achieving the treatment goals what the treatment entails, including: the need for assessments before and after the treatment the need to inject the drug into the affected muscles the possible need for repeat injections the benefits, where necessary, of analgesia, sedation or general anaesthesia the need to use serial casting or an orthosis after the treatment in some cases possible important adverse effects (see also recommendation 1.5.10). Botulinum toxin type A treatment (including assessment and administration) should be provided by healthcare professionals within the network team who have expertise in child neurology and musculoskeletal anatomy. ## Delivering treatment Before starting treatment with botulinum toxin type A, tell children and young people and their parents or carers: to be aware of the following rare but serious complications of botulinum toxin type A treatment: swallowing difficulties breathing difficulties how to recognise signs suggesting these complications are present that these complications may occur at any time during the first week after the treatment and that if these complications occur the child or young person should return to hospital immediately. To avoid distress to the child or young person undergoing treatment with botulinum toxin type A, think about the need for: topical or systemic analgesia or anaesthesia sedation (see the NICE guideline on sedation in under 19s). Consider ultrasound or electrical muscle stimulation to guide the injection of botulinum toxin type A. Consider injecting botulinum toxin type A into more than one muscle if this is appropriate to the treatment goal, but ensure that maximum dosages are not exceeded. After treatment with botulinum toxin type A, consider an orthosis to: enhance stretching of the temporarily weakened muscle and enable the child or young person to practice functional skills. If an orthosis is indicated after botulinum toxin type A, but limited passive range of movement would make this difficult, consider first using serial casting to stretch the muscle. To improve the child or young person's ability to tolerate the cast, and to improve muscle stretching, delay casting until 2 to 4 weeks after the botulinum toxin type A treatment. Ensure that children and young people who receive treatment with botulinum toxin type A are offered timely access to orthotic services. ## Continuing assessment Perform an assessment of muscle tone, range of movement and motor function: to 12 weeks after injections to assess the response to 26 weeks after injections to inform decisions about further injections. These assessments should preferably be performed by the same healthcare professionals who undertook the baseline assessment. Consider repeat injections of botulinum toxin type A if: the response in relation to the child or young person's treatment goal was satisfactory, and the treatment effect has worn off new goals amenable to this treatment are identified. # Intrathecal baclofen ## General principles Consider treatment with continuous pump-administered intrathecal baclofen in children and young people with spasticity if, despite the use of non-invasive treatments, spasticity or dystonia are causing difficulties with any of the following: pain or muscle spasms posture or function self-care (or ease of care by parents or carers).At the time of publication (July 2012), intrathecal baclofen did not have UK marketing authorisation for children younger than 4 years, nor did it have UK marketing authorisation for use in the treatment of dystonia associated with spasticity. Where appropriate, informed consent should be obtained and documented. Be aware that children and young people who benefit from continuous pump-administered intrathecal baclofen typically have: moderate or severe motor function problems (GMFCS level III, IV or V) bilateral spasticity affecting upper and lower limbs. Be aware of the following contraindications to treatment with continuous pump-administered intrathecal baclofen: the child or young person is too small to accommodate an infusion pump local or systemic intercurrent infection. Be aware of the following potential contraindications to treatment with continuous pump-administered intrathecal baclofen: co-existing medical conditions (for example, uncontrolled epilepsy or coagulation disorders) a previous spinal fusion procedure malnutrition, which increases the risk of post-surgical complications (for example, infection or delayed healing) respiratory disorders with a risk of respiratory failure. If continuous pump-administered intrathecal baclofen is indicated in a child or young person with spasticity in whom a spinal fusion procedure is likely to be necessary for scoliosis, implant the infusion pump before performing the spinal fusion. When considering continuous pump-administered intrathecal baclofen, balance the benefits of reducing spasticity against the risk of doing so because spasticity sometimes supports function (for example, by compensating for muscle weakness). Discuss these possible adverse effects with the child or young person and their parents or carers. When considering continuous pump-administered intrathecal baclofen, inform children and young people and their parents or carers verbally and in writing (or appropriate formats) about: the surgical procedure used to implant the pump the need for regular hospital follow-up visits the requirements for pump maintenance the risks associated with pump implantation, pump-related complications and adverse effects that might be associated with intrathecal baclofen infusion. ## Intrathecal baclofen testing Before making the final decision to implant the intrathecal baclofen pump, perform an intrathecal baclofen test to assess the therapeutic effect and to check for adverse effects. Before intrathecal baclofen testing, inform children and young people and their parents or carers verbally and in writing (or appropriate formats) about: what the test will entail adverse effects that might occur with testing how the test might help to indicate the response to treatment with continuous pump-administered intrathecal baclofen, including whether: the treatment goals are likely to be achieved adverse effects might occur. Before performing the intrathecal baclofen test, assess the following where relevant to the treatment goals: spasticity dystonia the presence of pain or muscle spasms postural difficulties, including head control functional difficulties difficulties with self-care (or ease of care by parents or carers).If necessary, assess passive range of movement under general anaesthesia. The test dose or doses of intrathecal baclofen should be administered using a catheter inserted under general anaesthesia. Assess the response to intrathecal baclofen testing within 3 to 5 hours of administration. If the child or young person is still sedated from the general anaesthetic at this point, repeat the assessment later when they have recovered. When deciding whether the response to intrathecal baclofen is satisfactory, assess the following where relevant to the treatment goals: reduction in spasticity reduction in dystonia reduction in pain or muscle spasms improved posture, including head control improved function improved self-care (or ease of care by parents or carers). Discuss with the child or young person and their parents or carers their views on the response to the intrathecal baclofen test. This should include their assessment of the effect on self-care (or ease of care by parents or carers). Consider using a standardised questionnaire to document their feedback. Intrathecal baclofen testing should be: performed in a specialist neurosurgical centre within the network that has the expertise to carry out the necessary assessments undertaken in an inpatient setting to support a reliable process for assessing safety and effectiveness. Initial and post-test assessments should be performed by the same healthcare professionals in the specialist neurosurgical centre. ## Continuous pump-administered intrathecal baclofen Before implanting the intrathecal baclofen pump, inform children and young people and their parents or carers, verbally and in writing (or appropriate formats), about: safe and effective management of continuous pump-administered intrathecal baclofen the effects of intrathecal baclofen, possible adverse effects, and symptoms and signs suggesting the dose is too low or too high the potential for pump-related complications the danger of stopping the continuous pump-administered intrathecal baclofen infusion suddenly the need to attend hospital for follow-up appointments, for example to refill and reprogram the infusion pump the importance of seeking advice from a healthcare professional with expertise in intrathecal baclofen before stopping the treatment. Implant the infusion pump and start treatment with continuous pump-administered intrathecal baclofen within 3 months of a satisfactory response to intrathecal baclofen testing (see recommendation 1.6.13). Support children and young people receiving treatment with continuous pump-administered intrathecal baclofen and their parents or carers by offering regular follow-up with the network team, and a consistent point of contact with the specialist neurosurgical centre. Monitor the response to continuous pump-administered intrathecal baclofen. This monitoring should preferably be performed by the healthcare professionals in the regional specialist neurosurgical centre who performed the pre-implantation assessments. When deciding whether the response to continuous pump-administered intrathecal baclofen is satisfactory, assess the following where relevant to the treatment goals: reduction in spasticity reduction in dystonia reduction in pain or muscle spasms improved posture, including head control improved function improved self-care (or ease of care by parents or carers). Titrate the dose of intrathecal baclofen after pump implantation, if necessary, to optimise effectiveness. If treatment with continuous pump-administered intrathecal baclofen does not result in a satisfactory response (see recommendation 1.6.21), check that there are no technical faults in the delivery system and that the catheter is correctly placed to deliver the drug to the intrathecal space. If no such problems are identified, consider reducing the dose gradually to determine whether spasticity and associated symptoms increase. If continuous pump-administered intrathecal baclofen therapy is unsatisfactory, the specialist neurosurgical centre and other members of the network team should discuss removing the pump and alternative management options with the child or young person and their parents or carers. As the infusion pump approaches the end of its expected lifespan, consider reducing the dose gradually to enable the child or young person and their parents or carers to decide whether or not to have a new pump implanted. # Orthopaedic surgery Consider orthopaedic surgery as an important adjunct to other interventions in the management programme for some children and young people with spasticity. Timely surgery can prevent deterioration and improve function. An assessment should be performed by an orthopaedic surgeon within the network team if: based on clinical findings (see recommendation 1.1.16) or radiological monitoring, there is concern that the hip may be displaced based on clinical or radiological findings there is concern about spinal deformity. Consider an assessment by an orthopaedic surgeon in the network team for children and young people with: hip migration greater than 30% or hip migration percentage increasing by more than 10 percentage points per year. Consider an assessment by an orthopaedic surgeon in the network team if any of the following are present: limb function is limited (for example, in walking or getting dressed) by unfavourable posture or pain, as a result of muscle shortening, contractures or bony deformities contractures of the shoulder, elbow, wrist or hand cause difficulty with skin hygiene the cosmetic appearance of the upper limb causes significant concern for the child or young person. Before undertaking orthopaedic surgery, the network team should discuss and agree with the child or young person and their parents or carers: the possible goals of surgery and the likelihood of achieving them what the surgery will entail, including any specific risks the rehabilitation programme, including: how and where it will be delivered what the components will be, for example a programme of adapted physical therapy, the use of orthoses, oral drugs or botulinum toxin type A. Orthopaedic surgery should: be undertaken by surgeons in the network team who are expert in the concepts and techniques involved in surgery for this group of patients and take place in a paediatric setting. The decision to perform orthopaedic surgery to improve gait should be informed by a thorough pre-operative functional assessment, preferably including gait analysis. If a child or young person will need several surgical procedures at different anatomical sites to improve their gait, perform them together if possible (single-event multilevel surgery), rather than individually over a period of time. Assess the outcome of orthopaedic surgery undertaken to improve gait 1 to 2 years later. By then full recovery may be expected and the outcome of the procedure can be more accurately determined. # Selective dorsal rhizotomy Consider selective dorsal rhizotomy to improve walking ability in children and young people with spasticity at GMFCS level II or III: Patient selection and treatment should be carried out by a multidisciplinary team with specialist training and expertise in the care of spasticity, and with access to the full range of treatment options. Discuss the irreversibility of the treatment, the known complications and the uncertainties over long-term outcomes with children and young people, and their parents and/or carers (see also the NICE interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy). Teams offering selective dorsal rhizotomy should participate in a coordinated national agreed programme to collect information on short- and long-term outcomes on all patients assessed for selective dorsal rhizotomy, whether or not selective dorsal rhizotomy is performed. These recorded outcomes should include measures of muscle tone, gross motor function, neurological impairment, spinal deformity, quality of life and need for additional operations, with nationally agreed consistent definitions. # Terms used in this guideline ## Botulinum toxin type A A neurotoxin produced by the bacterium Clostridium botulinum that blocks neurotransmitter release at peripheral cholinergic nerve terminals. Injection into a muscle reduces spasticity. ## Constraint-induced movement therapy An approach to physical therapy in which an unaffected arm is temporarily restrained to encourage use of the other arm. ## Continuous pump-administered intrathecal baclofen treatment Direct administration of baclofen into the fluid-filled space around the spinal cord (the intrathecal space) using a catheter and infusion pump. The pump is implanted in the abdominal cavity and allows a continual controlled delivery of baclofen adjusted according to need. ## Contracture Shortening of muscle tendons, ligaments and soft tissues resulting in a limitation of joint movement. Usually, muscle shortening is the primary abnormality, but prolonged immobility or scarring may also contribute. ## Dystonia Involuntary, sustained, or intermittent muscle contractions that cause twitching and repetitive movements, abnormal postures or both. ## Equinus deformity Abnormal ankle plantarflexion (movement of the foot at the ankle joint in a downward direction). This can, for example, result in the child or young person walking on tiptoe. ## Fine motor function The ability to use small muscle groups, often in coordination with the eyes, to perform precision activities such as writing or fastening buttons. ## Focal dystonia Dystonia involving a specific muscle or group of muscles. ## Focal spasticity Spasticity involving a specific muscle or group of muscles. ## Function The ability to perform normal activities or actions. Such function may be impaired by spasticity and associated motor disorders and by the complications of spasticity. ## Gait analysis A detailed approach to analysing the component phases of walking using instrumentation or video analysis in addition to clinical observation. This is undertaken to evaluate a child or young person's ability and style of walking and to plan or assess treatment. ## Gross motor function The ability to use large muscle groups to perform body movements such as sitting, standing, walking and running. ## Gross Motor Function Classification System A 5-point scale that describes gross motor function: level I, walks without restrictions; level II, walks without assistive devices; level III, walks with assistive devices; level IV, has limited self-mobility; level V, has severely limited self-mobility even with assistive devices. ## Hip migration Movement of the top of the thigh bone that connects with the pelvis (the femoral head) from its normal position in the socket joint of the hip (the acetabulum). This movement is often measured by reporting the degree of displacement seen on X-ray (known as the hip migration percentage). ## Intrathecal baclofen testing Direct injection of baclofen into the fluid-filled space around the spinal cord (the intrathecal space) using a lumbar puncture needle or a temporary spinal catheter in order to assess the likely response to continuous pump-administered baclofen treatment. ## Kyphosis Abnormal curvature of the spine when viewed from the side of the body that results in a hunched or slouching position. ## Low-load active stretching A physical therapy intervention in which the child or young person actively stretches their muscles with the aim of increasing range of movement. ## Low-load passive stretching A physical therapy intervention involving sustained stretching using positioning with equipment, orthoses or serial casting. ## Muscle tone The normal state of continuous passive partial contraction in a resting muscle. Muscle tone is important in maintaining posture. Increased muscle tone (hypertonia) is associated with an abnormal resistance to passive stretch, while reduced muscle tone (hypotonia) is associated with floppiness of the limbs or trunk and poor posture. ## Network of care Linked groups of healthcare professionals and organisations working in an agreed and coordinated manner to deliver a clinical service. A network is not constrained by existing professional, organisational or institutional boundaries. ## Network team A multidisciplinary group of healthcare and other professionals working in a network of care to deliver a clinical service. ## Orthosis (plural, orthoses) An artificial device or appliance used to support, align, prevent, or correct deformities or to improve musculoskeletal function. ## Passive range of movement The degree of motion through which a joint can be moved by an outside force without active participation by the child or young person themself (for example, movement by another person). ## Range of movement The range of motion, usually measured in degrees, through which a joint can move. ## Scoliosis An abnormal lateral curvature of the spine viewed from in front of or behind the child or young person. ## Secondary complication of spasticity An adverse effect on musculoskeletal structure that occurs as a result of spasticity (for example, a contracture or abnormal torsion). ## Secondary consequence of spasticity Any effect experienced by a child or young person as a result of spasticity. This may be symptomatic (for example, pain or difficulty walking) or a complication affecting the structure of the musculoskeletal system (see secondary complication of spasticity). ## Selective dorsal rhizotomy A neurosurgical procedure in which some of the sensory nerves that contribute to spasticity in the lower limb are cut at the point where they enter the spinal cord. ## Serial casting The successive use of casts with the aim of progressively lengthening muscles and other non-bony tissues such as ligaments and tendons thereby reducing the effect of contractures by passive stretching to gradually improve the range of movement. ## Spasticity A specific form of increased muscle tone (hypertonia) in which one or both of the following are present: the resistance to externally imposed movement increases with increasing speed of stretch and varies with the direction of joint movement the resistance to externally imposed movement increases rapidly beyond a threshold speed or joint angle. ## Spinal fusion A surgical procedure where two or more vertebrae are joined to prevent movement between them. ## Task-focused active-use therapy A physiotherapy technique where a specific goal is identified and the child or young person carries out exercises or activities using the affected limb or limbs to improve their performance.# Recommendations for research The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline. # Inhibitors of functional ability What are the greatest inhibitors of functional ability in children and young people with upper motor neurone lesions? ## Why this is important Children and young people with upper motor neurone lesions may experience: reduced muscle strength selective muscle control spasticity. The relationships between these factors, and the extent to which the child or young person can develop or maintain functional ability, remain unclear. Prospective cohort studies, or large cross-sectional studies, are needed to explore the relationships between positive and negative effects of upper motor neurone lesions and to determine which factor is the greatest inhibitor of functional ability. The studies should incorporate classification of functional ability based on validated scales, such as the GMFCS. # Botulinum toxin type A What is the clinical and cost effectiveness of botulinum toxin type A when used routinely or according to clinical need in children and young people who are at GMFCS level I, II or III? ## Why this is important The GDG's recommendation to consider offering botulinum toxin type A to children and young people with focal spasticity of an upper or lower limb reflected available evidence relating to the safety and effectiveness of botulinum toxin type A. In making their recommendations, the GDG emphasised the importance of establishing individualised goals that justify the use of this potentially harmful toxin to treat spasticity. The cost of the procedure combined with the risk of side effects means that clear treatment goals that will positively influence the child or young person's life should be identified before offering this treatment. The evidence reviewed for the guideline provided limited support for botulinum toxin type A in terms of achieving clinically important goals (including those related to function), and this discouraged the GDG from making a strong recommendation to offer treatment with botulinum toxin type A to all children and young people who are at GMFCS level I, II or III. Further research is needed to evaluate the effectiveness of botulinum toxin type A in comparison with other treatment options, particularly when used over long time periods (for example, 10 years) and involving repeat injections, in this population of children and young people. Outcomes relating to improvements in gross motor function and participation in activities, and the psychological impacts of these factors, should be evaluated as part of the research. # Intrathecal baclofen What is the clinical and cost effectiveness of continuous pump-administered intrathecal baclofen compared with usual care in children and young people who are at GMFCS level IV or V? ## Why this is important The GDG's recommendation to consider offering continuous pump-administered intrathecal baclofen focused on children and young people in whom the use of appropriate non-invasive treatments did not relieve difficulties associated with spasticity (specifically pain or muscle spasms, posture or function, or ease of care). Such children and young people will typically be at GMFCS level IV or V. Further research is needed to evaluate the clinical and cost effectiveness of continuous pump-administered intrathecal baclofen compared with usual care in these children and young people. Relevant research designs include randomised controlled trials, prospective cohort studies and qualitative studies. The outcomes to be investigated as part of the research include: quality of life; reduction of pain; reduction of tone; acceptability and tolerability; participation or inclusion; and adverse effects and their association with any potential predisposing factors. # Selective dorsal rhizotomy Does selective dorsal rhizotomy followed by intensive rehabilitation performed between the ages of 3 and 9 years in children who are at GMFCS level II or III result in good community mobility as a young adult? ## Why this is important The available evidence relating to selective dorsal rhizotomy suggests that the procedure results in some short- and medium-term improvements in motor function. The effects reported were not consistent across all studies nor sustained across all durations of follow-up investigated (6 to 24 months). The GDG considered that if the observed improvements could be maintained through to adult life then the outcomes of selective dorsal rhizotomy would be clinically important. Further research is urgently needed to evaluate long-term outcomes (including adverse effects) of selective dorsal rhizotomy followed by an intensive rehabilitation programme involving physical therapy (and prioritising targeted strength training) compared with physical therapy alone. The research could be conducted using a range of designs, including randomised controlled trials and audits of outcomes from procedures already performed. The research should focus on selective dorsal rhizotomy performed between the ages of 3 and 9 years in children who are at GMFCS level II or III (because these children are likely to benefit most from selective dorsal rhizotomy) and before the development of significant contractures at the ankles, knees and hips. The research should be coordinated through a multicentre research programme; use nationally agreed outcome measures (such as incidence of neurological impairment and spinal deformity, the need for additional operations, and assessment of disability, social inclusion and quality of life) and follow-up periods to facilitate national audit; and include assessment of the child's clinical condition before and after selective dorsal rhizotomy using the same formally validated assessment techniques. The full guideline includes further considerations relating to criteria for identifying children who could be included in the research, the timing of selective dorsal rhizotomy in relation to other treatments such as orthopaedic surgery, and information that should be given to children and their parents or carers to facilitate informed decision making about participation in research.	{'Introduction': "This guideline covers the management of spasticity and co-existing motor disorders and their early musculoskeletal complications in children and young people (from birth up to their 19th birthday) with non-progressive brain disorders.\n\nCerebral palsy is the most common condition associated with spasticity in children and young people. The incidence of cerebral palsy is not known, but its prevalence in the UK is 186 per 100,000 population, with a total of 110,000 people affected. The guideline covers the management of spasticity associated with cerebral palsy, but not all aspects of the management of cerebral palsy.\n\nThe impact of spasticity and co-existing motor disorders and their early musculoskeletal complications on the child or young person varies. Common problems include impaired motor function affecting the person's ability to participate in society, pain from muscle spasms, motor developmental delay and difficulties with daily care due to the onset of secondary complications of spasticity. Management should be tailored to meet the problems faced by the individual child or young person and their individual goals.\n\nThere is considerable variation in practice in managing spasticity, including variation in the availability of treatments and the intensity of their use. This guideline will help healthcare professionals to select and use appropriate treatments for individual children and young people.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles of care\n\n## Delivering care\n\nChildren and young people with spasticity should have access to a network of care that uses agreed care pathways supported by effective communication and integrated team working.\n\nThe network of care should provide access to a team of healthcare professionals experienced in the care of children and young people with spasticity. The network team should provide local expertise in paediatrics, nursing, physiotherapy and occupational therapy. Access to other expertise, including orthotics, orthopaedic surgery and/or neurosurgery and paediatric neurology, may be provided locally or regionally.\n\nIf a child or young person receives treatment for spasticity from healthcare professionals outside the network team, this should be planned and undertaken in discussion with the network team to ensure integrated care and effective subsequent management.\n\n## Management programmes\n\nFollowing diagnosis, ensure that all children and young people with spasticity are referred without delay to an appropriate member of the network team.\n\nOffer a management programme that is:\n\ndeveloped and implemented in partnership with the child or young person and their parents or carers\n\nindividualised\n\ngoal focused.\n\nWhen formulating a management programme take into account its possible impact on the individual child or young person and their family.\n\nCarefully assess the impact of spasticity in children and young people with cognitive impairments:\n\nbe aware that the possible benefit of treatments may be more difficult to assess in a child or young person with limited communication\n\nensure that the child or young person has access to all appropriate services.\n\nIdentify and agree with children and young people and their parents or carers assessments and goals that:\n\nare age and developmentally appropriate\n\nfocus on the following domains of the World Health Organization's International Classification of Functioning, Disability and Health:\n\n\n\nbody functions\n\nbody structures\n\nactivities and participation\n\nenvironmental factors.\n\n\n\nRecord the child or young person's individualised goals and share these goals with healthcare professionals in the network team and, where appropriate, other people involved in their care.\n\nHelp children and young people and their parents or carers to be partners in developing and implementing the management programme by offering:\n\nrelevant, and age and developmentally appropriate, information and educational materials\n\nregular opportunities for discussion and\n\nadvice on their developmental potential and how different treatment options may affect this.\n\n## Supporting the child or young person and their parents or carers\n\nOffer contact details of patient organisations that can provide support, befriending, counselling, information and advocacy.\n\nEnsure that children and young people have timely access to equipment necessary for their management programme (for example, postural management equipment such as sleeping, sitting or standing systems).\n\nThe network team should have a central role in transition to prepare young people and their parents or carers for the young person's transfer to adult services.\n\n## Monitoring\n\nMonitor the child or young person's condition for:\n\nthe response to treatments\n\nworsening of spasticity\n\ndeveloping secondary consequences of spasticity, for example pain or contractures\n\nthe need to change their individualised goals.\n\nThe network of care should have a pathway for monitoring children and young people at increased risk of hip displacement.\n\nRecognise the following clinical findings as possible indicators of hip displacement (hip migration greater than 30%):\n\npain arising from the hip\n\nclinically important leg length difference\n\ndeterioration in hip abduction or range of hip movement\n\nincreasing hip muscle tone\n\ndeterioration in sitting or standing\n\nincreasing difficulty with perineal care or hygiene.\n\nOffer a hip X-ray to assess for hip displacement:\n\nif there are clinical concerns about possible hip displacement\n\nat 24 months in children with bilateral cerebral palsy.\n\nConsider repeating the hip X-ray annually in children or young people who are at Gross Motor Function Classification System (GMFCS) level III, IV or V.\n\nConsider repeating the hip X-ray after 6\xa0months in children and young people where the initial hip migration is greater than 30%, and then consider repeating the hip X-ray every 6\xa0months after this if the hip migration is increasing by more than 10 percentage points per year.\n\n# Physical therapy (physiotherapy and/or occupational therapy)\n\n## General principles\n\nAll children and young people with spasticity referred to the network team should be promptly assessed by a physiotherapist and, where necessary, an occupational therapist.\n\nOffer a physical therapy (physiotherapy and/or occupational therapy) programme tailored to the child or young person's individual needs and aimed at specific goals, such as:\n\nenhancing skill development, function and ability to participate in everyday activities\n\npreventing consequences such as pain or contractures.\n\nGive children and young people and their parents or carers verbal and written (or appropriate formats) information about the physical therapy interventions needed to achieve the intended goals. This information should emphasise the balance between possible benefits and difficulties (for example, time commitment or discomfort), to enable them to participate in choosing a suitable physical therapy programme.\n\nWhen formulating a physical therapy programme for children and young people take into account:\n\nthe views of the child or young person and their parents or carers\n\nthe likelihood of achieving the treatment goals\n\npossible difficulties in implementing the programme\n\nimplications for the individual child or young person and their parents or carers, including the time and effort involved and potential individual barriers.\n\nWhen deciding who should deliver physical therapy, take into account:\n\nwhether the child or young person and their parents or carers are able to deliver the specific therapy\n\nwhat training the child or young person or their parents or carers might need\n\nthe wishes of the child or young person and their parents or carers.\n\nEnsure that any equipment or techniques used in the physical therapy programme are safe and appropriate, in particular for children or young people with any of the following:\n\npoorly controlled epilepsy\n\nrespiratory compromise\n\nincreased risk of pulmonary aspiration\n\nincreased risk of bone fracture due to osteoporosis (for example, those who are unable to walk, malnourished or taking anti-epileptic therapy).\n\nEncourage children and young people and their parents or carers to incorporate physical therapy into daily activities (for example, standing at the sink while brushing teeth in order to stretch leg muscles).\n\n## Specific strategies\n\nConsider including in the physical therapy programme 24-hour postural management strategies to:\n\nprevent or delay the development of contractures or skeletal deformities in children and young people at risk of developing these\n\nenable the child or young person to take part in activities appropriate to their stage of development.\n\nWhen using 24-hour postural management strategies consider on an individual basis low-load active stretching or low-load passive stretching.\n\nOffer training to parents and carers involved in delivering postural management strategies.\n\nConsider task-focused active-use therapy such as constraint-induced movement therapy (temporary restraint of an unaffected arm to encourage use of the other arm) followed by bimanual therapy (unrestrained use of both arms) to enhance manual skills.\n\nWhen undertaking task-focused active-use therapy consider an intensive programme over a short time period (for example, 4\xa0to\xa08\xa0weeks).\n\nConsider muscle-strengthening therapy where the assessment indicates that muscle weakness is contributing to loss of function or postural difficulties.\n\nDirect muscle-strengthening therapy towards specific goals using progressive repetitive exercises performed against resistance.\n\nFollowing treatment with botulinum toxin type\xa0A, continuous pump-administered intrathecal baclofen, orthopaedic surgery or selective dorsal rhizotomy, provide an adapted physical therapy programme as an essential component of management.\n\nEnsure that children and young people and their parents or carers understand that an adapted physical therapy programme will be an essential component of management following treatment with botulinum toxin type\xa0A, continuous pump-administered intrathecal baclofen, orthopaedic surgery or selective dorsal rhizotomy.\n\n## Continuing assessment\n\nReassess the physical therapy programme at regular intervals to ensure that:\n\nthe goals are being achieved\n\nthe programme remains appropriate to the child or young person's needs.\n\n# Orthoses\n\n## General principles\n\nConsider orthoses for children and young people with spasticity based on their individual needs and aimed at specific goals, such as:\n\nimproving posture\n\nimproving upper limb function\n\nimproving walking efficiency\n\npreventing or slowing development of contractures\n\npreventing or slowing hip migration\n\nrelieving discomfort or pain\n\npreventing or treating tissue injury, for example by relieving pressure points.\n\nWhen considering an orthosis, discuss with the child or young person and their parents or carers the balance of possible benefits against risks. For example, discuss its cosmetic appearance, the possibility of discomfort or pressure sores or of muscle wasting through lack of muscle use.\n\nAssess whether an orthosis might:\n\ncause difficulties with self-care or care by others\n\ncause difficulties in relation to hygiene\n\nbe unacceptable to the child or young person because of its appearance.\n\nEnsure that orthoses are appropriately designed for the individual child or young person and are sized and fitted correctly. If necessary seek expert advice from an orthotist within the network team.\n\nBe aware when considering a rigid orthosis that it may cause discomfort or pressure injuries in a child or young person with marked dyskinesia. They should be monitored closely to ensure that the orthosis is not causing such difficulties.\n\nThe network of care should have a pathway that aims to minimise delay in:\n\nsupplying an orthosis once measurements for fit have been performed and\n\nrepairing a damaged orthosis.\n\nInform children and young people who are about to start using an orthosis, and their parents or carers:\n\nhow to apply and wear it\n\nwhen to wear it and for how long:\n\n\n\nan orthosis designed to maintain stretch to prevent contractures is more likely to be effective if worn for longer periods of time, for example at least 6\xa0hours a day\n\nan orthosis designed to support a specific function should be worn only when needed\n\n\n\nwhen and where to seek advice.\n\nAdvise children and young people and their parents or carers that they may remove an orthosis if it is causing pain that is not relieved despite their repositioning the limb in the orthosis or adjusting the strapping.\n\n## Specific uses\n\nConsider the following orthoses for children and young people with upper limb spasticity:\n\nelbow gaiters to maintain extension and improve function\n\nrigid wrist orthoses to prevent contractures and limit wrist and hand flexion deformity\n\ndynamic orthoses to improve hand function (for example, a non-rigid thumb abduction splint allowing some movement for a child or young person with a 'thumb in palm' deformity).\n\nConsider ankle–foot orthoses for children and young people with serious functional limitations (GMFCS level IV or V) to improve foot position for sitting, transfers between sitting and standing, and assisted standing.\n\nBe aware that in children and young people with secondary complications of spasticity, for example contractures and abnormal torsion, ankle–foot orthoses may not be beneficial.\n\nFor children and young people with equinus deformities that impair their gait consider:\n\na solid ankle–foot orthosis if they have poor control of knee or hip extension\n\na hinged ankle–foot orthosis if they have good control of knee or hip extension.\n\nConsider ground reaction force ankle–foot orthoses to assist with walking if the child or young person has a crouch gait and good passive range of movement at the hip and knee.\n\nConsider body trunk orthoses for children and young people with co-existing scoliosis or kyphosis if this will help with sitting.\n\nConsider the overnight use of orthoses to:\n\nimprove posture\n\nprevent or delay hip migration\n\nprevent or delay contractures.\n\nConsider the overnight use of orthoses for muscles that control two joints. Immobilising the two adjacent joints provides better stretch and night-time use avoids causing functional difficulties.\n\nIf an orthosis is used overnight, check that it:\n\nis acceptable to the child or young person and does not cause injury\n\ndoes not disturb sleep.\n\n## Continuing assessment\n\nThe network team should review the use of orthoses at every contact with the child or young person. Ensure that the orthosis:\n\nis still acceptable to the child or young person and their parents or carers\n\nremains appropriate to treatment goals\n\nis being used as advised\n\nremains well fitting and in good repair\n\nis not causing adverse effects such as discomfort, pain, sleep disturbance, injury or excessive muscle wasting.\n\n# Oral drugs\n\nConsider oral diazepam in children and young people if spasticity is contributing to one or more of the following:\n\ndiscomfort or pain\n\nmuscle spasms (for example, night-time muscle spasms)\n\nfunctional disability. Diazepam is particularly useful if a rapid effect is desirable (for example, in a pain crisis).\n\nConsider oral baclofen if spasticity is contributing to one or more of the following:\n\ndiscomfort or pain\n\nmuscle spasms (for example, night-time muscle spasms)\n\nfunctional disability. Baclofen is particularly useful if a sustained long-term effect is desired (for example, to relieve continuous discomfort or to improve motor function).\n\nIf oral diazepam is initially used because of its rapid onset of action, consider changing to oral baclofen if long-term treatment is indicated.\n\nGive oral diazepam treatment as a bedtime dose. If the response is unsatisfactory consider:\n\nincreasing the dose or\n\nadding a daytime dose.\n\nStart oral baclofen treatment with a low dose and increase the dose stepwise over about 4\xa0weeks to achieve the optimum therapeutic effect.\n\nContinue using oral diazepam or oral baclofen if they have a clinical benefit and are well tolerated, but think about stopping the treatment whenever the child or young person's management programme is reviewed and at least every 6\xa0months.\n\nIf adverse effects (such as drowsiness) occur with oral diazepam or oral baclofen, think about reducing the dose or stopping treatment.\n\nIf the response to oral diazepam and oral baclofen used individually for 4\xa0to\xa06\xa0weeks is unsatisfactory, consider a trial of combined treatment using both drugs.\n\nIf a child or young person has been receiving oral diazepam and/or baclofen for several weeks, ensure that when stopping these drugs the dose is reduced in stages to avoid withdrawal symptoms.\n\nIn children and young people with spasticity in whom dystonia is considered to contribute significantly to problems with posture, function and pain, consider a trial of oral drug treatment, for example with trihexyphenidyl, levodopa or baclofen.At the time of publication (July 2012), trihexyphenidyl, levodopa (which is always marketed in combination with an extra-cerebral dopa-decarboxylase inhibitor) and baclofen did not have UK marketing authorisation for use in the treatment of dystonia associated with spasticity, and their use is not recommended in children. However, they are used in the UK for the treatment of dystonia in children and young people with spasticity. Informed consent should be obtained and documented.\n\n# Botulinum toxin type\xa0A\n\n## General principles\n\nAt the time of publication (July 2012), some botulinum toxin type\xa0A products had UK marketing authorisation for use in the treatment of focal spasticity in children, young people and adults, including the treatment of dynamic equinus foot deformity due to spasticity in ambulant paediatric cerebral palsy patients, 2 years of age or older. Other products had UK marketing authorisation only for use on the face in adults or for post-stroke spasticity of the upper limb in adults. Botulinum toxin units are not interchangeable from one product to another. Details of licensed indications and doses for individual products are available at the electronic Medicines Compendium. Where appropriate, informed consent should be obtained and documented.\n\nConsider botulinum toxin type\xa0A treatment in children and young people in whom focal spasticity of the upper limb is:\n\nimpeding fine motor function\n\ncompromising care and hygiene\n\ncausing pain\n\nimpeding tolerance of other treatments, such as orthoses\n\ncausing cosmetic concerns to the child or young person. Consider botulinum toxin type\xa0A treatment where focal spasticity of the lower limb is:\n\nimpeding gross motor function\n\ncompromising care and hygiene\n\ncausing pain\n\ndisturbing sleep\n\nimpeding tolerance of other treatments, such as orthoses and use of equipment to support posture\n\ncausing cosmetic concerns to the child or young person.\n\nConsider botulinum toxin type\xa0A treatment after an acquired non-progressive brain injury if rapid-onset spasticity is causing postural or functional difficulties.\n\nConsider a trial of botulinum toxin type\xa0A treatment in children and young people with spasticity in whom focal dystonia is causing serious problems, such as postural or functional difficulties or pain.\n\nDo not offer botulinum toxin type\xa0A treatment if the child or young person:\n\nhas severe muscle weakness\n\nhad a previous adverse reaction or allergy to botulinum toxin type\xa0A\n\nis receiving aminoglycoside treatment.\n\nBe cautious when considering botulinum toxin type\xa0A treatment if:\n\nthe child or young person has any of the following:\n\n\n\na bleeding disorder, for example due to anti-coagulant therapy\n\ngeneralised spasticity\n\nfixed muscle contractures\n\nmarked bony deformity or\n\n\n\nthere are concerns about the child or young person's likelihood of engaging with the post-treatment adapted physical therapy programme (see recommendation 1.2.15).\n\nWhen considering botulinum toxin type\xa0A treatment, perform a careful assessment of muscle tone, range of movement and motor function to:\n\ninform the decision as to whether the treatment is appropriate\n\nprovide a baseline against which the response to treatment can be measured.A physiotherapist or an occupational therapist should be involved in the assessment.\n\nWhen considering botulinum toxin type\xa0A treatment, give the child or young person and their parents or carers information about:\n\nthe possible benefits and the likelihood of achieving the treatment goals\n\nwhat the treatment entails, including:\n\n\n\nthe need for assessments before and after the treatment\n\nthe need to inject the drug into the affected muscles\n\nthe possible need for repeat injections\n\nthe benefits, where necessary, of analgesia, sedation or general anaesthesia\n\nthe need to use serial casting or an orthosis after the treatment in some cases\n\n\n\npossible important adverse effects (see also recommendation 1.5.10).\n\nBotulinum toxin type\xa0A treatment (including assessment and administration) should be provided by healthcare professionals within the network team who have expertise in child neurology and musculoskeletal anatomy.\n\n## Delivering treatment\n\nBefore starting treatment with botulinum toxin type\xa0A, tell children and young people and their parents or carers:\n\nto be aware of the following rare but serious complications of botulinum toxin type\xa0A treatment:\n\n\n\nswallowing difficulties\n\nbreathing difficulties\n\n\n\nhow to recognise signs suggesting these complications are present\n\nthat these complications may occur at any time during the first week after the treatment and\n\nthat if these complications occur the child or young person should return to hospital immediately.\n\nTo avoid distress to the child or young person undergoing treatment with botulinum toxin type\xa0A, think about the need for:\n\ntopical or systemic analgesia or anaesthesia\n\nsedation (see the NICE guideline on sedation in under\xa019s).\n\nConsider ultrasound or electrical muscle stimulation to guide the injection of botulinum toxin type\xa0A.\n\nConsider injecting botulinum toxin type\xa0A into more than one muscle if this is appropriate to the treatment goal, but ensure that maximum dosages are not exceeded.\n\nAfter treatment with botulinum toxin type\xa0A, consider an orthosis to:\n\nenhance stretching of the temporarily weakened muscle and\n\nenable the child or young person to practice functional skills.\n\nIf an orthosis is indicated after botulinum toxin type\xa0A, but limited passive range of movement would make this difficult, consider first using serial casting to stretch the muscle. To improve the child or young person's ability to tolerate the cast, and to improve muscle stretching, delay casting until 2\xa0to\xa04\xa0weeks after the botulinum toxin type\xa0A treatment.\n\nEnsure that children and young people who receive treatment with botulinum toxin type\xa0A are offered timely access to orthotic services.\n\n## Continuing assessment\n\nPerform an assessment of muscle tone, range of movement and motor function:\n\nto\xa012\xa0weeks after injections to assess the response\n\nto\xa026\xa0weeks after injections to inform decisions about further injections. These assessments should preferably be performed by the same healthcare professionals who undertook the baseline assessment.\n\nConsider repeat injections of botulinum toxin type\xa0A if:\n\nthe response in relation to the child or young person's treatment goal was satisfactory, and the treatment effect has worn off\n\nnew goals amenable to this treatment are identified.\n\n# Intrathecal baclofen\n\n## General principles\n\nConsider treatment with continuous pump-administered intrathecal baclofen in children and young people with spasticity if, despite the use of non-invasive treatments, spasticity or dystonia are causing difficulties with any of the following:\n\npain or muscle spasms\n\nposture or function\n\nself-care (or ease of care by parents or carers).At the time of publication (July 2012), intrathecal baclofen did not have UK marketing authorisation for children younger than 4 years, nor did it have UK marketing authorisation for use in the treatment of dystonia associated with spasticity. Where appropriate, informed consent should be obtained and documented.\n\nBe aware that children and young people who benefit from continuous pump-administered intrathecal baclofen typically have:\n\nmoderate or severe motor function problems (GMFCS level III, IV or V)\n\nbilateral spasticity affecting upper and lower limbs.\n\nBe aware of the following contraindications to treatment with continuous pump-administered intrathecal baclofen:\n\nthe child or young person is too small to accommodate an infusion pump\n\nlocal or systemic intercurrent infection.\n\nBe aware of the following potential contraindications to treatment with continuous pump-administered intrathecal baclofen:\n\nco-existing medical conditions (for example, uncontrolled epilepsy or coagulation disorders)\n\na previous spinal fusion procedure\n\nmalnutrition, which increases the risk of post-surgical complications (for example, infection or delayed healing)\n\nrespiratory disorders with a risk of respiratory failure.\n\nIf continuous pump-administered intrathecal baclofen is indicated in a child or young person with spasticity in whom a spinal fusion procedure is likely to be necessary for scoliosis, implant the infusion pump before performing the spinal fusion.\n\nWhen considering continuous pump-administered intrathecal baclofen, balance the benefits of reducing spasticity against the risk of doing so because spasticity sometimes supports function (for example, by compensating for muscle weakness). Discuss these possible adverse effects with the child or young person and their parents or carers.\n\nWhen considering continuous pump-administered intrathecal baclofen, inform children and young people and their parents or carers verbally and in writing (or appropriate formats) about:\n\nthe surgical procedure used to implant the pump\n\nthe need for regular hospital follow-up visits\n\nthe requirements for pump maintenance\n\nthe risks associated with pump implantation, pump-related complications and adverse effects that might be associated with intrathecal baclofen infusion.\n\n## Intrathecal baclofen testing\n\nBefore making the final decision to implant the intrathecal baclofen pump, perform an intrathecal baclofen test to assess the therapeutic effect and to check for adverse effects.\n\nBefore intrathecal baclofen testing, inform children and young people and their parents or carers verbally and in writing (or appropriate formats) about:\n\nwhat the test will entail\n\nadverse effects that might occur with testing\n\nhow the test might help to indicate the response to treatment with continuous pump-administered intrathecal baclofen, including whether:\n\n\n\nthe treatment goals are likely to be achieved\n\nadverse effects might occur.\n\n\n\nBefore performing the intrathecal baclofen test, assess the following where relevant to the treatment goals:\n\nspasticity\n\ndystonia\n\nthe presence of pain or muscle spasms\n\npostural difficulties, including head control\n\nfunctional difficulties\n\ndifficulties with self-care (or ease of care by parents or carers).If necessary, assess passive range of movement under general anaesthesia.\n\nThe test dose or doses of intrathecal baclofen should be administered using a catheter inserted under general anaesthesia.\n\nAssess the response to intrathecal baclofen testing within 3\xa0to\xa05\xa0hours of administration. If the child or young person is still sedated from the general anaesthetic at this point, repeat the assessment later when they have recovered.\n\nWhen deciding whether the response to intrathecal baclofen is satisfactory, assess the following where relevant to the treatment goals:\n\nreduction in spasticity\n\nreduction in dystonia\n\nreduction in pain or muscle spasms\n\nimproved posture, including head control\n\nimproved function\n\nimproved self-care (or ease of care by parents or carers).\n\nDiscuss with the child or young person and their parents or carers their views on the response to the intrathecal baclofen test. This should include their assessment of the effect on self-care (or ease of care by parents or carers). Consider using a standardised questionnaire to document their feedback.\n\nIntrathecal baclofen testing should be:\n\nperformed in a specialist neurosurgical centre within the network that has the expertise to carry out the necessary assessments\n\nundertaken in an inpatient setting to support a reliable process for assessing safety and effectiveness.\n\nInitial and post-test assessments should be performed by the same healthcare professionals in the specialist neurosurgical centre.\n\n## Continuous pump-administered intrathecal baclofen\n\nBefore implanting the intrathecal baclofen pump, inform children and young people and their parents or carers, verbally and in writing (or appropriate formats), about:\n\nsafe and effective management of continuous pump-administered intrathecal baclofen\n\nthe effects of intrathecal baclofen, possible adverse effects, and symptoms and signs suggesting the dose is too low or too high\n\nthe potential for pump-related complications\n\nthe danger of stopping the continuous pump-administered intrathecal baclofen infusion suddenly\n\nthe need to attend hospital for follow-up appointments, for example to refill and reprogram the infusion pump\n\nthe importance of seeking advice from a healthcare professional with expertise in intrathecal baclofen before stopping the treatment.\n\nImplant the infusion pump and start treatment with continuous pump-administered intrathecal baclofen within 3\xa0months of a satisfactory response to intrathecal baclofen testing (see recommendation 1.6.13).\n\nSupport children and young people receiving treatment with continuous pump-administered intrathecal baclofen and their parents or carers by offering regular follow-up with the network team, and a consistent point of contact with the specialist neurosurgical centre.\n\nMonitor the response to continuous pump-administered intrathecal baclofen. This monitoring should preferably be performed by the healthcare professionals in the regional specialist neurosurgical centre who performed the pre-implantation assessments.\n\nWhen deciding whether the response to continuous pump-administered intrathecal baclofen is satisfactory, assess the following where relevant to the treatment goals:\n\nreduction in spasticity\n\nreduction in dystonia\n\nreduction in pain or muscle spasms\n\nimproved posture, including head control\n\nimproved function\n\nimproved self-care (or ease of care by parents or carers).\n\nTitrate the dose of intrathecal baclofen after pump implantation, if necessary, to optimise effectiveness.\n\nIf treatment with continuous pump-administered intrathecal baclofen does not result in a satisfactory response (see recommendation 1.6.21), check that there are no technical faults in the delivery system and that the catheter is correctly placed to deliver the drug to the intrathecal space. If no such problems are identified, consider reducing the dose gradually to determine whether spasticity and associated symptoms increase.\n\nIf continuous pump-administered intrathecal baclofen therapy is unsatisfactory, the specialist neurosurgical centre and other members of the network team should discuss removing the pump and alternative management options with the child or young person and their parents or carers.\n\nAs the infusion pump approaches the end of its expected lifespan, consider reducing the dose gradually to enable the child or young person and their parents or carers to decide whether or not to have a new pump implanted.\n\n# Orthopaedic surgery\n\nConsider orthopaedic surgery as an important adjunct to other interventions in the management programme for some children and young people with spasticity. Timely surgery can prevent deterioration and improve function.\n\nAn assessment should be performed by an orthopaedic surgeon within the network team if:\n\nbased on clinical findings (see recommendation 1.1.16) or radiological monitoring, there is concern that the hip may be displaced\n\nbased on clinical or radiological findings there is concern about spinal deformity.\n\nConsider an assessment by an orthopaedic surgeon in the network team for children and young people with:\n\nhip migration greater than 30% or\n\nhip migration percentage increasing by more than 10 percentage points per year.\n\nConsider an assessment by an orthopaedic surgeon in the network team if any of the following are present:\n\nlimb function is limited (for example, in walking or getting dressed) by unfavourable posture or pain, as a result of muscle shortening, contractures or bony deformities\n\ncontractures of the shoulder, elbow, wrist or hand cause difficulty with skin hygiene\n\nthe cosmetic appearance of the upper limb causes significant concern for the child or young person.\n\nBefore undertaking orthopaedic surgery, the network team should discuss and agree with the child or young person and their parents or carers:\n\nthe possible goals of surgery and the likelihood of achieving them\n\nwhat the surgery will entail, including any specific risks\n\nthe rehabilitation programme, including:\n\n\n\nhow and where it will be delivered\n\nwhat the components will be, for example a programme of adapted physical therapy, the use of orthoses, oral drugs or botulinum toxin type\xa0A.\n\n\n\nOrthopaedic surgery should:\n\nbe undertaken by surgeons in the network team who are expert in the concepts and techniques involved in surgery for this group of patients and\n\ntake place in a paediatric setting.\n\nThe decision to perform orthopaedic surgery to improve gait should be informed by a thorough pre-operative functional assessment, preferably including gait analysis.\n\nIf a child or young person will need several surgical procedures at different anatomical sites to improve their gait, perform them together if possible (single-event multilevel surgery), rather than individually over a period of time.\n\nAssess the outcome of orthopaedic surgery undertaken to improve gait 1\xa0to\xa02\xa0years later. By then full recovery may be expected and the outcome of the procedure can be more accurately determined.\n\n# Selective dorsal rhizotomy\n\nConsider selective dorsal rhizotomy to improve walking ability in children and young people with spasticity at GMFCS level II or III:\n\nPatient selection and treatment should be carried out by a multidisciplinary team with specialist training and expertise in the care of spasticity, and with access to the full range of treatment options.\n\nDiscuss the irreversibility of the treatment, the known complications and the uncertainties over long-term outcomes with children and young people, and their parents and/or carers (see also the NICE interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy).\n\nTeams offering selective dorsal rhizotomy should participate in a coordinated national agreed programme to collect information on short- and long-term outcomes on all patients assessed for selective dorsal rhizotomy, whether or not selective dorsal rhizotomy is performed. These recorded outcomes should include measures of muscle tone, gross motor function, neurological impairment, spinal deformity, quality of life and need for additional operations, with nationally agreed consistent definitions.\n\n# Terms used in this guideline\n\n## Botulinum toxin type\xa0A\n\nA neurotoxin produced by the bacterium Clostridium botulinum that blocks neurotransmitter release at peripheral cholinergic nerve terminals. Injection into a muscle reduces spasticity.\n\n## Constraint-induced movement therapy\n\nAn approach to physical therapy in which an unaffected arm is temporarily restrained to encourage use of the other arm.\n\n## Continuous pump-administered intrathecal baclofen treatment\n\nDirect administration of baclofen into the fluid-filled space around the spinal cord (the intrathecal space) using a catheter and infusion pump. The pump is implanted in the abdominal cavity and allows a continual controlled delivery of baclofen adjusted according to need.\n\n## Contracture\n\nShortening of muscle tendons, ligaments and soft tissues resulting in a limitation of joint movement. Usually, muscle shortening is the primary abnormality, but prolonged immobility or scarring may also contribute.\n\n## Dystonia\n\nInvoluntary, sustained, or intermittent muscle contractions that cause twitching and repetitive movements, abnormal postures or both.\n\n## Equinus deformity\n\nAbnormal ankle plantarflexion (movement of the foot at the ankle joint in a downward direction). This can, for example, result in the child or young person walking on tiptoe.\n\n## Fine motor function\n\nThe ability to use small muscle groups, often in coordination with the eyes, to perform precision activities such as writing or fastening buttons.\n\n## Focal dystonia\n\nDystonia involving a specific muscle or group of muscles.\n\n## Focal spasticity\n\nSpasticity involving a specific muscle or group of muscles.\n\n## Function\n\nThe ability to perform normal activities or actions. Such function may be impaired by spasticity and associated motor disorders and by the complications of spasticity.\n\n## Gait analysis\n\nA detailed approach to analysing the component phases of walking using instrumentation or video analysis in addition to clinical observation. This is undertaken to evaluate a child or young person's ability and style of walking and to plan or assess treatment.\n\n## Gross motor function\n\nThe ability to use large muscle groups to perform body movements such as sitting, standing, walking and running.\n\n## Gross Motor Function Classification System\n\nA 5-point scale that describes gross motor function: level I, walks without restrictions; level II, walks without assistive devices; level III, walks with assistive devices; level IV, has limited self-mobility; level V, has severely limited self-mobility even with assistive devices.\n\n## Hip migration\n\nMovement of the top of the thigh bone that connects with the pelvis (the femoral head) from its normal position in the socket joint of the hip (the acetabulum). This movement is often measured by reporting the degree of displacement seen on X-ray (known as the hip migration percentage).\n\n## Intrathecal baclofen testing\n\nDirect injection of baclofen into the fluid-filled space around the spinal cord (the intrathecal space) using a lumbar puncture needle or a temporary spinal catheter in order to assess the likely response to continuous pump-administered baclofen treatment.\n\n## Kyphosis\n\nAbnormal curvature of the spine when viewed from the side of the body that results in a hunched or slouching position.\n\n## Low-load active stretching\n\nA physical therapy intervention in which the child or young person actively stretches their muscles with the aim of increasing range of movement.\n\n## Low-load passive stretching\n\nA physical therapy intervention involving sustained stretching using positioning with equipment, orthoses or serial casting.\n\n## Muscle tone\n\nThe normal state of continuous passive partial contraction in a resting muscle. Muscle tone is important in maintaining posture. Increased muscle tone (hypertonia) is associated with an abnormal resistance to passive stretch, while reduced muscle tone (hypotonia) is associated with floppiness of the limbs or trunk and poor posture.\n\n## Network of care\n\nLinked groups of healthcare professionals and organisations working in an agreed and coordinated manner to deliver a clinical service. A network is not constrained by existing professional, organisational or institutional boundaries.\n\n## Network team\n\nA multidisciplinary group of healthcare and other professionals working in a network of care to deliver a clinical service.\n\n## Orthosis (plural, orthoses)\n\nAn artificial device or appliance used to support, align, prevent, or correct deformities or to improve musculoskeletal function.\n\n## Passive range of movement\n\nThe degree of motion through which a joint can be moved by an outside force without active participation by the child or young person themself (for example, movement by another person).\n\n## Range of movement\n\nThe range of motion, usually measured in degrees, through which a joint can move.\n\n## Scoliosis\n\nAn abnormal lateral curvature of the spine viewed from in front of or behind the child or young person.\n\n## Secondary complication of spasticity\n\nAn adverse effect on musculoskeletal structure that occurs as a result of spasticity (for example, a contracture or abnormal torsion).\n\n## Secondary consequence of spasticity\n\nAny effect experienced by a child or young person as a result of spasticity. This may be symptomatic (for example, pain or difficulty walking) or a complication affecting the structure of the musculoskeletal system (see secondary complication of spasticity).\n\n## Selective dorsal rhizotomy\n\nA neurosurgical procedure in which some of the sensory nerves that contribute to spasticity in the lower limb are cut at the point where they enter the spinal cord.\n\n## Serial casting\n\nThe successive use of casts with the aim of progressively lengthening muscles and other non-bony tissues such as ligaments and tendons thereby reducing the effect of contractures by passive stretching to gradually improve the range of movement.\n\n## Spasticity\n\nA specific form of increased muscle tone (hypertonia) in which one or both of the following are present:\n\nthe resistance to externally imposed movement increases with increasing speed of stretch and varies with the direction of joint movement\n\nthe resistance to externally imposed movement increases rapidly beyond a threshold speed or joint angle.\n\n## Spinal fusion\n\nA surgical procedure where two or more vertebrae are joined to prevent movement between them.\n\n## Task-focused active-use therapy\n\nA physiotherapy technique where a specific goal is identified and the child or young person carries out exercises or activities using the affected limb or limbs to improve their performance.", 'Recommendations for research': "The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# Inhibitors of functional ability\n\nWhat are the greatest inhibitors of functional ability in children and young people with upper motor neurone lesions?\n\n## Why this is important\n\nChildren and young people with upper motor neurone lesions may experience:\n\nreduced muscle strength\n\nselective muscle control\n\nspasticity.\n\nThe relationships between these factors, and the extent to which the child or young person can develop or maintain functional ability, remain unclear. Prospective cohort studies, or large cross-sectional studies, are needed to explore the relationships between positive and negative effects of upper motor neurone lesions and to determine which factor is the greatest inhibitor of functional ability. The studies should incorporate classification of functional ability based on validated scales, such as the GMFCS.\n\n# Botulinum toxin type\xa0A\n\nWhat is the clinical and cost effectiveness of botulinum toxin type\xa0A when used routinely or according to clinical need in children and young people who are at GMFCS level I, II or III?\n\n## Why this is important\n\nThe GDG's recommendation to consider offering botulinum toxin type\xa0A to children and young people with focal spasticity of an upper or lower limb reflected available evidence relating to the safety and effectiveness of botulinum toxin type\xa0A. In making their recommendations, the GDG emphasised the importance of establishing individualised goals that justify the use of this potentially harmful toxin to treat spasticity. The cost of the procedure combined with the risk of side effects means that clear treatment goals that will positively influence the child or young person's life should be identified before offering this treatment. The evidence reviewed for the guideline provided limited support for botulinum toxin type\xa0A in terms of achieving clinically important goals (including those related to function), and this discouraged the GDG from making a strong recommendation to offer treatment with botulinum toxin type\xa0A to all children and young people who are at GMFCS level I, II or III. Further research is needed to evaluate the effectiveness of botulinum toxin type\xa0A in comparison with other treatment options, particularly when used over long time periods (for example, 10\xa0years) and involving repeat injections, in this population of children and young people. Outcomes relating to improvements in gross motor function and participation in activities, and the psychological impacts of these factors, should be evaluated as part of the research.\n\n# Intrathecal baclofen\n\nWhat is the clinical and cost effectiveness of continuous pump-administered intrathecal baclofen compared with usual care in children and young people who are at GMFCS level IV or V?\n\n## Why this is important\n\nThe GDG's recommendation to consider offering continuous pump-administered intrathecal baclofen focused on children and young people in whom the use of appropriate non-invasive treatments did not relieve difficulties associated with spasticity (specifically pain or muscle spasms, posture or function, or ease of care). Such children and young people will typically be at GMFCS level IV or V. Further research is needed to evaluate the clinical and cost effectiveness of continuous pump-administered intrathecal baclofen compared with usual care in these children and young people. Relevant research designs include randomised controlled trials, prospective cohort studies and qualitative studies. The outcomes to be investigated as part of the research include: quality of life; reduction of pain; reduction of tone; acceptability and tolerability; participation or inclusion; and adverse effects and their association with any potential predisposing factors.\n\n# Selective dorsal rhizotomy\n\nDoes selective dorsal rhizotomy followed by intensive rehabilitation performed between the ages of 3 and 9\xa0years in children who are at GMFCS level II or III result in good community mobility as a young adult?\n\n## Why this is important\n\nThe available evidence relating to selective dorsal rhizotomy suggests that the procedure results in some short- and medium-term improvements in motor function. The effects reported were not consistent across all studies nor sustained across all durations of follow-up investigated (6\xa0to\xa024\xa0months). The GDG considered that if the observed improvements could be maintained through to adult life then the outcomes of selective dorsal rhizotomy would be clinically important. Further research is urgently needed to evaluate long-term outcomes (including adverse effects) of selective dorsal rhizotomy followed by an intensive rehabilitation programme involving physical therapy (and prioritising targeted strength training) compared with physical therapy alone. The research could be conducted using a range of designs, including randomised controlled trials and audits of outcomes from procedures already performed. The research should focus on selective dorsal rhizotomy performed between the ages of 3\xa0and 9\xa0years in children who are at GMFCS level II or III (because these children are likely to benefit most from selective dorsal rhizotomy) and before the development of significant contractures at the ankles, knees and hips. The research should be coordinated through a multicentre research programme; use nationally agreed outcome measures (such as incidence of neurological impairment and spinal deformity, the need for additional operations, and assessment of disability, social inclusion and quality of life) and follow-up periods to facilitate national audit; and include assessment of the child's clinical condition before and after selective dorsal rhizotomy using the same formally validated assessment techniques. The full guideline includes further considerations relating to criteria for identifying children who could be included in the research, the timing of selective dorsal rhizotomy in relation to other treatments such as orthopaedic surgery, and information that should be given to children and their parents or carers to facilitate informed decision making about participation in research."}	https://www.nice.org.uk/guidance/cg145	This guideline covers managing spasticity and co-existing motor disorders and their early musculoskeletal complications in children and young people (from birth up to their 19th birthday) with non-progressive brain disorders. It aims to reduce variation in practice and help healthcare professionals to select and use appropriate treatments.
28360a6fc6068d2a13689f02b1e59ece254cb18f	nice	Dapagliflozin in combination therapy for treating type 2 diabetes	Dapagliflozin in combination therapy for treating type 2 diabetes Evidence-based recommendations on dapagliflozin (Forxiga) given with other drugs for treating type 2 diabetes in adults. # Guidance Dapagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if: a sulfonylurea is contraindicated or not tolerated or the person is at significant risk of hypoglycaemia or its consequences. Dapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes. This recommendation has been updated and replaced by NICE's technology appraisal guidance on dapagliflozin in triple therapy for treating type 2 diabetes. People currently receiving dapagliflozin in a dual therapy regimen that is not recommended for them in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Dapagliflozin (Forxiga, Bristol‑Myers Squibb and AstraZeneca) is a sodium–glucose cotransporter‑2 (SGLT‑2) inhibitor that blocks the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine. It has a UK marketing authorisation 'in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as: monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance add-on combination therapy with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control'. The subject of this appraisal is the add-on therapy indication. The summary of product characteristics lists the following adverse reactions for dapagliflozin: hypoglycaemia (when used with a sulfonylurea or insulin), urinary tract and genital infection, back pain, dysuria, polyuria, dyslipidaemia and elevated haematocrit. Dapagliflozin is not recommended for use in people with moderate to severe renal impairment (patients with a creatinine clearance rate of less than 60 ml/min or an estimated glomerular filtration rate of less than 60 ml/min/1.73 m2) because its efficacy is dependent on renal function. Dapagliflozin is also not recommended for use in combination with pioglitazone. For full details of adverse reactions and contraindications, see the summary of product characteristics. The list price of dapagliflozin is £36.59 for 28 5‑mg or 10‑mg tablets (excluding VAT; 'British national formulary' edition 64). Dapagliflozin is administered orally as a single dose of 10 mg per day. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturers' submission The Appraisal Committee considered evidence from a number of sources. See the committee papers for full details of the evidence. # Clinical effectiveness The manufacturers carried out a systematic literature search to identify all relevant trials of dapagliflozin and potential comparators in adults with type 2 diabetes. The manufacturers identified 5 randomised controlled trials of dapagliflozin (10 mg once daily): 3 in patients with type 2 diabetes inadequately controlled with metformin alone (studies 14, 12 and 4), and 2 in patients with type 2 diabetes inadequately controlled with insulin with or without oral antidiabetic drugs (studies 9 and 6). Of the 3 trials of dapagliflozin as an add-on to metformin, 2 were placebo controlled with follow-up of 24 weeks (studies 14 and 12) and 1 compared dapagliflozin with a sulfonylurea for up to 52 weeks of follow-up (study 4). The primary outcomes assessed were change in HbA1c from baseline (studies 14 and 4) and changes in body weight from baseline (study 12). Secondary outcomes included change in fasting plasma glucose, the proportion of patients whose HbA1c levels reached a specific target, change in body weight, change in blood pressure, the proportion of patients reporting hypoglycaemia, adverse reactions and tolerability. Baseline patient characteristics in the 3 trials were broadly similar: mean age 52.7–60.8 years, HbA1c level 7.16–8.11%, body weight 86.1–92.1 kg and systolic blood pressure 126.0–135.9 mmHg. The 2 trials of dapagliflozin as an add-on to insulin were both placebo controlled, with follow-up of 12 weeks (study 9) and 24 weeks (study 6). The primary outcome assessed was change in HbA1c from baseline. Secondary outcomes included change in fasting plasma glucose, the proportion of patients whose HbA1c reached a specific target, change in body weight, change in the daily dose of insulin, adverse reactions and tolerability. Baseline patient characteristics in the 2 trials were broadly similar: mean age 55.7–59.3 years, HbA1c level 8.40–8.57%, body weight 94.5–103.4 kg and systolic blood pressure 128.9–140.6 mmHg. In the add-on to metformin trials (studies 12 and 14), dapagliflozin was associated with a statistically significant reduction in HbA1c compared with placebo at 24 weeks. In study 14 (n=272), reduction in HbA1c was −0.84% for dapagliflozin versus −0.30% for placebo (p<0.0001). In study 12 (n=182), reduction in HbA1c was −0.39% for dapagliflozin compared with −0.10% for placebo (p<0.0001). Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo at 24 weeks in both study 12 (−2.96 kg versus −0.88 kg, p<0.0001) and study 14 (−2.86 kg versus −0.89 kg, p<0.0001). Dapagliflozin was associated with a reduction in systolic blood pressure compared with placebo at 24 weeks in both study 14 (−5.1 mmHg versus −0.2 mmHg, p value not reported) and study 12 (−2.70 mmHg versus +0.10 mmHg, p=0.06). Dapagliflozin was not associated with a statistically significant increased risk of hypoglycaemia compared with placebo at 24 weeks in either study. In study 4 (n=814), dapagliflozin was shown to be non-inferior (based on a non-inferiority margin of 0.35%) to a sulfonylurea with respect to HbA1c reduction at 52 weeks. Dapagliflozin was associated with a statistically significant change in body weight compared with a sulfonylurea at 52 weeks (−3.22 kg versus +1.44 kg, p<0.0001). Dapagliflozin was associated with a statistically significant change in systolic blood pressure compared with a sulfonylurea at 52 weeks in study 4 (−4.3 mmHg versus +0.8 mmHg, p<0.0001). Dapagliflozin also resulted in a statistically significantly lower proportion of patients experiencing at least 1 hypoglycaemic event (3.5% versus 40.8%, p<0.0001) compared with a sulfonylurea by 52 weeks. In the add-on to insulin trials, dapagliflozin was associated with a reduction in HbA1c compared with placebo at 12 weeks (study 9) and 24 weeks (study 6). In the 12‑week study (n=47), the change in HbA1c was −0.61% for dapagliflozin versus +0.09% for placebo (p value not reported). In the 24‑week study (n=387), the reduction in HbA1c was −0.96 for dapagliflozin versus −0.39 for placebo (p<0.001). Dapagliflozin was associated with a statistically significant reduction in body weight (−1.67 kg versus +0.02 kg, p<0.0001) and systolic blood pressure (−6.9 mmHg versus −3.9 mmHg, p=0.02) compared with placebo at 24 weeks. A higher proportion of patients treated with dapagliflozin had experienced at least 1 hypoglycaemic event (42.3% versus 35.0%) compared with placebo by 24 weeks. Dapagliflozin was associated with a statistically significant reduction in the calculated mean daily insulin dose (−1.16 versus +5.08 international units per day, p<0.0001) compared with placebo at 24 weeks. The manufacturers conducted pre-planned analyses to determine if there were any variations in the clinical effectiveness of dapagliflozin for the following subgroups (as defined by the manufacturers): race, ethnicity, baseline HbA1c, age, sex and baseline body mass index (BMI). Subgroup analyses were conducted on pooled data as well as some of the individual studies of dapagliflozin. The manufacturers reported that no statistically significant differences in clinical effectiveness across subgroups were observed, except for baseline HbA1c. Dapagliflozin treatment generally resulted in greater HbA1c reductions from baseline in people with higher baseline HbA1c. The manufacturers conducted network meta-analyses to compare the clinical effectiveness of dapagliflozin as an add-on to metformin or insulin with comparator therapies listed in the scope. Four outcomes were assessed: mean change in HbA1c from baseline, mean change in weight from baseline, mean change in systolic blood pressure from baseline, and the proportion of patients experiencing at least 1 hypoglycaemic episode. Random-effects models were selected over fixed-effects models because of variations in the study characteristics. The manufacturers presented analyses that were both adjusted and unadjusted for the potential modifying effects of baseline HbA1c. For dapagliflozin as an add-on to metformin, the manufacturers created separate networks for the outcome of systolic blood pressure at 24 weeks (±6 weeks) and for the other 3 outcomes at 24 weeks (±6 weeks) and 52 weeks (±6 weeks). For the 24‑week analysis of systolic blood pressure, the network included dapagliflozin, dipeptidyl peptidase-4 (DPP‑4) inhibitors, glucagon-like peptide-1 (GLP‑1) analogues, sulfonylureas, thiazolidinediones and placebo in 8 studies. For the 24‑week analysis of outcomes other than systolic blood pressure, the network included dapagliflozin, DPP‑4 inhibitors, GLP‑1 analogues, thiazolidinediones and placebo in 15 studies. For the 52‑week analysis, the network included dapagliflozin, DPP‑4 inhibitors, thiazolidinediones and sulfonylureas in 6 studies. The numerical results of the 24‑week network meta-analyses for the add-on to metformin comparisons were provided as academic in confidence. After adjusting for baseline HbA1c, dapagliflozin was associated with a statistically significant reduction in HbA1c compared with placebo. No statistically significant differences in the change in HbA1c were reported between dapagliflozin and other therapies. Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo, DPP‑4 inhibitors and thiazolidinediones, but not compared with GLP‑1 analogues. Dapagliflozin was associated with a statistically significant reduction in systolic blood pressure compared with placebo and sulfonylureas. However, no statistically significant differences in change in systolic blood pressure were reported between dapagliflozin and the other 3 drug therapies. No statistically significant differences in the risk of hypoglycaemia were reported between dapagliflozin and other drug therapies. For dapagliflozin as an add-on to insulin, the manufacturers conducted a single network meta-analysis for all outcomes except systolic blood pressure at 24 weeks (±8 weeks). The network included dapagliflozin, DPP‑4 inhibitors, thiazolidinediones and placebo in 4 studies. The 12‑week study of dapagliflozin (study 9) and 3 other studies comparing thiazolidinediones with placebo were excluded from this analysis because they allowed up-titration of insulin to maintain glycaemic control. One of the studies identified, a study comparing thiazolidinediones with placebo, was excluded from the main analysis of mean change in HbA1c at 24 weeks because of the higher reported baseline HbA1c values compared with the other 3 studies. The outcome of change in systolic blood pressure at 24 weeks could not be analysed because, of the 4 identified studies, 3 either did not report changes in systolic blood pressure or involved up-titration of insulin. Results of the 24‑week network meta-analyses for the add-on to insulin comparisons were provided as academic in confidence. Dapagliflozin was associated with a statistically significant reduction in HbA1c compared with placebo. No statistically significant differences in changes in HbA1c were reported between dapagliflozin and DPP‑4 inhibitors. When the study comparing thiazolidinediones with placebo was included as a sensitivity analysis, dapagliflozin was less effective in reducing HbA1c compared with thiazolidinediones. Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo and DPP‑4 inhibitors, and changes were reported to be similar to thiazolidinediones. Dapagliflozin was associated with a statistically significantly lower risk of experiencing a hypoglycaemic event compared with thiazolidinediones. However, no statistically significant differences were reported for the comparison of dapagliflozin with DPP‑4 inhibitors and placebo. Data on the risks of adverse reactions associated with dapagliflozin were presented using pooled results from the placebo-controlled randomised controlled trials, including dapagliflozin as monotherapy and add-on therapy. Most results presented were based on short-term studies (24 weeks). The manufacturers reported that dapagliflozin was associated with a higher incidence of genital and urinary tract infections and a slightly higher incidence of volume depletion events (hypotension, hypovolaemia or dehydration) compared with placebo. Renal impairment or failure events were reported for a small proportion of patients (less than 1.5%) with no apparent difference between treatment groups. The manufacturers reported that the incidence of cancer was similar between patients who received dapagliflozin (1.47%) and patients who received placebo (1.35%). However, rates of bladder cancer (0.16% versus 0.03%), prostate cancer (0.34% versus 0.16%) and breast cancer (0.40% versus 0.22%) were higher in patients treated with dapagliflozin than in those treated with placebo respectively. In terms of cardiovascular safety, a meta-analysis of 14 randomised controlled trials did not find any evidence that dapagliflozin is associated with increased cardiovascular risk for a composite end point of cardiovascular death, myocardial infarction and stroke (hazard ratio 0.79, 95% CI 0.54 to 1.17). Evidence on the clinical and cost effectiveness of dapagliflozin in triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and a sulfonylurea was submitted in an addendum to address the comparisons specified in the scope. The manufacturers stated that dapagliflozin is currently being studied in an ongoing trial as a triple therapy add-on to 2 other oral agents. Therefore, data were pooled from a subset of people who were given metformin and a sulfonylurea at baseline from 2 placebo-controlled trials (studies 18 and 19), which were designed to assess the efficacy and safety of dapagliflozin in older people (average age 63–64 years) with type 2 diabetes and cardiovascular disease. A post-hoc analysis of this subset was conducted for changes from baseline in HbA1c, weight, systolic blood pressure and hypoglycaemic events at 24 weeks (results provided as academic in confidence). No trials of dapagliflozin compared with active comparators in triple therapy were reported by the manufacturers. Therefore, the assessment of the clinical effectiveness of dapagliflozin compared with DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones was based on indirect evidence. The manufacturers did not conduct a systematic review of triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and a sulfonylurea. However, they referred to a literature review of add-on therapy to metformin and sulfonylureas for type 2 diabetes produced in 2009 by the Canadian Agency for Drugs and Technologies in Health. A summary of the results of this review suggested that DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones were associated with statistically significant reductions in HbA1c compared with continued therapy with metformin and sulfonylureas. No statistically significant differences in HbA1c reduction were reported between DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones. Thiazolidinediones, but not DPP‑4 inhibitors or GLP‑1 analogues, were associated with statistically significant weight gain compared with metformin and sulfonylureas. The manufacturers noted that since 2009, new data have become available including studies of the DPP‑4 inhibitors linagliptin and saxagliptin. # Cost effectiveness The manufacturers submitted an economic model to evaluate the cost effectiveness of dapagliflozin for use: in dual therapy as an add-on to metformin in adults with type 2 diabetes for whom metformin alone (with diet and exercise) does not provide adequate glycaemic control as an add-on to insulin (with or without other oral antidiabetic therapies) when the underlying treatment regimen including insulin does not provide adequate glycaemic control and in triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and a sulfonylurea. For the add-on to metformin analysis, the comparator treatments were sulfonylureas, DPP‑4 inhibitors and thiazolidinediones (pioglitazone). For the add-on to insulin analysis, the comparator treatments were DPP‑4 inhibitors. For the triple therapy analysis, the comparator treatments were DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues. The manufacturers developed a simulation model run within an Excel front end but with the main calculations performed using C++ programming. The patient cohort entered the model with a set of baseline patient characteristics and modifiable risk factors that included HbA1c, total body weight, total cholesterol to high-density lipoprotein cholesterol ratio and systolic blood pressure. The value of these variables changed as the model simulation progressed, as a result of the effects of antidiabetic treatment and through natural progression, calculated from the UK Prospective Diabetes Study (UKPDS number 68) risk factor equations. The model then predicted the incidence of 7 specific macro- and microvascular events on the basis of the UKPDS 68 event risk equations. Macrovascular events predicted in the model included ischaemic heart disease, myocardial infarction, congestive heart failure and stroke. Microvascular events included amputation, nephropathy (end-stage renal failure) and blindness. The model also calculated the probability of drug-related hypoglycaemic events (non-severe and severe), other adverse events including urinary tract infections and genital infections, and treatment discontinuation caused by adverse events. Simulated patients moved through the model in 6‑month cycles over a 40-year time horizon. At the start of the model, patients were assumed to have no complications associated with type 2 diabetes. At the end of the first 6‑month cycle, the UKPDS risk equations determined the probability of fatal and non-fatal complications in addition to diabetes-related deaths (myocardial infarction, congestive heart failure, stroke and amputation) and deaths from other causes (estimated separately from UK life tables). If a patient survived beyond the first cycle, they moved to the next cycle in which they remained at risk of treatment-related adverse events and long-term macro- or microvascular events. Once a diabetes-related death or death from other causes occurred, then costs, life years and quality-adjusted life years (QALYs) were updated and the simulation ended for that patient. The model simulated a cohort of patients who received dapagliflozin (the 'treatment' cohort), and a cohort with the same baseline characteristics who received comparator treatments (the 'comparator' cohort). Simulated patients in each cohort received a particular therapy until their HbA1c increased up to a specified threshold (representing inadequate glycaemic control), at which point they stopped therapy and moved on to the second-line therapy (assumed to be the same in both cohorts). For the metformin and insulin add-on analyses, the model included up to 2 additional therapy lines after dapagliflozin and the comparator. The manufacturers assumed that second-line therapy was metformin and insulin, and third-line therapy for the remainder of the patients' simulated lifetime was intensified insulin (assumed to be a 50% increase from the starting dose). For the insulin add-on analysis, second-line therapy was intensified insulin for the remainder of the simulation. For the triple therapy analysis, all comparator triple therapies were assumed to be preceded by dual therapy with metformin and a sulfonylurea. The manufacturers assumed that after triple therapy, all patients would receive metformin and insulin. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%. For the metformin add-on analyses, baseline patient characteristics, clinical-effectiveness data and adverse event rates were taken from study 4 for the comparison of dapagliflozin and a sulfonylurea and from the manufacturers' network meta-analysis (at 24 weeks) for all of the other comparisons. For the insulin add-on analysis, baseline patient characteristics, clinical-effectiveness data and adverse event rates were taken from the network meta-analysis (at 24 weeks). For the triple therapy analysis, clinical-effectiveness data were drawn from a pooled analysis of a subset of patients treated with dapagliflozin in 2 clinical trials (studies 18 and 19) and the Canadian Agency for Drugs and Technologies in Health's review of oral antidiabetic drugs as triple therapy. The manufacturers commented that the baseline patient characteristics from studies 18 and 19 were not representative of the triple therapy patient population. Therefore, baseline patient characteristics were taken from study 4 comparing dapagliflozin with a sulfonylurea in patients with type 2 diabetes inadequately controlled with metformin alone. The HbA1c thresholds for switching treatment were based on baseline HbA1c values taken from the same sources. In the metformin add-on analyses, a threshold value of 7.72% taken from study 4 was used for the comparison of dapagliflozin and a sulfonylurea and a value of 8.17% from the metformin add-on network meta-analyses was used for the comparison of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones. In the insulin add-on analysis, a threshold value of 8.90% was used based on the insulin add-on network meta-analyses. In the triple therapy analysis, the HbA1c threshold for switching treatment was 7.72%, taken from study 4. The economic model included changes in weight associated with treatment. UKPDS risk equations based on BMI were included in the model. Therefore, changes in patient weight over time were converted to a BMI value based on baseline weight and height characteristics. If a treatment was associated with weight loss, this involved assumptions about how long the weight loss was maintained for along with the subsequent time until the loss of effect and return to the baseline body weight. In the dapagliflozin therapy group for the add-on to metformin and insulin analyses, weight reduction was assumed to be maintained for 2 years in the model based on 2-year extension data from the trial of dapagliflozin compared with a sulfonylurea. After year 2, weight was assumed to return to its baseline value until treatment was switched in a linear trend for the dapagliflozin therapy group. After this, a natural progression in weight gain of 0.1 kg per year was assumed. Because no data were available for DPP‑4 inhibitors, the same assumptions were applied. All other treatments were associated with a weight gain, which was applied in the first year, after which a natural progression in weight gain of 0.1 kg per year was assumed. The model estimated the impact of macro- and microvascular complications of diabetes, changes in body weight and other adverse events on health-related quality of life. An age-dependent baseline utility function was derived from the Department of Health Survey for England (2003) which collected EQ‑5D data from patients with no major complications. Data on the impact on health-related quality of life of diabetes complications were taken from UKPDS (number 62) except for end-stage renal disease. In the UKPDS 62, the EQ‑5D questionnaire was completed by 3667 UK patients. This resulted in the following utility decrements: −0.09 (ischaemic heart disease), −0.055 (myocardial infarction), −0.108 (congestive heart failure), −0.164 (stroke), −0.28 (amputation) and −0.074 (blindness). The impact of end-stage renal disease on health-related quality of life was taken from the Health Outcomes Data Repository, a database of diabetic inpatients treated at Cardiff and Vale National Health Service Hospitals Trust, resulting in a loss in utility of −0.263. The impact of change in body weight on health-related quality of life was taken from a study of 100 Canadian patients with type 2 diabetes who completed a time trade-off exercise, which was commissioned by the manufacturers. Separate values were calculated for the changes in utility caused by a 1-unit decrease (+0.0171) or increase (−0.0472) in BMI. The impact of hypoglycaemic events on health-related quality of life was taken from a study by Currie et al. (2006) that estimated separate EQ‑5D utility decrements for symptomatic, nocturnal and severe events in UK patients with type 2 diabetes. The resulting utility decrements reported in the manufacturers' submissions were −0.042, −0.0084 and −0.047 respectively. The impact of urinary tract infections on health-related quality of life was taken from a study of urinary tract infections in ambulatory women, resulting in a utility decrement of −0.00283. In the absence of any other available data, the same utility values were used for genital infections. The economic model included the acquisition costs of antidiabetic drugs taken from the England and Wales drug tariff (February 2012). The cost of insulin in the model was applied as a cost per kilogram of body weight per day, and therefore, varied in line with changes in patient body weight in the model simulation. The manufacturers assumed that insulin used as second- or third-line treatment in the model (with or without an oral antidiabetic) involved a 50% increase in dose over the initial starting dose in the add-on to metformin analysis, and a 25% increase in the add-on to insulin analysis. The annual costs of macro- and microvascular diabetic complications, except for end-stage renal failure, were taken from UKPDS 65, which calculated the healthcare resource use of 3488 patients with type 2 diabetes. The UKPDS 65 study provided estimates of the first year event costs and the subsequent annual maintenance costs for patients who survived until the end of the simulation. The annual cost of end-stage renal failure (£34,806) was based on the weighted average cost of automated peritoneal dialysis, continuous ambulatory peritoneal dialysis, hospital haemodialysis and satellite unit-based haemodialysis, taken from a separate UK-based study. The cost of a severe hypoglycaemic event (£390) was taken from a study that measured health service costs incurred by 320 patients with type 2 diabetes in Germany, Spain and the UK who had experienced at least 1 hypoglycaemic event in the previous year. It was assumed that symptomatic and nocturnal hypoglycaemic events were not associated with any treatment costs. Urinary tract infections and genital infections were associated with the cost of a GP visit (£36). The costs of renal monitoring (£39), based on a GP visit and urine sample, were also included in the first year of the model only for the dapagliflozin treatment group. Treatment discontinuation was also assumed to incur the cost of a GP visit. The manufacturers' base-case deterministic cost-effectiveness results for the add-on to metformin analyses found that the comparison between dapagliflozin and a sulfonylurea resulted in an incremental cost-effectiveness ratio (ICER) of £2671 per QALY gained (incremental costs £1246, incremental QALYs 0.467). The comparisons between dapagliflozin and DPP‑4 inhibitors and between dapagliflozin and thiazolidinediones found that dapagliflozin resulted in higher QALYs (incremental gains of 0.02 and 0.42 respectively) and lower costs (−£149 and −£60 respectively). Dapagliflozin therefore dominated both comparator treatments. For the add-on to insulin analysis, the comparison between dapagliflozin and DPP‑4 inhibitors resulted in an ICER of £4358 per QALY gained (incremental costs £517, incremental QALYs 0.119). The manufacturers' base-case deterministic cost-effectiveness results for the triple therapy analyses as add-on to metformin and a sulfonylurea found that dapagliflozin dominated DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues, resulting in lower costs and higher QALYs. The manufacturers also presented 2 scenario analyses that included alternative BMI-related utility values. The scenarios applied utilities of ±0.0061 and ±0.0038 respectively for a ±1 unit change in BMI. Both values were taken from a study by Bagust et al. (2005) evaluating the impact of BMI on EQ‑5D utility in patients with type 2 diabetes, and had been used in NICE's guideline on type 2 diabetes and technology appraisal guidance on exenatide in combination with oral antidiabetic therapy. For the metformin add-on comparisons, the ICERs for dapagliflozin compared with a sulfonylurea were £8863 and £10,514 per QALY gained respectively. Dapagliflozin remained dominant for the comparison of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones. For the comparison of dapagliflozin with DPP‑4 inhibitors as add-on to insulin, the ICERs were also sensitive to changes to the BMI-related utility values. When changes in utility of ±0.0061 and ±0.0038 were applied, the ICERs increased to £21,171 and £32,409 per QALY gained respectively. ## Evidence Review Group comments The ERG commented on the scope of the appraisal and how the manufacturers addressed it in their submission. The ERG noted that the manufacturers did not include adults with type 2 diabetes that is inadequately controlled with sulfonylurea monotherapy in their submission. The ERG commented that the standard first-line monotherapy in type 2 diabetes is metformin, which is usually tolerated. The ERG noted that GLP‑1 analogues were not included as a comparator in the dual therapy setting, but considered that this was appropriate because their use in dual therapy is restricted. The ERG stated that NICE's guideline on type 2 diabetes recommends the use of pioglitazone as an alternative add-on treatment to a sulfonylurea in people with type 2 diabetes that is inadequately controlled by metformin. However, it also noted that there are increasing concerns about the adverse reactions associated with pioglitazone. The ERG commented that, in the triple therapy setting, DPP‑4 inhibitors would be expected to be given to patients before GLP‑1 analogues because they are cheaper and are administered orally. Overall, the ERG considered that DPP‑4 inhibitors are the key comparators for dapagliflozin in both the dual therapy and triple therapy settings. The ERG stated that the manufacturers' approach to the systematic review of clinical evidence for dapagliflozin, which involved separate network meta-analyses for dapagliflozin as add-on therapy to metformin and as an add-on to insulin, was appropriate. The ERG noted that analyses were conducted for outcomes at 24 weeks and at 52 weeks and that studies reporting outcomes at less than 18 weeks, between 30 and 46 weeks, or greater than 58 weeks were excluded from the review. The ERG commented that it was not clear whether studies of between 31 and 45 weeks or greater than 58 weeks were also identified in the review. However, in response to a request for clarification, the manufacturers provided a full list of identified trials, none of which were between 31 and 45 weeks' duration. The ERG also noted that, for the network meta-analysis of insulin add-on therapies, a post-hoc amendment to the protocol was made to include studies in the range of 24 weeks ±8 weeks instead of ±6 weeks, to allow more studies to be included in the analysis. The ERG commented that the manufacturers' approach to presenting the clinical effectiveness of dapagliflozin as a triple therapy add-on to metformin and a sulfonylurea was not very clear. Overall, the ERG considered that the methodology for the review of dapagliflozin in triple therapy (submitted as an addendum) was less robust than the main submission. However, the ERG acknowledged that the manufacturers had not intended to provide clinical-effectiveness data on dapagliflozin in triple therapy because of ongoing trial-based research due to report in 2013. The ERG noted that the decision to switch or intensify treatment in the manufacturers' economic model was based on HbA1c levels above the thresholds currently recommended in the NICE guideline on type 2 diabetes. The ERG also noted that, when the manufacturers changed the HbA1c threshold levels in scenario analyses, along with changes to other input parameters, the ICERs for dapagliflozin increased. Overall, the ERG considered that the HbA1c threshold levels for switching treatment applied in the model reduced its relevance to UK clinical practice. The ERG commented that the loss in utility associated with hypoglycaemic events, taken from Currie et al. (2006), may have been too large when applied within the model. The ERG noted from this study that a severe hypoglycaemic event in the previous 3 months was interpreted by the authors as causing a 4.7% loss in utility (−0.047). The ERG considered that the loss in utility associated with hypoglycaemic events should have been applied for 3 months rather than 12 months, resulting in QALY losses of −0.012 and −0.004 for severe and symptomatic hypoglycaemic events respectively. The ERG commented on the appropriateness of the utility values applied to weight change in the model. It noted that the majority of QALY gains associated with dapagliflozin arose from direct impact of weight change on health-related quality of life rather than diabetic complications or adverse events. The ERG noted that in study 12, the dapagliflozin treatment group experienced a lower gain in utility (0.018 versus 0.047) compared with placebo at 24 weeks. However, when the utility estimates associated with changes in BMI were applied to the observed weight changes in study 12, the dapagliflozin treatment group experienced a higher gain in utility (0.016 versus 0.000) compared with placebo at 24 weeks. The ERG also noted that the study by Bagust et al. involved a multivariate analysis of EQ‑5D utility values that controlled for the complications of diabetes and estimated a smaller change in utility (±0.0061) associated with a unit increase or decrease in BMI. The ERG considered these alternative utility values, which were applied in the manufacturers' scenario analyses, to be more reasonable. The ERG noted that the weighted average annual costs of pioglitazone (£414.07), based on the England and Wales NHS drug tariff for February 2012, were substantially higher than those estimated from the November 2012 tariff (£139.16). The ERG also estimated different annual costs of DPP‑4 inhibitors as add-on to metformin (£450.51 as opposed to £433.57) and GLP‑1 analogues as add-on to metformin and a sulfonylurea (£946.26 as opposed to £886.90). With regard to the costs of macro- and microvascular diabetic complications, the ERG noted that the UKPDS 65 study also included annual inpatient (£157) and non-inpatient (£159) costs for patients who did not experience a complication. The ERG commented that these annual costs of £483 (after inflating from 1999 to 2011 prices) should have been applied in the model for patients who did not experience a diabetic complication. The ERG noted that, although the model cycle length was 6 months, the probabilities of macro- and microvascular events estimated from the UKPDS 68 study appeared to be for a 12‑month period and that no adjustment was made for this in the model. Further, the ERG noted from the DSU report on the economic model that the annual costs of macro- and microvascular events were not halved to correspond with the 6‑month cycle length used in the model but were applied in full immediately on the event occurring. The ERG commented that this would increase the annual costs of these events by half of the annual maintenance costs associated with the event. The ERG noted that not all of the risk equations derived from the UKPDS 68 study were implemented in the model. From this study, the model implemented the risk of mortality in the year after a diabetic complication but not the risk of mortality in subsequent years after the event. Furthermore, risk equations for fatal myocardial infarction and fatal stroke were derived from a separate UKPDS study (number 66). This resulted in the risk of fatal myocardial infarction being a function of HbA1c and systolic blood pressure and the risk of fatal stroke being a function of systolic blood pressure only. The ERG considered that there was no obvious justification made by the manufacturers to include risk equations from this separate study. It also noted that this may have reduced the impact of HbA1c levels and increased the impact of systolic blood pressure in the model. The ERG noted that, in the UKPDS 68 risk equations, baseline HbA1c was based on patients with newly diagnosed type 2 diabetes. However, the baseline HbA1c values implemented in the model were the trial baseline value minus the treatment-specific effect on HbA1c and therefore baseline HbA1c values differed between treatment groups. The ERG considered that the baseline HbA1c should have been the same for both treatment groups in the model. It noted that using different treatment-specific baseline HbA1c values resulted in the risk factor curves for both treatment groups not converging over time, whereas if the baseline HbA1c values had been the same for both treatment groups, the curves would have converged after the initial treatment effects. Similar considerations would apply to the other risk factors used in the UKPDS equations. Overall, the ERG concluded that the implementation of the UKPDS risk factor equations in the manufacturers' economic model may have been incorrect. Similarly, the ERG noted that the event equation from UKPDS 68 used to estimate congestive heart failure included BMI at diagnosis. The ERG again noted that the baseline BMI values implemented in the model were the trial baseline value minus the treatment-specific effect on BMI and therefore that baseline BMI values differed between treatment groups. Because dapagliflozin was associated with a greater reduction in body weight compared with comparator drug therapies, the ERG considered that this may have biased the risk of congestive heart failure in favour of dapagliflozin. Furthermore, because the risk of congestive heart failure was associated with an increased risk of myocardial infarction and stroke, any overestimate of the rate of congestive heart failure would also result in an overestimate of the rate of myocardial infarction and stroke, along with the associated risk of fatality. In the triple therapy analyses, the ERG considered that it was unnecessary for the model to include dual therapy with metformin and a sulfonylurea before switching to triple therapy. Because the model structure only permitted 3 lines of treatment, this resulted in patients switching to insulin and metformin after triple therapy. Therefore, unlike the dual therapy analyses, the triple therapy analysis did not enable patients to receive intensified insulin, which is associated with higher costs and additional weight gain. ## Decision Support Unit comments The DSU was commissioned by NICE to examine the economic model submitted by the manufacturers. The DSU was asked to report on whether the model functioned as described in the manufacturers' submission, to report any important aspects of the model that were not described in the submission, to examine whether the C++ programming code followed the steps described by the manufacturers and used the data described in the submission, and to check that the economic model produced the results described in the submission. The DSU identified several differences between the economic model described in the submission and the executable model provided by the manufacturers. There were some differences between the macro- and microvascular event equations and risk factor equations in the model and those described in the manufacturers' submission. The effect of treatment on body weight was applied immediately in the model rather than gradually over the first year of treatment. All-cause mortality was not adjusted for fatal stroke and myocardial infarction events. The model did not apply the cost of renal monitoring to all patients who started treatment with dapagliflozin, although the DSU noted that this was unlikely to have a significant impact on the ICERs. There were some differences between the written submission and the model in regard to the time periods over which some of the costs and changes in utility were applied. The DSU also noted that the process used to sample from the relevant distributions in the probabilistic sensitivity analysis did not produce appropriately distributed samples, which may have underestimated the uncertainty around the QALYs estimated in the model. The DSU identified several aspects of the executable model that were not described in the manufacturers' submission. In the manufacturer's model, the probability of an event occurring in a 6‑month cycle was calculated as the difference between the output of the event equation for the current cycle and the output of the event equation for the previous cycle. Treatment discontinuations applied in the first cycle of the model resulted in the patient switching treatment immediately without incurring costs or QALYs from the initial treatment except for the cost of discontinuation. The impact of treatment-related changes to BMI on health-related quality of life in the probabilistic sensitivity analysis was based on mean parameter values, which may have resulted in an underestimate of the uncertainty around the QALY differences estimated in the model. The DSU commented that it was unable to reproduce the results of the probabilistic sensitivity analyses reported in the manufacturers' submission on the basis of the C++ programming code provided. However, the ICERs generated by the DSU did not vary substantially from those reported in the submission and it was noted that these differences may have arisen because of differences in the steps taken by the DSU to set up the probabilistic sensitivity analyses. When the DSU ran the model using the C++ programming code provided for the mean parameter values (deterministic analysis), it was also unable to reproduce the results of the deterministic analyses reported in the manufacturers' submission. Furthermore, when the DSU ran this code, it did not appear to have produced a stable estimate of the incremental QALYs after 100 runs. Finally, the DSU commented that the results generated by the programming code for the probabilistic sensitivity analyses when all parameters were set to their mean values did not match the results generated by the programming code that used mean parameter values. The DSU considered that similar results should have been produced and that this affected the confidence that could be placed on the results from the model. ## Manufacturers' response to the appraisal consultation document The manufacturers provided a response to the concerns raised by the DSU in its report on the economic model. The manufacturers stated that the economic model produced a stable estimate of the incremental costs and QALYs after 1000 rather than 100 simulations. The manufacturers implemented changes to the risk factor progression and event equations, and to the gamma and beta distributions applied to the cost and utility parameters in the probabilistic sensitivity analysis. The manufacturers also amended the model source code to correct for errors in the calculation of transition probabilities and the adjustment of all-cause mortality. The manufacturers presented revised network meta-analyses for the dual therapy and add-on to insulin therapy comparisons, based on the WinBUGs programme code included in the technical support documents published by the DSU (Technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials). The manufacturers also presented a validation exercise, which compared the results of the revised network meta-analyses with those presented in its original submission. The manufacturers commented that the revised analyses, which were provided as academic in confidence, produced similar results compared with the original analyses. The results of the revised 52‑week network meta-analysis were applied for the revised dual therapy analyses because these data enabled the same set of baseline characteristics and risk factors to be used for each comparator in the dual therapy analyses. The revised network meta-analysis at 24 weeks was applied for the add-on to insulin analysis in the manufacturers' revised economic model. The manufacturers provided further clarification about how changes in body weight were modelled over time for the different treatments. In addition, the manufacturers provided unpublished follow-up data from study 4 which, they stated, showed that patients who remained on dual therapy of dapagliflozin and metformin maintained their weight loss for up to 4 years. The manufacturers therefore suggested that, for treatments associated with weight loss, the assumption in the model that this weight loss was maintained for 2 years may have been conservative. The manufacturers made a number of revisions to the economic model to address the ERG's concerns. The revised economic model applied the same baseline risk factors for all treatment groups, which were taken from the revised network meta-analyses for the dual therapy and add-on to insulin analyses. The manufacturers applied an HbA1c threshold level of 7.5%, as currently recommended NICE's guideline on type 2 diabetes, for switching treatment for the dual therapy analyses. However, the manufacturers commented that this threshold may not reflect UK clinical practice because patients with type 2 diabetes are reviewed by their clinicians only once or twice a year and are therefore likely to have HbA1c levels that exceed 7.5% at the time of review. For the triple therapy and add-on to insulin analyses, the manufacturers applied HbA1c thresholds of 8.61% and 9.04% respectively for switching treatment. For the triple therapy analyses, the manufacturers also revised the sequence of treatments in the revised model so that the starting treatment was triple therapy rather than dual therapy. In their revised model, the manufacturers applied utility values of ±0.0061 per unit increase or decrease in BMI taken from the study by Bagust et al. The manufacturers commented that the ERG had misinterpreted how the loss in utility associated with hypoglycaemic events was applied over a 6‑month cycle in the economic model. Therefore, the manufacturers did not reduce the loss in QALYs associated with hypoglycaemia to −0.012 for a severe event and −0.004 for a symptomatic event in their revised base-case analyses (instead, retaining the original utility values). In scenario analyses, the manufacturers applied a range of upper (−0.0104) and lower (−0.000657) estimates of the loss in utility associated with urinary tract and genital infections taken from a systematic literature review as requested by the Committee. The manufacturers also reduced the average annual cost of pioglitazone from £414.07 to £112.18 and included an annual cost of £483 for people not experiencing diabetic complications in the revised economic model. The manufacturers presented ICERs for the revised dual therapy analyses, which included clinical-effectiveness data from the revised 52‑week network meta-analyses, changes to the model in response to the DSU report, the same baseline patient characteristics and risk factors for all treatment groups, and an HbA1c switch threshold of 7.5%. As a result of these changes, the ICER for the comparison between dapagliflozin and sulfonylureas was £1498 per QALY gained. For the comparisons between dapagliflozin and DPP‑4 inhibitors and thiazolidinediones, the ICERs were £689 and £5342 per QALY gained respectively. A scenario analysis which applied the upper and lower estimates of the loss in utility associated with urinary tract and genital infections resulted in very small changes to the ICERs for all comparisons. The manufacturers also presented ICERs for the revised dual therapy analyses which included the changes described in section 3.49 and additional changes, which included reduced costs of pioglitazone, adjusted costs of diabetic complications and utility values of ±0.0061 per unit increase or decrease in BMI. As a result of these additional changes, the ICER for the comparison between dapagliflozin and sulfonylureas was £7735 per QALY gained. For the comparisons between dapagliflozin and DPP‑4 inhibitors and between dapagliflozin and thiazolidinediones, the ICERs were £3337 and £77,615 per QALY gained respectively. The manufacturers presented ICERs for the revised add-on to insulin analyses, which included clinical-effectiveness data from the revised 24‑week network meta-analyses, changes to the model in response to the DSU report and an HbA1c switch threshold of 9.04%. As a result of these changes, the ICER for the comparison between dapagliflozin and DPP‑4 inhibitors was £2509 per QALY gained. A scenario analysis that applied the upper and lower estimates of the loss in utility associated with urinary tract and genital infections resulted in very small changes to the ICER. The manufacturers also presented an ICER that included adjusted costs of diabetic complications and utility values of ±0.0061 per unit increase or decrease in BMI. As a result of these additional changes, the ICER increased to £5634 per QALY gained. The manufacturers also presented ICERs for the revised triple therapy analyses, which included altering the treatment sequences in the model so that patients in the model started treatment with triple add-on therapy to metformin and a sulfonylurea, incorporating model structural changes and applying an HbA1c switch threshold of 8.61%. As a result of these changes, dapagliflozin continued to dominate DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues. The manufacturers did not present any additional scenario analyses for the relevant comparisons in triple therapy. The manufacturers presented the results of a validation exercise, which compared the results from the revised model with the results that would have been obtained from using the CORE diabetes model for all relevant comparisons in dual therapy, insulin add-on therapy, and triple therapy. For the dual therapy analyses, the CORE model produced an ICER of £8879 per QALY gained for the comparison of dapagliflozin with sulfonylureas and ICERs of £2014 and £7093 per QALY gained for the comparisons of dapagliflozin with DPP‑4 inhibitors and with thiazolidinediones. For the insulin add-on analyses, the CORE model resulted in an ICER of £1675 per QALY gained for dapagliflozin compared with DPP‑4 inhibitors. For the triple therapy analyses, the CORE model produced ICERs of £1759 per QALY gained for the comparison of dapagliflozin with DPP‑4 inhibitors and £16,054 per QALY gained for the comparison of dapagliflozin with thiazolidinediones. The CORE model also produced an ICER of £32,243 per QALY lost for the comparison of dapagliflozin with GLP‑1 analogues. Both the ERG and the DSU reviewed the manufacturers' revised economic model and analyses provided in response to the appraisal consultation document. Overall, the DSU considered that the manufacturers had adequately addressed all of the significant areas of concern about the model. The ERG noted that the revised dual therapy analyses used clinical-effectiveness data from the revised 52‑week network meta-analyses rather than the revised 24‑week network meta-analyses, which resulted in significant changes to the model input parameters. The ERG noted that, as a result of applying a lower HbA1c threshold for switching treatment, the revised model resulted in switching treatment earlier and thus reducing the costs of first-line dapagliflozin treatment whilst maintaining any long-term weight loss. The ERG also noted that the manufacturers' revised economic model had incorrectly amended the costs for people who did not experience diabetic complications. The ERG highlighted a number of concerns about how changes in body weight were modelled in the manufacturers' revised analyses. The ERG noted that the manufacturers stated that, in order to simulate a linear, gradual regain of weight, the time to loss of weight effect was set such that weight was regained by the time of switch to next treatment. However, the ERG noted that in the manufacturers' comparisons of dapagliflozin with sulfonylureas and with DPP‑4 inhibitors in the revised dual therapy analyses, weight loss associated with dapagliflozin was largely maintained and not reversed at the time of switching to next treatment. The ERG also noted that the manufacturers' revised economic model and analyses did not address the Committee's concerns about the duration over which differences in weight change were maintained between treatments. ## Additional DSU analysis in response to the revised manufacturers' model In response to the concerns about the manufacturers' revised economic model raised by the ERG, the DSU was asked to review the manufacturers' revised economic analyses and to assess further how changes in weight were modelled over time for different treatments in the revised model. The DSU was also asked to conduct a range of further exploratory analyses for dapagliflozin in dual therapy and add-on to insulin therapy. The DSU noted that, in the manufacturers' revised economic model, the assumptions about the duration over which any treatment-related weight change was reversed for the comparison of dapagliflozin with thiazolidinediones as add-on to metformin and the add-on to insulin analyses were consistent with those used in the original model. Therefore, for treatments associated with weight loss, weight was regained before first treatment switch. However, the DSU noted that for the comparisons of dapagliflozin as add-on to metformin with sulfonylureas and DPP‑4 inhibitors, treatment-related weight loss was not reversed at treatment switch in the revised model. The DSU suggested that the weight profiles for dapagliflozin and DPP‑4 inhibitors may have been incorrectly amended in the model. The DSU noted that, for second- and third-line treatments, the weight at the start of treatment in the revised model was based on the weight at the time of switching from the previous treatment. The DSU noted that this was problematic if the treatment switch occurred before the treatment-related weight loss was regained. The DSU stated that where this happened this resulted in a weight difference between treatment groups that is maintained throughout the duration of the model. The DSU amended the manufacturers' revised model to ensure that, if a treatment switch occurred before the weight loss was fully regained, the starting weight at the next line of treatment was set equal to the weight that would have been achieved after the weight regain for the previous treatment. This resulted in a convergence of weight profiles over time for treatments associated with weight loss. The DSU applied a number of changes and assumptions to the manufacturers' revised model, in addition to the amendment described in section 3.58. These included: for the dual therapy analyses, using clinical-effectiveness data from the revised 24‑week network meta-analyses for the comparisons of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones and from study 4 for the comparison of dapagliflozin with a sulfonylurea applying an HbA1c threshold of 7.5% for switching to second-line and third-line treatment in the dual therapy analysis and for switching to second-line treatment in the add-on to insulin analysis for any treatments associated with weight loss, assuming weight regain during year 3 to the level expected in a patient who experiences a natural weight gain of 0.1 kg per year from the start of treatment assuming no diabetic complications at the start of treatment reducing the loss in QALYs associated with hypoglycaemia to –0.012 for a severe event and –0.004 for a symptomatic event using utility values associated with weight change of ±0.0061 per unit of BMI reducing the annual cost of pioglitazone to £69.09 based on the latest NHS drug tariff using an annual cost of £483 for people not experiencing diabetic complications. For the dual therapy analyses, using data from the 24‑week network meta-analysis, the DSU base-case deterministic pair-wise analysis resulted in ICERs of £13,338 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £13,947 per QALY gained for the comparison of DPP‑4 inhibitors with thiazolidinediones. An incremental analysis resulted in ICERs of £13,338 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £16,847 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin (based on incremental costs of £136 and incremental QALYs of 0.008). Using data from study 4, the pair-wise comparison of dapagliflozin and sulfonylureas resulted in an ICER of £12,405 per QALY gained. The DSU also conducted a probabilistic sensitivity analysis based on a mean of 1000 samples. Using data from the 24‑week network meta-analysis, the analysis resulted in pair-wise ICERs of £15,257 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £15,511 per QALY gained for the comparison of DPP‑4 inhibitors with thiazolidinediones. An incremental analysis resulted in ICERs of £15,257 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £41,654 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin (based on incremental costs of £17 and incremental QALYs of less than 0.001). Using data from study 4, the comparison of dapagliflozin and sulfonylureas resulted in an ICER of £15,148 per QALY gained. The DSU noted that in the probabilistic sensitivity analysis, people spent longer on first-line treatment because of the interaction between baseline HbA1c values, treatment switching threshold and effectiveness data, thus resulting in higher incremental costs and ICERs than the deterministic analysis. The results of these probabilistic sensitivity analyses also showed that, at £20,000 per QALY gained, dapagliflozin had the highest probability (40.4%) of being cost effective compared with DPP‑4 inhibitors (35.5%) and thiazolidinediones (24.1%) and also the highest probability (61.0%) of being cost effective compared with sulfonylureas. The DSU conducted a scenario analysis that applied the manufacturers' original utility values associated with hypoglycaemia (–0.047 for a severe event and –0.042 for a symptomatic event). As a result of this change, dapagliflozin was extendedly dominated by DPP‑4 inhibitors and thiazolidinediones, because the ICER of dapagliflozin compared with thiazolidinediones was higher than that of the next most effective alternative (DPP‑4 inhibitors). The comparison of dapagliflozin and sulfonylureas resulted in an ICER of £10,317 per QALY gained. The DSU also conducted a scenario analysis which used the same clinical-effectiveness data from the 52‑week network meta-analysis as those used in the manufacturers' revised model, thus allowing all treatments to be compared with each other in a single analysis. On the basis of a full incremental analysis, DPP‑4 inhibitors were dominated by thiazolidinediones. The comparison of thiazolidinediones and sulfonylureas resulted in an ICER of £12,108 per QALY gained and the comparison of dapagliflozin and thiazolidinediones resulted in an ICER of £94,466 per QALY gained. The DSU conducted an additional scenario analysis to explore the impact of weight convergence between treatment groups at the time of switching to the last line of treatment. In the manufacturers' revised model for the dual therapy analyses, the DSU modelled weight convergence between dapagliflozin (associated with weight loss) and a sulfonylurea (associated with weight gain) by increasing the weight gain for the last treatment in the sequence (insulin treatment). For this scenario analysis the DSU presented pair-wise ICERs using the data from the 24‑week network meta-analysis and separately the data from study 4. Applying the 24‑week meta-analysis data resulted in a higher ICER of £60,965 per QALY gained for the pair-wise comparison of dapagliflozin with thiazolidinediones and an ICER of £16,847 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin. The ERG noted that the latter ICER was largely unchanged from its base-case analysis because the weight profiles at last treatment switch were very similar across the 2 treatment groups. The pair-wise comparison of dapagliflozin and sulfonylureas using study 4 data resulted in an ICER of £21,200 per QALY gained. The DSU noted that in the manufacturers' revised add-on to insulin analysis, the time to weight regain was set to occur before first treatment switch based on an HbA1c threshold of 9.04%, resulting in a switch to second-line treatment at 8 years. The DSU explored the impact of setting a time to weight regain of 1 year and an HbA1c switching threshold of 7.5% in line with the dual therapy analyses. The DSU also applied all other changes as described in section 3.59. The DSU base-case deterministic pair-wise analysis of dapagliflozin compared with DPP‑4 inhibitors resulted in an ICER of £3706 per QALY gained. The probabilistic sensitivity analysis resulted in a longer duration of first-line treatment and incremental costs for dapagliflozin, and consequently in a higher ICER of £7402 per QALY gained. When the DSU applied the manufacturers' original utility values associated with hypoglycaemia, the ICER was reduced to £2959 per QALY gained. When the DSU applied the assumption of weight convergence at last treatment switch, the ICER increased to £12,879 per QALY gained. The DSU noted that this scenario resulted in longer first-line treatment duration for people before switching to insulin treatment in both treatment groups and consequently, higher incremental costs for dapagliflozin.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dapagliflozin, having considered evidence on the nature of dapagliflozin and the value placed on the benefits of dapagliflozin by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the clinical treatment pathway for type 2 diabetes. The Committee heard from the clinical specialists that treatment for type 2 diabetes is individualised for each patient (focusing on HbA1c reduction without weight gain or hypoglycaemia), resulting in some variation in clinical practice. However, although treatment is individualised, current UK practice broadly follows the NICE guideline on type 2 diabetes, which recommends a stepwise approach that includes using diet and exercise, various antidiabetic drugs and insulin. The Committee heard from the clinical specialists that each of the existing antidiabetic therapies had various advantages and disadvantages affecting their suitability for patients and that many patients do not achieve target HbA1c levels with existing therapies. The Committee heard from the clinical specialists that dapagliflozin may be more likely to be used as a triple therapy but could be used as a dual therapy if there was a perceived risk of hypoglycaemia. It was noted that its use may be limited by the restrictions in the marketing authorisation, which states that dapagliflozin is not recommended for use in people with moderate to severe renal impairment. The Committee understood that a new treatment providing an additional option would be valued by clinicians. The Committee discussed the antidiabetic drugs that were used at each point in the treatment pathway for type 2 diabetes. The Committee heard from the clinical specialists that most people start treatment with metformin and that the use of a sulfonylurea as first-line therapy is diminishing because of the associated weight gain and the high incidence of hypoglycaemia compared with other oral therapies. The Committee heard from the clinical specialists that a sulfonylurea is often added to metformin as a dual therapy but if patients are unable to take a sulfonylurea because of concerns about weight gain or hypoglycaemia, then thiazolidinediones (pioglitazone), DPP‑4 inhibitors and GLP‑1 analogues may be used. The clinical specialists also commented that the same treatments could be used in triple therapy and as add-on to insulin therapy. The Committee heard from the clinical specialists that the use of DPP‑4 inhibitors was increasing and that the use of pioglitazone was decreasing because of concerns about safety. It was also aware that GLP‑1 analogues were used less frequently and usually later on in the treatment pathway because they are administered by subcutaneous injection and are more costly than other antidiabetic drugs. The Committee concluded that on the basis of the evidence from the clinical specialists, dapagliflozin was most likely to be used if a sulfonylurea was not appropriate, and the main comparator for dapagliflozin would be the DPP‑4 inhibitors. The Committee heard evidence from the patient experts that an advantage of dapagliflozin is that it will provide a further treatment option for people with type 2 diabetes who are reluctant to start treatment with insulin or wish to avoid insulin therapy because of fear of hypoglycaemia and its impact on their lifestyle (for example, the threat of losing their driving licence or their job). The Committee heard from the patient experts that the potential disadvantages of dapagliflozin include more frequent urinary tract and genital infections. However, the patient experts commented that the importance of these events would vary between individual patients and that, for some patients, the higher risk of urinary or genital infections could be balanced by the lower risk of hypoglycaemia. The Committee also heard from the patient experts that because dapagliflozin causes the excretion of glucose through the urine, this may cause anxiety for some patients who understand an absence of glucose in the urine to be a sign of good diabetes management and that this may lead to non-adherence to dapagliflozin therapy. However, the clinical specialists suggested that this was a risk that could be managed by providing appropriate information to people with diabetes. # Clinical effectiveness The Committee considered the evidence on the clinical effectiveness of dapagliflozin compared with other antidiabetic therapies, noting that most of the data came from the network meta-analyses submitted by the manufacturers. The Committee noted that, although the WinBUGs programme code used to run the original network meta-analyses provided in the manufacturers' submission differed from the code recommended by the NICE DSU in their technical support document, the manufacturers had also provided revised network meta-analyses that were based on the recommended code. The Committee also noted that the results of the manufacturers' revised network meta-analyses were similar to those from the original analyses. The Committee concluded that the results of the manufacturers' revised network meta-analyses provided an appropriate basis for making decisions about the clinical effectiveness of dapagliflozin and other antidiabetic therapies. The Committee discussed the outcomes collected in the clinical trials and network meta-analyses, noting that the primary outcomes were intermediate rather than clinical outcomes. The Committee noted that studies including the UKPDS had then been used to provide a link between these intermediate outcomes and long-term clinical outcomes including micro- and macrovascular complications. The Committee heard from the clinical specialists that there was some uncertainty about the impact of HbA1c reduction on longer-term macrovascular complications. The Committee also heard from the manufacturers that follow-up data were available for the clinical trials of dapagliflozin but that, because most of the trials of other antidiabetic drug therapies were of shorter duration, the clinical-effectiveness data used in the cost-effectiveness analysis had to be based on the short-term clinical trial data. The Committee concluded that, despite some uncertainty about the impact of HbA1c reduction on longer-term macrovascular complications, it was prepared to accept the link between the intermediate outcomes collected in the clinical trials and the longer-term clinical outcomes. The Committee considered the clinical effectiveness of dapagliflozin in dual therapy for people whose type 2 diabetes is inadequately controlled by metformin alone. The Committee noted that the evidence came from 3 clinical trials and a network meta-analysis. The Committee also noted that only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylureas), and that the clinical trial results were based on a relatively small number of patients who were given dapagliflozin at its licensed dose. However, on the basis of these clinical trial results, the Committee considered dapagliflozin to have greater efficacy than sulfonylureas for the outcomes of weight loss and systolic blood pressure reduction and similar efficacy for HbA1c reduction. The Committee concluded that, on the basis of the results of the network meta-analyses (see sections 3.10 and 3.45), dapagliflozin in dual therapy as add-on to metformin appeared to provide similar glycaemic control to other antidiabetic drugs but may result in greater weight loss. The Committee further considered the clinical effectiveness of dapagliflozin as dual therapy, noting that the manufacturers had not provided data on dapagliflozin as add-on therapy to a sulfonylurea, despite clinical trial data being available. The Committee accepted that most of the patients would start on metformin monotherapy, but noted the evidence provided by the clinical specialists that a proportion of patients who cannot tolerate metformin or for whom it is contraindicated would receive sulfonylurea monotherapy. It noted that the clinical effectiveness of dapagliflozin as an add-on to a sulfonylurea appeared to be consistent with its effectiveness when used as an add-on to metformin. The Committee concluded that, because the manufacturers had not provided clinical evidence on dapagliflozin as an add-on to a sulfonylurea, it could not make recommendations on this combination regimen. The Committee considered the clinical effectiveness of dapagliflozin for people whose type 2 diabetes is inadequately controlled by insulin, noting that the evidence came from 2 clinical trials and a network meta-analysis. The Committee noted that both trials were placebo controlled and that 1 of these was of 12 weeks' duration only. Again, the Committee noted that the clinical trial results for dapagliflozin were based on a relatively small number of patients who were treated with dapagliflozin at its licensed dose. Further, the Committee noted that the network meta-analysis excluded trials of GLP‑1 analogues because they were not comparable to other trials included in the analysis and therefore consideration of the full range of possible comparators was restricted by the available evidence. The Committee concluded that, on the basis of the results of the network meta-analyses (see sections 3.12 and 3.45), dapagliflozin as add-on therapy to insulin appeared to have greater efficacy than DPP‑4 inhibitors for the outcome of weight loss and similar efficacy for HbA1c reduction. The Committee considered the evidence on the clinical effectiveness of dapagliflozin in triple therapy. The Committee noted that dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents and that, in the absence of any other currently available clinical-effectiveness data, the manufacturers provided a post-hoc analysis of pooled data from a subset of older patients with type 2 diabetes and cardiovascular disease recruited in 2 trials of dapagliflozin as an add-on to metformin and a sulfonylurea. The Committee also noted that no direct head-to-head studies comparing dapagliflozin with other antidiabetic drugs currently exist and that the clinical-effectiveness data used to indirectly compare dapagliflozin with other antidiabetic drugs were taken from a previously published systematic review that had not been updated since 2009. It was aware of the limitations of these analyses highlighted by the manufacturer and therefore concluded that significant caution should be taken when interpreting the results of these preliminary analyses on the clinical effectiveness of dapagliflozin in the triple therapy setting. The Committee considered the adverse events associated with dapagliflozin. It noted that common adverse events included urinary tract and genital infections and that these events were more common in women than in men. However, the Committee heard from the manufacturers that the recurrence of these events in the clinical trials was low. It also heard from the manufacturers that, because of the mechanism of action of dapagliflozin, the clinical trials had actively looked for such infections and that only a small proportion of these infections needed treatment. The Committee also noted that the incidence of hypoglycaemia was low when dapagliflozin was added to metformin and that the currently available evidence suggested that dapagliflozin was not associated with increased risk of cardiovascular events. However, it was aware that regulatory agencies had identified some uncertainty about the risk of some cancers associated with dapagliflozin. The Committee heard from the patient experts that adverse events were a concern for patients with type 2 diabetes if they result in the need for additional drug therapies, especially for patients who are already receiving many drug therapies for their condition. However, it also recognised that a new drug therapy that was associated with a lower risk of hypoglycaemia than some other existing therapies would also be valued by patients for whom driving might be a significant factor in their lifestyle or livelihood. The Committee concluded that the adverse-events profile of dapagliflozin was different from those of other antidiabetic therapies and that it was important to examine these adverse events when considering the manufacturers' economic model. # Cost effectiveness The Committee considered the cost effectiveness of dapagliflozin as an add-on to metformin and insulin and as triple therapy in the manufacturers' submission, and the critique and exploratory analyses provided by the DSU and the ERG. The Committee noted that the manufacturers had provided a revised economic model in order to address concerns raised by the DSU about the original model and that the DSU considered that their concerns had been addressed. However, it also noted that the DSU and the ERG had identified a number of errors in the revised model which were subsequently addressed by the DSU in its exploratory analyses. The Committee concluded that the manufacturers' revised economic model with the subsequent amendments made by the DSU was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type 2 diabetes. The Committee discussed the validation report provided by the manufacturers which compared the results from the revised model with the results that would have been obtained using the CORE diabetes model, which has been used in previous appraisals of treatments for type 2 diabetes (such as NICE's technology appraisal guidance on liraglutide and exenatide in combination with oral antidiabetic therapy). The Committee noted that the results generated from the CORE diabetes model were comparable to those obtained from the manufacturers' original and revised economic models for the dual therapy and insulin add-on therapy analyses. The Committee concluded that the results of the validation exercise with the CORE diabetes model provided reassurance about the integrity of the results obtained from the manufacturers' revised economic model. The Committee discussed the cost-effectiveness analyses presented by the manufacturers, noting that these included a more restricted set of comparators than were specified in the scope. It was aware that GLP‑1 analogues had been included in the network meta-analysis for dual therapy but then subsequently excluded from the cost-effectiveness analysis. The Committee considered that it would have been more appropriate for all treatments in the network meta-analysis to have been included in the cost-effectiveness analysis. However, it noted the comments from the ERG and clinical specialists that GLP‑1 analogues were used in dual therapy on a restricted basis. On balance, the Committee concluded that the manufacturers had included an adequate range of comparators for the cost-effectiveness analysis of dapagliflozin in dual therapy as an add-on to metformin. The Committee discussed the clinical-effectiveness data that were applied in the economic models. The Committee noted that the DSU had completed analyses of dual therapy add-on to metformin using different sources of clinical-effectiveness data. One analysis used the 24‑week network meta-analysis data for dapagliflozin, DPP‑4 inhibitors and thiazolidinediones and presented a separate comparison using head-to-head data from study 4 for dapagliflozin and sulfonylureas. The other analysis considered all treatments in a single analysis using the 52‑week network meta-analysis data. It heard from the manufacturers that, for the metformin add-on analyses, the trials of other antidiabetic therapies as add-on to metformin used a fixed dose but the trials of sulfonylureas did not have a stable dose over 24 weeks. Therefore, trials of sulfonylureas as an add-on to metformin were excluded from the 24‑week network meta-analysis. The Committee discussed which set of analyses was the most appropriate, noting that the estimates of efficacy differed between analyses. It considered that it was more appropriate to use a single source as was available in the 52‑week network meta-analysis, but was aware of the limited number of trials informing this analysis. The Committee noted that the 24‑week network meta-analysis only excluded sulfonylureas, and that the evidence from the clinical specialists suggested that dapagliflozin would be used where sulfonylureas were not appropriate. On this basis the 24‑week network meta-analysis data were appropriate. The Committee concluded that the results of the revised 24‑week network meta-analysis provided the most appropriate clinical-effectiveness data for the dual therapy analyses. The Committee discussed the manufacturers' assumptions about the decision to switch or intensify treatment in the model, noting that this was based on baseline HbA1c levels taken from the clinical trials and network meta-analysis. The Committee noted that the HbA1c threshold levels for switching treatment in the original dual therapy and triple therapy analyses were above those recommended in NICE's guideline on type 2 diabetes and therefore may not reflect UK clinical practice. However, the Committee noted that the DSU's revised analyses applied an HbA1c threshold for switching treatment that is currently recommended in NICE's guideline on type 2 diabetes. The Committee heard from the DSU that the results from the revised model were sensitive to the timing of treatment switching in the model which was dependent on the relationship between HbA1c at the start of treatment, treatment-related changes in HbA1c levels and the HbA1c threshold levels for switching treatment. The Committee concluded that HbA1c threshold levels for switching treatment as recommended in NICE's guideline on type 2 diabetes were appropriate to use in the economic modelling and as a basis for decision-making. The Committee discussed the manufacturers' approach to modelling changes in body weight. The Committee noted that in the revised model the effect of treatment on changes in weight was applied gradually over the course of the first year, and considered that this was more plausible than the original model in which the effect of treatment on changes in weight was applied immediately. The Committee noted that, for treatments associated with weight loss, the manufacturers made assumptions about how long weight loss was maintained in the model (weight plateau), and about how long it took for the weight to increase to its baseline level after the plateau (loss of effect). The Committee understood that the changes made by the DSU meant that for treatments associated with weight loss, the weight profiles of the treatment groups now converged over time, but that for treatments associated with weight gain, differences in weight were maintained over the model time horizon. The Committee acknowledged that unpublished data from the clinical study of dapagliflozin and sulfonylureas as add-on to metformin provided by the manufacturers showed that patients who remained on dapagliflozin treatment without switching to other treatments maintained their weight loss over 4 years. However, the Committee considered that uncertainty remained about the effects of stopping treatment with dapagliflozin and the impact on weight gain. Therefore, it concluded that the scenario analysis conducted by the DSU, which involved the convergence of differences in weight profiles between treatment groups at the time of switching to the last line of treatment, was more appropriate for decision-making. The Committee considered the utility values applied in the model, noting that in all analyses the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than from a reduction of diabetic complications and other adverse events. The Committee noted that utility values associated with changes in BMI were taken from a study commissioned by the manufacturers and that the methods by which these values were obtained were not in line with the NICE reference case for measuring and valuing health effects. The Committee also noted that this study produced different utility values associated with a 1-unit increase or decrease in BMI and that these were larger than other utility values that were identified in the literature. The Committee acknowledged that the manufacturers presented scenario analyses using alternative utility values for weight change and that these resulted in higher ICERs for the metformin and insulin add-on analyses. The Committee also noted that the loss in utility associated with a 1-unit increase in BMI (−0.0472) was similar to the loss in utility associated with a myocardial infarction (−0.055), which may not be credible. The Committee concluded that the utility values associated with changes in weight may have been too large and that the values (±0.0061 per BMI unit decrease or increase) applied in the manufacturers' scenario analyses and DSU analyses were more reasonable. The Committee considered the utility values associated with hypoglycaemic events. The Committee heard from the ERG that they considered that the loss in QALYs associated with hypoglycaemic events may have been too large. The Committee was also aware that the loss in utility associated with severe hypoglycaemic events (−0.047) was higher than that applied in the economic model of third-line therapy with insulins, thiazolidinediones or exenatide in NICE's guideline on type 2 diabetes (−0.010). However, the Committee noted that after the publication of this guideline, the Driving and Vehicle Licensing Agency issued new regulations for people who have experienced a severe hypoglycaemic event in the previous 12 months. Therefore, the Committee acknowledged that any loss in utility associated with severe hypoglycaemic events may be higher in people for whom driving might be a significant factor in their lifestyle or livelihood. The Committee noted that the DSU had completed analyses that included both the higher and lower estimates of loss of utility associated with hypoglycaemic events, and that these had made small differences to the estimates of the ICER. The Committee therefore concluded that the utility values associated with hypoglycaemic events were not a critical factor in the decision-making. The Committee considered the utility values applied to urinary tract and genital infections in the model, noting that the loss in utility associated with these events was much smaller than the loss in utility associated with other adverse events. The Committee considered that it was likely that there would be a greater loss in utility associated with these events than had been proposed by the manufacturers. The Committee also noted that the study commissioned by the manufacturers to examine the impact of weight change on health-related quality of life had also estimated the impact of urinary tract and genital infections, although these data were not presented in the manufacturers' submission. The Committee noted that in scenario analyses the manufacturers had applied a range of estimates for the loss in utility associated with urinary tract and genital infections. It was also aware that the results of the revised analyses were not sensitive to changes in these utility values. The Committee concluded that, although the loss in utility associated with urinary tract and genital infections was likely to be greater than that proposed by the manufacturers, it was satisfied that this did not significantly impact on the relative cost effectiveness of dapagliflozin as dual therapy or add-on to insulin. The Committee was aware that the ERG had proposed alternative estimates for some costs, including drug acquisition costs for pioglitazone and the costs associated with diabetic complications. The Committee noted that pioglitazone is now off-patent and that the latest acquisition costs are substantially lower than those presented in the manufacturers' submission. The Committee acknowledged that the manufacturers were unable to provide this estimate in their submission, but considered that the DSU estimate of an average annual cost of £69.09 was reasonable. The Committee also noted that the manufacturers' revised model did not correctly adjust the annual inpatient and non-inpatient costs (estimated as £483 in the UKPDS 65 study) for people who did not experience a macro- or microvascular diabetic complication. The Committee concluded that it was appropriate to consider the latest acquisition cost of pioglitazone and that the manufacturers' revised model should be amended to correctly account for the annual costs incurred by people who did not experience a macro- or microvascular diabetic complication. The Committee considered the most plausible ICERs for dapagliflozin as dual therapy in combination with metformin. The Committee considered that, on the basis of clinical specialist opinion that suggested that the use of pioglitazone in UK clinical practice was decreasing, a thiazolidinedione was not a key comparator in the dual therapy setting. The Committee also noted the evidence from the clinical specialists supported by the manufacturers that, in clinical practice, dapagliflozin would predominantly be used in combination with metformin when a sulfonylurea is not appropriate. Therefore, the Committee also considered that sulfonylureas were not a relevant comparator in the dual therapy setting. The Committee considered the DSU deterministic analysis and scenario analyses, which included the convergence of differences in weight between treatment groups at the time of switching to the last line of treatment. It noted that these showed that DPP‑4 inhibitors were associated with higher costs and QALYs than dapagliflozin, but that these differences were small. It noted further that in the DSU probabilistic sensitivity analysis these differences were even smaller. The Committee noted that the differences in QALYs were largely explained by the changes in health-related quality of life (utility) associated with changes in weight (BMI). Overall, the Committee concluded that because of the small differences in costs and QALYs between dapagliflozin and DPP‑4 inhibitors, dapagliflozin in a dual therapy regimen in combination with metformin could be recommended as a treatment option for people with type 2 diabetes that is inadequately controlled with metformin alone if it is used in the same scenario as described for the use of DPP‑4 inhibitors in NICE's guideline on type 2 diabetes. The Committee considered the most plausible ICERs for dapagliflozin as add-on to insulin. It noted that in all the analyses conducted by the DSU the estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors was below £20,000 per QALY gained. The Committee considered that, in comparison to DPP‑4 inhibitors, dapagliflozin had been shown to be a cost-effective use of NHS resources. The Committee recommended dapagliflozin as a treatment option for people with diabetes inadequately controlled by insulin with or without other oral antidiabetic drugs. The Committee discussed the results of the manufacturers' revised base-case analyses for dapagliflozin as triple therapy add-on to metformin and a sulfonylurea. It noted that the sequence of treatments in the manufacturers' revised economic model had been amended so that the approach was consistent with the dual therapy and insulin add-on analyses, with patients in the model starting treatment with triple add-on therapy. The Committee noted that in both the manufacturers' original and revised triple therapy analyses, dapagliflozin dominated other comparator drug therapies, meaning that dapagliflozin was associated with lower costs and higher QALYs than the comparators. However, the Committee noted that the clinical-effectiveness data applied in the triple therapy model were based on an indirect comparison of pooled data of 2 trials of dapagliflozin and a separate systematic review of other antidiabetic drug therapies conducted in 2009. The Committee was also aware that dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents. The Committee considered that the cost-effectiveness analyses should be considered as exploratory in nature. The Committee concluded that dapagliflozin as triple therapy in combination with metformin and a sulfonylurea should not be recommended for treating type 2 diabetes except as part of the ongoing clinical trials. # Summary of Appraisal Committee's key conclusions TA288 Appraisal title: Dapagliflozin in combination therapy for treating type 2 diabetes Section Key conclusion Dapagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if it is used as described for dipeptidyl peptidase-4 (DPP‑4) inhibitors in the NICE guideline on type 2 diabetes. Dapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes. For dapagliflozin dual therapy regimens in combination with metformin, the Committee concluded that because of the small differences in costs and QALYs between dapagliflozin and DPP‑4 inhibitors, dapagliflozin in a dual therapy regimen in combination with metformin could be recommended. For dapagliflozin as add-on to insulin all the analyses conducted by the DSU produced an estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors below £20,000 per QALY. Dapagliflozin in a triple therapy regimen is currently being studied as an add-on to 2 other oral agents. The Committee considered that the cost-effectiveness analyses should be considered as exploratory in nature. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard evidence from the patient experts that an advantage of dapagliflozin is that it will provide a further treatment option for people with type 2 diabetes who are reluctant to start treatment with insulin or wish to avoid insulin therapy because of fear of hypoglycaemia and its impact on their lifestyle (for example, the threat of losing their driving licence or their job). The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee recognised that a new drug therapy that was associated with a lower risk of hypoglycaemia than some other existing therapies would be valued by patients for whom driving might be a significant factor in their lifestyle or livelihood. What is the position of the treatment in the pathway of care for the condition? The Committee heard from the clinical specialists that dapagliflozin may be more likely to be used as a triple therapy but could be used as a dual therapy if there was a perceived risk of hypoglycaemia. The Committee concluded that on the basis of the evidence from the clinical specialists, dapagliflozin was most likely to be used if a sulfonylurea was not appropriate, and the main comparator for dapagliflozin would be the DPP‑4 inhibitors. Adverse reactions Common adverse events included urinary tract and genital infections and these events were more common in women than in men. However, the Committee heard from the manufacturers that the recurrence of these events in the clinical trials was low. The Committee concluded that the adverse-events profile of dapagliflozin was different from those of other antidiabetic therapies and that these adverse events were important to examine when considering the manufacturers' economic model. Evidence for clinical effectiveness Availability, nature and quality of evidence For dapagliflozin as an add-on to metformin, the evidence came from 3 clinical trials and a network meta-analysis. Only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylurea) and the clinical effectiveness of dapagliflozin compared with DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues was based solely on network meta-analysis. The manufacturers had not provided clinical-effectiveness data on dapagliflozin as add-on therapy to a sulfonylurea, despite clinical trial data being available. The Committee concluded that, because the manufacturers had not provided clinical evidence of dapagliflozin as add-on to a sulfonylurea, it could not make recommendations on this combination regimen. For dapagliflozin as add-on therapy to insulin, the evidence came from 2 clinical trials and a network meta-analysis. Both trials were placebo controlled and 1 was of 12 weeks duration only. The trial results for dapagliflozin were based on a relatively small number of patients who were treated with dapagliflozin at its licensed dose. The network meta-analysis excluded trials of GLP‑1 analogues because they were not comparable to other trials included in the analysis and therefore consideration of the full range of possible comparators was restricted by the available evidence. Dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents and, in the absence of any other currently available clinical-effectiveness data, the manufacturers provided a post hoc analysis of pooled data from a subset of older patients with type 2 diabetes and cardiovascular disease recruited in 2 trials of dapagliflozin as an add-on to metformin and sulfonylurea. The Committee concluded that significant caution should be taken when interpreting the results of these preliminary analyses. Relevance to general clinical practice in the NHS The Committee discussed the outcomes collected in the clinical trials and network meta-analyses, noting that the primary outcomes were intermediate rather than clinical outcomes and that these were collected over a relatively short follow-up. Uncertainties generated by the evidence The Committee concluded that, despite some uncertainty about the impact of HbA1c reduction on longer-term macrovascular complications, it was prepared to accept the link between intermediate outcomes collected in the clinical trials and longer-term clinical outcomes. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that, on the basis of the results of the network meta-analyses, dapagliflozin in dual therapy as add-on to metformin appeared to provide similar glycaemic control to other antidiabetic drugs but may result in greater weight loss. The Committee concluded that, on the basis of the results of the network meta-analyses, dapagliflozin as add-on therapy to insulin appeared to have greater efficacy than DPP‑4 inhibitors for the outcome of weight loss and similar efficacy for HbA1c reduction. Evidence for cost effectiveness Availability and nature of evidence The manufacturers had provided a revised economic model in order to address concerns raised by the DSU about the original model and the DSU considered that their concerns had been addressed. However, the DSU and the ERG had identified a number of errors in the revised model which were subsequently addressed by the DSU in its exploratory analyses. The Committee concluded that the manufacturers' revised economic model with the subsequent amendments made by the DSU was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type 2 diabetes. The Committee concluded that the results of the validation exercise with the CORE diabetes model provided reassurance about the integrity of the results obtained from the manufacturers' revised economic model. Uncertainties around and plausibility of assumptions and inputs in the economic model In terms of the clinical-effectiveness data that were applied in the economic models, the Committee considered that it was more appropriate to use a single source as was available in the 52‑week network meta-analysis, but was aware of the limited number of trials informing this analysis. It also noted that the 24‑week network meta-analysis only excluded sulfonylureas, and that the evidence from the clinical specialists suggested that dapagliflozin would be used where a sulfonylurea was not appropriate. On this basis the 24‑week network meta-analysis data were appropriate. The Committee heard from the DSU that the results from the revised model were sensitive to the timing of treatment switching in the model which was dependent on the relationship between HbA1c at the start of treatment, treatment-related changes in HbA1c levels and the HbA1c threshold levels for switching treatment. The Committee considered that uncertainty remained about the effects of stopping treatment with dapagliflozin and the impact on weight gain. Therefore, it concluded that the scenario analysis conducted by the DSU, which involved the convergence of differences in weight profiles between treatment groups at the time of switching to the last line of treatment, was more appropriate for decision-making. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee considered the utility values applied in the model, noting that the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than a reduction of diabetic complications and other adverse events. The Committee concluded that the utility values associated with changes in weight may have been too large and that the values applied in the manufacturers' scenario analyses and DSU analyses were more reasonable. The Committee noted that the DSU had completed analyses that included both the higher and lower estimates of loss of utility associated with hypoglycaemic events, and that these had made small differences to the estimates of the ICER. The Committee concluded that, although the loss in utility associated with urinary tract and genital infections was likely to be greater than that proposed by the manufacturers, it was satisfied that this did not significantly impact on the relative cost effectiveness of dapagliflozin as dual therapy or add-on to insulin. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? The Committee noted that in all settings the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than from a reduction of diabetic complications and other adverse events. Most likely cost-effectiveness estimate (given as an ICER) For dapagliflozin as dual therapy in combination with metformin, the Committee considered the DSU deterministic analysis and scenario analyses, which included the convergence of differences in weight between treatment groups at the time of switching to the last line of treatment. It noted that these showed that DPP‑4 inhibitors were associated with higher costs and QALYs than dapagliflozin, but that these differences were small. It noted further that in the DSU probabilistic sensitivity analysis these differences were even smaller. For dapagliflozin as add-on to insulin, the Committee noted that in all the analyses conducted by the DSU the estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors was below £20,000 per QALY. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End-of-life considerations Not applicable. Equalities considerations and social value judgements The Committee concluded that its recommendations would not have a particular impact on any of the groups whose interests are protected by the equalities legislation and that there was no need to alter or add to its recommendations. # Recommendations for further research The Committee supported the ongoing research investigating dapagliflozin as part of a triple therapy regimen as add-on to 2 oral antidiabetic drugs.	{'Guidance': "Dapagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if:\n\na sulfonylurea is contraindicated or not tolerated or\n\nthe person is at significant risk of hypoglycaemia or its consequences.\n\nDapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type\xa02 diabetes.\n\nThis recommendation has been updated and replaced by NICE's technology appraisal guidance on dapagliflozin in triple therapy for treating type 2 diabetes.\n\nPeople currently receiving dapagliflozin in a dual therapy regimen that is not recommended for them in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.", 'The technology ': "Dapagliflozin (Forxiga, Bristol‑Myers Squibb and AstraZeneca) is a sodium–glucose cotransporter‑2 (SGLT‑2) inhibitor that blocks the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine. It has a UK marketing authorisation 'in adults aged 18\xa0years and older with type\xa02 diabetes mellitus to improve glycaemic control as:\n\nmonotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance\n\nadd-on combination therapy with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control'. The subject of this appraisal is the add-on therapy indication.\n\nThe summary of product characteristics lists the following adverse reactions for dapagliflozin: hypoglycaemia (when used with a sulfonylurea or insulin), urinary tract and genital infection, back pain, dysuria, polyuria, dyslipidaemia and elevated haematocrit. Dapagliflozin is not recommended for use in people with moderate to severe renal impairment (patients with a creatinine clearance rate of less than 60\xa0ml/min or an estimated glomerular filtration rate of less than 60\xa0ml/min/1.73\xa0m2) because its efficacy is dependent on renal function. Dapagliflozin is also not recommended for use in combination with pioglitazone. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe list price of dapagliflozin is £36.59 for 28 5‑mg or 10‑mg tablets (excluding VAT; 'British national formulary' [BNF] edition 64). Dapagliflozin is administered orally as a single dose of 10\xa0mg per day. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturers' submission": "The Appraisal Committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Clinical effectiveness\n\nThe manufacturers carried out a systematic literature search to identify all relevant trials of dapagliflozin and potential comparators in adults with type\xa02 diabetes. The manufacturers identified 5 randomised controlled trials of dapagliflozin (10\xa0mg once daily): 3 in patients with type\xa02 diabetes inadequately controlled with metformin alone (studies 14, 12 and 4), and 2 in patients with type\xa02 diabetes inadequately controlled with insulin with or without oral antidiabetic drugs (studies 9 and 6).\n\nOf the 3 trials of dapagliflozin as an add-on to metformin, 2 were placebo controlled with follow-up of 24\xa0weeks (studies 14 and 12) and 1 compared dapagliflozin with a sulfonylurea for up to 52\xa0weeks of follow-up (study\xa04). The primary outcomes assessed were change in HbA1c from baseline (studies 14 and 4) and changes in body weight from baseline (study 12). Secondary outcomes included change in fasting plasma glucose, the proportion of patients whose HbA1c levels reached a specific target, change in body weight, change in blood pressure, the proportion of patients reporting hypoglycaemia, adverse reactions and tolerability. Baseline patient characteristics in the 3 trials were broadly similar: mean age 52.7–60.8\xa0years, HbA1c level 7.16–8.11%, body weight 86.1–92.1\xa0kg and systolic blood pressure 126.0–135.9\xa0mmHg.\n\nThe 2 trials of dapagliflozin as an add-on to insulin were both placebo controlled, with follow-up of 12\xa0weeks (study 9) and 24\xa0weeks (study 6). The primary outcome assessed was change in HbA1c from baseline. Secondary outcomes included change in fasting plasma glucose, the proportion of patients whose HbA1c reached a specific target, change in body weight, change in the daily dose of insulin, adverse reactions and tolerability. Baseline patient characteristics in the 2 trials were broadly similar: mean age 55.7–59.3\xa0years, HbA1c level 8.40–8.57%, body weight 94.5–103.4\xa0kg and systolic blood pressure 128.9–140.6\xa0mmHg.\n\nIn the add-on to metformin trials (studies\xa012 and 14), dapagliflozin was associated with a statistically significant reduction in HbA1c compared with placebo at 24\xa0weeks. In study 14 (n=272), reduction in HbA1c was −0.84% for dapagliflozin versus −0.30% for placebo (p<0.0001). In study\xa012 (n=182), reduction in HbA1c was −0.39% for dapagliflozin compared with −0.10% for placebo (p<0.0001). Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo at 24\xa0weeks in both study\xa012 (−2.96\xa0kg versus −0.88\xa0kg, p<0.0001) and study\xa014 (−2.86\xa0kg versus −0.89\xa0kg, p<0.0001). Dapagliflozin was associated with a reduction in systolic blood pressure compared with placebo at 24\xa0weeks in both study\xa014 (−5.1\xa0mmHg versus −0.2\xa0mmHg, p value not reported) and study\xa012 (−2.70\xa0mmHg versus +0.10\xa0mmHg, p=0.06). Dapagliflozin was not associated with a statistically significant increased risk of hypoglycaemia compared with placebo at 24\xa0weeks in either study.\n\nIn study\xa04 (n=814), dapagliflozin was shown to be non-inferior (based on a non-inferiority margin of 0.35%) to a sulfonylurea with respect to HbA1c reduction at 52\xa0weeks. Dapagliflozin was associated with a statistically significant change in body weight compared with a sulfonylurea at 52\xa0weeks (−3.22\xa0kg versus +1.44\xa0kg, p<0.0001). Dapagliflozin was associated with a statistically significant change in systolic blood pressure compared with a sulfonylurea at 52\xa0weeks in study\xa04 (−4.3\xa0mmHg versus +0.8\xa0mmHg, p<0.0001). Dapagliflozin also resulted in a statistically significantly lower proportion of patients experiencing at least 1\xa0hypoglycaemic event (3.5% versus 40.8%, p<0.0001) compared with a sulfonylurea by 52\xa0weeks.\n\nIn the add-on to insulin trials, dapagliflozin was associated with a reduction in HbA1c compared with placebo at 12\xa0weeks (study 9) and 24\xa0weeks (study 6). In the 12‑week study (n=47), the change in HbA1c was −0.61% for dapagliflozin versus +0.09% for placebo (p value not reported). In the 24‑week study (n=387), the reduction in HbA1c was −0.96 for dapagliflozin versus −0.39 for placebo (p<0.001). Dapagliflozin was associated with a statistically significant reduction in body weight (−1.67\xa0kg versus +0.02\xa0kg, p<0.0001) and systolic blood pressure (−6.9\xa0mmHg versus −3.9\xa0mmHg, p=0.02) compared with placebo at 24\xa0weeks. A higher proportion of patients treated with dapagliflozin had experienced at least 1 hypoglycaemic event (42.3% versus 35.0%) compared with placebo by 24\xa0weeks. Dapagliflozin was associated with a statistically significant reduction in the calculated mean daily insulin dose (−1.16\xa0versus +5.08 international units per day, p<0.0001) compared with placebo at 24\xa0weeks.\n\nThe manufacturers conducted pre-planned analyses to determine if there were any variations in the clinical effectiveness of dapagliflozin for the following subgroups (as defined by the manufacturers): race, ethnicity, baseline HbA1c, age, sex and baseline body mass index (BMI). Subgroup analyses were conducted on pooled data as well as some of the individual studies of dapagliflozin. The manufacturers reported that no statistically significant differences in clinical effectiveness across subgroups were observed, except for baseline HbA1c. Dapagliflozin treatment generally resulted in greater HbA1c reductions from baseline in people with higher baseline HbA1c.\n\nThe manufacturers conducted network meta-analyses to compare the clinical effectiveness of dapagliflozin as an add-on to metformin or insulin with comparator therapies listed in the scope. Four outcomes were assessed: mean change in HbA1c from baseline, mean change in weight from baseline, mean change in systolic blood pressure from baseline, and the proportion of patients experiencing at least 1 hypoglycaemic episode. Random-effects models were selected over fixed-effects models because of variations in the study characteristics. The manufacturers presented analyses that were both adjusted and unadjusted for the potential modifying effects of baseline HbA1c.\n\nFor dapagliflozin as an add-on to metformin, the manufacturers created separate networks for the outcome of systolic blood pressure at 24\xa0weeks (±6\xa0weeks) and for the other 3\xa0outcomes at 24\xa0weeks (±6\xa0weeks) and 52\xa0weeks (±6\xa0weeks). For the 24‑week analysis of systolic blood pressure, the network included dapagliflozin, dipeptidyl peptidase-4 (DPP‑4) inhibitors, glucagon-like peptide-1 (GLP‑1) analogues, sulfonylureas, thiazolidinediones and placebo in 8 studies. For the 24‑week analysis of outcomes other than systolic blood pressure, the network included dapagliflozin, DPP‑4 inhibitors, GLP‑1 analogues, thiazolidinediones and placebo in 15 studies. For the 52‑week analysis, the network included dapagliflozin, DPP‑4 inhibitors, thiazolidinediones and sulfonylureas in 6 studies.\n\nThe numerical results of the 24‑week network meta-analyses for the add-on to metformin comparisons were provided as academic in confidence. After adjusting for baseline HbA1c, dapagliflozin was associated with a statistically significant reduction in HbA1c compared with placebo. No statistically significant differences in the change in HbA1c were reported between dapagliflozin and other therapies. Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo, DPP‑4 inhibitors and thiazolidinediones, but not compared with GLP‑1 analogues. Dapagliflozin was associated with a statistically significant reduction in systolic blood pressure compared with placebo and sulfonylureas. However, no statistically significant differences in change in systolic blood pressure were reported between dapagliflozin and the other 3 drug therapies. No statistically significant differences in the risk of hypoglycaemia were reported between dapagliflozin and other drug therapies.\n\nFor dapagliflozin as an add-on to insulin, the manufacturers conducted a single network meta-analysis for all outcomes except systolic blood pressure at 24\xa0weeks (±8\xa0weeks). The network included dapagliflozin, DPP‑4 inhibitors, thiazolidinediones and placebo in 4\xa0studies. The 12‑week study of dapagliflozin (study 9) and 3 other studies comparing thiazolidinediones with placebo were excluded from this analysis because they allowed up-titration of insulin to maintain glycaemic control. One of the studies identified, a study comparing thiazolidinediones with placebo, was excluded from the main analysis of mean change in HbA1c at 24\xa0weeks because of the higher reported baseline HbA1c values compared with the other 3 studies. The outcome of change in systolic blood pressure at 24\xa0weeks could not be analysed because, of the 4 identified studies, 3 either did not report changes in systolic blood pressure or involved up-titration of insulin.\n\nResults of the 24‑week network meta-analyses for the add-on to insulin comparisons were provided as academic in confidence. Dapagliflozin was associated with a statistically significant reduction in HbA1c compared with placebo. No statistically significant differences in changes in HbA1c were reported between dapagliflozin and DPP‑4 inhibitors. When the study comparing thiazolidinediones with placebo was included as a sensitivity analysis, dapagliflozin was less effective in reducing HbA1c compared with thiazolidinediones. Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo and DPP‑4 inhibitors, and changes were reported to be similar to thiazolidinediones. Dapagliflozin was associated with a statistically significantly lower risk of experiencing a hypoglycaemic event compared with thiazolidinediones. However, no statistically significant differences were reported for the comparison of dapagliflozin with DPP‑4 inhibitors and placebo.\n\nData on the risks of adverse reactions associated with dapagliflozin were presented using pooled results from the placebo-controlled randomised controlled trials, including dapagliflozin as monotherapy and add-on therapy. Most results presented were based on short-term studies (24\xa0weeks). The manufacturers reported that dapagliflozin was associated with a higher incidence of genital and urinary tract infections and a slightly higher incidence of volume depletion events (hypotension, hypovolaemia or dehydration) compared with placebo. Renal impairment or failure events were reported for a small proportion of patients (less than 1.5%) with no apparent difference between treatment groups. The manufacturers reported that the incidence of cancer was similar between patients who received dapagliflozin (1.47%) and patients who received placebo (1.35%). However, rates of bladder cancer (0.16% versus 0.03%), prostate cancer (0.34% versus 0.16%) and breast cancer (0.40% versus 0.22%) were higher in patients treated with dapagliflozin than in those treated with placebo respectively. In terms of cardiovascular safety, a meta-analysis of 14 randomised controlled trials did not find any evidence that dapagliflozin is associated with increased cardiovascular risk for a composite end point of cardiovascular death, myocardial infarction and stroke (hazard ratio [HR] 0.79, 95% CI 0.54 to 1.17).\n\nEvidence on the clinical and cost effectiveness of dapagliflozin in triple therapy for people with type\xa02 diabetes that is inadequately controlled with metformin and a sulfonylurea was submitted in an addendum to address the comparisons specified in the scope. The manufacturers stated that dapagliflozin is currently being studied in an ongoing trial as a triple therapy add-on to 2 other oral agents. Therefore, data were pooled from a subset of people who were given metformin and a sulfonylurea at baseline from 2 placebo-controlled trials (studies 18 and 19), which were designed to assess the efficacy and safety of dapagliflozin in older people (average age 63–64\xa0years) with type\xa02 diabetes and cardiovascular disease. A post-hoc analysis of this subset was conducted for changes from baseline in HbA1c, weight, systolic blood pressure and hypoglycaemic events at 24\xa0weeks (results provided as academic in confidence).\n\nNo trials of dapagliflozin compared with active comparators in triple therapy were reported by the manufacturers. Therefore, the assessment of the clinical effectiveness of dapagliflozin compared with DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones was based on indirect evidence. The manufacturers did not conduct a systematic review of triple therapy for people with type\xa02 diabetes that is inadequately controlled with metformin and a sulfonylurea. However, they referred to a literature review of add-on therapy to metformin and sulfonylureas for type\xa02 diabetes produced in 2009 by the Canadian Agency for Drugs and Technologies in Health. A summary of the results of this review suggested that DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones were associated with statistically significant reductions in HbA1c compared with continued therapy with metformin and sulfonylureas. No statistically significant differences in HbA1c reduction were reported between DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones. Thiazolidinediones, but not DPP‑4 inhibitors or GLP‑1 analogues, were associated with statistically significant weight gain compared with metformin and sulfonylureas. The manufacturers noted that since 2009, new data have become available including studies of the DPP‑4 inhibitors linagliptin and saxagliptin.\n\n# Cost effectiveness\n\nThe manufacturers submitted an economic model to evaluate the cost effectiveness of dapagliflozin for use:\n\nin dual therapy as an add-on to metformin in adults with type\xa02 diabetes for whom metformin alone (with diet and exercise) does not provide adequate glycaemic control\n\nas an add-on to insulin (with or without other oral antidiabetic therapies) when the underlying treatment regimen including insulin does not provide adequate glycaemic control and\n\nin triple therapy for people with type\xa02 diabetes that is inadequately controlled with metformin and a sulfonylurea. For the add-on to metformin analysis, the comparator treatments were sulfonylureas, DPP‑4 inhibitors and thiazolidinediones (pioglitazone). For the add-on to insulin analysis, the comparator treatments were DPP‑4 inhibitors. For the triple therapy analysis, the comparator treatments were DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues.\n\nThe manufacturers developed a simulation model run within an Excel front end but with the main calculations performed using C++ programming. The patient cohort entered the model with a set of baseline patient characteristics and modifiable risk factors that included HbA1c, total body weight, total cholesterol to high-density lipoprotein cholesterol ratio and systolic blood pressure. The value of these variables changed as the model simulation progressed, as a result of the effects of antidiabetic treatment and through natural progression, calculated from the UK Prospective Diabetes Study (UKPDS number 68) risk factor equations. The model then predicted the incidence of 7 specific macro- and microvascular events on the basis of the UKPDS 68 event risk equations. Macrovascular events predicted in the model included ischaemic heart disease, myocardial infarction, congestive heart failure and stroke. Microvascular events included amputation, nephropathy (end-stage renal failure) and blindness. The model also calculated the probability of drug-related hypoglycaemic events (non-severe and severe), other adverse events including urinary tract infections and genital infections, and treatment discontinuation caused by adverse events.\n\nSimulated patients moved through the model in 6‑month cycles over a 40-year time horizon. At the start of the model, patients were assumed to have no complications associated with type\xa02 diabetes. At the end of the first 6‑month cycle, the UKPDS risk equations determined the probability of fatal and non-fatal complications in addition to diabetes-related deaths (myocardial infarction, congestive heart failure, stroke and amputation) and deaths from other causes (estimated separately from UK life tables). If a patient survived beyond the first cycle, they moved to the next cycle in which they remained at risk of treatment-related adverse events and long-term macro- or microvascular events. Once a diabetes-related death or death from other causes occurred, then costs, life years and quality-adjusted life years (QALYs) were updated and the simulation ended for that patient.\n\nThe model simulated a cohort of patients who received dapagliflozin (the 'treatment' cohort), and a cohort with the same baseline characteristics who received comparator treatments (the 'comparator' cohort). Simulated patients in each cohort received a particular therapy until their HbA1c increased up to a specified threshold (representing inadequate glycaemic control), at which point they stopped therapy and moved on to the second-line therapy (assumed to be the same in both cohorts). For the metformin and insulin add-on analyses, the model included up to 2 additional therapy lines after dapagliflozin and the comparator. The manufacturers assumed that second-line therapy was metformin and insulin, and third-line therapy for the remainder of the patients' simulated lifetime was intensified insulin (assumed to be a 50% increase from the starting dose). For the insulin add-on analysis, second-line therapy was intensified insulin for the remainder of the simulation. For the triple therapy analysis, all comparator triple therapies were assumed to be preceded by dual therapy with metformin and a sulfonylurea. The manufacturers assumed that after triple therapy, all patients would receive metformin and insulin. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%.\n\nFor the metformin add-on analyses, baseline patient characteristics, clinical-effectiveness data and adverse event rates were taken from study\xa04 for the comparison of dapagliflozin and a sulfonylurea and from the manufacturers' network meta-analysis (at 24\xa0weeks) for all of the other comparisons. For the insulin add-on analysis, baseline patient characteristics, clinical-effectiveness data and adverse event rates were taken from the network meta-analysis (at 24\xa0weeks). For the triple therapy analysis, clinical-effectiveness data were drawn from a pooled analysis of a subset of patients treated with dapagliflozin in 2\xa0clinical trials (studies 18 and 19) and the Canadian Agency for Drugs and Technologies in Health's review of oral antidiabetic drugs as triple therapy. The manufacturers commented that the baseline patient characteristics from studies 18 and 19 were not representative of the triple therapy patient population. Therefore, baseline patient characteristics were taken from study\xa04 comparing dapagliflozin with a sulfonylurea in patients with type\xa02 diabetes inadequately controlled with metformin alone.\n\nThe HbA1c thresholds for switching treatment were based on baseline HbA1c values taken from the same sources. In the metformin add-on analyses, a threshold value of 7.72% taken from study\xa04 was used for the comparison of dapagliflozin and a sulfonylurea and a value of 8.17% from the metformin add-on network meta-analyses was used for the comparison of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones. In the insulin add-on analysis, a threshold value of 8.90% was used based on the insulin add-on network meta-analyses. In the triple therapy analysis, the HbA1c threshold for switching treatment was 7.72%, taken from study\xa04.\n\nThe economic model included changes in weight associated with treatment. UKPDS risk equations based on BMI were included in the model. Therefore, changes in patient weight over time were converted to a BMI value based on baseline weight and height characteristics. If a treatment was associated with weight loss, this involved assumptions about how long the weight loss was maintained for along with the subsequent time until the loss of effect and return to the baseline body weight. In the dapagliflozin therapy group for the add-on to metformin and insulin analyses, weight reduction was assumed to be maintained for 2\xa0years in the model based on 2-year extension data from the trial of dapagliflozin compared with a sulfonylurea. After year\xa02, weight was assumed to return to its baseline value until treatment was switched in a linear trend for the dapagliflozin therapy group. After this, a natural progression in weight gain of 0.1\xa0kg per year was assumed. Because no data were available for DPP‑4 inhibitors, the same assumptions were applied. All other treatments were associated with a weight gain, which was applied in the first year, after which a natural progression in weight gain of 0.1\xa0kg per year was assumed.\n\nThe model estimated the impact of macro- and microvascular complications of diabetes, changes in body weight and other adverse events on health-related quality of life. An age-dependent baseline utility function was derived from the Department of Health Survey for England (2003) which collected EQ‑5D data from patients with no major complications. Data on the impact on health-related quality of life of diabetes complications were taken from UKPDS (number\xa062) except for end-stage renal disease. In the UKPDS\xa062, the EQ‑5D questionnaire was completed by 3667 UK patients. This resulted in the following utility decrements: −0.09 (ischaemic heart disease), −0.055 (myocardial infarction), −0.108 (congestive heart failure), −0.164 (stroke), −0.28 (amputation) and −0.074 (blindness). The impact of end-stage renal disease on health-related quality of life was taken from the Health Outcomes Data Repository, a database of diabetic inpatients treated at Cardiff and Vale National Health Service Hospitals Trust, resulting in a loss in utility of −0.263. The impact of change in body weight on health-related quality of life was taken from a study of 100 Canadian patients with type\xa02 diabetes who completed a time trade-off exercise, which was commissioned by the manufacturers. Separate values were calculated for the changes in utility caused by a 1-unit decrease (+0.0171) or increase (−0.0472) in BMI. The impact of hypoglycaemic events on health-related quality of life was taken from a study by Currie et al. (2006) that estimated separate EQ‑5D utility decrements for symptomatic, nocturnal and severe events in UK patients with type\xa02 diabetes. The resulting utility decrements reported in the manufacturers' submissions were −0.042, −0.0084 and −0.047 respectively. The impact of urinary tract infections on health-related quality of life was taken from a study of urinary tract infections in ambulatory women, resulting in a utility decrement of −0.00283. In the absence of any other available data, the same utility values were used for genital infections.\n\nThe economic model included the acquisition costs of antidiabetic drugs taken from the England and Wales drug tariff (February 2012). The cost of insulin in the model was applied as a cost per kilogram of body weight per day, and therefore, varied in line with changes in patient body weight in the model simulation. The manufacturers assumed that insulin used as second- or third-line treatment in the model (with or without an oral antidiabetic) involved a 50% increase in dose over the initial starting dose in the add-on to metformin analysis, and a 25% increase in the add-on to insulin analysis.\n\nThe annual costs of macro- and microvascular diabetic complications, except for end-stage renal failure, were taken from UKPDS 65, which calculated the healthcare resource use of 3488 patients with type\xa02 diabetes. The UKPDS 65 study provided estimates of the first year event costs and the subsequent annual maintenance costs for patients who survived until the end of the simulation. The annual cost of end-stage renal failure (£34,806) was based on the weighted average cost of automated peritoneal dialysis, continuous ambulatory peritoneal dialysis, hospital haemodialysis and satellite unit-based haemodialysis, taken from a separate UK-based study. The cost of a severe hypoglycaemic event (£390) was taken from a study that measured health service costs incurred by 320 patients with type\xa02 diabetes in Germany, Spain and the UK who had experienced at least 1 hypoglycaemic event in the previous year. It was assumed that symptomatic and nocturnal hypoglycaemic events were not associated with any treatment costs. Urinary tract infections and genital infections were associated with the cost of a GP visit (£36). The costs of renal monitoring (£39), based on a GP visit and urine sample, were also included in the first year of the model only for the dapagliflozin treatment group. Treatment discontinuation was also assumed to incur the cost of a GP visit.\n\nThe manufacturers' base-case deterministic cost-effectiveness results for the add-on to metformin analyses found that the comparison between dapagliflozin and a sulfonylurea resulted in an incremental cost-effectiveness ratio (ICER) of £2671 per QALY gained (incremental costs £1246, incremental QALYs 0.467). The comparisons between dapagliflozin and DPP‑4 inhibitors and between dapagliflozin and thiazolidinediones found that dapagliflozin resulted in higher QALYs (incremental gains of 0.02 and 0.42 respectively) and lower costs (−£149 and −£60 respectively). Dapagliflozin therefore dominated both comparator treatments. For the add-on to insulin analysis, the comparison between dapagliflozin and DPP‑4 inhibitors resulted in an ICER of £4358 per QALY gained (incremental costs £517, incremental QALYs 0.119). The manufacturers' base-case deterministic cost-effectiveness results for the triple therapy analyses as add-on to metformin and a sulfonylurea found that dapagliflozin dominated DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues, resulting in lower costs and higher QALYs.\n\nThe manufacturers also presented 2 scenario analyses that included alternative BMI-related utility values. The scenarios applied utilities of ±0.0061 and ±0.0038 respectively for a ±1 unit change in BMI. Both values were taken from a study by Bagust et al. (2005) evaluating the impact of BMI on EQ‑5D utility in patients with type\xa02 diabetes, and had been used in NICE's guideline on type 2 diabetes and technology appraisal guidance on exenatide in combination with oral antidiabetic therapy. For the metformin add-on comparisons, the ICERs for dapagliflozin compared with a sulfonylurea were £8863 and £10,514 per QALY gained respectively. Dapagliflozin remained dominant for the comparison of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones. For the comparison of dapagliflozin with DPP‑4 inhibitors as add-on to insulin, the ICERs were also sensitive to changes to the BMI-related utility values. When changes in utility of ±0.0061 and ±0.0038 were applied, the ICERs increased to £21,171 and £32,409 per QALY gained respectively.\n\n## Evidence Review Group comments\n\nThe ERG commented on the scope of the appraisal and how the manufacturers addressed it in their submission. The ERG noted that the manufacturers did not include adults with type\xa02 diabetes that is inadequately controlled with sulfonylurea monotherapy in their submission. The ERG commented that the standard first-line monotherapy in type\xa02 diabetes is metformin, which is usually tolerated. The ERG noted that GLP‑1 analogues were not included as a comparator in the dual therapy setting, but considered that this was appropriate because their use in dual therapy is restricted. The ERG stated that NICE's guideline on type 2 diabetes recommends the use of pioglitazone as an alternative add-on treatment to a sulfonylurea in people with type\xa02 diabetes that is inadequately controlled by metformin. However, it also noted that there are increasing concerns about the adverse reactions associated with pioglitazone. The ERG commented that, in the triple therapy setting, DPP‑4 inhibitors would be expected to be given to patients before GLP‑1 analogues because they are cheaper and are administered orally. Overall, the ERG considered that DPP‑4 inhibitors are the key comparators for dapagliflozin in both the dual therapy and triple therapy settings.\n\nThe ERG stated that the manufacturers' approach to the systematic review of clinical evidence for dapagliflozin, which involved separate network meta-analyses for dapagliflozin as add-on therapy to metformin and as an add-on to insulin, was appropriate. The ERG noted that analyses were conducted for outcomes at 24\xa0weeks and at 52\xa0weeks and that studies reporting outcomes at less than 18\xa0weeks, between 30 and 46\xa0weeks, or greater than 58\xa0weeks were excluded from the review. The ERG commented that it was not clear whether studies of between 31 and 45 weeks or greater than 58 weeks were also identified in the review. However, in response to a request for clarification, the manufacturers provided a full list of identified trials, none of which were between 31 and 45 weeks' duration. The ERG also noted that, for the network meta-analysis of insulin add-on therapies, a post-hoc amendment to the protocol was made to include studies in the range of 24\xa0weeks ±8\xa0weeks instead of ±6\xa0weeks, to allow more studies to be included in the analysis.\n\nThe ERG commented that the manufacturers' approach to presenting the clinical effectiveness of dapagliflozin as a triple therapy add-on to metformin and a sulfonylurea was not very clear. Overall, the ERG considered that the methodology for the review of dapagliflozin in triple therapy (submitted as an addendum) was less robust than the main submission. However, the ERG acknowledged that the manufacturers had not intended to provide clinical-effectiveness data on dapagliflozin in triple therapy because of ongoing trial-based research due to report in 2013.\n\nThe ERG noted that the decision to switch or intensify treatment in the manufacturers' economic model was based on HbA1c levels above the thresholds currently recommended in the NICE guideline on type 2 diabetes. The ERG also noted that, when the manufacturers changed the HbA1c threshold levels in scenario analyses, along with changes to other input parameters, the ICERs for dapagliflozin increased. Overall, the ERG considered that the HbA1c threshold levels for switching treatment applied in the model reduced its relevance to UK clinical practice.\n\nThe ERG commented that the loss in utility associated with hypoglycaemic events, taken from Currie et al. (2006), may have been too large when applied within the model. The ERG noted from this study that a severe hypoglycaemic event in the previous 3\xa0months was interpreted by the authors as causing a 4.7% loss in utility (−0.047). The ERG considered that the loss in utility associated with hypoglycaemic events should have been applied for 3 months rather than 12 months, resulting in QALY losses of −0.012 and −0.004 for severe and symptomatic hypoglycaemic events respectively.\n\nThe ERG commented on the appropriateness of the utility values applied to weight change in the model. It noted that the majority of QALY gains associated with dapagliflozin arose from direct impact of weight change on health-related quality of life rather than diabetic complications or adverse events. The ERG noted that in study\xa012, the dapagliflozin treatment group experienced a lower gain in utility (0.018 versus 0.047) compared with placebo at 24\xa0weeks. However, when the utility estimates associated with changes in BMI were applied to the observed weight changes in study\xa012, the dapagliflozin treatment group experienced a higher gain in utility (0.016 versus 0.000) compared with placebo at 24\xa0weeks. The ERG also noted that the study by Bagust et al. involved a multivariate analysis of EQ‑5D utility values that controlled for the complications of diabetes and estimated a smaller change in utility (±0.0061) associated with a unit increase or decrease in BMI. The ERG considered these alternative utility values, which were applied in the manufacturers' scenario analyses, to be more reasonable.\n\nThe ERG noted that the weighted average annual costs of pioglitazone (£414.07), based on the England and Wales NHS drug tariff for February 2012, were substantially higher than those estimated from the November 2012 tariff (£139.16). The ERG also estimated different annual costs of DPP‑4 inhibitors as add-on to metformin (£450.51 as opposed to £433.57) and GLP‑1 analogues as add-on to metformin and a sulfonylurea (£946.26 as opposed to £886.90). With regard to the costs of macro- and microvascular diabetic complications, the ERG noted that the UKPDS 65 study also included annual inpatient (£157) and non-inpatient (£159) costs for patients who did not experience a complication. The ERG commented that these annual costs of £483 (after inflating from 1999 to 2011 prices) should have been applied in the model for patients who did not experience a diabetic complication.\n\nThe ERG noted that, although the model cycle length was 6\xa0months, the probabilities of macro- and microvascular events estimated from the UKPDS 68 study appeared to be for a 12‑month period and that no adjustment was made for this in the model. Further, the ERG noted from the DSU report on the economic model that the annual costs of macro- and microvascular events were not halved to correspond with the 6‑month cycle length used in the model but were applied in full immediately on the event occurring. The ERG commented that this would increase the annual costs of these events by half of the annual maintenance costs associated with the event.\n\nThe ERG noted that not all of the risk equations derived from the UKPDS 68 study were implemented in the model. From this study, the model implemented the risk of mortality in the year after a diabetic complication but not the risk of mortality in subsequent years after the event. Furthermore, risk equations for fatal myocardial infarction and fatal stroke were derived from a separate UKPDS study (number 66). This resulted in the risk of fatal myocardial infarction being a function of HbA1c and systolic blood pressure and the risk of fatal stroke being a function of systolic blood pressure only. The ERG considered that there was no obvious justification made by the manufacturers to include risk equations from this separate study. It also noted that this may have reduced the impact of HbA1c levels and increased the impact of systolic blood pressure in the model.\n\nThe ERG noted that, in the UKPDS 68 risk equations, baseline HbA1c was based on patients with newly diagnosed type\xa02 diabetes. However, the baseline HbA1c values implemented in the model were the trial baseline value minus the treatment-specific effect on HbA1c and therefore baseline HbA1c values differed between treatment groups. The ERG considered that the baseline HbA1c should have been the same for both treatment groups in the model. It noted that using different treatment-specific baseline HbA1c values resulted in the risk factor curves for both treatment groups not converging over time, whereas if the baseline HbA1c values had been the same for both treatment groups, the curves would have converged after the initial treatment effects. Similar considerations would apply to the other risk factors used in the UKPDS equations. Overall, the ERG concluded that the implementation of the UKPDS risk factor equations in the manufacturers' economic model may have been incorrect.\n\nSimilarly, the ERG noted that the event equation from UKPDS 68 used to estimate congestive heart failure included BMI at diagnosis. The ERG again noted that the baseline BMI values implemented in the model were the trial baseline value minus the treatment-specific effect on BMI and therefore that baseline BMI values differed between treatment groups. Because dapagliflozin was associated with a greater reduction in body weight compared with comparator drug therapies, the ERG considered that this may have biased the risk of congestive heart failure in favour of dapagliflozin. Furthermore, because the risk of congestive heart failure was associated with an increased risk of myocardial infarction and stroke, any overestimate of the rate of congestive heart failure would also result in an overestimate of the rate of myocardial infarction and stroke, along with the associated risk of fatality.\n\nIn the triple therapy analyses, the ERG considered that it was unnecessary for the model to include dual therapy with metformin and a sulfonylurea before switching to triple therapy. Because the model structure only permitted 3 lines of treatment, this resulted in patients switching to insulin and metformin after triple therapy. Therefore, unlike the dual therapy analyses, the triple therapy analysis did not enable patients to receive intensified insulin, which is associated with higher costs and additional weight gain.\n\n## Decision Support Unit comments\n\nThe DSU was commissioned by NICE to examine the economic model submitted by the manufacturers. The DSU was asked to report on whether the model functioned as described in the manufacturers' submission, to report any important aspects of the model that were not described in the submission, to examine whether the C++ programming code followed the steps described by the manufacturers and used the data described in the submission, and to check that the economic model produced the results described in the submission.\n\nThe DSU identified several differences between the economic model described in the submission and the executable model provided by the manufacturers. There were some differences between the macro- and microvascular event equations and risk factor equations in the model and those described in the manufacturers' submission. The effect of treatment on body weight was applied immediately in the model rather than gradually over the first year of treatment. All-cause mortality was not adjusted for fatal stroke and myocardial infarction events. The model did not apply the cost of renal monitoring to all patients who started treatment with dapagliflozin, although the DSU noted that this was unlikely to have a significant impact on the ICERs. There were some differences between the written submission and the model in regard to the time periods over which some of the costs and changes in utility were applied. The DSU also noted that the process used to sample from the relevant distributions in the probabilistic sensitivity analysis did not produce appropriately distributed samples, which may have underestimated the uncertainty around the QALYs estimated in the model.\n\nThe DSU identified several aspects of the executable model that were not described in the manufacturers' submission. In the manufacturer's model, the probability of an event occurring in a 6‑month cycle was calculated as the difference between the output of the event equation for the current cycle and the output of the event equation for the previous cycle. Treatment discontinuations applied in the first cycle of the model resulted in the patient switching treatment immediately without incurring costs or QALYs from the initial treatment except for the cost of discontinuation. The impact of treatment-related changes to BMI on health-related quality of life in the probabilistic sensitivity analysis was based on mean parameter values, which may have resulted in an underestimate of the uncertainty around the QALY differences estimated in the model.\n\nThe DSU commented that it was unable to reproduce the results of the probabilistic sensitivity analyses reported in the manufacturers' submission on the basis of the C++ programming code provided. However, the ICERs generated by the DSU did not vary substantially from those reported in the submission and it was noted that these differences may have arisen because of differences in the steps taken by the DSU to set up the probabilistic sensitivity analyses. When the DSU ran the model using the C++ programming code provided for the mean parameter values (deterministic analysis), it was also unable to reproduce the results of the deterministic analyses reported in the manufacturers' submission. Furthermore, when the DSU ran this code, it did not appear to have produced a stable estimate of the incremental QALYs after 100 runs. Finally, the DSU commented that the results generated by the programming code for the probabilistic sensitivity analyses when all parameters were set to their mean values did not match the results generated by the programming code that used mean parameter values. The DSU considered that similar results should have been produced and that this affected the confidence that could be placed on the results from the model.\n\n## Manufacturers' response to the appraisal consultation document\n\nThe manufacturers provided a response to the concerns raised by the DSU in its report on the economic model. The manufacturers stated that the economic model produced a stable estimate of the incremental costs and QALYs after 1000 rather than 100\xa0simulations. The manufacturers implemented changes to the risk factor progression and event equations, and to the gamma and beta distributions applied to the cost and utility parameters in the probabilistic sensitivity analysis. The manufacturers also amended the model source code to correct for errors in the calculation of transition probabilities and the adjustment of all-cause mortality.\n\nThe manufacturers presented revised network meta-analyses for the dual therapy and add-on to insulin therapy comparisons, based on the WinBUGs programme code included in the technical support documents published by the DSU (Technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials). The manufacturers also presented a validation exercise, which compared the results of the revised network meta-analyses with those presented in its original submission. The manufacturers commented that the revised analyses, which were provided as academic in confidence, produced similar results compared with the original analyses. The results of the revised 52‑week network meta-analysis were applied for the revised dual therapy analyses because these data enabled the same set of baseline characteristics and risk factors to be used for each comparator in the dual therapy analyses. The revised network meta-analysis at 24\xa0weeks was applied for the add-on to insulin analysis in the manufacturers' revised economic model.\n\nThe manufacturers provided further clarification about how changes in body weight were modelled over time for the different treatments. In addition, the manufacturers provided unpublished follow-up data from study\xa04 which, they stated, showed that patients who remained on dual therapy of dapagliflozin and metformin maintained their weight loss for up to 4\xa0years. The manufacturers therefore suggested that, for treatments associated with weight loss, the assumption in the model that this weight loss was maintained for 2\xa0years may have been conservative.\n\nThe manufacturers made a number of revisions to the economic model to address the ERG's concerns. The revised economic model applied the same baseline risk factors for all treatment groups, which were taken from the revised network meta-analyses for the dual therapy and add-on to insulin analyses. The manufacturers applied an HbA1c threshold level of 7.5%, as currently recommended NICE's guideline on type 2 diabetes, for switching treatment for the dual therapy analyses. However, the manufacturers commented that this threshold may not reflect UK clinical practice because patients with type\xa02 diabetes are reviewed by their clinicians only once or twice a year and are therefore likely to have HbA1c levels that exceed 7.5% at the time of review. For the triple therapy and add-on to insulin analyses, the manufacturers applied HbA1c thresholds of 8.61% and 9.04% respectively for switching treatment. For the triple therapy analyses, the manufacturers also revised the sequence of treatments in the revised model so that the starting treatment was triple therapy rather than dual therapy.\n\nIn their revised model, the manufacturers applied utility values of ±0.0061 per unit increase or decrease in BMI taken from the study by Bagust et al. The manufacturers commented that the ERG had misinterpreted how the loss in utility associated with hypoglycaemic events was applied over a 6‑month cycle in the economic model. Therefore, the manufacturers did not reduce the loss in QALYs associated with hypoglycaemia to −0.012 for a severe event and −0.004 for a symptomatic event in their revised base-case analyses (instead, retaining the original utility values). In scenario analyses, the manufacturers applied a range of upper (−0.0104) and lower (−0.000657) estimates of the loss in utility associated with urinary tract and genital infections taken from a systematic literature review as requested by the Committee. The manufacturers also reduced the average annual cost of pioglitazone from £414.07 to £112.18 and included an annual cost of £483 for people not experiencing diabetic complications in the revised economic model.\n\nThe manufacturers presented ICERs for the revised dual therapy analyses, which included clinical-effectiveness data from the revised 52‑week network meta-analyses, changes to the model in response to the DSU report, the same baseline patient characteristics and risk factors for all treatment groups, and an HbA1c switch threshold of 7.5%. As a result of these changes, the ICER for the comparison between dapagliflozin and sulfonylureas was £1498 per QALY gained. For the comparisons between dapagliflozin and DPP‑4 inhibitors and thiazolidinediones, the ICERs were £689 and £5342 per QALY gained respectively. A scenario analysis which applied the upper and lower estimates of the loss in utility associated with urinary tract and genital infections resulted in very small changes to the ICERs for all comparisons.\n\nThe manufacturers also presented ICERs for the revised dual therapy analyses which included the changes described in section 3.49 and additional changes, which included reduced costs of pioglitazone, adjusted costs of diabetic complications and utility values of ±0.0061 per unit increase or decrease in BMI. As a result of these additional changes, the ICER for the comparison between dapagliflozin and sulfonylureas was £7735 per QALY gained. For the comparisons between dapagliflozin and DPP‑4 inhibitors and between dapagliflozin and thiazolidinediones, the ICERs were £3337 and £77,615 per QALY gained respectively.\n\nThe manufacturers presented ICERs for the revised add-on to insulin analyses, which included clinical-effectiveness data from the revised 24‑week network meta-analyses, changes to the model in response to the DSU report and an HbA1c switch threshold of 9.04%. As a result of these changes, the ICER for the comparison between dapagliflozin and DPP‑4 inhibitors was £2509 per QALY gained. A scenario analysis that applied the upper and lower estimates of the loss in utility associated with urinary tract and genital infections resulted in very small changes to the ICER. The manufacturers also presented an ICER that included adjusted costs of diabetic complications and utility values of ±0.0061 per unit increase or decrease in BMI. As a result of these additional changes, the ICER increased to £5634 per QALY gained.\n\nThe manufacturers also presented ICERs for the revised triple therapy analyses, which included altering the treatment sequences in the model so that patients in the model started treatment with triple add-on therapy to metformin and a sulfonylurea, incorporating model structural changes and applying an HbA1c switch threshold of 8.61%. As a result of these changes, dapagliflozin continued to dominate DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues. The manufacturers did not present any additional scenario analyses for the relevant comparisons in triple therapy.\n\nThe manufacturers presented the results of a validation exercise, which compared the results from the revised model with the results that would have been obtained from using the CORE diabetes model for all relevant comparisons in dual therapy, insulin add-on therapy, and triple therapy. For the dual therapy analyses, the CORE model produced an ICER of £8879 per QALY gained for the comparison of dapagliflozin with sulfonylureas and ICERs of £2014 and £7093 per QALY gained for the comparisons of dapagliflozin with DPP‑4 inhibitors and with thiazolidinediones. For the insulin add-on analyses, the CORE model resulted in an ICER of £1675 per QALY gained for dapagliflozin compared with DPP‑4 inhibitors. For the triple therapy analyses, the CORE model produced ICERs of £1759 per QALY gained for the comparison of dapagliflozin with DPP‑4 inhibitors and £16,054 per QALY gained for the comparison of dapagliflozin with thiazolidinediones. The CORE model also produced an ICER of £32,243 per QALY lost for the comparison of dapagliflozin with GLP‑1 analogues.\n\nBoth the ERG and the DSU reviewed the manufacturers' revised economic model and analyses provided in response to the appraisal consultation document. Overall, the DSU considered that the manufacturers had adequately addressed all of the significant areas of concern about the model. The ERG noted that the revised dual therapy analyses used clinical-effectiveness data from the revised 52‑week network meta-analyses rather than the revised 24‑week network meta-analyses, which resulted in significant changes to the model input parameters. The ERG noted that, as a result of applying a lower HbA1c threshold for switching treatment, the revised model resulted in switching treatment earlier and thus reducing the costs of first-line dapagliflozin treatment whilst maintaining any long-term weight loss. The ERG also noted that the manufacturers' revised economic model had incorrectly amended the costs for people who did not experience diabetic complications.\n\nThe ERG highlighted a number of concerns about how changes in body weight were modelled in the manufacturers' revised analyses. The ERG noted that the manufacturers stated that, in order to simulate a linear, gradual regain of weight, the time to loss of weight effect was set such that weight was regained by the time of switch to next treatment. However, the ERG noted that in the manufacturers' comparisons of dapagliflozin with sulfonylureas and with DPP‑4 inhibitors in the revised dual therapy analyses, weight loss associated with dapagliflozin was largely maintained and not reversed at the time of switching to next treatment. The ERG also noted that the manufacturers' revised economic model and analyses did not address the Committee's concerns about the duration over which differences in weight change were maintained between treatments.\n\n## Additional DSU analysis in response to the revised manufacturers' model\n\nIn response to the concerns about the manufacturers' revised economic model raised by the ERG, the DSU was asked to review the manufacturers' revised economic analyses and to assess further how changes in weight were modelled over time for different treatments in the revised model. The DSU was also asked to conduct a range of further exploratory analyses for dapagliflozin in dual therapy and add-on to insulin therapy.\n\nThe DSU noted that, in the manufacturers' revised economic model, the assumptions about the duration over which any treatment-related weight change was reversed for the comparison of dapagliflozin with thiazolidinediones as add-on to metformin and the add-on to insulin analyses were consistent with those used in the original model. Therefore, for treatments associated with weight loss, weight was regained before first treatment switch. However, the DSU noted that for the comparisons of dapagliflozin as add-on to metformin with sulfonylureas and DPP‑4 inhibitors, treatment-related weight loss was not reversed at treatment switch in the revised model. The DSU suggested that the weight profiles for dapagliflozin and DPP‑4 inhibitors may have been incorrectly amended in the model.\n\nThe DSU noted that, for second- and third-line treatments, the weight at the start of treatment in the revised model was based on the weight at the time of switching from the previous treatment. The DSU noted that this was problematic if the treatment switch occurred before the treatment-related weight loss was regained. The DSU stated that where this happened this resulted in a weight difference between treatment groups that is maintained throughout the duration of the model. The DSU amended the manufacturers' revised model to ensure that, if a treatment switch occurred before the weight loss was fully regained, the starting weight at the next line of treatment was set equal to the weight that would have been achieved after the weight regain for the previous treatment. This resulted in a convergence of weight profiles over time for treatments associated with weight loss.\n\nThe DSU applied a number of changes and assumptions to the manufacturers' revised model, in addition to the amendment described in section 3.58. These included:\n\nfor the dual therapy analyses, using clinical-effectiveness data from the revised 24‑week network meta-analyses for the comparisons of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones and from study\xa04 for the comparison of dapagliflozin with a sulfonylurea\n\napplying an HbA1c threshold of 7.5% for switching to second-line and third-line treatment in the dual therapy analysis and for switching to second-line treatment in the add-on to insulin analysis\n\nfor any treatments associated with weight loss, assuming weight regain during year\xa03 to the level expected in a patient who experiences a natural weight gain of 0.1\xa0kg per year from the start of treatment\n\nassuming no diabetic complications at the start of treatment\n\nreducing the loss in QALYs associated with hypoglycaemia to –0.012 for a severe event and –0.004 for a symptomatic event\n\nusing utility values associated with weight change of ±0.0061 per unit of BMI\n\nreducing the annual cost of pioglitazone to £69.09 based on the latest NHS drug tariff\n\nusing an annual cost of £483 for people not experiencing diabetic complications.\n\nFor the dual therapy analyses, using data from the 24‑week network meta-analysis, the DSU base-case deterministic pair-wise analysis resulted in ICERs of £13,338 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £13,947 per QALY gained for the comparison of DPP‑4 inhibitors with thiazolidinediones. An incremental analysis resulted in ICERs of £13,338 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £16,847 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin (based on incremental costs of £136 and incremental QALYs of 0.008). Using data from study\xa04, the pair-wise comparison of dapagliflozin and sulfonylureas resulted in an ICER of £12,405 per QALY gained.\n\nThe DSU also conducted a probabilistic sensitivity analysis based on a mean of 1000 samples. Using data from the 24‑week network meta-analysis, the analysis resulted in pair-wise ICERs of £15,257 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £15,511 per QALY gained for the comparison of DPP‑4 inhibitors with thiazolidinediones. An incremental analysis resulted in ICERs of £15,257 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £41,654 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin (based on incremental costs of £17 and incremental QALYs of less than 0.001). Using data from study\xa04, the comparison of dapagliflozin and sulfonylureas resulted in an ICER of £15,148 per QALY gained. The DSU noted that in the probabilistic sensitivity analysis, people spent longer on first-line treatment because of the interaction between baseline HbA1c values, treatment switching threshold and effectiveness data, thus resulting in higher incremental costs and ICERs than the deterministic analysis. The results of these probabilistic sensitivity analyses also showed that, at £20,000 per QALY gained, dapagliflozin had the highest probability (40.4%) of being cost effective compared with DPP‑4 inhibitors (35.5%) and thiazolidinediones (24.1%) and also the highest probability (61.0%) of being cost effective compared with sulfonylureas.\n\nThe DSU conducted a scenario analysis that applied the manufacturers' original utility values associated with hypoglycaemia (–0.047 for a severe event and –0.042 for a symptomatic event). As a result of this change, dapagliflozin was extendedly dominated by DPP‑4 inhibitors and thiazolidinediones, because the ICER of dapagliflozin compared with thiazolidinediones was higher than that of the next most effective alternative (DPP‑4 inhibitors). The comparison of dapagliflozin and sulfonylureas resulted in an ICER of £10,317 per QALY gained. The DSU also conducted a scenario analysis which used the same clinical-effectiveness data from the 52‑week network meta-analysis as those used in the manufacturers' revised model, thus allowing all treatments to be compared with each other in a single analysis. On the basis of a full incremental analysis, DPP‑4 inhibitors were dominated by thiazolidinediones. The comparison of thiazolidinediones and sulfonylureas resulted in an ICER of £12,108 per QALY gained and the comparison of dapagliflozin and thiazolidinediones resulted in an ICER of £94,466 per QALY gained.\n\nThe DSU conducted an additional scenario analysis to explore the impact of weight convergence between treatment groups at the time of switching to the last line of treatment. In the manufacturers' revised model for the dual therapy analyses, the DSU modelled weight convergence between dapagliflozin (associated with weight loss) and a sulfonylurea (associated with weight gain) by increasing the weight gain for the last treatment in the sequence (insulin treatment). For this scenario analysis the DSU presented pair-wise ICERs using the data from the 24‑week network meta-analysis and separately the data from study\xa04. Applying the 24‑week meta-analysis data resulted in a higher ICER of £60,965 per QALY gained for the pair-wise comparison of dapagliflozin with thiazolidinediones and an ICER of £16,847 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin. The ERG noted that the latter ICER was largely unchanged from its base-case analysis because the weight profiles at last treatment switch were very similar across the 2\xa0treatment groups. The pair-wise comparison of dapagliflozin and sulfonylureas using study\xa04 data resulted in an ICER of £21,200 per QALY gained.\n\nThe DSU noted that in the manufacturers' revised add-on to insulin analysis, the time to weight regain was set to occur before first treatment switch based on an HbA1c threshold of 9.04%, resulting in a switch to second-line treatment at 8\xa0years. The DSU explored the impact of setting a time to weight regain of 1\xa0year and an HbA1c switching threshold of 7.5% in line with the dual therapy analyses. The DSU also applied all other changes as described in section 3.59. The DSU base-case deterministic pair-wise analysis of dapagliflozin compared with DPP‑4 inhibitors resulted in an ICER of £3706 per QALY gained. The probabilistic sensitivity analysis resulted in a longer duration of first-line treatment and incremental costs for dapagliflozin, and consequently in a higher ICER of £7402 per QALY gained. When the DSU applied the manufacturers' original utility values associated with hypoglycaemia, the ICER was reduced to £2959 per QALY gained. When the DSU applied the assumption of weight convergence at last treatment switch, the ICER increased to £12,879 per QALY gained. The DSU noted that this scenario resulted in longer first-line treatment duration for people before switching to insulin treatment in both treatment groups and consequently, higher incremental costs for dapagliflozin.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dapagliflozin, having considered evidence on the nature of dapagliflozin and the value placed on the benefits of dapagliflozin by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the clinical treatment pathway for type\xa02 diabetes. The Committee heard from the clinical specialists that treatment for type\xa02 diabetes is individualised for each patient (focusing on HbA1c reduction without weight gain or hypoglycaemia), resulting in some variation in clinical practice. However, although treatment is individualised, current UK practice broadly follows the NICE guideline on type 2 diabetes, which recommends a stepwise approach that includes using diet and exercise, various antidiabetic drugs and insulin. The Committee heard from the clinical specialists that each of the existing antidiabetic therapies had various advantages and disadvantages affecting their suitability for patients and that many patients do not achieve target HbA1c levels with existing therapies. The Committee heard from the clinical specialists that dapagliflozin may be more likely to be used as a triple therapy but could be used as a dual therapy if there was a perceived risk of hypoglycaemia. It was noted that its use may be limited by the restrictions in the marketing authorisation, which states that dapagliflozin is not recommended for use in people with moderate to severe renal impairment. The Committee understood that a new treatment providing an additional option would be valued by clinicians.\n\nThe Committee discussed the antidiabetic drugs that were used at each point in the treatment pathway for type\xa02 diabetes. The Committee heard from the clinical specialists that most people start treatment with metformin and that the use of a sulfonylurea as first-line therapy is diminishing because of the associated weight gain and the high incidence of hypoglycaemia compared with other oral therapies. The Committee heard from the clinical specialists that a sulfonylurea is often added to metformin as a dual therapy but if patients are unable to take a sulfonylurea because of concerns about weight gain or hypoglycaemia, then thiazolidinediones (pioglitazone), DPP‑4 inhibitors and GLP‑1 analogues may be used. The clinical specialists also commented that the same treatments could be used in triple therapy and as add-on to insulin therapy. The Committee heard from the clinical specialists that the use of DPP‑4 inhibitors was increasing and that the use of pioglitazone was decreasing because of concerns about safety. It was also aware that GLP‑1 analogues were used less frequently and usually later on in the treatment pathway because they are administered by subcutaneous injection and are more costly than other antidiabetic drugs. The Committee concluded that on the basis of the evidence from the clinical specialists, dapagliflozin was most likely to be used if a sulfonylurea was not appropriate, and the main comparator for dapagliflozin would be the DPP‑4 inhibitors.\n\nThe Committee heard evidence from the patient experts that an advantage of dapagliflozin is that it will provide a further treatment option for people with type\xa02 diabetes who are reluctant to start treatment with insulin or wish to avoid insulin therapy because of fear of hypoglycaemia and its impact on their lifestyle (for example, the threat of losing their driving licence or their job). The Committee heard from the patient experts that the potential disadvantages of dapagliflozin include more frequent urinary tract and genital infections. However, the patient experts commented that the importance of these events would vary between individual patients and that, for some patients, the higher risk of urinary or genital infections could be balanced by the lower risk of hypoglycaemia. The Committee also heard from the patient experts that because dapagliflozin causes the excretion of glucose through the urine, this may cause anxiety for some patients who understand an absence of glucose in the urine to be a sign of good diabetes management and that this may lead to non-adherence to dapagliflozin therapy. However, the clinical specialists suggested that this was a risk that could be managed by providing appropriate information to people with diabetes.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence on the clinical effectiveness of dapagliflozin compared with other antidiabetic therapies, noting that most of the data came from the network meta-analyses submitted by the manufacturers. The Committee noted that, although the WinBUGs programme code used to run the original network meta-analyses provided in the manufacturers' submission differed from the code recommended by the NICE DSU in their technical support document, the manufacturers had also provided revised network meta-analyses that were based on the recommended code. The Committee also noted that the results of the manufacturers' revised network meta-analyses were similar to those from the original analyses. The Committee concluded that the results of the manufacturers' revised network meta-analyses provided an appropriate basis for making decisions about the clinical effectiveness of dapagliflozin and other antidiabetic therapies.\n\nThe Committee discussed the outcomes collected in the clinical trials and network meta-analyses, noting that the primary outcomes were intermediate rather than clinical outcomes. The Committee noted that studies including the UKPDS had then been used to provide a link between these intermediate outcomes and long-term clinical outcomes including micro- and macrovascular complications. The Committee heard from the clinical specialists that there was some uncertainty about the impact of HbA1c reduction on longer-term macrovascular complications. The Committee also heard from the manufacturers that follow-up data were available for the clinical trials of dapagliflozin but that, because most of the trials of other antidiabetic drug therapies were of shorter duration, the clinical-effectiveness data used in the cost-effectiveness analysis had to be based on the short-term clinical trial data. The Committee concluded that, despite some uncertainty about the impact of HbA1c reduction on longer-term macrovascular complications, it was prepared to accept the link between the intermediate outcomes collected in the clinical trials and the longer-term clinical outcomes.\n\nThe Committee considered the clinical effectiveness of dapagliflozin in dual therapy for people whose type\xa02 diabetes is inadequately controlled by metformin alone. The Committee noted that the evidence came from 3 clinical trials and a network meta-analysis. The Committee also noted that only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylureas), and that the clinical trial results were based on a relatively small number of patients who were given dapagliflozin at its licensed dose. However, on the basis of these clinical trial results, the Committee considered dapagliflozin to have greater efficacy than sulfonylureas for the outcomes of weight loss and systolic blood pressure reduction and similar efficacy for HbA1c reduction. The Committee concluded that, on the basis of the results of the network meta-analyses (see sections 3.10 and 3.45), dapagliflozin in dual therapy as add-on to metformin appeared to provide similar glycaemic control to other antidiabetic drugs but may result in greater weight loss.\n\nThe Committee further considered the clinical effectiveness of dapagliflozin as dual therapy, noting that the manufacturers had not provided data on dapagliflozin as add-on therapy to a sulfonylurea, despite clinical trial data being available. The Committee accepted that most of the patients would start on metformin monotherapy, but noted the evidence provided by the clinical specialists that a proportion of patients who cannot tolerate metformin or for whom it is contraindicated would receive sulfonylurea monotherapy. It noted that the clinical effectiveness of dapagliflozin as an add-on to a sulfonylurea appeared to be consistent with its effectiveness when used as an add-on to metformin. The Committee concluded that, because the manufacturers had not provided clinical evidence on dapagliflozin as an add-on to a sulfonylurea, it could not make recommendations on this combination regimen.\n\nThe Committee considered the clinical effectiveness of dapagliflozin for people whose type\xa02 diabetes is inadequately controlled by insulin, noting that the evidence came from 2 clinical trials and a network meta-analysis. The Committee noted that both trials were placebo controlled and that 1 of these was of 12\xa0weeks' duration only. Again, the Committee noted that the clinical trial results for dapagliflozin were based on a relatively small number of patients who were treated with dapagliflozin at its licensed dose. Further, the Committee noted that the network meta-analysis excluded trials of GLP‑1 analogues because they were not comparable to other trials included in the analysis and therefore consideration of the full range of possible comparators was restricted by the available evidence. The Committee concluded that, on the basis of the results of the network meta-analyses (see sections 3.12 and 3.45), dapagliflozin as add-on therapy to insulin appeared to have greater efficacy than DPP‑4 inhibitors for the outcome of weight loss and similar efficacy for HbA1c reduction.\n\nThe Committee considered the evidence on the clinical effectiveness of dapagliflozin in triple therapy. The Committee noted that dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents and that, in the absence of any other currently available clinical-effectiveness data, the manufacturers provided a post-hoc analysis of pooled data from a subset of older patients with type\xa02 diabetes and cardiovascular disease recruited in 2 trials of dapagliflozin as an add-on to metformin and a sulfonylurea. The Committee also noted that no direct head-to-head studies comparing dapagliflozin with other antidiabetic drugs currently exist and that the clinical-effectiveness data used to indirectly compare dapagliflozin with other antidiabetic drugs were taken from a previously published systematic review that had not been updated since 2009. It was aware of the limitations of these analyses highlighted by the manufacturer and therefore concluded that significant caution should be taken when interpreting the results of these preliminary analyses on the clinical effectiveness of dapagliflozin in the triple therapy setting.\n\nThe Committee considered the adverse events associated with dapagliflozin. It noted that common adverse events included urinary tract and genital infections and that these events were more common in women than in men. However, the Committee heard from the manufacturers that the recurrence of these events in the clinical trials was low. It also heard from the manufacturers that, because of the mechanism of action of dapagliflozin, the clinical trials had actively looked for such infections and that only a small proportion of these infections needed treatment. The Committee also noted that the incidence of hypoglycaemia was low when dapagliflozin was added to metformin and that the currently available evidence suggested that dapagliflozin was not associated with increased risk of cardiovascular events. However, it was aware that regulatory agencies had identified some uncertainty about the risk of some cancers associated with dapagliflozin. The Committee heard from the patient experts that adverse events were a concern for patients with type\xa02 diabetes if they result in the need for additional drug therapies, especially for patients who are already receiving many drug therapies for their condition. However, it also recognised that a new drug therapy that was associated with a lower risk of hypoglycaemia than some other existing therapies would also be valued by patients for whom driving might be a significant factor in their lifestyle or livelihood. The Committee concluded that the adverse-events profile of dapagliflozin was different from those of other antidiabetic therapies and that it was important to examine these adverse events when considering the manufacturers' economic model.\n\n# Cost effectiveness\n\nThe Committee considered the cost effectiveness of dapagliflozin as an add-on to metformin and insulin and as triple therapy in the manufacturers' submission, and the critique and exploratory analyses provided by the DSU and the ERG. The Committee noted that the manufacturers had provided a revised economic model in order to address concerns raised by the DSU about the original model and that the DSU considered that their concerns had been addressed. However, it also noted that the DSU and the ERG had identified a number of errors in the revised model which were subsequently addressed by the DSU in its exploratory analyses. The Committee concluded that the manufacturers' revised economic model with the subsequent amendments made by the DSU was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type\xa02 diabetes.\n\nThe Committee discussed the validation report provided by the manufacturers which compared the results from the revised model with the results that would have been obtained using the CORE diabetes model, which has been used in previous appraisals of treatments for type\xa02 diabetes (such as NICE's technology appraisal guidance on liraglutide and exenatide in combination with oral antidiabetic therapy). The Committee noted that the results generated from the CORE diabetes model were comparable to those obtained from the manufacturers' original and revised economic models for the dual therapy and insulin add-on therapy analyses. The Committee concluded that the results of the validation exercise with the CORE diabetes model provided reassurance about the integrity of the results obtained from the manufacturers' revised economic model.\n\nThe Committee discussed the cost-effectiveness analyses presented by the manufacturers, noting that these included a more restricted set of comparators than were specified in the scope. It was aware that GLP‑1 analogues had been included in the network meta-analysis for dual therapy but then subsequently excluded from the cost-effectiveness analysis. The Committee considered that it would have been more appropriate for all treatments in the network meta-analysis to have been included in the cost-effectiveness analysis. However, it noted the comments from the ERG and clinical specialists that GLP‑1 analogues were used in dual therapy on a restricted basis. On balance, the Committee concluded that the manufacturers had included an adequate range of comparators for the cost-effectiveness analysis of dapagliflozin in dual therapy as an add-on to metformin.\n\nThe Committee discussed the clinical-effectiveness data that were applied in the economic models. The Committee noted that the DSU had completed analyses of dual therapy add-on to metformin using different sources of clinical-effectiveness data. One analysis used the 24‑week network meta-analysis data for dapagliflozin, DPP‑4 inhibitors and thiazolidinediones and presented a separate comparison using head-to-head data from study\xa04 for dapagliflozin and sulfonylureas. The other analysis considered all treatments in a single analysis using the 52‑week network meta-analysis data. It heard from the manufacturers that, for the metformin add-on analyses, the trials of other antidiabetic therapies as add-on to metformin used a fixed dose but the trials of sulfonylureas did not have a stable dose over 24\xa0weeks. Therefore, trials of sulfonylureas as an add-on to metformin were excluded from the 24‑week network meta-analysis. The Committee discussed which set of analyses was the most appropriate, noting that the estimates of efficacy differed between analyses. It considered that it was more appropriate to use a single source as was available in the 52‑week network meta-analysis, but was aware of the limited number of trials informing this analysis. The Committee noted that the 24‑week network meta-analysis only excluded sulfonylureas, and that the evidence from the clinical specialists suggested that dapagliflozin would be used where sulfonylureas were not appropriate. On this basis the 24‑week network meta-analysis data were appropriate. The Committee concluded that the results of the revised 24‑week network meta-analysis provided the most appropriate clinical-effectiveness data for the dual therapy analyses.\n\nThe Committee discussed the manufacturers' assumptions about the decision to switch or intensify treatment in the model, noting that this was based on baseline HbA1c levels taken from the clinical trials and network meta-analysis. The Committee noted that the HbA1c threshold levels for switching treatment in the original dual therapy and triple therapy analyses were above those recommended in NICE's guideline on type 2 diabetes and therefore may not reflect UK clinical practice. However, the Committee noted that the DSU's revised analyses applied an HbA1c threshold for switching treatment that is currently recommended in NICE's guideline on type 2 diabetes. The Committee heard from the DSU that the results from the revised model were sensitive to the timing of treatment switching in the model which was dependent on the relationship between HbA1c at the start of treatment, treatment-related changes in HbA1c levels and the HbA1c threshold levels for switching treatment. The Committee concluded that HbA1c threshold levels for switching treatment as recommended in NICE's guideline on type 2 diabetes were appropriate to use in the economic modelling and as a basis for decision-making.\n\nThe Committee discussed the manufacturers' approach to modelling changes in body weight. The Committee noted that in the revised model the effect of treatment on changes in weight was applied gradually over the course of the first year, and considered that this was more plausible than the original model in which the effect of treatment on changes in weight was applied immediately. The Committee noted that, for treatments associated with weight loss, the manufacturers made assumptions about how long weight loss was maintained in the model (weight plateau), and about how long it took for the weight to increase to its baseline level after the plateau (loss of effect). The Committee understood that the changes made by the DSU meant that for treatments associated with weight loss, the weight profiles of the treatment groups now converged over time, but that for treatments associated with weight gain, differences in weight were maintained over the model time horizon. The Committee acknowledged that unpublished data from the clinical study of dapagliflozin and sulfonylureas as add-on to metformin provided by the manufacturers showed that patients who remained on dapagliflozin treatment without switching to other treatments maintained their weight loss over 4\xa0years. However, the Committee considered that uncertainty remained about the effects of stopping treatment with dapagliflozin and the impact on weight gain. Therefore, it concluded that the scenario analysis conducted by the DSU, which involved the convergence of differences in weight profiles between treatment groups at the time of switching to the last line of treatment, was more appropriate for decision-making.\n\nThe Committee considered the utility values applied in the model, noting that in all analyses the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than from a reduction of diabetic complications and other adverse events. The Committee noted that utility values associated with changes in BMI were taken from a study commissioned by the manufacturers and that the methods by which these values were obtained were not in line with the NICE reference case for measuring and valuing health effects. The Committee also noted that this study produced different utility values associated with a 1-unit increase or decrease in BMI and that these were larger than other utility values that were identified in the literature. The Committee acknowledged that the manufacturers presented scenario analyses using alternative utility values for weight change and that these resulted in higher ICERs for the metformin and insulin add-on analyses. The Committee also noted that the loss in utility associated with a 1-unit increase in BMI (−0.0472) was similar to the loss in utility associated with a myocardial infarction (−0.055), which may not be credible. The Committee concluded that the utility values associated with changes in weight may have been too large and that the values (±0.0061 per BMI unit decrease or increase) applied in the manufacturers' scenario analyses and DSU analyses were more reasonable.\n\nThe Committee considered the utility values associated with hypoglycaemic events. The Committee heard from the ERG that they considered that the loss in QALYs associated with hypoglycaemic events may have been too large. The Committee was also aware that the loss in utility associated with severe hypoglycaemic events (−0.047) was higher than that applied in the economic model of third-line therapy with insulins, thiazolidinediones or exenatide in NICE's guideline on type 2 diabetes (−0.010). However, the Committee noted that after the publication of this guideline, the Driving and Vehicle Licensing Agency issued new regulations for people who have experienced a severe hypoglycaemic event in the previous 12\xa0months. Therefore, the Committee acknowledged that any loss in utility associated with severe hypoglycaemic events may be higher in people for whom driving might be a significant factor in their lifestyle or livelihood. The Committee noted that the DSU had completed analyses that included both the higher and lower estimates of loss of utility associated with hypoglycaemic events, and that these had made small differences to the estimates of the ICER. The Committee therefore concluded that the utility values associated with hypoglycaemic events were not a critical factor in the decision-making.\n\nThe Committee considered the utility values applied to urinary tract and genital infections in the model, noting that the loss in utility associated with these events was much smaller than the loss in utility associated with other adverse events. The Committee considered that it was likely that there would be a greater loss in utility associated with these events than had been proposed by the manufacturers. The Committee also noted that the study commissioned by the manufacturers to examine the impact of weight change on health-related quality of life had also estimated the impact of urinary tract and genital infections, although these data were not presented in the manufacturers' submission. The Committee noted that in scenario analyses the manufacturers had applied a range of estimates for the loss in utility associated with urinary tract and genital infections. It was also aware that the results of the revised analyses were not sensitive to changes in these utility values. The Committee concluded that, although the loss in utility associated with urinary tract and genital infections was likely to be greater than that proposed by the manufacturers, it was satisfied that this did not significantly impact on the relative cost effectiveness of dapagliflozin as dual therapy or add-on to insulin.\n\nThe Committee was aware that the ERG had proposed alternative estimates for some costs, including drug acquisition costs for pioglitazone and the costs associated with diabetic complications. The Committee noted that pioglitazone is now off-patent and that the latest acquisition costs are substantially lower than those presented in the manufacturers' submission. The Committee acknowledged that the manufacturers were unable to provide this estimate in their submission, but considered that the DSU estimate of an average annual cost of £69.09 was reasonable. The Committee also noted that the manufacturers' revised model did not correctly adjust the annual inpatient and non-inpatient costs (estimated as £483 in the UKPDS\xa065 study) for people who did not experience a macro- or microvascular diabetic complication. The Committee concluded that it was appropriate to consider the latest acquisition cost of pioglitazone and that the manufacturers' revised model should be amended to correctly account for the annual costs incurred by people who did not experience a macro- or microvascular diabetic complication.\n\nThe Committee considered the most plausible ICERs for dapagliflozin as dual therapy in combination with metformin. The Committee considered that, on the basis of clinical specialist opinion that suggested that the use of pioglitazone in UK clinical practice was decreasing, a thiazolidinedione was not a key comparator in the dual therapy setting. The Committee also noted the evidence from the clinical specialists supported by the manufacturers that, in clinical practice, dapagliflozin would predominantly be used in combination with metformin when a sulfonylurea is not appropriate. Therefore, the Committee also considered that sulfonylureas were not a relevant comparator in the dual therapy setting. The Committee considered the DSU deterministic analysis and scenario analyses, which included the convergence of differences in weight between treatment groups at the time of switching to the last line of treatment. It noted that these showed that DPP‑4 inhibitors were associated with higher costs and QALYs than dapagliflozin, but that these differences were small. It noted further that in the DSU probabilistic sensitivity analysis these differences were even smaller. The Committee noted that the differences in QALYs were largely explained by the changes in health-related quality of life (utility) associated with changes in weight (BMI). Overall, the Committee concluded that because of the small differences in costs and QALYs between dapagliflozin and DPP‑4 inhibitors, dapagliflozin in a dual therapy regimen in combination with metformin could be recommended as a treatment option for people with type\xa02 diabetes that is inadequately controlled with metformin alone if it is used in the same scenario as described for the use of DPP‑4 inhibitors in NICE's guideline on type 2 diabetes.\n\nThe Committee considered the most plausible ICERs for dapagliflozin as add-on to insulin. It noted that in all the analyses conducted by the DSU the estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors was below £20,000 per QALY gained. The Committee considered that, in comparison to DPP‑4 inhibitors, dapagliflozin had been shown to be a cost-effective use of NHS resources. The Committee recommended dapagliflozin as a treatment option for people with diabetes inadequately controlled by insulin with or without other oral antidiabetic drugs.\n\nThe Committee discussed the results of the manufacturers' revised base-case analyses for dapagliflozin as triple therapy add-on to metformin and a sulfonylurea. It noted that the sequence of treatments in the manufacturers' revised economic model had been amended so that the approach was consistent with the dual therapy and insulin add-on analyses, with patients in the model starting treatment with triple add-on therapy. The Committee noted that in both the manufacturers' original and revised triple therapy analyses, dapagliflozin dominated other comparator drug therapies, meaning that dapagliflozin was associated with lower costs and higher QALYs than the comparators. However, the Committee noted that the clinical-effectiveness data applied in the triple therapy model were based on an indirect comparison of pooled data of 2\xa0trials of dapagliflozin and a separate systematic review of other antidiabetic drug therapies conducted in 2009. The Committee was also aware that dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents. The Committee considered that the cost-effectiveness analyses should be considered as exploratory in nature. The Committee concluded that dapagliflozin as triple therapy in combination with metformin and a sulfonylurea should not be recommended for treating type\xa02 diabetes except as part of the ongoing clinical trials.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA288\n\nAppraisal title: Dapagliflozin in combination therapy for treating type\xa02 diabetes\n\nSection\n\nKey conclusion\n\nDapagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type\xa02 diabetes, only if it is used as described for dipeptidyl peptidase-4 (DPP‑4) inhibitors in the NICE guideline on type 2 diabetes.\n\nDapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type\xa02 diabetes.\n\n, 1.2\n\nFor dapagliflozin dual therapy regimens in combination with metformin, the Committee concluded that because of the small differences in costs and QALYs between dapagliflozin and DPP‑4 inhibitors, dapagliflozin in a dual therapy regimen in combination with metformin could be recommended.\n\nFor dapagliflozin as add-on to insulin all the analyses conducted by the DSU produced an estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors below £20,000 per QALY.\n\nDapagliflozin in a triple therapy regimen is currently being studied as an add-on to 2 other oral agents. The Committee considered that the cost-effectiveness analyses should be considered as exploratory in nature.\n\n, 4.23, 4.24\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard evidence from the patient experts that an advantage of dapagliflozin is that it will provide a further treatment option for people with type\xa02 diabetes who are reluctant to start treatment with insulin or wish to avoid insulin therapy because of fear of hypoglycaemia and its impact on their lifestyle (for example, the threat of losing their driving licence or their job).\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee recognised that a new drug therapy that was associated with a lower risk of hypoglycaemia than some other existing therapies would be valued by patients for whom driving might be a significant factor in their lifestyle or livelihood.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that dapagliflozin may be more likely to be used as a triple therapy but could be used as a dual therapy if there was a perceived risk of hypoglycaemia. The Committee concluded that on the basis of the evidence from the clinical specialists, dapagliflozin was most likely to be used if a sulfonylurea was not appropriate, and the main comparator for dapagliflozin would be the DPP‑4 inhibitors.\n\n, 4.3\n\nAdverse reactions\n\nCommon adverse events included urinary tract and genital infections and these events were more common in women than in men. However, the Committee heard from the manufacturers that the recurrence of these events in the clinical trials was low.\n\nThe Committee concluded that the adverse-events profile of dapagliflozin was different from those of other antidiabetic therapies and that these adverse events were important to examine when considering the manufacturers' economic model.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nFor dapagliflozin as an add-on to metformin, the evidence came from 3 clinical trials and a network meta-analysis. Only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylurea) and the clinical effectiveness of dapagliflozin compared with DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues was based solely on network meta-analysis.\n\n\n\n\n\nThe manufacturers had not provided clinical-effectiveness data on dapagliflozin as add-on therapy to a sulfonylurea, despite clinical trial data being available. The Committee concluded that, because the manufacturers had not provided clinical evidence of dapagliflozin as add-on to a sulfonylurea, it could not make recommendations on this combination regimen.\n\n\n\nFor dapagliflozin as add-on therapy to insulin, the evidence came from 2 clinical trials and a network meta-analysis. Both trials were placebo controlled and 1 was of 12\xa0weeks duration only. The trial results for dapagliflozin were based on a relatively small number of patients who were treated with dapagliflozin at its licensed dose. The network meta-analysis excluded trials of GLP‑1 analogues because they were not comparable to other trials included in the analysis and therefore consideration of the full range of possible comparators was restricted by the available evidence.\n\n\n\nDapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents and, in the absence of any other currently available clinical-effectiveness data, the manufacturers provided a post hoc analysis of pooled data from a subset of older patients with type\xa02 diabetes and cardiovascular disease recruited in 2 trials of dapagliflozin as an add-on to metformin and sulfonylurea. The Committee concluded that significant caution should be taken when interpreting the results of these preliminary analyses.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee discussed the outcomes collected in the clinical trials and network meta-analyses, noting that the primary outcomes were intermediate rather than clinical outcomes and that these were collected over a relatively short follow-up.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that, despite some uncertainty about the impact of HbA1c reduction on longer-term macrovascular complications, it was prepared to accept the link between intermediate outcomes collected in the clinical trials and longer-term clinical outcomes.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that, on the basis of the results of the network meta-analyses, dapagliflozin in dual therapy as add-on to metformin appeared to provide similar glycaemic control to other antidiabetic drugs but may result in greater weight loss.\n\n\n\nThe Committee concluded that, on the basis of the results of the network meta-analyses, dapagliflozin as add-on therapy to insulin appeared to have greater efficacy than DPP‑4 inhibitors for the outcome of weight loss and similar efficacy for HbA1c reduction.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturers had provided a revised economic model in order to address concerns raised by the DSU about the original model and the DSU considered that their concerns had been addressed. However, the DSU and the ERG had identified a number of errors in the revised model which were subsequently addressed by the DSU in its exploratory analyses. The Committee concluded that the manufacturers' revised economic model with the subsequent amendments made by the DSU was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type\xa02 diabetes.\n\n\n\nThe Committee concluded that the results of the validation exercise with the CORE diabetes model provided reassurance about the integrity of the results obtained from the manufacturers' revised economic model.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nIn terms of the clinical-effectiveness data that were applied in the economic models, the Committee considered that it was more appropriate to use a single source as was available in the 52‑week network meta-analysis, but was aware of the limited number of trials informing this analysis. It also noted that the 24‑week network meta-analysis only excluded sulfonylureas, and that the evidence from the clinical specialists suggested that dapagliflozin would be used where a sulfonylurea was not appropriate. On this basis the 24‑week network meta-analysis data were appropriate.\n\n\n\nThe Committee heard from the DSU that the results from the revised model were sensitive to the timing of treatment switching in the model which was dependent on the relationship between HbA1c at the start of treatment, treatment-related changes in HbA1c levels and the HbA1c threshold levels for switching treatment.\n\n\n\nThe Committee considered that uncertainty remained about the effects of stopping treatment with dapagliflozin and the impact on weight gain. Therefore, it concluded that the scenario analysis conducted by the DSU, which involved the convergence of differences in weight profiles between treatment groups at the time of switching to the last line of treatment, was more appropriate for decision-making.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee considered the utility values applied in the model, noting that the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than a reduction of diabetic complications and other adverse events. The Committee concluded that the utility values associated with changes in weight may have been too large and that the values applied in the manufacturers' scenario analyses and DSU analyses were more reasonable.\n\n\n\nThe Committee noted that the DSU had completed analyses that included both the higher and lower estimates of loss of utility associated with hypoglycaemic events, and that these had made small differences to the estimates of the ICER.\n\n\n\nThe Committee concluded that, although the loss in utility associated with urinary tract and genital infections was likely to be greater than that proposed by the manufacturers, it was satisfied that this did not significantly impact on the relative cost effectiveness of dapagliflozin as dual therapy or add-on to insulin.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that in all settings the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than from a reduction of diabetic complications and other adverse events.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nFor dapagliflozin as dual therapy in combination with metformin, the Committee considered the DSU deterministic analysis and scenario analyses, which included the convergence of differences in weight between treatment groups at the time of switching to the last line of treatment. It noted that these showed that DPP‑4 inhibitors were associated with higher costs and QALYs than dapagliflozin, but that these differences were small. It noted further that in the DSU probabilistic sensitivity analysis these differences were even smaller.\n\n\n\nFor dapagliflozin as add-on to insulin, the Committee noted that in all the analyses conducted by the DSU the estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors was below £20,000 per QALY.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee concluded that its recommendations would not have a particular impact on any of the groups whose interests are protected by the equalities legislation and that there was no need to alter or add to its recommendations.\n\n", 'Recommendations for further research': 'The Committee supported the ongoing research investigating dapagliflozin as part of a triple therapy regimen as add-on to 2\xa0oral antidiabetic drugs.'}	https://www.nice.org.uk/guidance/ta288	Evidence-based recommendations on dapagliflozin (Forxiga) given with other drugs for treating type 2 diabetes in adults.
94f496087054fc1871dda7ed28b516a1a2235305	nice	Percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture	Percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture Evidence-based recommendations on percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture in adults. This involves inserting an implant into the spine to restore the vertebral height. # Recommendations The evidence on percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture raises no major safety concerns. Evidence on its efficacy is adequate. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Patient selection and treatment should be done by a specialist multidisciplinary team that includes a radiologist and a spinal surgeon. The procedure should be limited to patients whose pain is refractory to more conservative treatment.# Indications and current treatments Vertebral compression fractures usually occur when the front of the vertebral body collapses, and may be caused by trauma, cancer or osteoporosis. Pain is the most common symptom in patients with vertebral compression fractures. Fractures can also cause progressive spinal deformity with abnormal curvature (kyphosis). This can lead to increased risk of further fracture at adjacent levels and progressive malalignment, deformity and pain. Treating vertebral compression fractures aims to reduce pain, improve function and minimise the incidence of new fractures. Non‑invasive treatment (such as pain medication, bed rest, and back braces) focuses on relieving symptoms and supporting the spine. Surgery such as percutaneous vertebroplasty and balloon kyphoplasty may be considered in patients whose condition is refractory to medical therapy and when there is continued vertebral collapse and severe pain. Sometimes more invasive surgery with vertebral body realignment and instrumented fusion (bone grafts and spinal rods) may be needed.# The procedure Percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture aims to restore vertebral height and augment the fractured vertebral body to relieve pain and increase mobility. Vertebral craniocaudal expandable implants are inserted under general, regional or local anaesthesia. With the patient in a prone position, using fluoroscopic guidance, trocars are inserted through the vertebral pedicles into the vertebral body, which is then cannulated. Unexpanded implants, mounted on a bespoke instrument, are placed inside the vertebral body and expanded to restore vertebral height. High-viscosity bone cement is injected into and around each implant, filling the space in the surrounding bone.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a randomised controlled trial (RCT) of 300 patients treated by a vertebral craniocaudal expandable implant (n=153) or by balloon kyphoplasty (n=147), procedure success at 12 months was 94% (120/127) in the implant group and 98% in the balloon kyphoplasty group (no statistically significant difference between groups; -3%, Bayesian credible interval 9% to 2%). Procedure success was defined as a reduction in pain by 15 mm or more from baseline on the 100 mm visual analogue scale (VAS), maintenance of function (did not worsen by 10 or more points) or improvement in function from baseline on the 100-point Oswestry disability index (ODI), and no device-related serious adverse events. In the RCT of 300 patients treated by a vertebral craniocaudal expandable implant (n=153) or by balloon kyphoplasty (n=147), there was a statistically significant improvement from baseline in the mean VAS scores for pain (0 to 100 mm, from no pain to worst imaginable pain) in both groups at follow-up. In the implant group, the mean VAS score changes (± standard deviation, SD) from baseline were: ‑59.8±28.9 (n=140) at 30 days, ‑68.6±25.9 (n=135) at 6 months and -70.8±26.3 (n=127) at 12 months. In the balloon kyphoplasty group, the mean VAS score changes from baseline were -61.1±26.9 (n=135) at 30 days, -65.2± 27.4 (n=126) at 6 months and -71.8±23.5 (n=126) at 12 months. No statistically significant differences between groups were seen at follow-up. In a retrospective matched-paired comparative study of 52 patients treated by a vertebral craniocaudal expandable implant (n=26) or by balloon kyphoplasty (n=26), the mean VAS scores (±SD) improved in both groups from 87.6±12.8 before the procedure to 10.8±20.8 at 6 months in the implant group and from 83.1±14.9 to 24.6±11.0 in the balloon kyphoplasty group (p value within group not reported). VAS scores 6 months after the procedure were statistically significantly different between groups (p<0.0001). In an observational study of 103 patients treated by a craniocaudal expandable implant, the rate of patients with no analgesic treatment improved from 6% (6/103) at baseline to 27% (28/103) at 48-hour follow-up, 67% (61/91) at 3-month follow-up and 73% (57/78) at 12-month follow up (p value not reported). In the RCT of 300 patients treated by a vertebral craniocaudal expandable implant (n=153) or by balloon kyphoplasty (n=147), the mean ODI score (0 to 100, from no disability to maximum disability) changes from baseline were -31.4±21.9 (n=140) at 30 days, -37.7±20.1 (n=135) at 6 months and -38.1±19.8 (n=127) at 12 months in the implant group. In the balloon kyphoplasty group, the mean ODI score changes from baseline were ‑34.6±20.4 (n=135) at 30 days, ‑38.4±20.4 (n=126) at 6 months and -42.2±21.7 (n=126) at 12 months. There was a statistically significant improvement in ODI scores within groups but not between groups (level of statistical significance not reported). In an RCT of 185 patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93), there was a statistically significant improvement in the mean short-form (SF)-36 (physical functioning domain) scores in both groups from 32±11 before the procedure to 65.8±15.6 at 1 year in the implant group and from 28±12 to 68±19.8 in the balloon kyphoplasty group (p=0.001 for both groups compared with baseline, but no statistically significant difference between groups at 1-year follow‑up, p=0.72). There was also a statistically significant improvement in the mean SF‑36 (mental health domain) scores in both groups, from 42±10 before the procedure to 64±11 at 1 year in the implant group and from 41±9 to 62±10 in the balloon kyphoplasty group (p=0.001 for both groups compared with baseline but no statistically significant difference between groups at 1-year follow-up, p=0.64). In an RCT of 300 patients treated by a vertebral craniocaudal expandable implant (n=150) or by balloon kyphoplasty (n=150), there was a statistically significantly greater increase in vertebral body height after the procedure in the implant group than in the kyphoplasty group (p<0.05). In the implant group, vertebral height was restored by more than 50% in 85% of patients, by less than 50% in 12% of patients and there was no change in 3%. In the balloon kyphoplasty group, vertebral height was restored by more than 50% in 58% of patients, by less than 50% in 26% of patients and there was no change in 16%. In the retrospective matched‑paired comparative study of 52 patients treated by a vertebral craniocaudal expandable implant (n=26) or by balloon kyphoplasty (n=26), there was a statistically significant increase in anterior and mid-vertebral height (mean±SD) in both groups after the procedure. This increased from 21.06 ± 2.77 mm before the procedure to 22.41± 7.14 mm after the procedure (anterior) and from 18.36± 5.64 mm to 20.89± 6.00 mm (mid) in the implant group, and from 21.68 ± 2.08 mm to 25.09± 2.54 mm (anterior) and from 21.97± 1.78 mm to 25.29± 2.10 mm (mid) in the balloon kyphoplasty group (p<0.001 for the within-group comparison). At 6 months, vertebral height had not changed much from after the procedure in both groups: in the implant group, anterior vertebral height was 22.28 ± 6.85 mm and mid-vertebral height was 21.19± 6.08 mm, and in the balloon kyphoplasty group, anterior vertebral height was 24.56± 2.27 mm and mid-vertebral height was 24.91± 2.08 mm. In a prospective case series of 32 patients, the mean (±SD) Beck index (anterior edge height divided by posterior edge height) changed from 0.75± 0.14 before the procedure to 0.77± 0.14 at 12 months. In the RCT of 185 patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93) there was a statistically significant decrease in mean (±SD) wedge angle only in the implant group, from 13.7±7 degrees before the procedure to 7.80±6 degrees after the procedure (p=0.009). The mean wedge angle in the balloon kyphoplasty group decreased from 14.9±8 degrees to 11.5±7 degrees (p=0.067). Wedge angles after the procedure were not statistically significantly different between groups (p=0.11). In the prospective case series of 32 patients, there was a statistically significant decrease in the mean (±SD) vertebral kyphotic angle and in the mean Cobb angle from 9.0± 5.8 degrees before the procedure to 8.3± 5.6 degrees at 3 days and 8.3± 5.5 degrees at 12 months. For the mean (±SD) Cobb angle there was a statistically significant decrease from 12.3± 16.4 degrees before the procedure to 10.8± 16.4 degrees at 3 days and 10.8± 16.3 degrees at 12 months (p<0.05 for the comparisons at 12 months versus baseline). In the RCT of 185 patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93), there was residual kyphosis of 5 degrees or more at the final observation in 84% (69/82) of spines in the implant group and in 100% (86/86) of spines in the balloon kyphoplasty group (p<0.001). The specialist advisers listed the following key efficacy outcomes: radiological parameters such as restoring and maintaining vertebral body height, alignment and sagittal balance, and functional outcome measures.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Death was reported in 2 patients in an observational study of 103 patients treated by a vertebral craniocaudal expandable implant. The first death occurred 52 days after the procedure and was caused by acute kidney failure; the other death occurred 204 days after the procedure and was caused by an acute respiratory syndrome. The authors stated that the deaths were neither implant- nor procedure-related. Pneumonia was reported in 1 patient out of 36 in the vertebral craniocaudal expandable implant group and in 2 patients out of 39 in the vertebroplasty group in a retrospective comparative study of 75 patients, within 12-month follow-up (no further details provided). Cement extravasation measured immediately after the procedure and assessed on X-ray by an independent laboratory was reported in 55% (98/177) of vertebra levels in patients treated by a vertebral craniocaudal expandable implant and in 58% (103/178) of levels in patients treated by balloon kyphoplasty in a randomised controlled trial (RCT) of 300 patients treated by an implant (n=153) or by balloon kyphoplasty (n=147). There was no statistically significant difference between the groups (‑3%, Bayesian credible interval ‑13% to 8%). However, in a secondary analysis, cement extravasation was reported statistically significantly less frequently in the implant group than in the balloon kyphoplasty group (17% of levels compared with 26% of levels, difference -9%, BCI -17% to -0.33%). Cement leaks were reported statistically significantly less frequently in the implant group (3% of vertebras) than in the balloon kyphoplasty group (10% of vertebras; p≤0.05) in an RCT of 185 patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93). Intracanal leaks were reported in none of the patients treated by the implant and in 2% (2/86) treated by balloon kyphoplasty. Cement leaks identified by CT scan were reported in 14% (11/77) of patients in a retrospective case series of 77 patients treated by a vertebral craniocaudal expandable implant. All patients had post-traumatic fractures. One patient had nerve root pain caused by the cement leaking along a secondary fracture line in the pedicle (see section 5.5). Dural tear was reported in 1 patient in a case series of 57 patients. It occurred during the initial pedicle access with the Jamshidi needle. It was treated with Gelfoam and there were no residual or permanent sequelae. Adjacent level fracture was reported in 21% (28/134) of the as-treated population in the implant group and in 22% (29/130) of the as-treated population in the balloon kyphoplasty group in the RCT of 300 patients treated by an implant (n=153) or by balloon kyphoplasty (n=147). There was no statistically significant difference between the groups (-1%, BCI -11% to 8%). In the same study, a fractured pedicle was reported in 1 patient in the implant group. It was associated with the use of the implant in the setting of sclerotic bone. This resulted in back pain at the time of discharge, which was treated with analgesics. New fractures were reported in 12% (3/26) of patients in the implant group and in 54% (14/26) of patients in the balloon kyphoplasty group in a retrospective matched-paired comparative study of 52 patients. The difference between the groups was statistically significant, p<0.0001. Adjacent fractures were reported in 8% (2/26) of patients in the implant group and in 35% (9/26) of patients in the balloon kyphoplasty group. Pain after the procedure was reported in 1 patient in the implant group in the RCT of 300 patients treated by an implant (n=153) or by balloon kyphoplasty (n=147). Skin infection that started in hospital was reported in 1 patient in the retrospective case series of 77 patients. The infection was probably caused by contamination from an oral infection and was treated with antibiotics. Urinary tract infection was reported in 17% (6/36) of patients in the vertebral craniocaudal expandable implant group and in 21% (8/39) of patients in the vertebroplasty group in the retrospective comparative study of 75 patients (no further details provided). Haematoma was reported in 1 patient in a prospective case series of 32 patients treated by a vertebral craniocaudal expandable implant; revision was not needed. Minor loss of height of the stabilised L2 vertebral body in an osteoporotic fracture was reported in 1 patient in the prospective case series of 32 patients. The Beck Index changed after the procedure from 1.0 to 0.96 and the Cobb angle changed from 11 degrees to 13 degrees. The visual analogue scale score remained unchanged. Collapse of the treated vertebral body resulting in canal compromise, haematoma and neurological symptoms was reported in 1 patient 16 days after the procedure in the observational study of 103 patients; the condition of the patient had improved at 12‑month follow-up (no further details reported). Dislocation of posterior wall secondary to surgery and leading to a sensory deficit was reported in 1 patient 4 days after the procedure in the observational study of 103 patients. The patient had been treated outside of the device instructions for use and was subsequently treated by decompression and posterior instrumentation. Device migration was reported in 1 patient in the retrospective case series of 77 patients; this reflected a technical problem that occurred with an instrument prototype. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: incorrect placement of the implant, implant tilt in osteoporotic bone and endplate fracture so that vertebral body height was not restored. They considered that the following were theoretical adverse events: failure to deploy the implant correctly and implant-related problems such as failure to raise the endplates.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2162-1	{'Recommendations': 'The evidence on percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture raises no major safety concerns. Evidence on its efficacy is adequate. Therefore, this procedure may be used provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection and treatment should be done by a specialist multidisciplinary team that includes a radiologist and a spinal surgeon.\n\nThe procedure should be limited to patients whose pain is refractory to more conservative treatment.', 'Indications and current treatments': 'Vertebral compression fractures usually occur when the front of the vertebral body collapses, and may be caused by trauma, cancer or osteoporosis.\n\nPain is the most common symptom in patients with vertebral compression fractures. Fractures can also cause progressive spinal deformity with abnormal curvature (kyphosis). This can lead to increased risk of further fracture at adjacent levels and progressive malalignment, deformity and pain.\n\nTreating vertebral compression fractures aims to reduce pain, improve function and minimise the incidence of new fractures. Non‑invasive treatment (such as pain medication, bed rest, and back braces) focuses on relieving symptoms and supporting the spine.\n\nSurgery such as percutaneous vertebroplasty and balloon kyphoplasty may be considered in patients whose condition is refractory to medical therapy and when there is continued vertebral collapse and severe pain. Sometimes more invasive surgery with vertebral body realignment and instrumented fusion (bone grafts and spinal rods) may be needed.', 'The procedure': 'Percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture aims to restore vertebral height and augment the fractured vertebral body to relieve pain and increase mobility.\n\nVertebral craniocaudal expandable implants are inserted under general, regional or local anaesthesia. With the patient in a prone position, using fluoroscopic guidance, trocars are inserted through the vertebral pedicles into the vertebral body, which is then cannulated. Unexpanded implants, mounted on a bespoke instrument, are placed inside the vertebral body and expanded to restore vertebral height. High-viscosity bone cement is injected into and around each implant, filling the space in the surrounding bone.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 300\xa0patients treated by a vertebral craniocaudal expandable implant (n=153) or by balloon kyphoplasty (n=147), procedure success at 12\xa0months was 94% (120/127) in the implant group and 98% in the balloon kyphoplasty group (no statistically significant difference between groups; -3%, Bayesian credible interval 9% to 2%). Procedure success was defined as a reduction in pain by 15\xa0mm or more from baseline on the 100\xa0mm visual analogue scale (VAS), maintenance of function (did not worsen by 10 or more points) or improvement in function from baseline on the 100-point Oswestry disability index (ODI), and no device-related serious adverse events.\n\nIn the RCT of 300\xa0patients treated by a vertebral craniocaudal expandable implant (n=153) or by balloon kyphoplasty (n=147), there was a statistically significant improvement from baseline in the mean VAS scores for pain (0 to 100\xa0mm, from no pain to worst imaginable pain) in both groups at follow-up. In the implant group, the mean VAS score changes (± standard deviation, SD) from baseline were: ‑59.8±28.9 (n=140) at 30\xa0days, ‑68.6±25.9 (n=135) at 6\xa0months and -70.8±26.3 (n=127) at 12\xa0months. In the balloon kyphoplasty group, the mean VAS score changes from baseline were -61.1±26.9 (n=135) at 30\xa0days, -65.2± 27.4 (n=126) at 6\xa0months and -71.8±23.5 (n=126) at 12\xa0months. No statistically significant differences between groups were seen at follow-up. In a retrospective matched-paired comparative study of 52\xa0patients treated by a vertebral craniocaudal expandable implant (n=26) or by balloon kyphoplasty (n=26), the mean VAS scores (±SD) improved in both groups from 87.6±12.8 before the procedure to 10.8±20.8 at 6\xa0months in the implant group and from 83.1±14.9 to 24.6±11.0 in the balloon kyphoplasty group (p value within group not reported). VAS scores 6\xa0months after the procedure were statistically significantly different between groups (p<0.0001).\n\nIn an observational study of 103\xa0patients treated by a craniocaudal expandable implant, the rate of patients with no analgesic treatment improved from 6% (6/103) at baseline to 27% (28/103) at 48-hour follow-up, 67% (61/91) at 3-month follow-up and 73% (57/78) at 12-month follow up (p value not reported).\n\nIn the RCT of 300\xa0patients treated by a vertebral craniocaudal expandable implant (n=153) or by balloon kyphoplasty (n=147), the mean ODI score (0 to 100, from no disability to maximum disability) changes from baseline were -31.4±21.9 (n=140) at 30\xa0days, -37.7±20.1 (n=135) at 6\xa0months and -38.1±19.8 (n=127) at 12\xa0months in the implant group. In the balloon kyphoplasty group, the mean ODI score changes from baseline were ‑34.6±20.4 (n=135) at 30\xa0days, ‑38.4±20.4 (n=126) at 6\xa0months and -42.2±21.7 (n=126) at 12\xa0months. There was a statistically significant improvement in ODI scores within groups but not between groups (level of statistical significance not reported).\n\nIn an RCT of 185\xa0patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93), there was a statistically significant improvement in the mean short-form (SF)-36 (physical functioning domain) scores in both groups from 32±11 before the procedure to 65.8±15.6 at 1\xa0year in the implant group and from 28±12 to 68±19.8 in the balloon kyphoplasty group (p=0.001 for both groups compared with baseline, but no statistically significant difference between groups at 1-year follow‑up, p=0.72). There was also a statistically significant improvement in the mean SF‑36 (mental health domain) scores in both groups, from 42±10 before the procedure to 64±11 at 1\xa0year in the implant group and from 41±9 to 62±10 in the balloon kyphoplasty group (p=0.001 for both groups compared with baseline but no statistically significant difference between groups at 1-year follow-up, p=0.64).\n\nIn an RCT of 300\xa0patients treated by a vertebral craniocaudal expandable implant (n=150) or by balloon kyphoplasty (n=150), there was a statistically significantly greater increase in vertebral body height after the procedure in the implant group than in the kyphoplasty group (p<0.05). In the implant group, vertebral height was restored by more than 50% in 85% of patients, by less than 50% in 12% of patients and there was no change in 3%. In the balloon kyphoplasty group, vertebral height was restored by more than 50% in 58% of patients, by less than 50% in 26% of patients and there was no change in 16%. In the retrospective matched‑paired comparative study of 52\xa0patients treated by a vertebral craniocaudal expandable implant (n=26) or by balloon kyphoplasty (n=26), there was a statistically significant increase in anterior and mid-vertebral height (mean±SD) in both groups after the procedure. This increased from 21.06 ± 2.77\xa0mm before the procedure to 22.41± 7.14\xa0mm after the procedure (anterior) and from 18.36± 5.64\xa0mm to 20.89± 6.00\xa0mm (mid) in the implant group, and from 21.68 ± 2.08\xa0mm to 25.09± 2.54\xa0mm (anterior) and from 21.97± 1.78\xa0mm to 25.29± 2.10\xa0mm (mid) in the balloon kyphoplasty group (p<0.001 for the within-group comparison). At 6\xa0months, vertebral height had not changed much from after the procedure in both groups: in the implant group, anterior vertebral height was 22.28 ± 6.85\xa0mm and mid-vertebral height was 21.19± 6.08\xa0mm, and in the balloon kyphoplasty group, anterior vertebral height was 24.56± 2.27\xa0mm and mid-vertebral height was 24.91± 2.08\xa0mm. In a prospective case series of 32\xa0patients, the mean (±SD) Beck index (anterior edge height divided by posterior edge height) changed from 0.75± 0.14 before the procedure to 0.77± 0.14 at 12\xa0months.\n\nIn the RCT of 185\xa0patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93) there was a statistically significant decrease in mean (±SD) wedge angle only in the implant group, from 13.7±7\xa0degrees before the procedure to 7.80±6\xa0degrees after the procedure (p=0.009). The mean wedge angle in the balloon kyphoplasty group decreased from 14.9±8\xa0degrees to 11.5±7\xa0degrees (p=0.067). Wedge angles after the procedure were not statistically significantly different between groups (p=0.11). In the prospective case series of 32 patients, there was a statistically significant decrease in the mean (±SD) vertebral kyphotic angle and in the mean Cobb angle from 9.0± 5.8 degrees before the procedure to 8.3± 5.6 degrees at 3\xa0days and 8.3± 5.5 degrees at 12\xa0months. For the mean (±SD) Cobb angle there was a statistically significant decrease from 12.3± 16.4 degrees before the procedure to 10.8± 16.4 degrees at 3\xa0days and 10.8± 16.3 degrees at 12\xa0months (p<0.05 for the comparisons at 12\xa0months versus baseline).\n\nIn the RCT of 185\xa0patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93), there was residual kyphosis of 5\xa0degrees or more at the final observation in 84% (69/82) of spines in the implant group and in 100% (86/86) of spines in the balloon kyphoplasty group (p<0.001).\n\nThe specialist advisers listed the following key efficacy outcomes: radiological parameters such as restoring and maintaining vertebral body height, alignment and sagittal balance, and functional outcome measures.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nDeath was reported in 2\xa0patients in an observational study of 103\xa0patients treated by a vertebral craniocaudal expandable implant. The first death occurred 52\xa0days after the procedure and was caused by acute kidney failure; the other death occurred 204\xa0days after the procedure and was caused by an acute respiratory syndrome. The authors stated that the deaths were neither implant- nor procedure-related.\n\nPneumonia was reported in 1\xa0patient out of 36 in the vertebral craniocaudal expandable implant group and in 2\xa0patients out of 39 in the vertebroplasty group in a retrospective comparative study of 75\xa0patients, within 12-month follow-up (no further details provided).\n\nCement extravasation measured immediately after the procedure and assessed on X-ray by an independent laboratory was reported in 55% (98/177) of vertebra levels in patients treated by a vertebral craniocaudal expandable implant and in 58% (103/178) of levels in patients treated by balloon kyphoplasty in a randomised controlled trial (RCT) of 300\xa0patients treated by an implant (n=153) or by balloon kyphoplasty (n=147). There was no statistically significant difference between the groups (‑3%, Bayesian credible interval [BCI] ‑13% to 8%). However, in a secondary analysis, cement extravasation was reported statistically significantly less frequently in the implant group than in the balloon kyphoplasty group (17% [30/177] of levels compared with 26% [46/178] of levels, difference -9%, BCI -17% to -0.33%). Cement leaks were reported statistically significantly less frequently in the implant group (3% [4/133] of vertebras) than in the balloon kyphoplasty group (10% [12/122] of vertebras; p≤0.05) in an RCT of 185\xa0patients treated by a vertebral craniocaudal expandable implant (n=92) or by balloon kyphoplasty (n=93). Intracanal leaks were reported in none of the patients treated by the implant and in 2% (2/86) treated by balloon kyphoplasty. Cement leaks identified by CT scan were reported in 14% (11/77) of patients in a retrospective case series of 77\xa0patients treated by a vertebral craniocaudal expandable implant. All patients had post-traumatic fractures. One patient had nerve root pain caused by the cement leaking along a secondary fracture line in the pedicle (see section\xa05.5).\n\nDural tear was reported in 1\xa0patient in a case series of 57\xa0patients. It occurred during the initial pedicle access with the Jamshidi needle. It was treated with Gelfoam and there were no residual or permanent sequelae.\n\nAdjacent level fracture was reported in 21% (28/134) of the as-treated population in the implant group and in 22% (29/130) of the as-treated population in the balloon kyphoplasty group in the RCT of 300\xa0patients treated by an implant (n=153) or by balloon kyphoplasty (n=147). There was no statistically significant difference between the groups (-1%, BCI -11% to 8%). In the same study, a fractured pedicle was reported in 1\xa0patient in the implant group. It was associated with the use of the implant in the setting of sclerotic bone. This resulted in back pain at the time of discharge, which was treated with analgesics. New fractures were reported in 12% (3/26) of patients in the implant group and in 54% (14/26) of patients in the balloon kyphoplasty group in a retrospective matched-paired comparative study of 52\xa0patients. The difference between the groups was statistically significant, p<0.0001. Adjacent fractures were reported in 8% (2/26) of patients in the implant group and in 35% (9/26) of patients in the balloon kyphoplasty group.\n\nPain after the procedure was reported in 1\xa0patient in the implant group in the RCT of 300\xa0patients treated by an implant (n=153) or by balloon kyphoplasty (n=147).\n\nSkin infection that started in hospital was reported in 1\xa0patient in the retrospective case series of 77\xa0patients. The infection was probably caused by contamination from an oral infection and was treated with antibiotics. Urinary tract infection was reported in 17% (6/36) of patients in the vertebral craniocaudal expandable implant group and in 21% (8/39) of patients in the vertebroplasty group in the retrospective comparative study of 75\xa0patients (no further details provided).\n\nHaematoma was reported in 1\xa0patient in a prospective case series of 32\xa0patients treated by a vertebral craniocaudal expandable implant; revision was not needed.\n\nMinor loss of height of the stabilised L2 vertebral body in an osteoporotic fracture was reported in 1\xa0patient in the prospective case series of 32\xa0patients. The Beck Index changed after the procedure from 1.0 to 0.96 and the Cobb angle changed from 11\xa0degrees to 13\xa0degrees. The visual analogue scale score remained unchanged.\n\nCollapse of the treated vertebral body resulting in canal compromise, haematoma and neurological symptoms was reported in 1\xa0patient 16\xa0days after the procedure in the observational study of 103\xa0patients; the condition of the patient had improved at 12‑month follow-up (no further details reported).\n\nDislocation of posterior wall secondary to surgery and leading to a sensory deficit was reported in 1\xa0patient 4\xa0days after the procedure in the observational study of 103\xa0patients. The patient had been treated outside of the device instructions for use and was subsequently treated by decompression and posterior instrumentation.\n\nDevice migration was reported in 1\xa0patient in the retrospective case series of 77\xa0patients; this reflected a technical problem that occurred with an instrument prototype.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: incorrect placement of the implant, implant tilt in osteoporotic bone and endplate fracture so that vertebral body height was not restored. They considered that the following were theoretical adverse events: failure to deploy the implant correctly and implant-related problems such as failure to raise the endplates.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2162-1'}	https://www.nice.org.uk/guidance/ipg568	Evidence-based recommendations on percutaneous insertion of craniocaudal expandable implants for vertebral compression fracture in adults. This involves inserting an implant into the spine to restore the vertebral height.
78eb77d9335cd63efbe4b8844d7e825a48e76137	nice	Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy for treating morbid obesity	Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy for treating morbid obesity Evidence-based recommendations on single-anastomosis duodeno-ileal bypass with sleeve gastrectomy for treating morbid obesity. This involves reducing the size of the stomach and small intestine to reduce the amount of food absorbed. # Recommendations Current evidence on the safety of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI‑S) for treating morbid obesity shows that there are well-recognised complications. Evidence on efficacy is limited in both quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wishing to do SADI‑S for treating morbid obesity should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Clinicians should review local clinical outcomes and enter details about all patients having SADI‑S for treating morbid obesity onto the National Bariatric Surgery Registry. Patient selection should be done by a multidisciplinary team experienced in managing morbid obesity. Treatment should be done by surgeons with specific training in the procedure, in centres with expertise in the treatment of morbid obesity. NICE encourages further research into SADI‑S for treating morbid obesity, particularly research examining long-term outcomes. NICE may update the guidance on publication of further evidence.# Indications and current treatments Morbid obesity is defined as a body mass index of 40 kg/m2 or more, or of 35 to 40 kg/m2 with significant medical problems related to body weight. Comorbidities include type 2 diabetes, coronary heart disease and hypertension. Weight loss reduces the comorbidities and improves long-term survival. Morbid obesity is managed by lifestyle changes including exercise and diet and medication. Bariatric surgery is a treatment option in selected patients if they have not lost enough weight using non-surgical measures. Surgical procedures aim to help patients lose weight by restricting the size of the stomach (for example, gastric banding or sleeve gastrectomy), or by decreasing the patient's capacity to absorb food (for example, Roux‑en‑Y gastric bypass or biliopancreatic diversion).# The procedure Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI‑S) for treating morbid obesity is usually done laparoscopically with the patient under general anaesthesia. Initially, the stomach is reduced in size by a sleeve gastrectomy, which involves devascularising and excising the greater curve. This leaves a tube of stomach passing from the oesophagus to the pylorus and duodenum. The duodenum is then mobilised and divided at the level of the gastroduodenal artery using a linear stapler. This leaves a short stump of duodenum attached to the pylorus. The distal end of the duodenum is closed off permanently. A loop of small bowel, usually 200 to 300 cm from the ileocaecal valve, is anastomosed to the remnant of duodenum arising from the pylorus to restore the continuity of the gut. This anastomosis is usually sutured in 2 layers, but may be stapled. In patients at high risk because of extreme obesity, the procedure may be done in 2 stages, first sleeve gastrectomy, and then duodenal transection and duodeno-ileal anastomosis in a subsequent procedure once the patient's risks from surgery are reduced by weight loss induced by sleeve gastrectomy. After surgery, patients are maintained on a low-calorie diet. Multivitamin, calcium and iron supplements are prescribed as needed to maintain normal blood levels.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a case series of 100 patients with morbid obesity or metabolic disease treated with single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI‑S), the mean excess weight loss (EWL calculated from an ideal body mass index of 25 kg/m2) was 95% at 12 months. This was maintained for maximum of 48 months of follow-up, with no significant differences between those who had SADI‑S 200 cm from the ileocecal valve and those with SADI‑S 250 cm. In a case series of 97 patients with obesity and type 2 diabetes treated with SADI‑S, EWL was 92% (74/80) at 2‑year follow-up and 98% (425/32) at 5‑year follow-up. Six percent (6/97) of patients failed to reach 50% EWL. In a case series of 123 patients with morbid obesity treated with stomach intestinal pylorus sparing (SIPS) procedure, EWL was 72% (64/102) at 1‑year follow-up. In the case series of 97 patients, overall weight loss was 39% at 2‑year follow-up and 38% at 5‑year follow-up. In the case series of 123 patients, overall weight loss was 39% and patients had an average change in BMI of 19 kg/m2 at 1‑year follow-up. In the case series of 100 patients, the mean glycaemia level decreased from 178.2 mg/dl at baseline to 94.2 mg/dl at 1‑year follow-up and to 79.6 mg/dl at 4‑year follow-up. The mean glycated haemoglobin (HbA1c) level decreased from 7.9% at baseline to 5.3% at 1‑year follow-up and to 5.0% at 4‑year follow-up. In the case series of 97 patients, the mean glycaemia level reduced from 167.6 mg/dl at baseline to 93.0 mg/dl at 1‑year follow-up and to 101.6 mg/dl at 5‑year follow-up. The mean HbA1c level reduced from 7.6% at baseline to 5.1% at 1‑year follow-up and to 5.5% at 5‑year follow-up. In the case series of 97 patients, the overall diabetes remission rate (defined as HbA1c below 6% without antidiabetic medication for more than 1‑year) was 77% at 2 years and 52% at 5 years. Remission rates were higher for those having oral therapy (n=14) than for those having insulin therapy (n=40) (97% versus 54% at 2 years; 75% versus 38% at 5 years). In the case series of 97 patients, type 2 diabetes recurred in 8% (4/97) of patients within 5 years (308 patient-years follow-up). In the case series of 123 patients, mean values for the nutritional data (Vitamin A, B1, B12, D and albumin) were at normal levels at 1‑year follow-up. The specialist advisers listed key efficacy outcomes as weight loss, remission of type 2 diabetes, resolution of obesity-related comorbidities and improvement in quality of life.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Mortality due to progressive respiratory insufficiency occurred at 3 months in 1 patient in a case series of 50 patients. Myocardial infarction occurred at 6 months in 1 patient in the case series of 50 patients. Gastric haemorrhage occurred in 1 patient in a case series of 100 patients (timing not stated). Patient had endoscopic coagulation but further details were not reported. Postoperative gastric leaks occurred in 2% (2/100) of patients in the case series of 100 patients. One leak was visible with a barium swallow but uneventful, and the patient was discharged on the thirteenth day. One clinical leak was managed with an abdominal drain, and the patient was discharged after 5 weeks. Duodenal anastomotic leak (treated conservatively) occurred in 1 patient in the case series of 100 patients. Haemoperitoneum occurred in 1 patient in a case series of 97 patients. Further details were not reported. Abdominal haematoma occurred in 3% (4/123) of patients in the case series of 123 patients. Further details were not reported. Acute trocar site herniation occurred in 1 patient in the case series of 100 patients. The patient had another operation and prosthetic/mesh repair. Incarcerated umbilical hernia occurred in 1 patient in the case series of 97 patients. The patient had another operation. Subphrenic abscess (drained under radiological guidance) occurred in 1 patient in the case series of 50 patients. Stricture in the gastric sleeve (which led to dysphagia) needing dilatation occurred in 1 patient in the case series of 123 patients. Reoperation due to early postoperative ulcer was needed in 1 patient in the case series of 123 patients. Acute cholecystitis occurred within 1 year of the procedure in 4% (2/50) of patients in the case series of 50 patients. One patient had cholecystectomy and another patient was waiting to have surgery at the time of the report. Clinical hypoalbuminemia occurred in 4% (4/100) patients in the case series of 100 patients. In 1 patient, it was related to severe diarrhoea and treated with metronidazole. In another patient it was due to intra-abdominal infection and the abscess was drained. In 2 other patients, it was due to reduced food intake; the patients were given counselling and their oral intake increased. Because of recurrent hypoproteinaemia, 2 of the patients had revision to the Roux‑en‑Y duodenal switch with a longer gut. Hypoalbuminemia was detected in 12% of patients, low vitamin A levels in 53% and high parathormone levels in 54% at 3 years follow-up in the case series of 97 patients. Sporadic vomiting occurred in 1 patient in the case series of 50 patients. Further details were not reported. Diarrhoea was reported in 2% (2/123) of patients in the case series of 123 patients. Further details were not reported. Constipation was reported in 2% (2/123) of patients in the case series of 123 patients. Further details were not reported. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers reported no anecdotal adverse events. They considered that the following were theoretical adverse events: malnutrition, vitamin and mineral deficiencies.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2164-5	{'Recommendations': "Current evidence on the safety of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI‑S) for treating morbid obesity shows that there are well-recognised complications. Evidence on efficacy is limited in both quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do SADI‑S for treating morbid obesity should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nClinicians should review local clinical outcomes and enter details about all patients having SADI‑S for treating morbid obesity onto the National Bariatric Surgery Registry.\n\nPatient selection should be done by a multidisciplinary team experienced in managing morbid obesity.\n\nTreatment should be done by surgeons with specific training in the procedure, in centres with expertise in the treatment of morbid obesity.\n\nNICE encourages further research into SADI‑S for treating morbid obesity, particularly research examining long-term outcomes. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': "Morbid obesity is defined as a body mass index of 40\xa0kg/m2 or more, or of 35 to 40\xa0kg/m2 with significant medical problems related to body weight. Comorbidities include type\xa02 diabetes, coronary heart disease and hypertension. Weight loss reduces the comorbidities and improves long-term survival.\n\nMorbid obesity is managed by lifestyle changes including exercise and diet and medication. Bariatric surgery is a treatment option in selected patients if they have not lost enough weight using non-surgical measures.\n\nSurgical procedures aim to help patients lose weight by restricting the size of the stomach (for example, gastric banding or sleeve gastrectomy), or by decreasing the patient's capacity to absorb food (for example, Roux‑en‑Y gastric bypass or biliopancreatic diversion).", 'The procedure': "Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI‑S) for treating morbid obesity is usually done laparoscopically with the patient under general anaesthesia.\n\nInitially, the stomach is reduced in size by a sleeve gastrectomy, which involves devascularising and excising the greater curve. This leaves a tube of stomach passing from the oesophagus to the pylorus and duodenum. The duodenum is then mobilised and divided at the level of the gastroduodenal artery using a linear stapler. This leaves a short stump of duodenum attached to the pylorus. The distal end of the duodenum is closed off permanently. A loop of small bowel, usually 200 to 300\xa0cm from the ileocaecal valve, is anastomosed to the remnant of duodenum arising from the pylorus to restore the continuity of the gut. This anastomosis is usually sutured in 2\xa0layers, but may be stapled. In patients at high risk because of extreme obesity, the procedure may be done in 2\xa0stages, first sleeve gastrectomy, and then duodenal transection and duodeno-ileal anastomosis in a subsequent procedure once the patient's risks from surgery are reduced by weight loss induced by sleeve gastrectomy.\n\nAfter surgery, patients are maintained on a low-calorie diet. Multivitamin, calcium and iron supplements are prescribed as needed to maintain normal blood levels.", 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a case series of 100\xa0patients with morbid obesity or metabolic disease treated with single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI‑S), the mean excess weight loss (EWL calculated from an ideal body mass index [BMI] of 25\xa0kg/m2) was 95% at 12\xa0months. This was maintained for maximum of 48\xa0months of follow-up, with no significant differences between those who had SADI‑S 200\xa0cm from the ileocecal valve and those with SADI‑S 250\xa0cm. In a case series of 97\xa0patients with obesity and type\xa02 diabetes treated with SADI‑S, EWL was 92% (74/80) at 2‑year follow-up and 98% (425/32) at 5‑year follow-up. Six percent (6/97) of patients failed to reach 50% EWL. In a case series of 123\xa0patients with morbid obesity treated with stomach intestinal pylorus sparing (SIPS) procedure, EWL was 72% (64/102) at 1‑year follow-up.\n\nIn the case series of 97\xa0patients, overall weight loss was 39% at 2‑year follow-up and 38% at 5‑year follow-up. In the case series of 123\xa0patients, overall weight loss was 39% and patients had an average change in BMI of 19\xa0kg/m2 at 1‑year follow-up.\n\nIn the case series of 100\xa0patients, the mean glycaemia level decreased from 178.2\xa0mg/dl at baseline to 94.2\xa0mg/dl at 1‑year follow-up and to 79.6\xa0mg/dl at 4‑year follow-up. The mean glycated haemoglobin (HbA1c) level decreased from 7.9% at baseline to 5.3% at 1‑year follow-up and to 5.0% at 4‑year follow-up. In the case series of 97\xa0patients, the mean glycaemia level reduced from 167.6\xa0mg/dl at baseline to 93.0\xa0mg/dl at 1‑year follow-up and to 101.6\xa0mg/dl at 5‑year follow-up. The mean HbA1c level reduced from 7.6% at baseline to 5.1% at 1‑year follow-up and to 5.5% at 5‑year follow-up.\n\nIn the case series of 97\xa0patients, the overall diabetes remission rate (defined as HbA1c below 6% without antidiabetic medication for more than 1‑year) was 77% at 2\xa0years and 52% at 5 years. Remission rates were higher for those having oral therapy (n=14) than for those having insulin therapy (n=40) (97% versus 54% at 2\xa0years; 75% versus 38% at 5\xa0years).\n\nIn the case series of 97\xa0patients, type\xa02 diabetes recurred in 8% (4/97) of patients within 5\xa0years (308\xa0patient-years follow-up).\n\nIn the case series of 123\xa0patients, mean values for the nutritional data (Vitamin A, B1, B12, D and albumin) were at normal levels at 1‑year follow-up.\n\nThe specialist advisers listed key efficacy outcomes as weight loss, remission of type\xa02 diabetes, resolution of obesity-related comorbidities and improvement in quality of life.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nMortality due to progressive respiratory insufficiency occurred at 3\xa0months in 1\xa0patient in a case series of 50\xa0patients.\n\nMyocardial infarction occurred at 6\xa0months in 1\xa0patient in the case series of 50\xa0patients.\n\nGastric haemorrhage occurred in 1\xa0patient in a case series of 100\xa0patients (timing not stated). Patient had endoscopic coagulation but further details were not reported.\n\nPostoperative gastric leaks occurred in 2% (2/100) of patients in the case series of 100\xa0patients. One leak was visible with a barium swallow but uneventful, and the patient was discharged on the thirteenth day. One clinical leak was managed with an abdominal drain, and the patient was discharged after 5\xa0weeks. Duodenal anastomotic leak (treated conservatively) occurred in 1\xa0patient in the case series of 100\xa0patients.\n\nHaemoperitoneum occurred in 1\xa0patient in a case series of 97\xa0patients. Further details were not reported. Abdominal haematoma occurred in 3% (4/123) of patients in the case series of 123\xa0patients. Further details were not reported.\n\nAcute trocar site herniation occurred in 1\xa0patient in the case series of 100\xa0patients. The patient had another operation and prosthetic/mesh repair. Incarcerated umbilical hernia occurred in 1\xa0patient in the case series of 97\xa0patients. The patient had another operation.\n\nSubphrenic abscess (drained under radiological guidance) occurred in 1\xa0patient in the case series of 50\xa0patients.\n\nStricture in the gastric sleeve (which led to dysphagia) needing dilatation occurred in 1\xa0patient in the case series of 123\xa0patients.\n\nReoperation due to early postoperative ulcer was needed in 1\xa0patient in the case series of 123\xa0patients.\n\nAcute cholecystitis occurred within 1\xa0year of the procedure in 4% (2/50) of patients in the case series of 50\xa0patients. One patient had cholecystectomy and another patient was waiting to have surgery at the time of the report.\n\nClinical hypoalbuminemia occurred in 4% (4/100) patients in the case series of 100\xa0patients. In 1\xa0patient, it was related to severe diarrhoea and treated with metronidazole. In another patient it was due to intra-abdominal infection and the abscess was drained. In 2\xa0other patients, it was due to reduced food intake; the patients were given counselling and their oral intake increased. Because of recurrent hypoproteinaemia, 2\xa0of the patients had revision to the Roux‑en‑Y duodenal switch with a longer gut. Hypoalbuminemia was detected in 12% of patients, low vitamin A levels in 53% and high parathormone levels in 54% at 3\xa0years follow-up in the case series of 97\xa0patients.\n\nSporadic vomiting occurred in 1\xa0patient in the case series of 50\xa0patients. Further details were not reported.\n\nDiarrhoea was reported in 2% (2/123) of patients in the case series of 123\xa0patients. Further details were not reported.\n\nConstipation was reported in 2% (2/123) of patients in the case series of 123\xa0patients. Further details were not reported.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers reported no anecdotal adverse events. They considered that the following were theoretical adverse events: malnutrition, vitamin and mineral deficiencies.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2164-5'}	https://www.nice.org.uk/guidance/ipg569	Evidence-based recommendations on single-anastomosis duodeno-ileal bypass with sleeve gastrectomy for treating morbid obesity. This involves reducing the size of the stomach and small intestine to reduce the amount of food absorbed.
8647c685e00ef81cc1d734d3e64d0f168b509221	nice	Endoscopic transluminal pancreatic necrosectomy	Endoscopic transluminal pancreatic necrosectomy Evidence-based recommendations on endoscopic transluminal pancreatic necrosectomy in adults. This involves removing dead tissue from the pancreas. # Recommendations Current evidence on the safety of endoscopic transluminal pancreatic necrosectomy shows that there are serious but well‑recognised complications. Evidence on efficacy is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Patient selection should be done by a multidisciplinary team experienced in the management of the condition. Endoscopic transluminal pancreatic necrosectomy should only be done in a specialist centre by a team experienced in the management of complex pancreatic disease.# Indications and current treatments Pancreatic necrosis (also called necrotising pancreatitis) is a serious complication of pancreatitis that can occur in some patients. It can occur with or without the formation of pseudocysts and is associated with significant morbidity and high mortality, particularly if it becomes infected. Patients usually need a long stay in hospital with treatment in intensive care. Current treatment options for pancreatic necrosis include conventional open or laparoscopic necrosectomy.# The procedure Endoscopic transluminal pancreatic necrosectomy is done with the patient under sedation or general anaesthesia, using upper gastrointestinal endoscopy and endosonographic or fluoroscopic guidance or both. The stomach is distended with carbon dioxide. The area where the necrotic tissue has collected is usually identified as a bulge in the stomach wall. An opening is made in the posterior wall of the stomach. The opening is dilated with a balloon over a guide wire to allow the endoscope to pass through into the area of necrotic tissue. Any fluid that has collected is drained. Necrotic tissue is removed through the endoscope using suction, forceps and irrigation. One or more self-expanding stents or irrigation catheters may be left in place in the stomach wall to help further drainage from the retroperitoneal space into the stomach. Repeated sessions may be needed over many days until the cavity is clean and lined with granulation tissue. The procedure aims to avoid the need for open or laparoscopic necrosectomy and its associated morbidity.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review of 938 patients, the mean clinical success rate of endoscopic necrosectomy was 89% (range 50 to 100%). In a non-randomised comparative study (included in the systematic review), 24 patients were treated by endoscopic necrosectomy or a step-up approach (percutaneous catheter drainage with possible surgery). Clinical resolution (defined as resolution of primary symptoms and no abdominal pain, nausea, vomiting, fever, leucocytosis or sepsis) was reported in 92% (11/12) of patients after endoscopic necrosectomy and 25% (3/12) of patients after percutaneous catheter drainage in the step-up approach group (p=0.0028). In a systematic review of 455 patients, 16% (73/455) of patients needed additional interventions after endoscopic necrosectomy (18 percutaneous, 46 surgical, 7 percutaneous and surgical, 2 other). In a case series of 81 patients (included in the systematic review of 938 patients), small collections of necrotic tissue and fluid that caused symptoms recurred in 4% (3/72) of patients. These patients needed additional endoscopic treatment, which resulted in complete resolution. In a case series of 57 patients (included in the systematic review of 938 patients), 5% (3/57) of patients had a recurrent cavity after 2 to 8 months; they were successfully treated by endoscopic or percutaneous drainage. In a randomised controlled trial of 20 patients treated by endoscopic or surgical necrosectomy (included in the systematic reviews), hospital stays after randomisation were 45 and 36 days respectively (p=0.91). In a non-randomised comparative study of 32 patients treated by endoscopic or surgical necrosectomy (included in the systematic review of 938 patients), median length of hospital stay was 32 and 74 days respectively (p=0.006). The specialist advisers listed the key efficacy outcomes as resolution of the necrotic cavity, reduced length of stay in a high dependency or intensive care unit, and quality of life.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Overall mortality after endoscopic necrosectomy was reported as 5% (range 0 to 25% per study) in a systematic review of 938 patients. Death was reported in 10% (1/10) of patients treated by endoscopic necrosectomy and 40% (4/10) of patients treated by surgical necrosectomy (p=0.30) in a randomised controlled trial of 20 patients (included in the systematic review). The death rate was 0% (0/11) in patients treated by endoscopic necrosectomy compared with 14% (3/21) in patients treated by surgical necrosectomy (p=0.53) in a non-randomised comparative study of 32 patients (included in the systematic review). In-hospital mortality was 0% (0/12) for patients treated by endoscopic necrosectomy compared with 8% (1/12) for patients treated by a step-up approach in a non-randomised comparative study of 24 patients (included in the systematic review). Fatal gas embolism after endoscopic transgastric necrosectomy with carbon dioxide insufflation was described in a case report. Air embolism was reported in less than 1% (4/938) of patients in the systematic review of 938 patients. Bleeding was reported in 11% (103/938) of patients in the systematic review of 938 patients. Bleeding was reported in 8% (1/12) of patients treated by endoscopic necrosectomy and 50% (6/12) of patients treated by surgical necrosectomy in the non-randomised comparative study of 24 patients (included in the systematic review). Pancreatic fistula was reported in 5% (9/187) of patients in a systematic review of 455 patients. It was also reported in 10% (1/10) of patients treated by endoscopic necrosectomy and 70% (7/10) of patients treated by surgical necrosectomy (p=0.02) in the randomised controlled trial of 20 patients (included in the systematic review). Pancreatic fistula was reported in 0% (0/11) in patients treated by endoscopic necrosectomy compared with 38% (8/21) of patients treated by surgical necrosectomy (p=0.03) in a non-randomised comparative study of 32 patients. Spontaneous perforation of a hollow organ (apart from the stomach or duodenum because of the intervention) was reported in 4% (9/249) of patients in the systematic review of 455 patients. Bowel perforation was reported in 1 patient treated by endoscopic necrosectomy in the non-randomised comparative study of 32 patients. Perforation was reported in 5% (3/57) of patients in the case series of 57 patients. New-onset organ failure was reported in 18% (2/11) of patients treated by endoscopic necrosectomy and 17% (5/21) of patients treated by surgical necrosectomy (p=0.99) in the non-randomised comparative study of 32 patients. Stent complication (not further described) was reported in 9% (2/11) of patients treated by endoscopic necrosectomy in the non-randomised comparative study of 32 patients. Pneumoperitoneum, without the need for intervention or treated by needle aspiration, was reported in 5% (4/81) of patients in the case series of 81 patients. New-onset diabetes (assessed 6 months after hospital discharge) was reported in 22% (2/9) of patients treated by endoscopic necrosectomy and 50% (3/6) of patients treated by surgical necrosectomy (p=0.33) in the randomised controlled trial of 20 patients. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: slipping of irrigation tube, stent migration, prolonged hospital stay, and sedation-related adverse reactions. They considered that the following were theoretical adverse events: splenic vein thrombosis with portal hypertension and oesophageal varices, introduction or exacerbation of infection, and fluid overload.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2160-7	{'Recommendations': 'Current evidence on the safety of endoscopic transluminal pancreatic necrosectomy shows that there are serious but well‑recognised complications. Evidence on efficacy is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be done by a multidisciplinary team experienced in the management of the condition.\n\nEndoscopic transluminal pancreatic necrosectomy should only be done in a specialist centre by a team experienced in the management of complex pancreatic disease.', 'Indications and current treatments': 'Pancreatic necrosis (also called necrotising pancreatitis) is a serious complication of pancreatitis that can occur in some patients. It can occur with or without the formation of pseudocysts and is associated with significant morbidity and high mortality, particularly if it becomes infected. Patients usually need a long stay in hospital with treatment in intensive care.\n\nCurrent treatment options for pancreatic necrosis include conventional open or laparoscopic necrosectomy.', 'The procedure': 'Endoscopic transluminal pancreatic necrosectomy is done with the patient under sedation or general anaesthesia, using upper gastrointestinal endoscopy and endosonographic or fluoroscopic guidance or both. The stomach is distended with carbon dioxide. The area where the necrotic tissue has collected is usually identified as a bulge in the stomach wall. An opening is made in the posterior wall of the stomach. The opening is dilated with a balloon over a guide wire to allow the endoscope to pass through into the area of necrotic tissue. Any fluid that has collected is drained. Necrotic tissue is removed through the endoscope using suction, forceps and irrigation. One or more self-expanding stents or irrigation catheters may be left in place in the stomach wall to help further drainage from the retroperitoneal space into the stomach. Repeated sessions may be needed over many days until the cavity is clean and lined with granulation tissue. The procedure aims to avoid the need for open or laparoscopic necrosectomy and its associated morbidity.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review of 938\xa0patients, the mean clinical success rate of endoscopic necrosectomy was 89% (range 50 to 100%). In a non-randomised comparative study (included in the systematic review), 24\xa0patients were treated by endoscopic necrosectomy or a step-up approach (percutaneous catheter drainage with possible surgery). Clinical resolution (defined as resolution of primary symptoms and no abdominal pain, nausea, vomiting, fever, leucocytosis or sepsis) was reported in 92% (11/12) of patients after endoscopic necrosectomy and 25% (3/12) of patients after percutaneous catheter drainage in the step-up approach group (p=0.0028).\n\nIn a systematic review of 455\xa0patients, 16% (73/455) of patients needed additional interventions after endoscopic necrosectomy (18\xa0percutaneous, 46\xa0surgical, 7\xa0percutaneous and surgical, 2\xa0other). In a case series of 81\xa0patients (included in the systematic review of 938\xa0patients), small collections of necrotic tissue and fluid that caused symptoms recurred in 4% (3/72) of patients. These patients needed additional endoscopic treatment, which resulted in complete resolution. In a case series of 57\xa0patients (included in the systematic review of 938\xa0patients), 5% (3/57) of patients had a recurrent cavity after 2 to 8\xa0months; they were successfully treated by endoscopic or percutaneous drainage.\n\nIn a randomised controlled trial of 20\xa0patients treated by endoscopic or surgical necrosectomy (included in the systematic reviews), hospital stays after randomisation were 45 and 36\xa0days respectively (p=0.91). In a non-randomised comparative study of 32\xa0patients treated by endoscopic or surgical necrosectomy (included in the systematic review of 938\xa0patients), median length of hospital stay was 32 and 74\xa0days respectively (p=0.006).\n\nThe specialist advisers listed the key efficacy outcomes as resolution of the necrotic cavity, reduced length of stay in a high dependency or intensive care unit, and quality of life.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nOverall mortality after endoscopic necrosectomy was reported as 5% (range 0 to 25% per study) in a systematic review of 938\xa0patients. Death was reported in 10% (1/10) of patients treated by endoscopic necrosectomy and 40% (4/10) of patients treated by surgical necrosectomy (p=0.30) in a randomised controlled trial of 20\xa0patients (included in the systematic review). The death rate was 0% (0/11) in patients treated by endoscopic necrosectomy compared with 14% (3/21) in patients treated by surgical necrosectomy (p=0.53) in a non-randomised comparative study of 32\xa0patients (included in the systematic review). In-hospital mortality was 0% (0/12) for patients treated by endoscopic necrosectomy compared with 8% (1/12) for patients treated by a step-up approach in a non-randomised comparative study of 24\xa0patients (included in the systematic review).\n\nFatal gas embolism after endoscopic transgastric necrosectomy with carbon dioxide insufflation was described in a case report. Air embolism was reported in less than\xa01% (4/938) of patients in the systematic review of 938\xa0patients.\n\nBleeding was reported in 11% (103/938) of patients in the systematic review of 938\xa0patients. Bleeding was reported in 8% (1/12) of patients treated by endoscopic necrosectomy and 50% (6/12) of patients treated by surgical necrosectomy in the non-randomised comparative study of 24\xa0patients (included in the systematic review).\n\nPancreatic fistula was reported in 5% (9/187) of patients in a systematic review of 455\xa0patients. It was also reported in 10% (1/10) of patients treated by endoscopic necrosectomy and 70% (7/10) of patients treated by surgical necrosectomy (p=0.02) in the randomised controlled trial of 20\xa0patients (included in the systematic review). Pancreatic fistula was reported in 0% (0/11) in patients treated by endoscopic necrosectomy compared with 38% (8/21) of patients treated by surgical necrosectomy (p=0.03) in a non-randomised comparative study of 32\xa0patients.\n\nSpontaneous perforation of a hollow organ (apart from the stomach or duodenum because of the intervention) was reported in 4% (9/249) of patients in the systematic review of 455\xa0patients. Bowel perforation was reported in 1\xa0patient treated by endoscopic necrosectomy in the non-randomised comparative study of 32\xa0patients. Perforation was reported in 5% (3/57) of patients in the case series of 57\xa0patients.\n\nNew-onset organ failure was reported in 18% (2/11) of patients treated by endoscopic necrosectomy and 17% (5/21) of patients treated by surgical necrosectomy (p=0.99) in the non-randomised comparative study of 32\xa0patients.\n\nStent complication (not further described) was reported in 9% (2/11) of patients treated by endoscopic necrosectomy in the non-randomised comparative study of 32\xa0patients.\n\nPneumoperitoneum, without the need for intervention or treated by needle aspiration, was reported in 5% (4/81) of patients in the case series of 81\xa0patients.\n\nNew-onset diabetes (assessed 6\xa0months after hospital discharge) was reported in 22% (2/9) of patients treated by endoscopic necrosectomy and 50% (3/6) of patients treated by surgical necrosectomy (p=0.33) in the randomised controlled trial of 20\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: slipping of irrigation tube, stent migration, prolonged hospital stay, and sedation-related adverse reactions. They considered that the following were theoretical adverse events: splenic vein thrombosis with portal hypertension and oesophageal varices, introduction or exacerbation of infection, and fluid overload.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2160-7'}	https://www.nice.org.uk/guidance/ipg567	Evidence-based recommendations on endoscopic transluminal pancreatic necrosectomy in adults. This involves removing dead tissue from the pancreas.
0bcbcf3e80dedcb0e735bb7ea879106b2669e657	nice	Nivolumab for previously treated advanced renal cell carcinoma	Nivolumab for previously treated advanced renal cell carcinoma Evidence-based recommendations on nivolumab (Opdivo) for previously treated advanced renal cell carcinoma in adults. # Recommendations Nivolumab is recommended, within its marketing authorisation, as an option for previously treated advanced renal cell carcinoma in adults, when the company provides nivolumab according to the commercial arrangement.# The technology Description of the technology Nivolumab (Opdivo, Bristol–Myers Squibb) is a human monoclonal antibody that blocks an immune checkpoint protein receptor called programmed cell death protein 1 (PD‑1) to promote an anti-tumour response. Marketing authorisation Nivolumab 'as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults'. Before the marketing authorisation was granted (April 2016), nivolumab was available in the NHS through the early access to medicines scheme. Adverse reactions The most common adverse reactions with nivolumab in clinical trials were tiredness, rash, pruritus, diarrhoea, nausea and decreased appetite (occurring in more than 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule mg/kg given intravenously every 2 weeks. Price The list price is £439 per 40‑mg vial or £1,097 per 100‑mg vial. The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Evidence The appraisal committee (section 6) considered evidence submitted by Bristol–Myers Squibb and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of nivolumab, having considered evidence on the nature of renal cell carcinoma and the value placed on the benefits of nivolumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee considered the experience of people with advanced renal cell carcinoma. It heard from the clinical and patient experts that nivolumab could extend life and improve its quality. It heard that nivolumab was generally well tolerated, and usually caused fewer side effects than other treatments such as axitinib and everolimus. The committee noted that one of the patient experts who had had nivolumab was able to continue working. The committee recognised nivolumab is an intravenous drug whereas axitinib and everolimus are oral. The committee heard that people prefer oral treatments that they can have at home, but are willing to travel to have intravenous infusions to get more effective therapy. The committee was aware of several comments received during consultation from patients and carers who emphasised the importance of having access to nivolumab. # Treatment pathway The committee heard from the clinical experts that most people in the NHS with newly diagnosed advanced renal cell carcinoma would be offered one of two tyrosine kinase inhibitors; either pazopanib or sunitinib, as recommended in NICE's technology appraisal guidance. If the disease progresses and they are fit enough to have further treatment, most people are then offered a different tyrosine kinase inhibitor, axitinib, as recommended in NICE's technology appraisal guidance. The committee understood that everolimus (a mammalian target of rapamycin inhibitor) is currently available through the Cancer Drugs Fund for people who have had treatment with only 1 tyrosine kinase inhibitor and for whom axitinib is contraindicated or not tolerated. It heard from the clinical experts that, if given a choice of axitinib or everolimus for previously treated renal cell carcinoma, they would prefer axitinib because they expect a better response to a second tyrosine kinase inhibitor than an mTOR inhibitor. The committee heard that, in current practice, everolimus is offered to people who have previously had tyrosine kinase inhibitor‑related adverse events such as hypertension, or who cannot tolerate axitinib, or for whom axitinib is contraindicated. The committee heard that after 2 treatments, no further treatments are available in the NHS and people are offered best supportive care. # Comparators The committee heard from the clinical experts that they would like to offer nivolumab to people who have had 1 or 2 previous treatments. The experts also advised that a small number of people cannot tolerate axitinib or everolimus, but may be able to have nivolumab because of its favourable toxicity profile. For people who have had 1 previous treatment, the committee agreed that the relevant comparator for nivolumab is: axitinib, for most people everolimus, for people who cannot have axitinib best supportive care, for people who cannot have axitinib or everolimus. The committee further concluded that, for people who have had 2 previous treatments, best supportive care is the appropriate comparator for nivolumab. # Clinical effectiveness ## Survival benefit of nivolumab compared with everolimus The committee noted that the evidence for nivolumab mostly came from CheckMate 025, a well-conducted open-label randomised controlled trial with 821 patients that compared nivolumab with everolimus. Overall survival was the primary outcome. The committee noted that, in CheckMate 025, patients randomised to nivolumab lived longer (median 25.0 months) than patients randomised to everolimus (median 19.6 months; 95% confidence interval 17.6 to 23.1), resulting in a hazard ratio of 0.73 (98.5% CI 0.57 to 0.93; p=0.002). The committee noted that the CheckMate 025 trial showed no difference in progression-free survival between nivolumab and everolimus. The committee concluded that, compared with everolimus, nivolumab extended overall survival, but not progression-free survival. The committee considered the extent to which nivolumab extends survival when compared with everolimus: The committee considered the survival data from CheckMate 025 to be immature because, at the time of the interim analysis that led to the study stopping (July 2015), 398 out of 821 (48%) patients had died and median follow‑up was only about 18 months. The company's submission stated that, when nivolumab is used to treat melanoma, survival curves show 'long tails' for overall survival meaning that some patients survive for a long time. The clinical experts advised that it was plausible that an overall survival curve with a 'long tail' would also be shown for renal cell carcinoma treated with nivolumab. The committee noted that this opinion was reiterated in the company's consultation response, which contained advice from 2 consultant oncologists.The committee concluded that the most robust results came from the larger CheckMate 025 trial, which showed that nivolumab extended life by a median of 5.4 months compared with everolimus, but also concluded that there was uncertainty about the extent of the survival benefit when measured over the long term. ## Generalisability of the CheckMate 025 population The committee heard from the clinical experts that the characteristics of the patients in CheckMate 025 were similar to those of the people in their NHS clinics. The committee concluded the trial results were generalisable to the NHS. ## Subgroups with 1 or 2 previous treatments The committee recognised that the trial included a mix of people who had had 1 previous treatment with a tyrosine kinase inhibitor (72% of patients) and people who had had 2 previous tyrosine kinase inhibitors (28%). During consultation the company clarified that a subgroup analysis based on number of previous treatments showed that the treatment effect of nivolumab compared with everolimus was clinically and statistically significant both for patients who had 1 previous tyrosine kinase inhibitor (hazard ratio 0.79; 95% CI 0.63 to 0.99) and patients who had 2 previous tyrosine kinase inhibitors (hazard ratio 0.65; 95% CI 0.43 to 0.99). The committee concluded that nivolumab prolonged overall survival compared with everolimus both for people who had had 1 previous treatment and people who had had 2 previous treatments. ## Subsequent treatments in CheckMate 025 The committee was aware that people generally continue having nivolumab until disease progression, or some time beyond it, after which some people then try other therapies. The committee heard from the company that the trial protocol prohibited patients from switching treatments during the trial (that is, patients randomised to everolimus could not have nivolumab after progression), yet patients in both the nivolumab and everolimus groups had subsequent treatments including everolimus and tyrosine kinase inhibitors. The committee heard from the clinical experts that these subsequent treatments extend survival, but that they are not given in NHS practice after people have had 2 treatments. The committee recognised the use of these treatments was unlikely to have been equal between both groups in CheckMate 025, which may have confounded the results, although the direction of the bias was not clear. The committee concluded that this should be taken into account in any analyses. ## Duration of nivolumab treatment The committee noted that the summary of product characteristics allows for nivolumab treatment to continue after disease progression, as did the trial. It heard from the clinical experts that about 10% of people have nivolumab for a short time after disease progression. The committee concluded that treatment after disease progression was likely to reflect NHS practice, and that the company had appropriately included this in its economic model. ## Network meta-analysis The committee understood that, because there were no head-to-head trials comparing nivolumab with axitinib or best supportive care, the company had done a network meta-analysis to compare the treatments indirectly. To compare nivolumab with best supportive care, the network linked CheckMate 025 (nivolumab compared with everolimus) with the RECORD‑1 trial (everolimus compared with best supportive care) using everolimus as a common comparator. To compare nivolumab with axitinib, the network joined these 2 trials to 2 other trials (TARGET, sorafenib compared with best supportive care; AXIS, axitinib compared with sorafenib). It noted advice from the evidence review group (ERG) that the results were likely to be biased because of differences between trials: Number of previous treatments: CheckMate 025 and RECORD-1 recruited patients who had had 1 or 2 previous tyrosine kinase inhibitors, while AXIS and TARGET recruited patients who had only had 1 previous treatment with a tyrosine kinase inhibitor. Choice of previous treatments: The committee heard from the clinical experts that previous therapy affects response to subsequent treatments. The committee acknowledged that the company had partly addressed this by only using data from the subgroup of patients in the AXIS trial who previously had sunitinib. But the trials still differed in the choice of previous treatments. Prognosis of patients at baseline: The committee noted that patients in AXIS had a poorer prognosis than those in CheckMate 025, measured using the Memorial Sloan Kettering Cancer Center (MSKCC) tool for predicting renal cancer prognosis. The committee heard from the company that both trials used the MSKCC tool, but that 1 component (performance status) was measured using different tools in each trial. The company stated that this explained the difference in prognosis and that the trial populations were similar. The committee concluded that there was no way to assess whether the prognosis of the trial patients was similar. Subsequent treatments: The ERG noted that Motzer et al. (2013) raised concerns that the results of the AXIS trial may have been confounded by differences between treatment groups with respect to subsequent treatments. The committee was concerned that the company had not explored whether an imbalance in the choice of subsequent treatments, which extended life and were not routinely available in the NHS, could have biased the AXIS results and hence the company's network meta-analysis. The committee assessed the effect of the limitations in the network meta-analysis. It heard from the ERG that in its opinion the poorer prognosis of patients in AXIS, and the impact of subsequent treatments in that trial, meant that the results were likely to have underestimated the effectiveness of axitinib, and so overestimated the relative effectiveness of nivolumab with respect to overall survival. The committee concluded that the company's network meta-analysis could potentially have been biased in favour of nivolumab. ## Effectiveness of axitinib compared with everolimus (and, by extension, nivolumab) The committee was aware that to be able to estimate the relative effectiveness of nivolumab compared with axitinib, the company's original model used the results of CheckMate 025 (nivolumab compared with everolimus) but adjusted the everolimus arm, using the network meta-analysis results to represent the effectiveness of axitinib. Two key inputs to the economic model were therefore the hazard ratios for progression-free survival and overall survival comparing axitinib with everolimus. The committee noted that the company's network meta-analysis showed axitinib was less effective than everolimus (the results are academic-in-confidence and cannot be reported here). The committee questioned the face-validity of this result. It heard from clinical experts that in their experience, axitinib and everolimus have similar treatment effects. The committee also heard that clinicians would usually choose axitinib over everolimus (unless a person could not tolerate tyrosine kinase inhibitors) because they expected a better response with a second tyrosine kinase inhibitor than with an mTOR inhibitor. The committee noted that a published indirect treatment comparison of axitinib and everolimus showed no difference in progression-free survival (Sherman et al. 2015). The committee acknowledged the limited evidence, but concluded that axitinib and everolimus were likely to have similar effectiveness and that it was appropriate to use a hazard ratio of 1 for overall survival and progression-free survival in the model. Both the company and ERG used hazard ratios of 1 in their revised base-case analyses submitted after consultation. # Cost effectiveness The committee agreed that the structure of the 6‑stage, partitioned-survival economic model was appropriate. It noted that the model represented patients who had had either 1 or 2 previous tyrosine kinase inhibitors. The committee would have preferred to consider separate analyses for patients who had 1 previous tyrosine kinase inhibitor and patients who had 2 previous tyrosine kinase inhibitors because the comparators that reflect NHS practice differ for each group (see section 4.3) and the patients in the groups likely differ in ways that might affect treatment effectiveness. However, neither the company nor the ERG presented subgroup analyses. The committee accepted that the analyses for the overall population (representing patients who had had either 1 or 2 previous tyrosine kinase inhibitors) were suitable for decision-making. ## Modelling overall survival Because the trial data were immature (see section 4.5), the committee was concerned that a large proportion of the benefit attributed to nivolumab for extending life was based on extrapolation rather than on trial data. The committee was aware that, for predicting overall survival with nivolumab and everolimus, the company fitted a generalised gamma model to extrapolate the data from CheckMate 025. The committee noted that this model relies on the 'accelerated failure‑time' assumption, but this assumption had not been formally tested by the company. In the committee's opinion, the survival curves converged suggesting that the assumption was not met. The committee noted that an alternative approach was to use independent models for each treatment group (that is, separate models for nivolumab and everolimus), as presented by the ERG in a scenario analysis requested by the committee for the second committee meeting. The committee noted that the independent log-logistic model predicted that 19% of patients treated with everolimus would be alive after 5 years, whereas the company's clinical experts predicted this would be only 10% to 12% in practice. The committee concluded that the independent log-logistic model overpredicted survival with everolimus. The committee preferred to base its decision on a single generalised gamma model to predict survival with both nivolumab and everolimus, as had been done in the company and ERG's base cases. The committee discussed the company's scenario analysis, provided after consultation, using a 'model averaging' approach. The company gave 50% weight to the base-case model and 50% weight to a model assuming a greater long-term survival benefit for nivolumab (see section 4.5). For the latter model, based on data from CheckMate 003 and advice from 2 oncologists, the company assumed that patients whose disease was treated with nivolumab who survive for 5 years would have the same risk of death after 5 years as the age-matched general population. This scenario analysis substantially improved the cost effectiveness of nivolumab compared with all comparators. The committee considered an alternative approach presented in a scenario analysis by the ERG. The ERG used the sample sizes of CheckMate 003 and CheckMate 010 to calculate a weighting that took into account the proportion of information given by each of these trials. The ERG's scenario gave a 4% weighting to the model assuming greater long-term survival, and 96% weighting to the base-case model. The committee noted that the base-case analysis already predicted that some patients would survive for a long time with nivolumab (6% of people survived for 10 years). It noted that there was little evidence to show that the survival benefit of nivolumab was greater than predicted in the base case, and the committee could not be sure that the 'long tail' seen in melanoma would also be seen in renal cell carcinoma. The committee preferred the methods in the company's base case for predicting survival with nivolumab, but it was willing to consider scenarios with predictions of better survival in its decision-making. ## Modelling time-to-stopping treatment The committee noted that the company fitted a complex spline model to predict time-to-stopping treatment with nivolumab and everolimus in its original submission. It considered that the simpler models used by the ERG (log normal and generalised gamma) appeared to fit the data better at the beginning of the trial, but less so at the end. Overall the committee preferred to use either a log‑normal or a generalised gamma distribution to predict time-to-stopping treatment, but was not confident that any of the curves presented by the company or the ERG provided a good fit to the entire Kaplan–Meier curve. It noted that the company had used a log-normal distribution in its revised base case submitted after consultation. ## Cost of nivolumab The committee noted that the company excluded the costs of missed doses and some of the delayed doses from its revised model. The committee heard from the company that nivolumab infusions are not prepared before the patient comes for treatment, meaning that the NHS would not pay for nivolumab drug costs for missed or delayed doses. The company further explained that if a dose was delayed for at least 7 days, the patient would be seen at the next weekly clinic and there would be at least 4 weeks between doses (in other words, delays of at least 7 days mean that patients skip a dose). Based on data from CheckMate 025, the company's revised base case excluded the costs of missed doses (2.5%) and doses that were delayed for at least 7 days (4%), resulting in a total 6.5% reduction in drug costs for nivolumab. The ERG did not agree that all of these missed and delayed doses would incur no drug costs for the NHS. In its revised base case, the ERG took the midpoint between the company's original 7.5% reduction in drug costs and no reduction in drug costs, resulting in a total 3.8% reduction. The committee remained concerned that, if a planned infusion of nivolumab was cancelled at short notice, the infusion would still be prepared and this would incur a cost for the NHS. It therefore considered both the 6.5% and 3.8% cost reductions in its decision-making, noting that the difference did not substantially affect the cost-effectiveness results. ## Cost of subsequent treatments The committee noted that the company's model included the costs of subsequent treatments, based on the treatments used in CheckMate 025. It recalled that these treatments are believed to have a survival benefit (see section 4.8) but are not used in the NHS. The committee would have preferred to see an analysis that excluded both the costs and the clinical benefits of subsequent treatments, but the company had not presented this analysis. The ERG presented an analysis that removed the costs of subsequent treatments, but the committee agreed that this was not appropriate because the clinical benefits were still included in the model. The committee concluded that, because all the analyses included the clinical benefits of subsequent treatments, it preferred to also include the costs of those treatments. In line with the committee's preference, the revised base cases from the company and ERG included the costs of subsequent treatments. ## Utility values The committee was aware that CheckMate 025 collected health-related quality-of-life data using EQ‑5D. In its original submission, the company took utility values for its model from CheckMate 025 for nivolumab and everolimus, and from AXIS for axitinib; the AXIS utilities were lower. The committee did not find the company's original utility values plausible because: The post-progression utility values for patients who had nivolumab and everolimus were higher than the pre-progression utility values for patients having axitinib or best supportive care. The utility values were lower for axitinib than for everolimus, but the committee heard from the clinical experts that in their experience, health-related quality of life was similar for people whose condition was being treated with these drugs.The committee concluded that the company's utility values were not appropriate and it preferred to use the same utility values for axitinib, everolimus and best supportive care. The committee acknowledged that the company's revised base case submitted after consultation did this. The revised base cases from both the company and the ERG took utility values for axitinib and best supportive care from the everolimus group in CheckMate 025. The committee heard from the company that this was the 'gold standard' approach to modelling because the utility values came from the main trial of nivolumab. The committee acknowledged its general preference for trial-based utilities, but also noted that the appropriate utility values are those taken from patients that most closely resemble the patients who would receive nivolumab in the NHS. The committee therefore considered the ERG's scenario analysis, which took utility values for all comparator treatments from the axitinib group in AXIS. In this scenario, the gain in utility for nivolumab compared with everolimus was taken from CheckMate 025. Compared with the ERG's base case, the scenario using AXIS utilities increased the incremental cost-effectiveness ratio (ICER) for nivolumab compared with all comparator treatments. The committee concluded that the trial population of CheckMate 025 was similar to NHS patients and so it was reasonable to use the utility values from CheckMate 025, as had been done in the base case. The committee considered that the AXIS patients may also be representative of some NHS patients who are more unwell, and therefore it was appropriate to explore scenarios using the AXIS utility values. The company assumed in its model that, even after disease progression and stopping treatment, people treated with nivolumab have a consistently higher quality of life than people treated with axitinib or everolimus. The committee heard from the clinical experts that a post-progression treatment benefit may exist for nivolumab compared with its comparators, because the adverse effects experienced with axitinib or everolimus take some time to resolve, but that the quality-of-life benefit would only be seen for a short time. The committee remained concerned that the company assumed a continual post-treatment benefit of nivolumab and had not presented to the committee analyses that excluded this benefit. ## Results of cost-effectiveness analyses In response to consultation, the company proposed a new simple discount patient access scheme for nivolumab. The level of discount is commercial in confidence. The committee used the results including the patient access scheme for nivolumab for decision-making, but this document does not present precise results because the discount is confidential. At the second committee meeting, the committee considered the company's revised pairwise comparisons, which included its preferred assumptions: assuming axitinib was as effective as everolimus for progression-free survival and overall survival (see section 4.11) using a log‑normal distribution to model time-to-stopping treatment (see section 4.15) assuming utility values for axitinib and everolimus were equal (see sections 4.18) including the costs of subsequent therapy (see section 4.17) using the survival benefit predicted in the base-case analysis (see section 4.15).The committee considered deterministic pairwise ICERs for nivolumab compared with axitinib, everolimus and best supportive care, using the company's revised base case (with a 6.5% cost reduction for missed and delayed doses) and the ERG's revised base case (with a 3.8% cost reduction). All analyses included the patient access schemes for nivolumab and axitinib. Most of the base-case ICERs from the company and ERG were below £50,000 per QALY gained. The committee acknowledged that the scenarios from the company and ERG using a model averaging approach with a greater long-term survival benefit with nivolumab (section 4.14) reduced the ICERs. # Innovation The committee considered whether nivolumab was an innovative treatment. It heard from patient experts that nivolumab represented a step change in terms of extension to life and the quality of life while on treatment. The committee agreed that nivolumab was an innovative treatment in renal cell carcinoma, but noted that it was not the first checkpoint inhibitor to gain a marketing authorisation for treating cancer. It also noted that before the marketing authorisation was granted, nivolumab was available for people in the NHS through the early access to medicines scheme, which aims to give patients access to promising innovative medicines and is granted by the UK Medicines and Healthcare products Regulatory Agency. The committee concluded that it had not been presented with any evidence of additional benefits of nivolumab that were not captured in the QALY measure. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee discussed whether nivolumab met the end-of-life criteria. It first discussed the life expectancy of people with previously treated advanced renal cell carcinoma having each of the 3 comparator treatments: Patients having axitinib lived for about 20 months (population studies, trial data). Patients having everolimus lived for about 19.6 months (CheckMate 025). Patients having best supportive care lived for less than 12 months (population studies, trial data).Although data on mean life expectancy were not available, on the balance of the evidence the committee concluded that average life expectancy was less than 24 months for people with advanced renal cell carcinoma and that the life-expectancy criterion was met. The committee discussed whether nivolumab extended life by at least 3 months, noting that the relevant comparators depended on treatment history (see section 4.3). For people who had 1 previous treatment the committee compared nivolumab with axitinib, everolimus and best supportive care. For people who had had 2 previous treatments it compared nivolumab with best supportive care. The committee recognised that the estimates of extensions to life were based on the overall trial population in CheckMate 025, which included a mixture of patients who had had 1 previous treatment and those who had had 2 previous treatments. The committee observed that CheckMate 025 had shown a median increase in survival of 5.4 months compared with everolimus. The committee had assumed axitinib was similarly effective to everolimus and so accepted that the extension to life for people having axitinib would also be greater than 3 months. The committee assumed that any extension to life would be even longer for nivolumab compared with best supportive care. The committee therefore agreed that nivolumab met the end-of-life criteria. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Conclusion The committee noted that most of the revised base-case ICERs from the company and ERG were below £50,000 per QALY gained for nivolumab compared with axitinib, everolimus or best supportive care. The committee was unsure whether the survival benefit of nivolumab would be greater than assumed in the base case because there was very little long-term evidence, but it noted that scenario analyses assuming a greater benefit reduced the ICER. The committee concluded that, given the greater weight for QALYs at the end of life, nivolumab could be considered a cost-effective use of NHS resources. # Summary of appraisal committee's key conclusions TA417 Appraisal title: Nivolumab for previously treated advanced renal cell carcinoma Section Key conclusion Nivolumab is recommended, within its marketing authorisation, as an option for previously treated advanced renal cell carcinoma in adults, when the company provides nivolumab according to the commercial arrangement. Nivolumab extended overall survival compared with everolimus, but there was uncertainty about the extent of the survival benefit when measured over the long term. Most of the incremental cost-effectiveness ratios (ICERs) for nivolumab compared with any comparator were below £50,000 per quality-adjusted life year (QALY) gained. The committee acknowledged that scenarios assuming a greater long-term survival benefit reduced the ICERs. It concluded that, when applying the maximum weighting to the QALY that is possible under the end-of-life criteria, the ICER for nivolumab fell within the range of a cost-effective treatment. Current practice Clinical need of patients, including the availability of alternative treatments People with newly diagnosed advanced renal cell carcinoma are usually offered one of two tyrosine kinase inhibitors; either pazopanib or sunitinib. If the disease progresses and they are fit enough to have further treatment, most people are then offered a different tyrosine kinase inhibitor; axitinib. Everolimus is currently available through the Cancer Drugs Fund for people who have had treatment with only 1 tyrosine kinase inhibitor and for whom axitinib is contraindicated or not tolerated. The committee heard that after 2 treatments, no further treatments are available in the NHS and people are offered best supportive care. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Nivolumab extends life compared with everolimus. Patient experts advised that nivolumab usually causes fewer side effects than other treatments such as axitinib and everolimus. Before the marketing authorisation was granted, nivolumab was available through the early access to medicines scheme. The committee agreed that nivolumab was an innovative treatment in renal cell carcinoma, although it was not the first checkpoint inhibitor to gain a marketing authorisation for treating cancer. What is the position of the treatment in the pathway of care for the condition? For people who have had 1 previous treatment, nivolumab is a potential alternative to: axitinib (which is offered to most people) everolimus (which is offered to people who cannot have axitinib) best supportive care (which is offered to people who cannot have axitinib or everolimus). For people who have had 2 previous treatments, nivolumab is a potential alternative to best supportive care. Adverse reactions The most common adverse reactions with nivolumab are tiredness, rash, pruritus, diarrhoea, nausea and decreased appetite. Evidence for clinical effectiveness Availability, nature and quality of evidence The evidence mostly came from CheckMate 025, an open-label randomised trial with 821 patients that compared nivolumab with everolimus. The company provided unpublished data from a phase I and a phase II trial (CheckMate 003 and CheckMate 010 respectively); these trials included longer-term follow‑up data on mortality. Relevance to general clinical practice in the NHS The committee concluded that the overall trial population of CheckMate 025 was similar to NHS patients and so the results were generalisable to the NHS. Uncertainties generated by the evidence The CheckMate 025 data were immature. The clinical experts advised that it was plausible that in the future an overall-survival curve with a 'long tail' (that is, an extended survival benefit) would be shown for renal cell carcinoma treated with nivolumab, based on the results of nivolumab for melanoma. The committee considered the additional evidence from CheckMate 003 and CheckMate 010 presented by the company during consultation which showed longer-term survival for renal cell carcinoma with nivolumab but was concerned that the sample sizes were small. It concluded that the most robust results came from CheckMate 025, which showed that nivolumab extended life by a median of 5.4 months compared with everolimus, but that there was uncertainty about the extent of the survival benefit when measured over the long term. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? CheckMate 025 included a mix of people who had had 1 previous treatment with a tyrosine kinase inhibitor and people who had had 2 previous tyrosine kinase inhibitors. During consultation the company clarified that the treatment effect of nivolumab was clinically and statistically significant for both subgroups. The committee concluded that nivolumab prolonged overall survival compared with everolimus both for people who had had 1 previous treatment and people who had had 2 previous treatments. Estimate of the size of the clinical effectiveness including strength of supporting evidence CheckMate 025 showed that nivolumab extended life by a median of 5.4 months compared with everolimus, but there was uncertainty about the extent of the survival benefit when measured over the long term. Data from CheckMate 003 and CheckMate 010 provided during consultation and clinical experts' opinion supported the expectation of a longer-term survival benefit, although it was uncertain how many patients, on average, this would affect. Evidence for cost effectiveness Availability and nature of evidence The company presented a 6‑stage, partitioned-survival economic model comparing nivolumab with axitinib, everolimus and best supportive care. Uncertainties around and plausibility of assumptions and inputs in the economic model The estimates of overall survival for nivolumab were uncertain because the CheckMate 025 trial data were immature. The network meta-analysis used to compare nivolumab with axitinib and best supportive care was highly uncertain. In line with clinical opinion, the committee preferred to assume that axitinib and everolimus had the same effectiveness, which the company presented in its revised base-case analysis following consultation. It was uncertain whether the NHS would incur the costs of delayed doses of nivolumab. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee preferred using equal utility values for axitinib, everolimus and best supportive care, which were included in the company's revised base-case analysis. The committee concluded it was reasonable to use the utility values derived from the CheckMate 025 trial. The committee was not presented with any evidence of additional benefits of nivolumab that were not captured in the QALY measure. Are there specific groups of people for whom the technology is particularly cost effective? No subgroup analyses were presented. What are the key drivers of cost effectiveness? Overall survival with nivolumab. The effectiveness of axitinib compared with everolimus. The choice of distribution for modelling time-to-stopping treatment. Most likely cost-effectiveness estimate (given as an ICER) When the confidential discounts for nivolumab and axitinib were included, the company's revised base-case ICERs and the majority of the evidence review group's (ERG's) revised base-case ICERs were below £50,000 per QALY gained for nivolumab compared with any comparator. Additional factors taken into account Patient access schemes (PPRS) A patient access scheme has been approved for nivolumab. The ERG presented analyses that included the confidential discounts for both nivolumab and axitinib. End-of-life considerations Nivolumab met the end-of-life criteria. Equalities considerations and social value judgements No equality issues were identified by consultees or the committee.	{'Recommendations': 'Nivolumab is recommended, within its marketing authorisation, as an option for previously treated advanced renal cell carcinoma in adults, when the company provides nivolumab according to the commercial arrangement.', 'The technology': "Description of the technology\n\nNivolumab (Opdivo, Bristol–Myers Squibb) is a human monoclonal antibody that blocks an immune checkpoint protein receptor called programmed cell death protein\xa01 (PD‑1) to promote an anti-tumour response.\n\nMarketing authorisation\n\nNivolumab 'as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults'.\n\nBefore the marketing authorisation was granted (April 2016), nivolumab was available in the NHS through the early access to medicines scheme.\n\nAdverse reactions\n\nThe most common adverse reactions with nivolumab in clinical trials were tiredness, rash, pruritus, diarrhoea, nausea and decreased appetite (occurring in more than 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nmg/kg given intravenously every 2\xa0weeks.\n\nPrice\n\nThe list price is £439 per 40‑mg vial or £1,097 per 100‑mg vial.\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Bristol–Myers Squibb and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of nivolumab, having considered evidence on the nature of renal cell carcinoma and the value placed on the benefits of nivolumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee considered the experience of people with advanced renal cell carcinoma. It heard from the clinical and patient experts that nivolumab could extend life and improve its quality. It heard that nivolumab was generally well tolerated, and usually caused fewer side effects than other treatments such as axitinib and everolimus. The committee noted that one of the patient experts who had had nivolumab was able to continue working. The committee recognised nivolumab is an intravenous drug whereas axitinib and everolimus are oral. The committee heard that people prefer oral treatments that they can have at home, but are willing to travel to have intravenous infusions to get more effective therapy. The committee was aware of several comments received during consultation from patients and carers who emphasised the importance of having access to nivolumab.\n\n# Treatment pathway\n\nThe committee heard from the clinical experts that most people in the NHS with newly diagnosed advanced renal cell carcinoma would be offered one of two tyrosine kinase inhibitors; either pazopanib or sunitinib, as recommended in NICE's technology appraisal guidance. If the disease progresses and they are fit enough to have further treatment, most people are then offered a different tyrosine kinase inhibitor, axitinib, as recommended in NICE's technology appraisal guidance. The committee understood that everolimus (a mammalian target of rapamycin [mTOR] inhibitor) is currently available through the Cancer Drugs Fund for people who have had treatment with only 1\xa0tyrosine kinase inhibitor and for whom axitinib is contraindicated or not tolerated. It heard from the clinical experts that, if given a choice of axitinib or everolimus for previously treated renal cell carcinoma, they would prefer axitinib because they expect a better response to a second tyrosine kinase inhibitor than an mTOR inhibitor. The committee heard that, in current practice, everolimus is offered to people who have previously had tyrosine kinase inhibitor‑related adverse events such as hypertension, or who cannot tolerate axitinib, or for whom axitinib is contraindicated. The committee heard that after 2\xa0treatments, no further treatments are available in the NHS and people are offered best supportive care.\n\n# Comparators\n\nThe committee heard from the clinical experts that they would like to offer nivolumab to people who have had 1\xa0or\xa02 previous treatments. The experts also advised that a small number of people cannot tolerate axitinib or everolimus, but may be able to have nivolumab because of its favourable toxicity profile. For people who have had 1\xa0previous treatment, the committee agreed that the relevant comparator for nivolumab is:\n\naxitinib, for most people\n\neverolimus, for people who cannot have axitinib\n\nbest supportive care, for people who cannot have axitinib or everolimus. The committee further concluded that, for people who have had 2\xa0previous treatments, best supportive care is the appropriate comparator for nivolumab.\n\n# Clinical effectiveness\n\n## Survival benefit of nivolumab compared with everolimus\n\nThe committee noted that the evidence for nivolumab mostly came from CheckMate\xa0025, a well-conducted open-label randomised controlled trial with 821\xa0patients that compared nivolumab with everolimus. Overall survival was the primary outcome. The committee noted that, in CheckMate\xa0025, patients randomised to nivolumab lived longer (median 25.0\xa0months) than patients randomised to everolimus (median 19.6\xa0months; 95% confidence interval [CI] 17.6\xa0to\xa023.1), resulting in a hazard ratio of 0.73 (98.5% CI 0.57\xa0to\xa00.93; p=0.002). The committee noted that the CheckMate\xa0025 trial showed no difference in progression-free survival between nivolumab and everolimus. The committee concluded that, compared with everolimus, nivolumab extended overall survival, but not progression-free survival.\n\nThe committee considered the extent to which nivolumab extends survival when compared with everolimus:\n\nThe committee considered the survival data from CheckMate\xa0025 to be immature because, at the time of the interim analysis that led to the study stopping (July\xa02015), 398 out of 821 (48%) patients had died and median follow‑up was only about 18\xa0months.\n\nThe company's submission stated that, when nivolumab is used to treat melanoma, survival curves show 'long tails' for overall survival meaning that some patients survive for a long time. The clinical experts advised that it was plausible that an overall survival curve with a 'long tail' would also be shown for renal cell carcinoma treated with nivolumab. The committee noted that this opinion was reiterated in the company's consultation response, which contained advice from 2 consultant oncologists.The committee concluded that the most robust results came from the larger CheckMate\xa0025 trial, which showed that nivolumab extended life by a median of 5.4\xa0months compared with everolimus, but also concluded that there was uncertainty about the extent of the survival benefit when measured over the long term.\n\n## Generalisability of the CheckMate\xa0025 population\n\nThe committee heard from the clinical experts that the characteristics of the patients in CheckMate\xa0025 were similar to those of the people in their NHS clinics. The committee concluded the trial results were generalisable to the NHS.\n\n## Subgroups with 1\xa0or\xa02 previous treatments\n\nThe committee recognised that the trial included a mix of people who had had 1\xa0previous treatment with a tyrosine kinase inhibitor (72% of patients) and people who had had 2\xa0previous tyrosine kinase inhibitors (28%). During consultation the company clarified that a subgroup analysis based on number of previous treatments showed that the treatment effect of nivolumab compared with everolimus was clinically and statistically significant both for patients who had 1\xa0previous tyrosine kinase inhibitor (hazard ratio 0.79; 95% CI 0.63 to 0.99) and patients who had 2\xa0previous tyrosine kinase inhibitors (hazard ratio 0.65; 95% CI 0.43 to 0.99). The committee concluded that nivolumab prolonged overall survival compared with everolimus both for people who had had 1 previous treatment and people who had had 2 previous treatments.\n\n## Subsequent treatments in CheckMate\xa0025\n\nThe committee was aware that people generally continue having nivolumab until disease progression, or some time beyond it, after which some people then try other therapies. The committee heard from the company that the trial protocol prohibited patients from switching treatments during the trial (that is, patients randomised to everolimus could not have nivolumab after progression), yet patients in both the nivolumab and everolimus groups had subsequent treatments including everolimus and tyrosine kinase inhibitors. The committee heard from the clinical experts that these subsequent treatments extend survival, but that they are not given in NHS practice after people have had 2\xa0treatments. The committee recognised the use of these treatments was unlikely to have been equal between both groups in CheckMate\xa0025, which may have confounded the results, although the direction of the bias was not clear. The committee concluded that this should be taken into account in any analyses.\n\n## Duration of nivolumab treatment\n\nThe committee noted that the summary of product characteristics allows for nivolumab treatment to continue after disease progression, as did the trial. It heard from the clinical experts that about 10% of people have nivolumab for a short time after disease progression. The committee concluded that treatment after disease progression was likely to reflect NHS practice, and that the company had appropriately included this in its economic model.\n\n## Network meta-analysis\n\nThe committee understood that, because there were no head-to-head trials comparing nivolumab with axitinib or best supportive care, the company had done a network meta-analysis to compare the treatments indirectly. To compare nivolumab with best supportive care, the network linked CheckMate\xa0025 (nivolumab compared with everolimus) with the RECORD‑1 trial (everolimus compared with best supportive care) using everolimus as a common comparator. To compare nivolumab with axitinib, the network joined these 2\xa0trials to 2\xa0other trials (TARGET, sorafenib compared with best supportive care; AXIS, axitinib compared with sorafenib). It noted advice from the evidence review group (ERG) that the results were likely to be biased because of differences between trials:\n\nNumber of previous treatments: CheckMate\xa0025 and RECORD-1 recruited patients who had had 1\xa0or\xa02 previous tyrosine kinase inhibitors, while AXIS and TARGET recruited patients who had only had 1\xa0previous treatment with a tyrosine kinase inhibitor.\n\nChoice of previous treatments: The committee heard from the clinical experts that previous therapy affects response to subsequent treatments. The committee acknowledged that the company had partly addressed this by only using data from the subgroup of patients in the AXIS trial who previously had sunitinib. But the trials still differed in the choice of previous treatments.\n\nPrognosis of patients at baseline: The committee noted that patients in AXIS had a poorer prognosis than those in CheckMate\xa0025, measured using the Memorial Sloan Kettering Cancer Center (MSKCC) tool for predicting renal cancer prognosis. The committee heard from the company that both trials used the MSKCC tool, but that 1\xa0component (performance status) was measured using different tools in each trial. The company stated that this explained the difference in prognosis and that the trial populations were similar. The committee concluded that there was no way to assess whether the prognosis of the trial patients was similar.\n\nSubsequent treatments: The ERG noted that Motzer et al. (2013) raised concerns that the results of the AXIS trial may have been confounded by differences between treatment groups with respect to subsequent treatments. The committee was concerned that the company had not explored whether an imbalance in the choice of subsequent treatments, which extended life and were not routinely available in the NHS, could have biased the AXIS results and hence the company's network meta-analysis.\n\nThe committee assessed the effect of the limitations in the network meta-analysis. It heard from the ERG that in its opinion the poorer prognosis of patients in AXIS, and the impact of subsequent treatments in that trial, meant that the results were likely to have underestimated the effectiveness of axitinib, and so overestimated the relative effectiveness of nivolumab with respect to overall survival. The committee concluded that the company's network meta-analysis could potentially have been biased in favour of nivolumab.\n\n## Effectiveness of axitinib compared with everolimus (and, by extension, nivolumab)\n\nThe committee was aware that to be able to estimate the relative effectiveness of nivolumab compared with axitinib, the company's original model used the results of CheckMate\xa0025 (nivolumab compared with everolimus) but adjusted the everolimus arm, using the network meta-analysis results to represent the effectiveness of axitinib. Two key inputs to the economic model were therefore the hazard ratios for progression-free survival and overall survival comparing axitinib with everolimus. The committee noted that the company's network meta-analysis showed axitinib was less effective than everolimus (the results are academic-in-confidence and cannot be reported here). The committee questioned the face-validity of this result.\n\nIt heard from clinical experts that in their experience, axitinib and everolimus have similar treatment effects.\n\nThe committee also heard that clinicians would usually choose axitinib over everolimus (unless a person could not tolerate tyrosine kinase inhibitors) because they expected a better response with a second tyrosine kinase inhibitor than with an mTOR inhibitor.\n\nThe committee noted that a published indirect treatment comparison of axitinib and everolimus showed no difference in progression-free survival (Sherman et al. 2015). The committee acknowledged the limited evidence, but concluded that axitinib and everolimus were likely to have similar effectiveness and that it was appropriate to use a hazard ratio of\xa01 for overall survival and progression-free survival in the model. Both the company and ERG used hazard ratios of 1 in their revised base-case analyses submitted after consultation.\n\n# Cost effectiveness\n\nThe committee agreed that the structure of the 6‑stage, partitioned-survival economic model was appropriate. It noted that the model represented patients who had had either 1\xa0or\xa02 previous tyrosine kinase inhibitors. The committee would have preferred to consider separate analyses for patients who had 1\xa0previous tyrosine kinase inhibitor and patients who had 2\xa0previous tyrosine kinase inhibitors because the comparators that reflect NHS practice differ for each group (see section\xa04.3) and the patients in the groups likely differ in ways that might affect treatment effectiveness. However, neither the company nor the ERG presented subgroup analyses. The committee accepted that the analyses for the overall population (representing patients who had had either 1 or 2\xa0previous tyrosine kinase inhibitors) were suitable for decision-making.\n\n## Modelling overall survival\n\nBecause the trial data were immature (see section\xa04.5), the committee was concerned that a large proportion of the benefit attributed to nivolumab for extending life was based on extrapolation rather than on trial data. The committee was aware that, for predicting overall survival with nivolumab and everolimus, the company fitted a generalised gamma model to extrapolate the data from CheckMate\xa0025. The committee noted that this model relies on the 'accelerated failure‑time' assumption, but this assumption had not been formally tested by the company. In the committee's opinion, the survival curves converged suggesting that the assumption was not met. The committee noted that an alternative approach was to use independent models for each treatment group (that is, separate models for nivolumab and everolimus), as presented by the ERG in a scenario analysis requested by the committee for the second committee meeting. The committee noted that the independent log-logistic model predicted that 19% of patients treated with everolimus would be alive after 5\xa0years, whereas the company's clinical experts predicted this would be only 10% to 12% in practice. The committee concluded that the independent log-logistic model overpredicted survival with everolimus. The committee preferred to base its decision on a single generalised gamma model to predict survival with both nivolumab and everolimus, as had been done in the company and ERG's base cases.\n\nThe committee discussed the company's scenario analysis, provided after consultation, using a 'model averaging' approach. The company gave 50% weight to the base-case model and 50% weight to a model assuming a greater long-term survival benefit for nivolumab (see section\xa04.5). For the latter model, based on data from CheckMate\xa0003 and advice from 2 oncologists, the company assumed that patients whose disease was treated with nivolumab who survive for 5\xa0years would have the same risk of death after 5\xa0years as the age-matched general population. This scenario analysis substantially improved the cost effectiveness of nivolumab compared with all comparators. The committee considered an alternative approach presented in a scenario analysis by the ERG. The ERG used the sample sizes of CheckMate\xa0003 and CheckMate\xa0010 to calculate a weighting that took into account the proportion of information given by each of these trials. The ERG's scenario gave a 4% weighting to the model assuming greater long-term survival, and 96% weighting to the base-case model. The committee noted that the base-case analysis already predicted that some patients would survive for a long time with nivolumab (6% of people survived for 10\xa0years). It noted that there was little evidence to show that the survival benefit of nivolumab was greater than predicted in the base case, and the committee could not be sure that the 'long tail' seen in melanoma would also be seen in renal cell carcinoma. The committee preferred the methods in the company's base case for predicting survival with nivolumab, but it was willing to consider scenarios with predictions of better survival in its decision-making.\n\n## Modelling time-to-stopping treatment\n\nThe committee noted that the company fitted a complex spline model to predict time-to-stopping treatment with nivolumab and everolimus in its original submission. It considered that the simpler models used by the ERG (log normal and generalised gamma) appeared to fit the data better at the beginning of the trial, but less so at the end. Overall the committee preferred to use either a log‑normal or a generalised gamma distribution to predict time-to-stopping treatment, but was not confident that any of the curves presented by the company or the ERG provided a good fit to the entire Kaplan–Meier curve. It noted that the company had used a log-normal distribution in its revised base case submitted after consultation.\n\n## Cost of nivolumab\n\nThe committee noted that the company excluded the costs of missed doses and some of the delayed doses from its revised model. The committee heard from the company that nivolumab infusions are not prepared before the patient comes for treatment, meaning that the NHS would not pay for nivolumab drug costs for missed or delayed doses. The company further explained that if a dose was delayed for at least 7\xa0days, the patient would be seen at the next weekly clinic and there would be at least 4\xa0weeks between doses (in other words, delays of at least 7\xa0days mean that patients skip a dose). Based on data from CheckMate\xa0025, the company's revised base case excluded the costs of missed doses (2.5%) and doses that were delayed for at least 7\xa0days (4%), resulting in a total 6.5% reduction in drug costs for nivolumab. The ERG did not agree that all of these missed and delayed doses would incur no drug costs for the NHS. In its revised base case, the ERG took the midpoint between the company's original 7.5% reduction in drug costs and no reduction in drug costs, resulting in a total 3.8% reduction. The committee remained concerned that, if a planned infusion of nivolumab was cancelled at short notice, the infusion would still be prepared and this would incur a cost for the NHS. It therefore considered both the 6.5% and 3.8% cost reductions in its decision-making, noting that the difference did not substantially affect the cost-effectiveness results.\n\n## Cost of subsequent treatments\n\nThe committee noted that the company's model included the costs of subsequent treatments, based on the treatments used in CheckMate\xa0025. It recalled that these treatments are believed to have a survival benefit (see section\xa04.8) but are not used in the NHS. The committee would have preferred to see an analysis that excluded both the costs and the clinical benefits of subsequent treatments, but the company had not presented this analysis. The ERG presented an analysis that removed the costs of subsequent treatments, but the committee agreed that this was not appropriate because the clinical benefits were still included in the model. The committee concluded that, because all the analyses included the clinical benefits of subsequent treatments, it preferred to also include the costs of those treatments. In line with the committee's preference, the revised base cases from the company and ERG included the costs of subsequent treatments.\n\n## Utility values\n\nThe committee was aware that CheckMate\xa0025 collected health-related quality-of-life data using EQ‑5D. In its original submission, the company took utility values for its model from CheckMate\xa0025 for nivolumab and everolimus, and from AXIS for axitinib; the AXIS utilities were lower. The committee did not find the company's original utility values plausible because:\n\nThe post-progression utility values for patients who had nivolumab and everolimus were higher than the pre-progression utility values for patients having axitinib or best supportive care.\n\nThe utility values were lower for axitinib than for everolimus, but the committee heard from the clinical experts that in their experience, health-related quality of life was similar for people whose condition was being treated with these drugs.The committee concluded that the company's utility values were not appropriate and it preferred to use the same utility values for axitinib, everolimus and best supportive care. The committee acknowledged that the company's revised base case submitted after consultation did this.\n\nThe revised base cases from both the company and the ERG took utility values for axitinib and best supportive care from the everolimus group in CheckMate\xa0025. The committee heard from the company that this was the 'gold standard' approach to modelling because the utility values came from the main trial of nivolumab. The committee acknowledged its general preference for trial-based utilities, but also noted that the appropriate utility values are those taken from patients that most closely resemble the patients who would receive nivolumab in the NHS. The committee therefore considered the ERG's scenario analysis, which took utility values for all comparator treatments from the axitinib group in AXIS. In this scenario, the gain in utility for nivolumab compared with everolimus was taken from CheckMate\xa0025. Compared with the ERG's base case, the scenario using AXIS utilities increased the incremental cost-effectiveness ratio (ICER) for nivolumab compared with all comparator treatments. The committee concluded that the trial population of CheckMate\xa0025 was similar to NHS patients and so it was reasonable to use the utility values from CheckMate\xa0025, as had been done in the base case. The committee considered that the AXIS patients may also be representative of some NHS patients who are more unwell, and therefore it was appropriate to explore scenarios using the AXIS utility values.\n\nThe company assumed in its model that, even after disease progression and stopping treatment, people treated with nivolumab have a consistently higher quality of life than people treated with axitinib or everolimus. The committee heard from the clinical experts that a post-progression treatment benefit may exist for nivolumab compared with its comparators, because the adverse effects experienced with axitinib or everolimus take some time to resolve, but that the quality-of-life benefit would only be seen for a short time. The committee remained concerned that the company assumed a continual post-treatment benefit of nivolumab and had not presented to the committee analyses that excluded this benefit.\n\n## Results of cost-effectiveness analyses\n\nIn response to consultation, the company proposed a new simple discount patient access scheme for nivolumab. The level of discount is commercial in confidence. The committee used the results including the patient access scheme for nivolumab for decision-making, but this document does not present precise results because the discount is confidential.\n\nAt the second committee meeting, the committee considered the company's revised pairwise comparisons, which included its preferred assumptions:\n\nassuming axitinib was as effective as everolimus for progression-free survival and overall survival (see section\xa04.11)\n\nusing a log‑normal distribution to model time-to-stopping treatment (see section\xa04.15)\n\nassuming utility values for axitinib and everolimus were equal (see\xa0sections 4.18)\n\nincluding the costs of subsequent therapy (see section\xa04.17)\n\nusing the survival benefit predicted in the base-case analysis (see section 4.15).The committee considered deterministic pairwise ICERs for nivolumab compared with axitinib, everolimus and best supportive care, using the company's revised base case (with a 6.5% cost reduction for missed and delayed doses) and the ERG's revised base case (with a 3.8% cost reduction). All analyses included the patient access schemes for nivolumab and axitinib. Most of the base-case ICERs from the company and ERG were below £50,000 per QALY gained. The committee acknowledged that the scenarios from the company and ERG using a model averaging approach with a greater long-term survival benefit with nivolumab (section\xa04.14) reduced the ICERs.\n\n# Innovation\n\nThe committee considered whether nivolumab was an innovative treatment. It heard from patient experts that nivolumab represented a step change in terms of extension to life and the quality of life while on treatment. The committee agreed that nivolumab was an innovative treatment in renal cell carcinoma, but noted that it was not the first checkpoint inhibitor to gain a marketing authorisation for treating cancer. It also noted that before the marketing authorisation was granted, nivolumab was available for people in the NHS through the early access to medicines scheme, which aims to give patients access to promising innovative medicines and is granted by the UK Medicines and Healthcare products Regulatory Agency. The committee concluded that it had not been presented with any evidence of additional benefits of nivolumab that were not captured in the QALY measure.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\nThe committee discussed whether nivolumab met the end-of-life criteria. It first discussed the life expectancy of people with previously treated advanced renal cell carcinoma having each of the 3\xa0comparator treatments:\n\nPatients having axitinib lived for about 20\xa0months (population studies, trial data).\n\nPatients having everolimus lived for about 19.6\xa0months (CheckMate\xa0025).\n\nPatients having best supportive care lived for less than 12\xa0months (population studies, trial data).Although data on mean life expectancy were not available, on the balance of the evidence the committee concluded that average life expectancy was less than 24\xa0months for people with advanced renal cell carcinoma and that the life-expectancy criterion was met.\n\nThe committee discussed whether nivolumab extended life by at least 3\xa0months, noting that the relevant comparators depended on treatment history (see section\xa04.3). For people who had 1\xa0previous treatment the committee compared nivolumab with axitinib, everolimus and best supportive care. For people who had had 2\xa0previous treatments it compared nivolumab with best supportive care. The committee recognised that the estimates of extensions to life were based on the overall trial population in CheckMate\xa0025, which included a mixture of patients who had had 1\xa0previous treatment and those who had had 2\xa0previous treatments. The committee observed that CheckMate\xa0025 had shown a median increase in survival of 5.4\xa0months compared with everolimus. The committee had assumed axitinib was similarly effective to everolimus and so accepted that the extension to life for people having axitinib would also be greater than 3\xa0months. The committee assumed that any extension to life would be even longer for nivolumab compared with best supportive care. The committee therefore agreed that nivolumab met the end-of-life criteria.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Conclusion\n\nThe committee noted that most of the revised base-case ICERs from the company and ERG were below £50,000 per QALY gained for nivolumab compared with axitinib, everolimus or best supportive care. The committee was unsure whether the survival benefit of nivolumab would be greater than assumed in the base case because there was very little long-term evidence, but it noted that scenario analyses assuming a greater benefit reduced the ICER. The committee concluded that, given the greater weight for QALYs at the end of life, nivolumab could be considered a cost-effective use of NHS resources.\n\n# Summary of appraisal committee's key conclusions\n\nTA417\n\nAppraisal title: Nivolumab for previously treated advanced renal cell carcinoma\n\nSection\n\nKey conclusion\n\nNivolumab is recommended, within its marketing authorisation, as an option for previously treated advanced renal cell carcinoma in adults, when the company provides nivolumab according to the commercial arrangement.\n\nNivolumab extended overall survival compared with everolimus, but there was uncertainty about the extent of the survival benefit when measured over the long term.\n\nMost of the incremental cost-effectiveness ratios (ICERs) for nivolumab compared with any comparator were below £50,000 per quality-adjusted life year (QALY) gained. The committee acknowledged that scenarios assuming a greater long-term survival benefit reduced the ICERs. It concluded that, when applying the maximum weighting to the QALY that is possible under the end-of-life criteria, the ICER for nivolumab fell within the range of a cost-effective treatment.\n\n, 4.4, 4.5, 4.23, 4.29\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nPeople with newly diagnosed advanced renal cell carcinoma are usually offered one of two tyrosine kinase inhibitors; either pazopanib or sunitinib. If the disease progresses and they are fit enough to have further treatment, most people are then offered a different tyrosine kinase inhibitor; axitinib. Everolimus is currently available through the Cancer Drugs Fund for people who have had treatment with only 1\xa0tyrosine kinase inhibitor and for whom axitinib is contraindicated or not tolerated. The committee heard that after 2\xa0treatments, no further treatments are available in the NHS and people are offered best supportive care.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nNivolumab extends life compared with everolimus. Patient experts advised that nivolumab usually causes fewer side effects than other treatments such as axitinib and everolimus.\n\nBefore the marketing authorisation was granted, nivolumab was available through the early access to medicines scheme. The committee agreed that nivolumab was an innovative treatment in renal cell carcinoma, although it was not the first checkpoint inhibitor to gain a marketing authorisation for treating cancer.\n\n, 4.1, 4.24\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nFor people who have had 1\xa0previous treatment, nivolumab is a potential alternative to:\n\naxitinib (which is offered to most people)\n\neverolimus (which is offered to people who cannot have axitinib)\n\nbest supportive care (which is offered to people who cannot have axitinib or everolimus).\n\nFor people who have had 2\xa0previous treatments, nivolumab is a potential alternative to best supportive care.\n\n\n\nAdverse reactions\n\nThe most common adverse reactions with nivolumab are tiredness, rash, pruritus, diarrhoea, nausea and decreased appetite.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence mostly came from CheckMate\xa0025, an open-label randomised trial with 821\xa0patients that compared nivolumab with everolimus. The company provided unpublished data from a phase\xa0I and a phase\xa0II trial (CheckMate\xa0003 and CheckMate\xa0010 respectively); these trials included longer-term follow‑up data on mortality.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that the overall trial population of CheckMate\xa0025 was similar to NHS patients and so the results were generalisable to the NHS.\n\n\n\nUncertainties generated by the evidence\n\nThe CheckMate\xa0025 data were immature. The clinical experts advised that it was plausible that in the future an overall-survival curve with a 'long tail' (that is, an extended survival benefit) would be shown for renal cell carcinoma treated with nivolumab, based on the results of nivolumab for melanoma. The committee considered the additional evidence from CheckMate\xa0003 and CheckMate\xa0010 presented by the company during consultation which showed longer-term survival for renal cell carcinoma with nivolumab but was concerned that the sample sizes were small. It concluded that the most robust results came from CheckMate\xa0025, which showed that nivolumab extended life by a median of 5.4\xa0months compared with everolimus, but that there was uncertainty about the extent of the survival benefit when measured over the long term.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nCheckMate\xa0025 included a mix of people who had had 1\xa0previous treatment with a tyrosine kinase inhibitor and people who had had 2\xa0previous tyrosine kinase inhibitors. During consultation the company clarified that the treatment effect of nivolumab was clinically and statistically significant for both subgroups. The committee concluded that nivolumab prolonged overall survival compared with everolimus both for people who had had 1\xa0previous treatment and people who had had 2\xa0previous treatments.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nCheckMate\xa0025 showed that nivolumab extended life by a median of 5.4\xa0months compared with everolimus, but there was uncertainty about the extent of the survival benefit when measured over the long term.\n\nData from CheckMate\xa0003 and CheckMate\xa0010 provided during consultation and clinical experts' opinion supported the expectation of a longer-term survival benefit, although it was uncertain how many patients, on average, this would affect.\n\n, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented a 6‑stage, partitioned-survival economic model comparing nivolumab with axitinib, everolimus and best supportive care.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe estimates of overall survival for nivolumab were uncertain because the CheckMate\xa0025 trial data were immature. The network meta-analysis used to compare nivolumab with axitinib and best supportive care was highly uncertain. In line with clinical opinion, the committee preferred to assume that axitinib and everolimus had the same effectiveness, which the company presented in its revised base-case analysis following consultation.\n\nIt was uncertain whether the NHS would incur the costs of delayed doses of nivolumab.\n\n, 4.10, 4.11, 4.12\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee preferred using equal utility values for axitinib, everolimus and best supportive care, which were included in the company's revised base-case analysis.\n\nThe committee concluded it was reasonable to use the utility values derived from the CheckMate\xa0025 trial.\n\nThe committee was not presented with any evidence of additional benefits of nivolumab that were not captured in the QALY measure.\n\n, 4.20, 4.24\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroup analyses were presented.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nOverall survival with nivolumab.\n\nThe effectiveness of axitinib compared with everolimus.\n\nThe choice of distribution for modelling time-to-stopping treatment.\n\n, 4.15, 4.12, 4.16\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nWhen the confidential discounts for nivolumab and axitinib were included, the company's revised base-case ICERs and the majority of the evidence review group's (ERG's) revised base-case ICERs were below £50,000 per QALY gained for nivolumab compared with any comparator.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nA patient access scheme has been approved for nivolumab. The ERG presented analyses that included the confidential discounts for both nivolumab and axitinib.\n\n–\n\nEnd-of-life considerations\n\nNivolumab met the end-of-life criteria.\n\n, 4.26\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified by consultees or the committee.\n\n–"}	https://www.nice.org.uk/guidance/ta417	Evidence-based recommendations on nivolumab (Opdivo) for previously treated advanced renal cell carcinoma in adults.
74afeabba831adb3420e5801e4342089be78445a	nice	Dapagliflozin in triple therapy for treating type 2 diabetes	Dapagliflozin in triple therapy for treating type 2 diabetes Evidence-based recommendations on dapagliflozin (Forxiga) given with 2 other drugs for treating type 2 diabetes in adults. # Recommendations Dapagliflozin in a triple therapy regimen is recommended as an option for treating type 2 diabetes in adults, only in combination with metformin and a sulfonylurea. This guidance is not intended to affect the position of patients whose treatment with dapagliflozin in other triple therapy regimens was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Dapagliflozin (Forxiga, AstraZeneca) is a selective sodium–glucose cotransporter 2 (SGLT‑2) inhibitor, which blocks the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine. Marketing authorisation Dapagliflozin has a UK marketing authorisation for treating type 2 diabetes mellitus to improve glycaemic control in adults: as monotherapy: when diet and exercise alone do not provide adequate glycaemic control in people for whom use of metformin is considered inappropriate due to intolerance or contraindications as add-on combination therapy: with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Adverse reactions The summary of product characteristics lists the following adverse reactions for dapagliflozin: back pain, balanitis, creatinine renal clearance decrease, dizziness, dysuria, dyslipidaemia, elevated haematocrit, polyuria, urinary tract and genital infection, and vulvovaginitis. Dapagliflozin is not recommended for people with moderate to severe renal impairment (people with a creatinine clearance rate of less than 60 ml/min or an estimated glomerular filtration rate of less than 60 ml/min/1.73 m2). For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended dosage is 10 mg dapagliflozin orally once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. Price The list price of dapagliflozin is £36.59 for a 28‑tablet pack of 5‑mg or 10‑mg tablets (excluding VAT; 'British national formulary' , accessed online August 2016). Costs may vary in different settings because of negotiated procurement discounts.# Evidence The appraisal committee (section 6) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of dapagliflozin, having considered evidence on the nature of type 2 diabetes and the value placed on the benefits of dapagliflozin by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Patient experience The patient expert described the benefits of treatment with dapagliflozin, which she took in addition to 3 other oral agents for diabetes. She felt that dapagliflozin was effective, and easy and flexible to take, which gave her more confidence in self-managing her disease. Because of this she had a more positive outlook and generally felt less stressed and anxious. As someone with needle-phobia, the patient expert particularly appreciated having an additional oral treatment option to delay progression to injectable treatments such as insulin. And she believed that an added bonus of her treatment with dapagliflozin is that it had reduced her blood pressure, meaning she did not have to add a blood pressure medication to her treatment regimen. The clinical experts confirmed that in addition to lowering haemoglobin A1c (HbA1c – a measure of blood glucose levels over the previous 2 to 3 months), selective sodium–glucose cotransporter 2 (SGLT‑2) inhibitors such as dapagliflozin have the added benefit of helping to reduce blood pressure. Another significant and characteristic benefit of the SGLT‑2 inhibitors is weight loss. This is a particularly important outcome for people with type 2 diabetes because there is a strong association with excess body weight and some treatments, such as insulin, can result in weight gain. The committee concluded that patients and their clinicians would value an additional effective oral treatment option for type 2 diabetes, particularly if it offered additional benefits such as weight loss and blood-pressure reduction. # Current clinical management of type 2 diabetes The committee noted that dapagliflozin has a licence, and has been previously been appraised by NICE, for both monotherapy (when metformin is contraindicated, recommended in NICE technology appraisal guidance 390) and also as part of combination therapy (NICE technology appraisal guidance 288 recommends dapagliflozin in specific dual therapy regimens, but not as triple therapy because of a lack of evidence at the time). This appraisal is a part review of TA288 focussing on triple therapy. The committee queried where dapagliflozin is used most frequently in the treatment pathway. It heard from the clinical experts that there is no consensus about where dapagliflozin would be most appropriate, but the most likely position is probably as dual therapy in combination with metformin. The committee asked the clinical experts what the most relevant comparators are for dapagliflozin as part of triple therapy, noting that the company had excluded the comparators pioglitazone (citing low use in triple therapy in clinical practice) and injectable treatments (stating that oral treatments are used before injectable treatments). It heard from the clinical experts that they considered both of these exclusions to be appropriate. They stated that although many people are taking pioglitazone, with a large number of annual prescriptions as highlighted by the evidence review group (ERG), this is not representative of the number of people being newly prescribed pioglitazone, which is decreasing year on year. The clinical experts stated that this decrease is probably related to concerns about the adverse effects of rosiglitazone (a drug in the same class as pioglitazone that was withdrawn from clinical use because of an increased risk of cardiovascular disorders) and because pioglitazone is associated with an increased risk of oedema and weight gain. When given a choice of treatments, patients almost always prefer a treatment such as dapagliflozin that is associated with weight loss, rather than one that is weight-neutral or causes weight gain. Also, for the population in the scope, the clinical experts stated that a third oral treatment is almost always preferable to an injectable treatment such as insulin. The committee concluded that the comparators included by the company, dipeptidyl peptidase‑4 (DPP‑4) inhibitors and other SGLT‑2 inhibitors, were appropriate for its decision-making. # Clinical effectiveness ## Population The committee noted that the population in the scope included people with type 2 diabetes that is not controlled on dual therapy with metformin and a sulfonylurea, or with metformin and a DPP-4 inhibitor. However, the company had only presented evidence for the former population because of a lack of evidence for the latter population, and also because it considered that metformin plus a sulfonylurea is the most commonly used regimen. The clinical experts stated that they agreed with the company that the majority of people on dual therapy, who would be eligible for dapagliflozin as a third treatment, would be taking a combination of metformin and a sulfonylurea. The committee concluded that the company had used the most relevant population in its analyses. ## Clinical evidence The committee was aware that the clinical trial evidence had demonstrated that dapagliflozin in triple therapy is more effective than placebo in reducing HbA1c and weight. In comparison with the other SGLT‑2 inhibitors and the DPP-4 inhibitors, the company's network meta-analyses demonstrated that dapagliflozin had a similar effect on HbA1c as the other SGLT‑2 inhibitors and DPP‑4 inhibitors, but that the SGLT‑2 inhibitors produced more weight loss than the DPP‑4 inhibitors. The committee heard from the clinical experts that although there are subtle pharmacological differences between the individual SGLT‑2 inhibitors, they can generally be considered as a class in terms of effectiveness. Patients with diabetes that does not respond to one SGLT‑2 inhibitor will probably not respond to another. However, in some instances, clinicians may prescribe the higher dose of canagliflozin (300 mg) because this is the only SGLT‑2 inhibitor that also has an effect on the SGLT‑1 mechanism. The committee concluded that it is reasonable to assume that the SGLT‑2 inhibitors have a class effect and, when compared with DPP‑4 inhibitors, are similarly effective for HbA1c reduction. However, SGLT‑2 inhibitors have the added benefit of weight loss. The committee noted that the clinical trial evidence (Study 5) at week 8 had also shown a statistically significant reduction in blood pressure when dapagliflozin was compared with placebo, but this was no longer apparent at week 52. However, it heard from the company, the ERG and the clinical experts that the result at week 52 was anomalous, and the company stated that in several other trials the effect on blood pressure had been maintained. The committee concluded that based on this consistent feedback, it is reasonably likely that dapagliflozin also has a sustained beneficial effect on blood pressure. ## Adverse effects of treatment The patient expert stated that she had not experienced any adverse effects of treatment with dapagliflozin. She noted that she had been advised to drink plenty of water, which she believed had probably helped reduce the risk of an adverse event. The committee was also aware that dapagliflozin is currently already used in clinical practice. It concluded that based on the currently available clinical evidence, dapagliflozin has an acceptable adverse event profile. # Cost effectiveness ## Model structure The committee was aware that the ERG had raised concerns about the transparency of the model used by the company. However, it was also aware that the model had been accepted as appropriate for decision making in previous NICE technology appraisals for type 2 diabetes. The committee noted that the ERG had disagreed with several parameter assumptions used in the company's model, such as the use of values from the network meta-analysis which did not match the clinical trial results. It had presented an alternative base case with several updated assumptions, including the equations used to inform the incidence of complications (section 4.9) and costs related to the duration of treatment (section 4.10). The committee concluded that the model structure was appropriate for decision making. ## Health-related quality of life The committee was aware that dapagliflozin is effective in reducing HbA1c but also has other beneficial effects, including reduction in weight and systolic blood pressure. It asked the company and the ERG whether these additional benefits had been fully captured in the model. It heard from the ERG that the company had assumed that weight loss was only maintained for 1 year, which was a pessimistic assumption because there is evidence that it lasts for longer. Therefore the model had not adequately captured the quality of life gain associated with weight loss. The clinical experts stated that weight reduction was a sustained effect, alongside the reduction in HbA1c. In addition, the committee heard from the company and the ERG that it was plausible that SGLT‑2 inhibitors have an effect on reducing the risk of heart failure. If this is the case, then the model had not captured this health benefit. The committee concluded that the company and the ERG's base cases had not fully captured the health-related quality of life benefits of dapagliflozin. ## Clinical effectiveness and cost assumptions The committee noted that the company had used older UK prospective diabetes study equations (UKPDS 68) to predict the incidence of diabetes-related complications in the model. However, it heard from the ERG that newer equations are available (UKPDS 82), and these should have been used because they are more up to date. The ERG explained that the newer UKPDS 82 equations predict a lower incidence of diabetes-related myocardial infarction, renal failure and death, and that the use of the older UKPDS 68 equations in the company's cost-effectiveness analysis was beneficial for dapagliflozin. In particular, the committee noted that the main differences in modelled costs between dapagliflozin and DPP‑4 inhibitors in the company's base case were differences related to the incidence of nephropathy. This was because the company assumed that dapagliflozin has a protective effect on renal function, and also because the older UKPDS 68 equations predict a higher incidence of renal failure than the newer UKPDS 82 equations. The committee heard from the clinical experts that they consider that dapagliflozin has a protective effect on renal function. The committee concluded that it was reasonable for the model to assume a protective effect of dapagliflozin on renal function, however the use of the older UKPDS 68 equations was questionable. ## Treatment costs The committee noted that when intensifying treatment to insulin in the model, the company assumed that oral therapies were stopped, whereas the ERG, based on expert clinical opinion, assumed that they continued. The clinical experts stated that drugs such as sulfonylureas may be stopped because of a risk of hypoglycaemia, but SGLT‑2 inhibitors would probably be continued. The committee concluded that the assumption in the ERG base case that oral treatments continued when intensifying to insulin is a more accurate reflection of NHS practice than the assumption used in the company model. ## Most plausible incremental cost-effectiveness ratio (ICER) The committee was aware that when comparing dapagliflozin with DPP‑4 inhibitors, the company model predicted that dapagliflozin would dominate (that is, would be cheaper and more effective than) DPP‑4 inhibitors, whereas the ERG base case for dapagliflozin was £37,997 per quality-adjusted life year (QALY) gained. However the committee noted that both estimates were based on very small differences in the costs and in the QALY gains between dapagliflozin and the DPP‑4 inhibitors, and therefore the cost-effectiveness estimates were unstable. The committee also noted that neither base case had taken into account all the health-related quality of life benefits of dapagliflozin (see section 4.8), particularly in relation to weight loss as noted by the ERG. It therefore considered the higher ICER to be an overestimate. The committee was aware that there were no discernible differences in costs and effectiveness between the different SGLT‑2 inhibitors, 2 of which are already recommended in triple therapy. It was also aware that individualised care is critical in diabetes management (as recommended in NICE's guideline on type 2 diabetes in adults). The committee agreed that it should be up to patients and their clinicians to decide which SGLT‑2 inhibitor is most appropriate for them. The committee concluded that dapagliflozin as part of triple therapy in combination with metformin and a sulfonylurea for type 2 diabetes can be recommended as a cost-effective use of NHS resources. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA418 Appraisal title: Dapagliflozin in triple therapy for treating type 2 diabetes Section Key conclusion When comparing dapagliflozin with dipeptidyl peptidase‑4 (DPP‑4) inhibitors, the company model predicted that dapagliflozin would dominate (that is, would be cheaper and more effective than) DPP‑4 inhibitors, whereas the evidence review group (ERG) base case for dapagliflozin was £37,997 per quality-adjusted life year (QALY) gained. However the committee noted that both estimates were based on very small differences in costs and QALYs, and therefore the cost-effectiveness estimates were unstable. The committee also noted that neither base case had taken into account all the health-related quality of life benefits of dapagliflozin. It therefore considered the higher incremental cost-effectiveness ratio (ICER) to be an overestimate. The committee was aware that there were no discernible differences in costs and effectiveness between the different selective sodium–glucose cotransporter 2 (SGLT‑2) inhibitors, 2 of which are already recommended in triple therapy. It was also aware that individualised care is critical in diabetes management. The committee agreed that it should be up to patients and their clinicians to decide which SGLT‑2 inhibitor is most appropriate for them. The committee concluded that dapagliflozin as part of triple therapy in combination with metformin and a sulfonylurea for type 2 diabetes can be recommended as a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments The patient expert felt that dapagliflozin was effective and easy and flexible to take, which gave her more confidence in self-managing her disease. As someone with needle-phobia, the patient expert particularly appreciated having an additional oral treatment option to delay progression to injectable treatments such as insulin. And she believed that an added bonus of her treatment with dapagliflozin is that it had reduced her blood pressure, meaning she did not have to add a blood pressure medication to her treatment regimen. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The clinical experts stated that in addition to lowering haemoglobin A1c (HbA1c), SGLT‑2 inhibitors such as dapagliflozin have the added benefit of helping to reduce blood pressure. Another very significant and characteristic benefit of the SGLT‑2 inhibitors is weight loss. This is a particularly important outcome for people with type 2 diabetes because there is a strong association with excess body weight and some treatments, such as insulin, can result in weight gain. What is the position of the treatment in the pathway of care for the condition? Dapagliflozin has a licence for monotherapy (when metformin is contraindicated) and also as part of combination therapy. The clinical experts stated that there is no consensus about where in the treatment pathway dapagliflozin would be most appropriate, but the most common position is probably as dual therapy in combination with metformin. For triple therapy, the comparators pioglitazone and injectable treatments were excluded by the company. The clinical experts considered both of these exclusions to be appropriate because the number of people being newly prescribed pioglitazone is decreasing year on year, and a third oral treatment is almost always preferable to an injectable treatment. Adverse reactions The patient expert stated that she had not experienced any adverse effects of treatment with dapagliflozin. The committee was also aware that dapagliflozin is currently already used in clinical practice. The committee concluded that based on the currently available clinical evidence, dapagliflozin has an acceptable adverse event profile. Evidence for clinical effectiveness Availability, nature and quality of evidence The clinical evidence included a trial (Study 5) and network meta-analyses. Relevance to general clinical practice in the NHS For triple therapy, the comparators pioglitazone and injectable treatments were excluded by the company. The clinical experts considered both of these exclusions to be appropriate because the number of people being newly prescribed pioglitazone is decreasing year on year, and a third oral treatment is almost always preferable to an injectable treatment. The committee concluded that the comparators included by the company, dipeptidyl peptidase‑4 (DPP‑4) inhibitors and other SGLT-2 inhibitors, were appropriate for its decision-making. The population in the scope included people with type 2 diabetes that is not controlled on dual therapy with metformin and a sulfonylurea, or with metformin and a DPP‑4 inhibitor. However, the company had only presented evidence for the former population because of a lack of evidence for the latter population, and also because it considered that metformin plus a sulfonylurea is the most commonly used regimen. The clinical experts stated that they agreed with the company. The committee concluded that the company had used the most relevant population in its analyses. Uncertainties generated by the evidence The company did not include all comparators or populations set out in the scope. However the clinical experts stated that the exclusions were appropriate, and the committee accepted the submitted population and comparators as appropriate for decision making. The Study 5 trial at week 8 had shown a statistically significant reduction in blood pressure when dapagliflozin was compared with placebo, but this was no longer apparent at week 52. However the company, the ERG and the clinical experts stated that the week 52 result was anomalous. The committee concluded that based on this consistent feedback, it is reasonably likely that dapagliflozin has a sustained beneficial effect on blood pressure. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable. Estimate of the size of the clinical effectiveness including strength of supporting evidence The clinical trial evidence demonstrated that dapagliflozin in triple therapy is more effective than placebo for reducing HbA1c and weight. In comparison with the other SGLT‑2 inhibitors and the DPP‑4 inhibitors, the company network meta-analyses demonstrated that dapagliflozin had a similar effect on HbA1c as the other SGLT‑2 inhibitors and DPP‑4 inhibitors, but that the SGLT‑2 inhibitors produced more weight loss than the DPP‑4 inhibitors. Week 8 blood pressure in the Study 5 trial had shown a statistically significant reduction in the dapagliflozin arm compared with placebo, but this was no longer apparent at week 52. However the committee heard from the company, the ERG and the clinical experts that the week 52 result was anomalous. It concluded that based on this consistent feedback, it is reasonably likely that dapagliflozin has a sustained beneficial effect on blood pressure. For reviews (except rapid reviews): How has the new clinical evidence that has emerged since the original appraisal (TA288) influenced the current recommendations? New clinical evidence (the Study 5 trial) is available for dapagliflozin in triple therapy regimens. The company also did new network meta-analyses. Evidence for cost effectiveness Availability and nature of evidence The ERG had raised concerns about the transparency of the model used by the company. However, the model had been accepted as appropriate for decision making in previous NICE technology appraisals for type 2 diabetes. The committee concluded that the model structure was appropriate for decision making. Uncertainties around and plausibility of assumptions and inputs in the economic model The ERG disagreed with several parameter assumptions used in the company's model and had presented an alternative base case with several updated assumptions. The committee concluded that the use of the older UKPDS 68 equations to inform the incidence of complications in the company model rather than using the more recent UKPDS 82 equations was questionable, and that the assumption in the ERG base case that oral treatments continued when intensifying to insulin is a more accurate reflection of NHS practice than the assumption used in the company model. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee heard from the ERG that the assumption by the company that weight loss was only maintained for 1 year was pessimistic because there is evidence that it lasts for longer. The committee also heard from the company and the ERG that it was plausible that SGLT‑2 inhibitors have an effect on reducing the risk of heart failure. The committee concluded that the company and the ERG's base cases had not fully captured the health-related quality of life benefits of dapagliflozin. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? The main differences in modelled costs between dapagliflozin and DPP‑4 inhibitors in the company's base case were differences related to the incidence of nephropathy. Cost-effectiveness estimates by both the company and the ERG were based on small cost and QALY differences, making the ICERs unstable. Most likely cost-effectiveness estimate (given as an ICER) When comparing dapagliflozin with DPP‑4 inhibitors, the company model predicted that dapagliflozin would dominate DPP‑4 inhibitors, whereas the ERG base case for dapagliflozin was £37,997 per QALY gained. However the committee noted that both estimates were based on very small differences in costs and QALYs, and therefore the cost-effectiveness estimates were unstable. The committee also noted that neither base case had taken into account all the health-related quality of life benefits of dapagliflozin. It therefore considered the higher ICER to be an overestimate. For reviews (except rapid reviews): How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA288) influenced the current recommendations? The company submitted a new economic model for dapagliflozin in triple therapy regimens. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End-of-life considerations Not applicable. Equalities considerations and social value judgements Not applicable.	{'Recommendations ': 'Dapagliflozin in a triple therapy regimen is recommended as an option for treating type\xa02 diabetes in adults, only in combination with metformin and a sulfonylurea.\n\nThis guidance is not intended to affect the position of patients whose treatment with dapagliflozin in other triple therapy regimens was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nDapagliflozin (Forxiga, AstraZeneca) is a selective sodium–glucose cotransporter\xa02 (SGLT‑2) inhibitor, which blocks the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine.\n\nMarketing authorisation\n\nDapagliflozin has a UK marketing authorisation for treating type\xa02 diabetes mellitus to improve glycaemic control in adults:\n\nas monotherapy: when diet and exercise alone do not provide adequate glycaemic control in people for whom use of metformin is considered inappropriate due to intolerance or contraindications\n\nas add-on combination therapy: with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.\n\nAdverse reactions\n\nThe summary of product characteristics lists the following adverse reactions for dapagliflozin: back pain, balanitis, creatinine renal clearance decrease, dizziness, dysuria, dyslipidaemia, elevated haematocrit, polyuria, urinary tract and genital infection, and vulvovaginitis. Dapagliflozin is not recommended for people with moderate to severe renal impairment (people with a creatinine clearance rate of less than 60\xa0ml/min or an estimated glomerular filtration rate [eGFR] of less than 60\xa0ml/min/1.73\xa0m2). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dosage is 10\xa0mg dapagliflozin orally once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin.\n\nPrice\n\nThe list price of dapagliflozin is £36.59 for a 28‑tablet pack of 5‑mg or 10‑mg tablets (excluding VAT; 'British national formulary' [BNF], accessed online August 2016). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of dapagliflozin, having considered evidence on the nature of type\xa02 diabetes and the value placed on the benefits of dapagliflozin by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Patient experience\n\nThe patient expert described the benefits of treatment with dapagliflozin, which she took in addition to 3\xa0other oral agents for diabetes. She felt that dapagliflozin was effective, and easy and flexible to take, which gave her more confidence in self-managing her disease. Because of this she had a more positive outlook and generally felt less stressed and anxious. As someone with needle-phobia, the patient expert particularly appreciated having an additional oral treatment option to delay progression to injectable treatments such as insulin. And she believed that an added bonus of her treatment with dapagliflozin is that it had reduced her blood pressure, meaning she did not have to add a blood pressure medication to her treatment regimen. The clinical experts confirmed that in addition to lowering haemoglobin A1c (HbA1c – a measure of blood glucose levels over the previous 2\xa0to\xa03\xa0months), selective sodium–glucose cotransporter\xa02 (SGLT‑2) inhibitors such as dapagliflozin have the added benefit of helping to reduce blood pressure. Another significant and characteristic benefit of the SGLT‑2 inhibitors is weight loss. This is a particularly important outcome for people with type\xa02 diabetes because there is a strong association with excess body weight and some treatments, such as insulin, can result in weight gain. The committee concluded that patients and their clinicians would value an additional effective oral treatment option for type\xa02 diabetes, particularly if it offered additional benefits such as weight loss and blood-pressure reduction.\n\n# Current clinical management of type\xa02 diabetes\n\nThe committee noted that dapagliflozin has a licence, and has been previously been appraised by NICE, for both monotherapy (when metformin is contraindicated, recommended in NICE technology appraisal guidance 390) and also as part of combination therapy (NICE technology appraisal guidance 288 recommends dapagliflozin in specific dual therapy regimens, but not as triple therapy because of a lack of evidence at the time). This appraisal is a part review of TA288 focussing on triple therapy. The committee queried where dapagliflozin is used most frequently in the treatment pathway. It heard from the clinical experts that there is no consensus about where dapagliflozin would be most appropriate, but the most likely position is probably as dual therapy in combination with metformin. The committee asked the clinical experts what the most relevant comparators are for dapagliflozin as part of triple therapy, noting that the company had excluded the comparators pioglitazone (citing low use in triple therapy in clinical practice) and injectable treatments (stating that oral treatments are used before injectable treatments). It heard from the clinical experts that they considered both of these exclusions to be appropriate. They stated that although many people are taking pioglitazone, with a large number of annual prescriptions as highlighted by the evidence review group (ERG), this is not representative of the number of people being newly prescribed pioglitazone, which is decreasing year on year. The clinical experts stated that this decrease is probably related to concerns about the adverse effects of rosiglitazone (a drug in the same class as pioglitazone that was withdrawn from clinical use because of an increased risk of cardiovascular disorders) and because pioglitazone is associated with an increased risk of oedema and weight gain. When given a choice of treatments, patients almost always prefer a treatment such as dapagliflozin that is associated with weight loss, rather than one that is weight-neutral or causes weight gain. Also, for the population in the scope, the clinical experts stated that a third oral treatment is almost always preferable to an injectable treatment such as insulin. The committee concluded that the comparators included by the company, dipeptidyl peptidase‑4 (DPP‑4) inhibitors and other SGLT‑2 inhibitors, were appropriate for its decision-making.\n\n# Clinical effectiveness\n\n## Population\n\nThe committee noted that the population in the scope included people with type\xa02 diabetes that is not controlled on dual therapy with metformin and a sulfonylurea, or with metformin and a DPP-4 inhibitor. However, the company had only presented evidence for the former population because of a lack of evidence for the latter population, and also because it considered that metformin plus a sulfonylurea is the most commonly used regimen. The clinical experts stated that they agreed with the company that the majority of people on dual therapy, who would be eligible for dapagliflozin as a third treatment, would be taking a combination of metformin and a sulfonylurea. The committee concluded that the company had used the most relevant population in its analyses.\n\n## Clinical evidence\n\nThe committee was aware that the clinical trial evidence had demonstrated that dapagliflozin in triple therapy is more effective than placebo in reducing HbA1c and weight. In comparison with the other SGLT‑2 inhibitors and the DPP-4 inhibitors, the company's network meta-analyses demonstrated that dapagliflozin had a similar effect on HbA1c as the other SGLT‑2 inhibitors and DPP‑4 inhibitors, but that the SGLT‑2 inhibitors produced more weight loss than the DPP‑4 inhibitors. The committee heard from the clinical experts that although there are subtle pharmacological differences between the individual SGLT‑2 inhibitors, they can generally be considered as a class in terms of effectiveness. Patients with diabetes that does not respond to one SGLT‑2 inhibitor will probably not respond to another. However, in some instances, clinicians may prescribe the higher dose of canagliflozin (300\xa0mg) because this is the only SGLT‑2 inhibitor that also has an effect on the SGLT‑1 mechanism. The committee concluded that it is reasonable to assume that the SGLT‑2 inhibitors have a class effect and, when compared with DPP‑4 inhibitors, are similarly effective for HbA1c reduction. However, SGLT‑2 inhibitors have the added benefit of weight loss.\n\nThe committee noted that the clinical trial evidence (Study\xa05) at week\xa08 had also shown a statistically significant reduction in blood pressure when dapagliflozin was compared with placebo, but this was no longer apparent at week\xa052. However, it heard from the company, the ERG and the clinical experts that the result at week\xa052 was anomalous, and the company stated that in several other trials the effect on blood pressure had been maintained. The committee concluded that based on this consistent feedback, it is reasonably likely that dapagliflozin also has a sustained beneficial effect on blood pressure.\n\n## Adverse effects of treatment\n\nThe patient expert stated that she had not experienced any adverse effects of treatment with dapagliflozin. She noted that she had been advised to drink plenty of water, which she believed had probably helped reduce the risk of an adverse event. The committee was also aware that dapagliflozin is currently already used in clinical practice. It concluded that based on the currently available clinical evidence, dapagliflozin has an acceptable adverse event profile.\n\n# Cost effectiveness\n\n## Model structure\n\nThe committee was aware that the ERG had raised concerns about the transparency of the model used by the company. However, it was also aware that the model had been accepted as appropriate for decision making in previous NICE technology appraisals for type\xa02 diabetes. The committee noted that the ERG had disagreed with several parameter assumptions used in the company's model, such as the use of values from the network meta-analysis which did not match the clinical trial results. It had presented an alternative base case with several updated assumptions, including the equations used to inform the incidence of complications (section\xa04.9) and costs related to the duration of treatment (section\xa04.10). The committee concluded that the model structure was appropriate for decision making.\n\n## Health-related quality of life\n\nThe committee was aware that dapagliflozin is effective in reducing HbA1c but also has other beneficial effects, including reduction in weight and systolic blood pressure. It asked the company and the ERG whether these additional benefits had been fully captured in the model. It heard from the ERG that the company had assumed that weight loss was only maintained for 1\xa0year, which was a pessimistic assumption because there is evidence that it lasts for longer. Therefore the model had not adequately captured the quality of life gain associated with weight loss. The clinical experts stated that weight reduction was a sustained effect, alongside the reduction in HbA1c. In addition, the committee heard from the company and the ERG that it was plausible that SGLT‑2 inhibitors have an effect on reducing the risk of heart failure. If this is the case, then the model had not captured this health benefit. The committee concluded that the company and the ERG's base cases had not fully captured the health-related quality of life benefits of dapagliflozin.\n\n## Clinical effectiveness and cost assumptions\n\nThe committee noted that the company had used older UK prospective diabetes study equations (UKPDS\xa068) to predict the incidence of diabetes-related complications in the model. However, it heard from the ERG that newer equations are available (UKPDS\xa082), and these should have been used because they are more up to date. The ERG explained that the newer UKPDS\xa082 equations predict a lower incidence of diabetes-related myocardial infarction, renal failure and death, and that the use of the older UKPDS\xa068 equations in the company's cost-effectiveness analysis was beneficial for dapagliflozin. In particular, the committee noted that the main differences in modelled costs between dapagliflozin and DPP‑4 inhibitors in the company's base case were differences related to the incidence of nephropathy. This was because the company assumed that dapagliflozin has a protective effect on renal function, and also because the older UKPDS\xa068 equations predict a higher incidence of renal failure than the newer UKPDS\xa082 equations. The committee heard from the clinical experts that they consider that dapagliflozin has a protective effect on renal function. The committee concluded that it was reasonable for the model to assume a protective effect of dapagliflozin on renal function, however the use of the older UKPDS\xa068 equations was questionable.\n\n## Treatment costs\n\nThe committee noted that when intensifying treatment to insulin in the model, the company assumed that oral therapies were stopped, whereas the ERG, based on expert clinical opinion, assumed that they continued. The clinical experts stated that drugs such as sulfonylureas may be stopped because of a risk of hypoglycaemia, but SGLT‑2 inhibitors would probably be continued. The committee concluded that the assumption in the ERG base case that oral treatments continued when intensifying to insulin is a more accurate reflection of NHS practice than the assumption used in the company model.\n\n## Most plausible incremental cost-effectiveness ratio (ICER)\n\nThe committee was aware that when comparing dapagliflozin with DPP‑4 inhibitors, the company model predicted that dapagliflozin would dominate (that is, would be cheaper and more effective than) DPP‑4 inhibitors, whereas the ERG base case for dapagliflozin was £37,997 per quality-adjusted life year (QALY) gained. However the committee noted that both estimates were based on very small differences in the costs and in the QALY gains between dapagliflozin and the DPP‑4 inhibitors, and therefore the cost-effectiveness estimates were unstable. The committee also noted that neither base case had taken into account all the health-related quality of life benefits of dapagliflozin (see section\xa04.8), particularly in relation to weight loss as noted by the ERG. It therefore considered the higher ICER to be an overestimate.\n\nThe committee was aware that there were no discernible differences in costs and effectiveness between the different SGLT‑2 inhibitors, 2 of which are already recommended in triple therapy. It was also aware that individualised care is critical in diabetes management (as recommended in NICE's guideline on type 2 diabetes in adults). The committee agreed that it should be up to patients and their clinicians to decide which SGLT‑2 inhibitor is most appropriate for them. The committee concluded that dapagliflozin as part of triple therapy in combination with metformin and a sulfonylurea for type\xa02 diabetes can be recommended as a cost-effective use of NHS resources.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA418\n\nAppraisal title: Dapagliflozin in triple therapy for treating type\xa02 diabetes\n\nSection\n\nKey conclusion\n\nWhen comparing dapagliflozin with dipeptidyl peptidase‑4 (DPP‑4) inhibitors, the company model predicted that dapagliflozin would dominate (that is, would be cheaper and more effective than) DPP‑4 inhibitors, whereas the evidence review group (ERG) base case for dapagliflozin was £37,997 per quality-adjusted life year (QALY) gained. However the committee noted that both estimates were based on very small differences in costs and QALYs, and therefore the cost-effectiveness estimates were unstable. The committee also noted that neither base case had taken into account all the health-related quality of life benefits of dapagliflozin. It therefore considered the higher incremental cost-effectiveness ratio (ICER) to be an overestimate. The committee was aware that there were no discernible differences in costs and effectiveness between the different selective sodium–glucose cotransporter\xa02 (SGLT‑2) inhibitors, 2\xa0of which are already recommended in triple therapy. It was also aware that individualised care is critical in diabetes management. The committee agreed that it should be up to patients and their clinicians to decide which SGLT‑2 inhibitor is most appropriate for them. The committee concluded that dapagliflozin as part of triple therapy in combination with metformin and a sulfonylurea for type\xa02 diabetes can be recommended as a cost-effective use of NHS resources.\n\n, 4.8, 4.11, 4.12\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe patient expert felt that dapagliflozin was effective and easy and flexible to take, which gave her more confidence in self-managing her disease. As someone with needle-phobia, the patient expert particularly appreciated having an additional oral treatment option to delay progression to injectable treatments such as insulin. And she believed that an added bonus of her treatment with dapagliflozin is that it had reduced her blood pressure, meaning she did not have to add a blood pressure medication to her treatment regimen.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical experts stated that in addition to lowering haemoglobin A1c (HbA1c), SGLT‑2 inhibitors such as dapagliflozin have the added benefit of helping to reduce blood pressure. Another very significant and characteristic benefit of the SGLT‑2 inhibitors is weight loss. This is a particularly important outcome for people with type\xa02 diabetes because there is a strong association with excess body weight and some treatments, such as insulin, can result in weight gain.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nDapagliflozin has a licence for monotherapy (when metformin is contraindicated) and also as part of combination therapy. The clinical experts stated that there is no consensus about where in the treatment pathway dapagliflozin would be most appropriate, but the most common position is probably as dual therapy in combination with metformin.\n\nFor triple therapy, the comparators pioglitazone and injectable treatments were excluded by the company. The clinical experts considered both of these exclusions to be appropriate because the number of people being newly prescribed pioglitazone is decreasing year on year, and a third oral treatment is almost always preferable to an injectable treatment.\n\n\n\nAdverse reactions\n\nThe patient expert stated that she had not experienced any adverse effects of treatment with dapagliflozin. The committee was also aware that dapagliflozin is currently already used in clinical practice. The committee concluded that based on the currently available clinical evidence, dapagliflozin has an acceptable adverse event profile.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe clinical evidence included a trial (Study\xa05) and network meta-analyses.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nFor triple therapy, the comparators pioglitazone and injectable treatments were excluded by the company. The clinical experts considered both of these exclusions to be appropriate because the number of people being newly prescribed pioglitazone is decreasing year on year, and a third oral treatment is almost always preferable to an injectable treatment. The committee concluded that the comparators included by the company, dipeptidyl peptidase‑4 (DPP‑4) inhibitors and other SGLT-2 inhibitors, were appropriate for its decision-making.\n\nThe population in the scope included people with type\xa02 diabetes that is not controlled on dual therapy with metformin and a sulfonylurea, or with metformin and a DPP‑4 inhibitor. However, the company had only presented evidence for the former population because of a lack of evidence for the latter population, and also because it considered that metformin plus a sulfonylurea is the most commonly used regimen. The clinical experts stated that they agreed with the company. The committee concluded that the company had used the most relevant population in its analyses.\n\n, 4.3\n\nUncertainties generated by the evidence\n\nThe company did not include all comparators or populations set out in the scope. However the clinical experts stated that the exclusions were appropriate, and the committee accepted the submitted population and comparators as appropriate for decision making.\n\nThe Study\xa05 trial at week\xa08 had shown a statistically significant reduction in blood pressure when dapagliflozin was compared with placebo, but this was no longer apparent at week\xa052. However the company, the ERG and the clinical experts stated that the week\xa052 result was anomalous. The committee concluded that based on this consistent feedback, it is reasonably likely that dapagliflozin has a sustained beneficial effect on blood pressure.\n\n, 4.3, 4.5\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe clinical trial evidence demonstrated that dapagliflozin in triple therapy is more effective than placebo for reducing HbA1c and weight. In comparison with the other SGLT‑2 inhibitors and the DPP‑4 inhibitors, the company network meta-analyses demonstrated that dapagliflozin had a similar effect on HbA1c as the other SGLT‑2 inhibitors and DPP‑4 inhibitors, but that the SGLT‑2 inhibitors produced more weight loss than the DPP‑4 inhibitors.\n\nWeek\xa08 blood pressure in the Study\xa05 trial had shown a statistically significant reduction in the dapagliflozin arm compared with placebo, but this was no longer apparent at week\xa052. However the committee heard from the company, the ERG and the clinical experts that the week\xa052 result was anomalous. It concluded that based on this consistent feedback, it is reasonably likely that dapagliflozin has a sustained beneficial effect on blood pressure.\n\n, 4.5\n\nFor reviews (except rapid reviews): How has the new clinical evidence that has emerged since the original appraisal (TA288) influenced the current recommendations?\n\nNew clinical evidence (the Study\xa05 trial) is available for dapagliflozin in triple therapy regimens. The company also did new network meta-analyses.\n\n, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe ERG had raised concerns about the transparency of the model used by the company. However, the model had been accepted as appropriate for decision making in previous NICE technology appraisals for type\xa02 diabetes. The committee concluded that the model structure was appropriate for decision making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe ERG disagreed with several parameter assumptions used in the company's model and had presented an alternative base case with several updated assumptions.\n\nThe committee concluded that the use of the older UKPDS\xa068 equations to inform the incidence of complications in the company model rather than using the more recent UKPDS\xa082 equations was questionable, and that the assumption in the ERG base case that oral treatments continued when intensifying to insulin is a more accurate reflection of NHS practice than the assumption used in the company model.\n\n, 4.9, 4.10\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee heard from the ERG that the assumption by the company that weight loss was only maintained for 1\xa0year was pessimistic because there is evidence that it lasts for longer. The committee also heard from the company and the ERG that it was plausible that SGLT‑2 inhibitors have an effect on reducing the risk of heart failure. The committee concluded that the company and the ERG's base cases had not fully captured the health-related quality of life benefits of dapagliflozin.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe main differences in modelled costs between dapagliflozin and DPP‑4 inhibitors in the company's base case were differences related to the incidence of nephropathy.\n\nCost-effectiveness estimates by both the company and the ERG were based on small cost and QALY differences, making the ICERs unstable.\n\n, 4.11, 4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nWhen comparing dapagliflozin with DPP‑4 inhibitors, the company model predicted that dapagliflozin would dominate DPP‑4 inhibitors, whereas the ERG base case for dapagliflozin was £37,997 per QALY gained. However the committee noted that both estimates were based on very small differences in costs and QALYs, and therefore the cost-effectiveness estimates were unstable. The committee also noted that neither base case had taken into account all the health-related quality of life benefits of dapagliflozin. It therefore considered the higher ICER to be an overestimate.\n\n, 4.12\n\nFor reviews (except rapid reviews): How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA288) influenced the current recommendations?\n\nThe company submitted a new economic model for dapagliflozin in triple therapy regimens.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNot applicable.\n\n–"}	https://www.nice.org.uk/guidance/ta418	Evidence-based recommendations on dapagliflozin (Forxiga) given with 2 other drugs for treating type 2 diabetes in adults.
ab000e7701ed8add138bad377421bfe4375d98cb	nice	Apremilast for treating moderate to severe plaque psoriasis	Apremilast for treating moderate to severe plaque psoriasis Evidence-based recommendations on apremilast (Otezla) for treating moderate to severe plaque psoriasis in adults. # Recommendations Apremilast is recommended as an option for treating chronic plaque psoriasis in adults whose disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and ultraviolet‑A light), or when these treatments are contraindicated or not tolerated, only if: the disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 treatment is stopped if the psoriasis has not responded adequately at 16 weeks; an adequate response is defined as: a 75% reduction in the PASI score (PASI 75) from when treatment started or a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from start of treatment the company provides apremilast with the discount agreed in the patient access scheme. When using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate. This guidance is not intended to affect the position of patients whose treatment with apremilast was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Apremilast (Otezla, Celgene) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast down-regulates the inflammatory response by modulating the expression of cytokines and mediators associated with psoriasis (including tumour necrosis factor ‑alpha and interleukin ‑23). Marketing authorisation 'For the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporin, methotrexate or psoralen and ultraviolet‑A light (PUVA)'. Recommended dose and schedule The recommended dosage is 30 mg twice daily after an initial titration schedule. A single 10 mg dose is given on the first day of treatment; this is titrated to 30 mg twice daily over 5 days (see the summary of product characteristics for the dose titration schedule). Price The price of apremilast is £550.00 for a 28‑day pack (56×30 mg tablets) (excluding VAT; British National Formulary online, accessed July 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Celgene and a review of this submission by the evidence review group. This appraisal was a rapid review of the published NICE technology appraisal guidance on apremilast for treating moderate to severe plaque psoriasis. It focused on cost-effectiveness analyses that included a patient access scheme agreement, which provides apremilast at a reduced cost. The discount is commercial in confidence. See the committee papers for full details of the rapid review evidence, and the history for full details of the evidence used for NICE's original technology appraisal guidance on apremilast for treating moderate to severe plaque psoriasis. See section 4.24 onwards for the rapid review consideration.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of apremilast, having considered evidence on the nature of psoriasis and the value placed on the benefits of apremilast by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical management The committee heard about the experience of people with psoriasis. It heard that the disease results in itchy, dry, scaly and thickened skin, which can be physically and psychologically debilitating, particularly if located on the hands, feet, face and genitals. Severe psoriasis is also associated with a shortened life expectancy. The committee heard that, because psoriasis is visible to others, it can make people feel isolated and lonely, which could lead to them losing self-confidence and avoiding social situations, and could also affect career opportunities and influence intimate relationships. It heard from clinical experts that people with severe psoriasis are about 6 times more likely to have suicidal thoughts or commit suicide than the general population. The committee agreed that severe psoriasis has a significant psychosocial impact and substantially decreases quality of life. The committee discussed how clinicians assess the severity of disease in people with psoriasis. It understood that several indices are used, and heard that clinicians routinely use both the Psoriasis Area Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) to monitor the disease. The committee was aware that the UK marketing authorisation for apremilast includes people with moderate and severe disease. It understood that, while the marketing authorisation did not specify the criteria for moderate or severe disease, the regulatory decision was based on trials that included people with a baseline PASI score of 12 or more (mean score 19), a 10% or greater of body surface area affected, and a static Physician Global Assessment score of at least 3. The committee noted that the trials did not stipulate that participants have a particular DLQI score at baseline. The committee was aware that previous NICE technology appraisals defined severe psoriasis as a PASI score of 10 or more and a DLQI of more than 10. It understood that there is no universally accepted definition of moderate psoriasis. However, the committee heard from clinical experts that, in practice, moderate disease would be characterised by a lower PASI score (between 5 and 9). It noted that the company, in its submission, presented analyses in people with a PASI score of 10 or more and a DLQI score of 10 or less to represent people with disease not severe enough to be treated with biologicals in the UK. Clinical experts explained that the disadvantages of the DLQI are that it is not specific to psoriasis and does not capture all of the impacts of the disease (such as anxiety and depression). Clinical and patient experts suggested that some people with chronic psoriasis can develop coping mechanisms and so adjust to the impact of the disease, resulting in lower DLQI scores. The committee heard that clinicians use the DLQI for treatment decisions with biologicals, but do not generally use it to define different levels of severity. The committee acknowledged that PASI and DLQI, which reflect the outcomes used in the trials, are relevant measures used in clinical practice in the NHS. The committee concluded that the evidence base for apremilast reflected people with severe disease, as defined in UK clinical practice. The committee considered the treatment pathway for people with psoriasis. It was aware that people have topical treatments as first-line treatment, followed by conventional (non‑biological) systemic therapies (such as methotrexate or ciclosporin), and phototherapy. If these treatments do not adequately control the psoriasis, people may have biological therapies, which they continue to have as long as the drugs work. The committee understood that if the disease no longer responds to a biological therapy, people will be offered another biological therapy. This pattern is likely to be repeated over their lifetime; clinical experts noted that people with psoriasis will often try many alternative biological agents in a short timeframe. The committee heard that, for people whose disease does not respond to multiple biological agents, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging. The committee questioned whether best supportive care was effective in treating psoriasis (that is, whether it improved PASI score or other measures of disease). It heard from clinical experts that best supportive care can be effective in the short term. The committee was aware that best supportive care can be accompanied by disutility because of the intensive time-consuming, inconvenient and unpleasant treatments, and that the psoriasis may worsen sooner than with biological therapies. The committee concluded that best supportive care is associated with limited, short-term efficacy and recognised the value of having a range of treatments with different mechanisms of action available. The committee considered the potential positioning of apremilast in the treatment pathway in NHS clinical practice. It noted that the marketing authorisation for apremilast allows it to be positioned: earlier in the treatment pathway than biological therapies (that is, after 1, but not all, other systemic therapies have failed; see section 4.5) after biological therapies (see section 4.6) instead of biological therapies (at the point when all other systemic therapies have failed; see section 4.7). The committee considered whether apremilast would be used before biological therapies were considered, that is, after 1 but not all other systemic treatments had failed. It noted that the company had not presented analyses for apremilast in this position, and that it did not hear from clinical experts that they would offer the drug at this point. The committee therefore did not consider this position further. The committee discussed whether apremilast would be used if biological therapies were not tolerated or after all biological therapies had failed. It heard from a clinical expert that apremilast would generally be prescribed for people who had already tried biological therapies, or for those who are unable to take them. The committee understood from the clinical experts that, in general, apremilast would not displace a biological therapy in the treatment pathway. It concluded that the most likely position for apremilast in the treatment pathway was if biological therapies were not tolerated or after all biological therapies had failed. The committee discussed whether apremilast would be used at the same point in the treatment pathway as biological therapies (that is, once all other systemic therapies had failed). It heard from clinical experts that the positioning of apremilast (either before, or instead of, a biological therapy) would be driven largely by patient choice and intolerance or contraindications to biological therapy such as serious infections. The committee heard from: the patient expert that, because apremilast is less effective than biological therapies, offering apremilast as a first-line treatment could delay more effective treatments, so patients may prefer biological therapies clinical experts that some people with psoriasis do not adhere to treatment, so it is important to consider patient choice to encourage adherence the patient expert that apremilast is taken orally, which some patients may prefer but others may find a burden, given its twice-daily dosing (by comparison, some biological therapies are administered only once every 3 months, by subcutaneous injection) the clinical experts that an advantage of apremilast over biological agents is that it is not contraindicated in people with tuberculosis.The committee agreed that apremilast may not be the preferred treatment at the point in the treatment pathway at which biological therapies are considered (that is, after all systemic treatment have failed), but clinicians would like to have the option to prescribe apremilast at this point. The committee recognised that the treatment decision would be driven by patient choice, and that patients may well choose not to have apremilast instead of biological therapies because it is considered to be less effective (see sections 4.8 to 4.12). # Clinical effectiveness The committee appreciated that the clinical evidence for apremilast came from 4 multicentre placebo-controlled double-blind randomised controlled trials (RCTs) in people with moderate to severe chronic plaque psoriasis: PSOR‑005, -008, -009 and -010. The primary endpoint was the same in all 4 trials: a 75% reduction in the PASI score at week 16 (known as a PASI 75 response). The randomised period of all trials was only until week 16. The committee considered the baseline characteristics of the patients in the apremilast trials and discussed whether the trials reflected the UK population with psoriasis who would be eligible to have apremilast. It noted the evidence review group (ERG's) comment that only 13% of the PSOR‑008 trial population would be eligible for apremilast. The committee heard from the company that, in its view, the ERG had misinterpreted the intended positioning of apremilast. The company clarified that, according to the UK marketing authorisation, apremilast could be used after only 1 conventional systemic treatment, which could be phototherapy. The company stated that about 65% of the PSOR‑008 and PSOR‑009 trial populations had any prior systemic therapy (including conventional therapies but also biological agents). The committee noted the ERG's comments that the PSOR‑008 and PSOR‑009 trials may have overestimated the benefit of apremilast; some patients in the trial had no previous systemic treatment, so their disease would have been more likely to respond to apremilast because it was less severe than in people who had more treatments. The committee heard from clinical experts that there is no robust evidence to suggest that previous treatment with conventional therapy affects response to subsequent treatment. The committee heard from the company that other criteria for inclusion and exclusion used in apremilast trials were similar to trials of biological therapies. The committee concluded that the apremilast trials provided an appropriate basis for its decision-making. The committee discussed the results of the placebo-controlled apremilast clinical trials, and considered the company's network meta-analysis, which indirectly compared apremilast with other biological agents specified in the scope. It noted that clinical trial evidence showed that apremilast was more effective than placebo for key outcomes at 16 weeks, and that this benefit was consistent across subgroups studied. The committee heard from clinical experts that biological therapies are more effective than apremilast for treating psoriasis, and was aware that the company's network meta-analysis showed that the probability of response to treatment is highest with biological therapies and lowest with apremilast. The committee heard from the ERG that the company's network meta-analysis was technically robust, but any bias from trials would carry through to the results from this analysis. The committee heard that the ERG compared the meta-analysis results for the apremilast: etanercept comparison with odds ratios calculated using results of the PSOR‑010 trial, confirming that psoriasis is more likely to respond to etanercept than apremilast. The committee was aware of the drawbacks of the PSOR‑010 study in that it was powered to compare apremilast with placebo and etanercept with placebo (but not apremilast with etanercept), but still concluded that apremilast is more effective than placebo, but not as effective as biological therapies. The committee discussed the long-term effectiveness of apremilast, noting that a substantial proportion of people who had a PASI 75 response after 16 weeks of apremilast treatment subsequently lost their PASI 75 response during the treatment withdrawal phase (marked as 'academic in confidence' by the company). The committee heard from the company that some of the people in the apremilast trials who lost response, later regained it. The company stated that everyone who had a PASI 75 response at week 16 had at least a PASI 50 response by week 52. The clinical experts stated that fluctuating PASI scores characterise the natural history of psoriasis and any decline in efficacy with apremilast is expected to be similar to a decline with biological therapies. The experts also stated that the same level of response would not be seen if patients were to stop and restart treatment with apremilast. The committee concluded that some response to treatment with apremilast is maintained up to 1 year, but noted uncertainty about longer-term effectiveness beyond the clinical trial data. When considering the tolerability of apremilast, the committee heard from clinical experts that apremilast is associated with a number of adverse events early in treatment. The committee heard that the most common adverse events with apremilast are related to the gastrointestinal tract (including diarrhoea and nausea), and that people are willing to tolerate gastrointestinal adverse effects if they are benefiting from the drug. The committee concluded that apremilast is associated with gastrointestinal adverse events, but these would not preclude the use of apremilast. The committee discussed the probability of people stopping apremilast treatment, and heard from clinical experts that the rate of withdrawal from apremilast is similar to (or potentially lower than) the rate of withdrawal from biological therapies. It heard from the company that the ERG's reference to a higher withdrawal rate with apremilast based on PSOR‑008 data was factually inaccurate (the company marked this withdrawal rate as 'academic in confidence'). The company stated that 2 year data from PSOR‑008 indicate a withdrawal rate of 19.5% per year for apremilast, which is similar to the company's assumption of a 20% withdrawal rate for biological therapies, which it chose based on the rate used for biological therapies in previous NICE appraisals (adalimumab, etanercept, infliximab, secukinumab and ustekinumab). The committee concluded that the probability of people stopping treatment with apremilast is likely to be similar to the probability of people stopping treatment with biological therapies. # Cost effectiveness The committee considered whether the company's health economic model included relevant treatment sequences and positions. The committee noted that the treatment sequences modelled by the company reflected the likely positioning of apremilast according to the clinical experts (see sections 4.4 to 4.7). The committee heard from clinical experts that etanercept is the least effective of the existing biological therapies for treating severe psoriasis. When queried, the company stated that it had selected etanercept for the model because it is the most used biological therapy for psoriasis in Europe. The ERG stated that this would not be a key driver of the results because the model includes biological therapies in both arms in the model and would not be displaced in the sequence including apremilast. Based on the likely positioning of apremilast in the treatment pathway (see sections 4.4 to 4.7), the committee concluded that, although the company did not compare the sequence in which apremilast came after biological therapies with a sequence without apremilast, the positions and comparisons modelled by the company were generally sufficient for decision-making. The committee discussed the sources used by the company to estimate resource use and costs associated with best supportive care. It noted that the incremental cost-effectiveness ratios (ICERs) were highly sensitive to these inputs, and specifically whether the model included hospitalisation rates and costs from Fonia et al. (2010; the ERG's preferred assumption of best supportive care costs of £348 per cycle based on 6.49 days of hospitalisation per year) or NICE's psoriasis guideline (the company's base case assuming best supportive care costs £888 per cycle based on 26.6 days of hospitalisation per year). The committee heard from the clinical experts that both sources were likely to overestimate the actual number of hospital days and resource use associated with best supportive care. This is in part because the populations described in Fonia et al. and NICE's guideline differed from the population covered in this appraisal; NICE's psoriasis guideline was for a specific, high-need subpopulation with very severe psoriasis, and Fonia et al. described care in a tertiary care centre known for treating the most severely affected people. The committee heard from the company that the Fonia et al. study reflected a site that offered day-care and therefore admitted fewer people to hospital than would normally be admitted in clinical practice. The clinical expert stated that the Fonia et al. study describes a day unit that offered on‑site hotel accommodation to people. The committee noted that this option is much less costly than a hospital stay because it would not incur nursing and other hospital costs and, increasingly, is the model of care for people with psoriasis in the NHS. The committee also heard from the clinical experts that, in recent years, the number of people hospitalised for severe psoriasis has fallen, and that clinicians give best supportive care to people during their outpatient visits; therefore, hospitalisation costs associated with psoriasis have fallen, and are continuing to fall. The committee noted that after consultation, the company provided NHS hospital episode statistics data that showed that the average length of hospital stay associated with best supportive care was 3.5 days. It heard from the company that in its view, these values underestimate actual length of NHS hospitalisation because they include people with different disease severities as well as people receiving concomitant medication and that, in patients who had received inpatient care, the average length of stay was 10.74 days. The clinical experts agreed that the hospital episode statistics data underestimated length of hospitalisation. The committee agreed with this, but considered that the most plausible estimate would be lower than the ERG and company assumptions of 6.49 and 26.6 days per year. With respect to the proportion of people admitted to hospital, the clinical experts noted that the actual proportion is much lower than the 30% annual probability assumed by Fonia et al. (the lower of the 2 estimates). The committee recognised the significant uncertainty in this model input, and agreed that the best supportive care costs are likely to be lower than in Fonia, and also noted that assuming a lower cost would increase the ICER. Additionally, the committee noted that costs associated with hospitalisation were consistently applied to all days in hospital. The committee, however, considered that it was reasonable to expect that the first few days in hospital would generate more expenses than later days; therefore the company may have overestimated the overall costs of best supportive care associated with hospitalisation in the model and accounting for this was likely to increase the ICERs presented. The committee recognised the considerable uncertainty and concluded that shortcomings exist among all sources of data for resource use, but that resource use for best supportive care is closer to Fonia et al. than to the estimates from NICE's guideline on psoriasis. The committee went on to discuss the cost estimates for people whose disease does not respond to one systemic treatment and who then go on to get another one, during which time they need elements of best supportive care. The committee recognised this as a significant driver of cost-effectiveness results. The committee heard that the company had originally assumed that this resource would be lower than best supportive care costs and included an estimate of £460 per cycle, based on their preferred best supportive care costs from the NICE guideline on psoriasis (see section 4.11). The ERG instead based its preferred estimate on the study by Fonia et al. (2010) and also assumed that this additional resource is the same as for best supportive care, therefore including an estimate of £348 per cycle. After consultation, the company explored the effect on the cost‑effectiveness results of using the costs from Fonia et al. for the 12 month period after patients start biological therapies. However the company noted that because it had already included costs for outpatients and systemic treatments in its model (also from Fonia et al.), it deducted these costs to avoid double counting, resulting in a cost for people whose condition does not respond of £45 per cycle. The committee agreed that avoiding double counting was appropriate, but also agreed with the ERG that using costs from the period after starting biological therapies includes costs for people whose condition responds, as well as costs for people whose condition does not respond to biological therapies; therefore underestimating the true costs. Instead, the committee preferred the ERG's inclusion of costs from Fonia et al. that reflect the 12 month period before a person starts a biological therapy while at the same time reducing the costs of outpatient and systemic treatments (£225 per cycle). The company agreed during the second committee meeting that this estimate was plausible, but highlighted that the ERG applied this cost to all people starting a new biological therapy for the 16 week 'trial' period, whereas a proportion of people on new treatments benefit immediately or at least quickly. The company acknowledged that there was uncertainty around the proportion of patients to which this 'non-responder' cost should apply. The clinical experts agreed that response varies among people who try new active treatments, and that it is unlikely that all people will incur the same 'non-responder' costs. The committee heard from the ERG that the costs from Fonia et al. include patients at different levels of response and therefore the model already accounted for variable non-responder costs during the period in which modelled patients try new drugs. The committee concluded that there was considerable uncertainty about the actual costs associated with starting a new therapy if a person's disease has previously not responded to another therapy in the model, but concluded that the ERG's estimate of £225 per cycle was the most plausible of those presented. The committee considered the quality-of-life and utility values used in the company's original model. It was aware that the company did not use the baseline EQ‑5D data collected in the apremilast clinical trials. The committee heard that the company sourced the baseline utility value in the model (0.7) from previous technology appraisals, and noted that people in the apremilast clinical trials had a baseline utility value of 0.8. The company stated that the baseline EQ‑5D value in the apremilast trials differed from the baseline value in trials of biological therapies (although other key baseline characteristics such as PASI score were consistent across the trials). The ERG confirmed that changing the baseline utility value used in the model would not significantly affect the cost-effectiveness results because the model is driven by the incremental changes in utility score from baseline. The committee then discussed the company's approach to incorporating utility increments associated with a response to treatment in the model. The committee was concerned that the company had included trial-based EQ‑5D data in its model reflecting a DLQI score of 10 or less but that, in the model reflecting a DLQI score of more than 10, the company had used a mapping algorithm instead of clinical trial data. The committee was also concerned that the company used etanercept data in the mapping algorithm instead of apremilast data. The company justified this on the basis that EQ‑5D data in the apremilast trials were subject to a ceiling effect. However, following the first committee meeting the company clarified that it had, in error, derived EQ‑5D data from US instead of UK tariffs. The company agreed that the updated trial-based EQ‑5D data was appropriate and presented revised results for the change in utility from baseline associated with the different PASI response categories in the model. The committee noted that the company's models did not take into account the disutility values associated with adverse events, but the ERG was unable to comment on how including these values would have affected the ICER. The committee concluded that the utility gains estimated from the company's revised model (for people with a DLQI score of more than 10) were plausible. The committee discussed the assumption in the company model that apremilast is associated with fewer visits to a clinician than biological therapies (1 annual visit for apremilast, compared with 4 visits per year with biological therapies). The committee heard from the clinical experts that because apremilast is a new drug dermatologists would be cautious in allowing fewer visits to a clinician and therefore the number of clinician visits (including GP visits in 'shared care' arrangements) for apremilast and biological therapies would be the same initially, but, in the long term, the clinical experts expected that the number of monitoring visits would be lower for apremilast. The committee did not consider it realistic that people receiving apremilast would visit their clinician only once each year, and concluded that 4 visits per year (including visits to GPs) is more appropriate (based on the company's assumption of 4 visits for biological therapies). The clinical experts agreed with this, but noted that monitoring costs for apremilast were likely to be lower than for biological therapies. The clinical experts also confirmed that for treatment with apremilast GPs could monitor patients under shared care arrangements. However, the committee noted that the cost of monitoring people on apremilast in primary care should reflect the assumption of additional payments to GPs, similar to arrangements for monitoring methotrexate. The committee noted that if lower monitoring costs for apremilast were incorporated in the model, this would lower the ICERs presented, but acknowledged the lack of robust estimates available. Therefore, the committee concluded that the assumption of equal monitoring visits was appropriate. The committee discussed the potential for waste with apremilast. The clinical experts acknowledged that when people did not adhere to or withdrew from treatment, some tablets would be wasted. The committee considered that it would be reasonable to account for some treatment waste with apremilast. It noted the company's revised model, which included an assumption of 14 days' wasted treatment; it heard from the ERG and experts that this was plausible. The company additionally stated that a waste assumption should be applied equally to biological therapies and apremilast. The ERG, however, considered that the waste for biological therapies in each arm of the model would cancel each other out but the company stated that would be true only if a lifetime horizon was assumed. The clinical experts also stated that while there will be waste with biological therapies, this is low because people get rigorous training before being prescribed biological therapies, in order to boost adherence. The committee concluded that the assumption of 14 days' apremilast waste in the revised model was appropriate. The committee discussed the company's assumption that the probability of response for each treatment was the same regardless of its position in the sequence. It heard from the company that clinical trials show that the efficacy of apremilast appears consistent across the positions in the treatment sequence. The company noted that the response was slightly lower if apremilast were positioned after biologicals, and that its model accounted for this reduced efficacy. The committee was satisfied that the company had included the efficacy of apremilast appropriately in its model. The committee considered the other assumptions in the company model in light of its clinical discussion. It concluded that the model should include the possibility that psoriasis can improve with best supportive care (in contrast to the company's assumption of no effectiveness, see section 4.3). The committee agreed with the company's assumptions that withdrawal rates are similar for apremilast and biologicals (see section 4.9), and that response rates remain relatively constant over time (see section 4.7). The committee discussed the ICERs for apremilast positioned before biological therapies in a population with a PASI score of 10 or more and a DLQI score of more than 10.The committee considered the company's revised base-case results and the ERG's exploratory analyses. The committee concluded that the most plausible ICER available for decision-making was about £30,300 per quality-adjusted life year (QALY) gained and noted that this was above the range normally considered cost effective. However it noted that there was considerable uncertainty about key factors driving this ICER, such as monitoring costs (see section 4.13), amount of drug waste (see section 4.14), the likely costs associated with best supportive care (see section 4.11) and the costs associated with 'non-responders' (see section 4.12). The committee considered that these uncertainties could drive the ICERs in different directions and the magnitude of impact was uncertain. However, the committee recalled its consideration in section 4.11 that the costs associated with best supportive care are likely to be even lower than those estimated by the ERG from Fonia et al. (2010) and accounting for this would increase the ICER. Moreover, being mindful that apremilast was not as effective as biological therapies, the committee noted comments from consultation and from the patient expert that apremilast in a sequence before biological therapies could delay access to more effective treatment, and may therefore not be preferred. The committee heard from the patient expert that achieving clear skin in the shortest possible time is important to people and that a PASI 75 response shown with apremilast means that people are still affected by psoriasis. Together with the uncertainties in the economic modelling, the committee concluded that apremilast could not be recommended for severe psoriasis after the failure of conventional systemic therapy but before biological therapy. The committee discussed the ICERs for apremilast positioned before biological therapies in a population with a PASI score of 10 or more and a DLQI score of 10 or less (moderate disease), and where best supportive care was the only comparator because patients with moderate disease are not offered biological therapies. At its first meeting, the committee concluded that the most plausible ICER for the apremilast sequence lay somewhere between £97,500 and £125,300 per QALY gained, taking into account its preferred assumptions. The committee noted that the company had not updated this analysis with the UK tariff-based utility values, and estimated, based on the original modelling, that the ICER in the less severely affected population could be twice that seen for the population with a PASI and DLQI of 10 or more, that is, about £60,000 per QALY gained. The committee noted that the evidence base for apremilast did not include people with moderate disease as defined in UK clinical practice (a PASI score of 5 to 9). Given that the company's model indicated that apremilast had a higher ICER in a less affected population (that is, people with a DLQI score of 10 or less), the committee concluded that the ICER for apremilast for treating moderate psoriasis would not be within the range considered to be a cost-effective use of NHS resources. The committee considered the company's cost-effectiveness results for apremilast positioned after biological therapies and before best supportive care. It noted that the sequence in which apremilast was positioned after biological therapy was dominated (provided fewer QALYs at a higher cost) by the sequence in which apremilast came before biological agents. Having already concluded that apremilast, as a treatment in a sequence before biological therapy, is not a cost-effective use of NHS resources (see section 4.17), the committee concluded that a treatment sequence that provides fewer QALYs but costs more could not be considered a cost-effective use of NHS resources. The committee considered the company's cost-effectiveness results for apremilast as a replacement treatment for 1 of the biological therapies in the sequence, even though the clinical experts stated that apremilast was unlikely to displace a biological agent in the treatment pathway. It noted that the sequences containing apremilast were cost saving – but less effective – than the comparator sequences, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £21,100 to £39,100 per QALY). The committee considered that the ICERs were based on uncertain assumptions and noted that that ICERs based on its preferred assumptions were not available. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The committee concluded that the ICERs for apremilast as a replacement for biological therapies for severe psoriasis were not within the range considered to be a cost-effective use of NHS resources. The committee heard differing views about whether apremilast was innovative in its potential to make a significant and substantial impact on health-related benefits. It agreed that apremilast appeared to be innovative in its novel use of an existing mechanism of action, and agreed that it demonstrated innovation by providing an additional novel oral therapy. However, the committee recalled that some people with psoriasis prefer less frequent injectable treatments to more frequent oral ones (see section 4.4) and therefore the committee concluded that, in this respect, there were no additional gains in health-related quality of life over those already included in the QALY calculations. The committee considered when appraising apremilast whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. The committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as an applicable consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view on the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was irrelevant for the consideration of cost effectiveness of apremilast. The committee discussed whether the recommendations could be considered unfair because a small group of people are unable to take any biological therapies because of contraindications that could be associated with protected characteristics according to the Equality Act. The committee concluded that these patients would otherwise have best supportive care, and although the company did not present a revised ICER comparing apremilast with best supportive care for this group, the committee expected the ICER to be around £60,000 per QALY gained. Considering that this was much higher than what is normally accepted as good use of NHS resources, the committee concluded that to recommend apremilast for this group would not achieve the legitimate aim of providing advice on cost-effective treatments. # Rapid review ## Population The committee noted that the company's revised analyses focused on people with severe disease, but the marketing authorisation also included people with moderate disease. The committee recalled its discussions with clinical experts that the evidence base for apremilast did not include people with moderate disease as defined in UK clinical practice. The committee concluded that there was no evidence for clinical or cost effectiveness available to enable it to make a decision for people with moderate disease. ## Key assumptions The committee noted that the company included the preferred assumptions in NICE's original appraisal of apremilast in the revised economic modelling (see table 1). ## Table 1 Company's preferred assumptions Parameter Committee's preferred inputs Discussion reference Cost of best supportive care per 28‑day cycle Section 4.14 Cost of non-response Section 4.15 Source of utility estimates Apremilast trial data Section 4.16 Efficacy of best supportive care National Clinical Guideline Centre model Section 4.3 Efficacy of active treatments Network meta-analysis including PSOR‑010 study Section 4.9 Wastage of apremilast weeks Not applicable Clinician visits Same number of visits for all active treatments Section 4.17 EQ‑5D value set UK value set Not applicable The ERG confirmed that the company did this appropriately, and the committee agreed that the company had presented results based on the committee's preferred inputs. ## Stopping rule The committee considered a stopping rule for apremilast. It heard during consultation of the rapid review appraisal document that NICE guidance for the biological therapies in psoriasis includes a stopping rule. The committee recognised that the summary of product characteristics states that 'if a patient shows no evidence of therapeutic benefit after 24 weeks, treatment should be reconsidered'. The committee understood, however, that the analyses it considered had included a stopping rule at 16 weeks. The committee recognised that NICE guidance for biological therapies for psoriasis defined 'no evidence of therapeutic benefit'; the committee did not hear anything during consultation or from the company during the appraisal of apremilast to change the criteria. The committee concluded that it was appropriate to include a stopping rule, and that this should be at 16 weeks and be defined in the same way as in NICE guidance for biological therapies in psoriasis. ## Treatment sequences The committee was aware that apremilast would be used in clinical practice after all systemic therapies had failed, but could be used before, after or instead of biological therapies (see sections 4.4 to 4.7). The company's base case compared a sequence of apremilast positioned before biological therapies against a sequence without apremilast. The company's scenario analysis compared a sequence of apremilast positioned before biological therapies against a sequence of apremilast after biological therapies. The ERG stated that the company had not explored a full range of sequences, so the optimal position of apremilast in the treatment pathway could not be established. The company clarified that it did not intend to position apremilast as an option only before biological therapies. The ERG also identified problems with external validity of treatment sequences that included biological therapies. The ERG found that, when comparing each biological therapy with best supportive care, the ICERs generated were more than £30,000 per QALY gained. The committee noted that the results were unexpected because these biological therapies have been previously recommended by NICE as a cost-effective use of NHS resources. The committee understood that this difference was driven by the incorporation of the committee's preferred assumptions, particularly around the costs of best supportive care. It was outside the committee's current remit to appraise the cost effectiveness of biological therapies, so it did not explore this further. The committee agreed with the ERG that any treatment sequence including a biological therapy resulted in a lower ICER for the sequence that included apremilast compared with the sequence that did not include apremilast because apremilast up-front delayed giving biological therapies found to be cost ineffective in these analyses. The committee therefore agreed that it could not make a decision using ICERs based on these comparisons. The company also presented results for sequences without biological therapies, defined as apremilast followed by best supportive care compared with best supportive care alone. The ERG considered this to be the only valid ICER available because the sequences did not include biological therapies (see section 4.26). The company's base-case ICER for apremilast followed by best supportive care was less than £30,000 per QALY gained compared with best supportive care alone (the precise ICER is commercial in confidence). The committee agreed that apremilast is a cost-effective use of NHS resources for people for whom best supportive care is the only option, that is, if biological therapies are not tolerated or after all biological therapies have failed. The committee considered whether it could use the analyses of best supportive care to appraise apremilast for people with severe psoriasis for whom treatment with biological therapies was an option. The committee noted that apremilast was not as effective as biological therapies, and it was less costly. The committee agreed that it would have valued a direct comparison with biological therapies to understand the cost saved for each QALY lost, but recognised it had not been presented with this. The committee reiterated that the positioning of apremilast (either before or instead of biological therapy) would be driven largely by patient choice. The committee was aware that the results were comparable with the ICERs for biological therapies compared with best supportive care in previous NICE technology appraisals. The committee noted that patients value having a range of treatment options. It concluded that, because the ICER for apremilast was comparable to those estimated previously for biological therapies, it could recommend apremilast as an option for treating severe chronic plaque psoriasis that has not responded to all systemic therapies, or when systemic therapy is contraindicated or not tolerated. This recommendation applies only when the company provides apremilast with the discount agreed in the patient access scheme. # Summary of appraisal committee's key conclusions TA419 Appraisal title: Apremilast for treating moderate to severe plaque psoriasis Section Key conclusion Apremilast is recommended as an option for treating chronic plaque psoriasis in adults whose disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and ultraviolet‑A light), or when these treatments are contraindicated or not tolerated, only if: the disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 treatment is stopped if the psoriasis has not responded adequately at 16 weeks; an adequate response is defined as: a 75% reduction in the PASI score (PASI 75) from when treatment started or a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from start of treatment the company provides apremilast with the discount agreed in the patient access scheme. Apremilast was cost effective when compared with best supportive care. Apremilast was less effective but also less costly than biological therapies. The cost-effectiveness analyses, which compared apremilast with biological therapies, included treatment sequences. These were not considered appropriate for decision-making because the biological therapies in the sequence were not in themselves cost effective, which biased the results. However, the incremental cost-effectiveness ratio (ICER) for apremilast compared with best supportive care was comparable to ICERs for biological therapies in previous NICE technology appraisals. The committee recognised that treatment choice will be largely driven by patient preference, and agreed apremilast was a cost-effective use of NHS resources. There was no clinical- or cost-effectiveness evidence available to make a decision for people with moderate disease. Current practice Clinical need of patients, including the availability of alternative treatments Severe psoriasis has a significant psychosocial impact and substantially decreases quality of life. People with psoriasis have topical treatments as first-line treatment, followed by conventional (non‑biological) systemic therapies and phototherapy. If these treatments do not adequately control the psoriasis, people may have biological therapies. People with psoriasis will often try many alternative biological agents in a short timeframe and, for people whose disease has not responded to multiple biological agents, the only remaining treatment option is best supportive care. Although best supportive care can provide limited, short‑term benefits, it is associated with disutility because of the intensive time-consuming, inconvenient and unpleasant treatments. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Apremilast provides a novel use of an existing mechanism of action, and an oral alternative to injectable biological therapies. However, some people with psoriasis prefer less frequent injectable treatments to more frequent oral ones. Another advantage of apremilast over biological agents is that apremilast is not contraindicated in people with tuberculosis. What is the position of the treatment in the pathway of care for the condition? The marketing authorisation for apremilast allows it to be positioned before, instead of, and after biological therapies. However, clinical experts did not consider that apremilast would displace a biological therapy in the treatment pathway, and agreed that the positioning of apremilast (either before or after biological therapy) would be largely driven by patient choice and intolerance or contraindications to biological therapy. Adverse reactions The most common adverse events with apremilast are related to the gastrointestinal tract (including diarrhoea and nausea), but these would not preclude the use of apremilast because people are willing to tolerate gastrointestinal adverse effects if they are benefiting from the drug. Evidence for clinical effectiveness Availability, nature and quality of evidence The clinical evidence for apremilast came from 4 multicentre, placebo-controlled, double-blind randomised controlled trials in people with moderate to severe chronic plaque psoriasis. The trials were good quality and the treatment groups were generally similar at baseline. Because PSOR‑010 was not powered to compare apremilast with etanercept, and there were no other head-to-head trials comparing apremilast with any of the biological therapies recommended by NICE for psoriasis, the company did a network meta-analysis that included 24 studies. The evidence review group (ERG) stated that the results from the company's network meta-analysis were likely to be reasonably reliable, but that the results of the company's sensitivity analysis should be interpreted with caution. Relevance to general clinical practice in the NHS Not everyone in the PSOR‑008 and PSOR‑009 trials had systemic therapies before starting the trial (a criterion of the UK marketing authorisation for apremilast). The ERG suggested that PSOR‑008 and PSOR‑009 might have overestimated the benefit of apremilast because some patients in the trial had no previous systemic treatment, so their disease would have been more likely to respond to apremilast because it was less severe than in people who had more treatments. Uncertainties generated by the evidence The evidence base for apremilast did not include people with moderate disease as defined in UK clinical practice (total PASI score between 5 and 9). The committee was uncertain about the longer-term effectiveness of apremilast, beyond the clinical trial data (beyond 1 year). Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that apremilast is more effective than placebo but not as effective as biological therapies. Evidence for cost effectiveness Availability and nature of evidence The company's base-case model included a treatment sequence positioning apremilast before biological therapies (adalimumab and etanercept) and best supportive care, compared with a treatment sequence without apremilast. The company provided scenario analyses assessing the cost effectiveness of apremilast positioned after biological therapies (compared with a sequence with apremilast positioned before biological therapies) and apremilast as a replacement treatment for 1 of the biological therapies in the sequence. Given that clinical experts suggested that apremilast would extend the treatment sequence (either before or after biological therapies), the committee concluded that, although the positions and comparisons modelled by the company differed from NICE's original scope for this appraisal, they were generally sufficient for decision-making. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee considered that the company's base-case results were based on uncertain assumptions about key factors driving the ICER, such as monitoring costs, amount of drug waste, the likely costs associated with best supportive care and the costs associated with non-response. The ERG addressed these uncertainties in their exploratory analyses. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? Following the first committee meeting the company clarified that it had, in error, derived EQ‑5D data from US instead of UK tariffs. The company agreed that the updated trial-based EQ‑5D data was appropriate and presented revised results for the change in utility from baseline associated with the different PASI response categories in the model. The committee noted that the company's models did not take into account the disutility values associated with adverse events, but the ERG was unable to comment on whether including these values would have affected the model results. The committee concluded that the utility gains estimated from the company's revised model (for people with a DLQI score of more than 10) were plausible. There were no additional gains in health‑related quality of life over those already included in the quality-adjusted life year (QALY) calculations. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable. What are the key drivers of cost effectiveness? The ICERs were highly sensitive to the costs associated with best supportive care, and specifically whether the model included hospitalisation rates and costs from Fonia et al. (2010) or NICE's psoriasis guideline. The committee concluded that resource use for best supportive care is closer to Fonia et al. than to estimates from NICE's guideline. Most likely cost-effectiveness estimate (given as an ICER) The committee considered that the most plausible ICER available for the apremilast treatment sequence (in which apremilast was positioned before biological therapies) was about £30,300 per QALY gained. However it noted that there was considerable uncertainty about key factors driving this ICER, such as monitoring costs, amount of drug waste, the likely costs associated with best supportive care and the costs associated with non-response. The committee estimated that the ICER in the less severely affected population could be twice that for the population with severe disease; that is, about £60,000 per QALY gained for apremilast positioned before biological therapies in a population with a PASI score of 10 or more and a DLQI score of 10 or less (moderate disease), and where best supportive care was the only comparator. The committee concluded that a treatment sequence in which apremilast is positioned after biological therapies would not be a cost-effective use of NHS resources because it is dominated by a sequence that was not considered cost effective (apremilast positioned before biological therapies). The committee noted that the sequences in which apremilast replaced 1 of the biological therapies were cost saving but less effective than the comparator sequences, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £21,100–£39,100 per QALY). Rapid review reconsideration The rapid review only considered severe disease. The committee agreed it could not use ICERs based on comparisons of treatment sequences for decision-making. This was because biological therapies were not cost effective in these analyses, biasing the results. With the patient access scheme included, the ICER for apremilast compared with best supportive care was under £30,000 per QALY gained (the precise ICER is commercial in confidence). The committee agreed that apremilast was cost effective after biological therapies had failed, when best supportive care is the only treatment option. The committee recognised that apremilast was less effective than biological therapies, but that patient preference (mainly relating to method of administration) would influence whether it would be an appropriate treatment option. It noted that the ICERs compared with best supportive care were comparable to the ICERs for the biological therapies in the respective technology appraisals. The committee agreed that, for people for whom systemic therapies had failed and biological therapies were a treatment option, apremilast was a cost-effective use of NHS resources. Additional factors taken into account Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast. The level of the discount is commercial in confidence. End-of-life considerations Not applicable. Equalities considerations and social value judgements When using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.	{'Recommendations': 'Apremilast is recommended as an option for treating chronic plaque psoriasis in adults whose disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and ultraviolet‑A light), or when these treatments are contraindicated or not tolerated, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) of 10\xa0or more and a Dermatology Life Quality Index (DLQI) of more than\xa010\n\ntreatment is stopped if the psoriasis has not responded adequately at 16\xa0weeks; an adequate response is defined as:\n\n\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from start of treatment\n\n\n\nthe company provides apremilast with the discount agreed in the patient access scheme.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThis guidance is not intended to affect the position of patients whose treatment with apremilast was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nApremilast (Otezla, Celgene) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast down-regulates the inflammatory response by modulating the expression of cytokines and mediators associated with psoriasis (including tumour necrosis factor [TNF]‑alpha and interleukin [IL]‑23).\n\nMarketing authorisation\n\n'For the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporin, methotrexate or psoralen and ultraviolet‑A light (PUVA)'.\n\nRecommended dose and schedule\n\nThe recommended dosage is 30\xa0mg twice daily after an initial titration schedule. A single 10\xa0mg dose is given on the first day of treatment; this is titrated to 30\xa0mg twice daily over 5\xa0days (see the summary of product characteristics for the dose titration schedule).\n\nPrice\n\nThe price of apremilast is £550.00 for a 28‑day pack (56×30\xa0mg tablets) (excluding VAT; British National Formulary online, accessed July\xa02016).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Celgene and a review of this submission by the evidence review group. This appraisal was a rapid review of the published NICE technology appraisal guidance on apremilast for treating moderate to severe plaque psoriasis. It focused on cost-effectiveness analyses that included a patient access scheme agreement, which provides apremilast at a reduced cost. The discount is commercial in confidence. See the committee papers for full details of the rapid review evidence, and the history for full details of the evidence used for NICE's original technology appraisal guidance on apremilast for treating moderate to severe plaque psoriasis. See section\xa04.24 onwards for the rapid review consideration.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of apremilast, having considered evidence on the nature of psoriasis and the value placed on the benefits of apremilast by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management\n\nThe committee heard about the experience of people with psoriasis. It heard that the disease results in itchy, dry, scaly and thickened skin, which can be physically and psychologically debilitating, particularly if located on the hands, feet, face and genitals. Severe psoriasis is also associated with a shortened life expectancy. The committee heard that, because psoriasis is visible to others, it can make people feel isolated and lonely, which could lead to them losing self-confidence and avoiding social situations, and could also affect career opportunities and influence intimate relationships. It heard from clinical experts that people with severe psoriasis are about 6\xa0times more likely to have suicidal thoughts or commit suicide than the general population. The committee agreed that severe psoriasis has a significant psychosocial impact and substantially decreases quality of life.\n\nThe committee discussed how clinicians assess the severity of disease in people with psoriasis. It understood that several indices are used, and heard that clinicians routinely use both the Psoriasis Area Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) to monitor the disease. The committee was aware that the UK marketing authorisation for apremilast includes people with moderate and severe disease. It understood that, while the marketing authorisation did not specify the criteria for moderate or severe disease, the regulatory decision was based on trials that included people with a baseline PASI score of 12\xa0or more (mean score\xa019), a 10% or greater of body surface area affected, and a static Physician Global Assessment score of at least\xa03. The committee noted that the trials did not stipulate that participants have a particular DLQI score at baseline. The committee was aware that previous NICE technology appraisals defined severe psoriasis as a PASI score of\xa010 or more and a DLQI of more than\xa010. It understood that there is no universally accepted definition of moderate psoriasis. However, the committee heard from clinical experts that, in practice, moderate disease would be characterised by a lower PASI score (between 5\xa0and\xa09). It noted that the company, in its submission, presented analyses in people with a PASI score of 10\xa0or more and a DLQI score of 10 or less to represent people with disease not severe enough to be treated with biologicals in the UK. Clinical experts explained that the disadvantages of the DLQI are that it is not specific to psoriasis and does not capture all of the impacts of the disease (such as anxiety and depression). Clinical and patient experts suggested that some people with chronic psoriasis can develop coping mechanisms and so adjust to the impact of the disease, resulting in lower DLQI scores. The committee heard that clinicians use the DLQI for treatment decisions with biologicals, but do not generally use it to define different levels of severity. The committee acknowledged that PASI and DLQI, which reflect the outcomes used in the trials, are relevant measures used in clinical practice in the NHS. The committee concluded that the evidence base for apremilast reflected people with severe disease, as defined in UK clinical practice.\n\nThe committee considered the treatment pathway for people with psoriasis. It was aware that people have topical treatments as first-line treatment, followed by conventional (non‑biological) systemic therapies (such as methotrexate or ciclosporin), and phototherapy. If these treatments do not adequately control the psoriasis, people may have biological therapies, which they continue to have as long as the drugs work. The committee understood that if the disease no longer responds to a biological therapy, people will be offered another biological therapy. This pattern is likely to be repeated over their lifetime; clinical experts noted that people with psoriasis will often try many alternative biological agents in a short timeframe. The committee heard that, for people whose disease does not respond to multiple biological agents, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging. The committee questioned whether best supportive care was effective in treating psoriasis (that is, whether it improved PASI score or other measures of disease). It heard from clinical experts that best supportive care can be effective in the short term. The committee was aware that best supportive care can be accompanied by disutility because of the intensive time-consuming, inconvenient and unpleasant treatments, and that the psoriasis may worsen sooner than with biological therapies. The committee concluded that best supportive care is associated with limited, short-term efficacy and recognised the value of having a range of treatments with different mechanisms of action available.\n\nThe committee considered the potential positioning of apremilast in the treatment pathway in NHS clinical practice. It noted that the marketing authorisation for apremilast allows it to be positioned:\n\nearlier in the treatment pathway than biological therapies (that is, after\xa01, but not all, other systemic therapies have failed; see section\xa04.5)\n\nafter biological therapies (see section\xa04.6)\n\ninstead of biological therapies (at the point when all other systemic therapies have failed; see section\xa04.7).\n\nThe committee considered whether apremilast would be used before biological therapies were considered, that is, after 1\xa0but not all other systemic treatments had failed. It noted that the company had not presented analyses for apremilast in this position, and that it did not hear from clinical experts that they would offer the drug at this point. The committee therefore did not consider this position further.\n\nThe committee discussed whether apremilast would be used if biological therapies were not tolerated or after all biological therapies had failed. It heard from a clinical expert that apremilast would generally be prescribed for people who had already tried biological therapies, or for those who are unable to take them. The committee understood from the clinical experts that, in general, apremilast would not displace a biological therapy in the treatment pathway. It concluded that the most likely position for apremilast in the treatment pathway was if biological therapies were not tolerated or after all biological therapies had failed.\n\nThe committee discussed whether apremilast would be used at the same point in the treatment pathway as biological therapies (that is, once all other systemic therapies had failed). It heard from clinical experts that the positioning of apremilast (either before, or instead of, a biological therapy) would be driven largely by patient choice and intolerance or contraindications to biological therapy such as serious infections. The committee heard from:\n\nthe patient expert that, because apremilast is less effective than biological therapies, offering apremilast as a first-line treatment could delay more effective treatments, so patients may prefer biological therapies\n\nclinical experts that some people with psoriasis do not adhere to treatment, so it is important to consider patient choice to encourage adherence\n\nthe patient expert that apremilast is taken orally, which some patients may prefer but others may find a burden, given its twice-daily dosing (by comparison, some biological therapies are administered only once every 3\xa0months, by subcutaneous injection)\n\nthe clinical experts that an advantage of apremilast over biological agents is that it is not contraindicated in people with tuberculosis.The committee agreed that apremilast may not be the preferred treatment at the point in the treatment pathway at which biological therapies are considered (that is, after all systemic treatment have failed), but clinicians would like to have the option to prescribe apremilast at this point. The committee recognised that the treatment decision would be driven by patient choice, and that patients may well choose not to have apremilast instead of biological therapies because it is considered to be less effective (see sections 4.8 to 4.12).\n\n# Clinical effectiveness\n\nThe committee appreciated that the clinical evidence for apremilast came from 4\xa0multicentre placebo-controlled double-blind randomised controlled trials (RCTs) in people with moderate to severe chronic plaque psoriasis: PSOR‑005, -008, -009 and -010. The primary endpoint was the same in all 4\xa0trials: a 75% reduction in the PASI score at week\xa016 (known as a PASI\xa075 response). The randomised period of all trials was only until week\xa016. The committee considered the baseline characteristics of the patients in the apremilast trials and discussed whether the trials reflected the UK population with psoriasis who would be eligible to have apremilast. It noted the evidence review group (ERG's) comment that only 13% of the PSOR‑008 trial population would be eligible for apremilast. The committee heard from the company that, in its view, the ERG had misinterpreted the intended positioning of apremilast. The company clarified that, according to the UK marketing authorisation, apremilast could be used after only 1\xa0conventional systemic treatment, which could be phototherapy. The company stated that about 65% of the PSOR‑008 and PSOR‑009 trial populations had any prior systemic therapy (including conventional therapies but also biological agents). The committee noted the ERG's comments that the PSOR‑008 and PSOR‑009 trials may have overestimated the benefit of apremilast; some patients in the trial had no previous systemic treatment, so their disease would have been more likely to respond to apremilast because it was less severe than in people who had more treatments. The committee heard from clinical experts that there is no robust evidence to suggest that previous treatment with conventional therapy affects response to subsequent treatment. The committee heard from the company that other criteria for inclusion and exclusion used in apremilast trials were similar to trials of biological therapies. The committee concluded that the apremilast trials provided an appropriate basis for its decision-making.\n\nThe committee discussed the results of the placebo-controlled apremilast clinical trials, and considered the company's network meta-analysis, which indirectly compared apremilast with other biological agents specified in the scope. It noted that clinical trial evidence showed that apremilast was more effective than placebo for key outcomes at 16\xa0weeks, and that this benefit was consistent across subgroups studied. The committee heard from clinical experts that biological therapies are more effective than apremilast for treating psoriasis, and was aware that the company's network meta-analysis showed that the probability of response to treatment is highest with biological therapies and lowest with apremilast. The committee heard from the ERG that the company's network meta-analysis was technically robust, but any bias from trials would carry through to the results from this analysis. The committee heard that the ERG compared the meta-analysis results for the apremilast: etanercept comparison with odds ratios calculated using results of the PSOR‑010 trial, confirming that psoriasis is more likely to respond to etanercept than apremilast. The committee was aware of the drawbacks of the PSOR‑010 study in that it was powered to compare apremilast with placebo and etanercept with placebo (but not apremilast with etanercept), but still concluded that apremilast is more effective than placebo, but not as effective as biological therapies.\n\nThe committee discussed the long-term effectiveness of apremilast, noting that a substantial proportion of people who had a PASI\xa075 response after 16\xa0weeks of apremilast treatment subsequently lost their PASI\xa075 response during the treatment withdrawal phase (marked as 'academic in confidence' by the company). The committee heard from the company that some of the people in the apremilast trials who lost response, later regained it. The company stated that everyone who had a PASI\xa075 response at week\xa016 had at least a PASI\xa050 response by week\xa052. The clinical experts stated that fluctuating PASI scores characterise the natural history of psoriasis and any decline in efficacy with apremilast is expected to be similar to a decline with biological therapies. The experts also stated that the same level of response would not be seen if patients were to stop and restart treatment with apremilast. The committee concluded that some response to treatment with apremilast is maintained up to 1\xa0year, but noted uncertainty about longer-term effectiveness beyond the clinical trial data.\n\nWhen considering the tolerability of apremilast, the committee heard from clinical experts that apremilast is associated with a number of adverse events early in treatment. The committee heard that the most common adverse events with apremilast are related to the gastrointestinal tract (including diarrhoea and nausea), and that people are willing to tolerate gastrointestinal adverse effects if they are benefiting from the drug. The committee concluded that apremilast is associated with gastrointestinal adverse events, but these would not preclude the use of apremilast.\n\nThe committee discussed the probability of people stopping apremilast treatment, and heard from clinical experts that the rate of withdrawal from apremilast is similar to (or potentially lower than) the rate of withdrawal from biological therapies. It heard from the company that the ERG's reference to a higher withdrawal rate with apremilast based on PSOR‑008 data was factually inaccurate (the company marked this withdrawal rate as 'academic in confidence'). The company stated that 2\xa0year data from PSOR‑008 indicate a withdrawal rate of 19.5%\xa0per year for apremilast, which is similar to the company's assumption of a 20%\xa0withdrawal rate for biological therapies, which it chose based on the rate used for biological therapies in previous NICE appraisals (adalimumab, etanercept, infliximab, secukinumab and ustekinumab). The committee concluded that the probability of people stopping treatment with apremilast is likely to be similar to the probability of people stopping treatment with biological therapies.\n\n# Cost effectiveness\n\nThe committee considered whether the company's health economic model included relevant treatment sequences and positions. The committee noted that the treatment sequences modelled by the company reflected the likely positioning of apremilast according to the clinical experts (see sections\xa04.4 to 4.7). The committee heard from clinical experts that etanercept is the least effective of the existing biological therapies for treating severe psoriasis. When queried, the company stated that it had selected etanercept for the model because it is the most used biological therapy for psoriasis in Europe. The ERG stated that this would not be a key driver of the results because the model includes biological therapies in both arms in the model and would not be displaced in the sequence including apremilast. Based on the likely positioning of apremilast in the treatment pathway (see sections\xa04.4 to 4.7), the committee concluded that, although the company did not compare the sequence in which apremilast came after biological therapies with a sequence without apremilast, the positions and comparisons modelled by the company were generally sufficient for decision-making.\n\nThe committee discussed the sources used by the company to estimate resource use and costs associated with best supportive care. It noted that the incremental cost-effectiveness ratios (ICERs) were highly sensitive to these inputs, and specifically whether the model included hospitalisation rates and costs from Fonia et al. (2010; the ERG's preferred assumption of best supportive care costs of £348 per cycle based on 6.49\xa0days of hospitalisation per year) or NICE's psoriasis guideline (the company's base case assuming best supportive care costs £888 per cycle based on 26.6\xa0days of hospitalisation per year). The committee heard from the clinical experts that both sources were likely to overestimate the actual number of hospital days and resource use associated with best supportive care. This is in part because the populations described in Fonia et al. and NICE's guideline differed from the population covered in this appraisal; NICE's psoriasis guideline was for a specific, high-need subpopulation with very severe psoriasis, and Fonia et al. described care in a tertiary care centre known for treating the most severely affected people. The committee heard from the company that the Fonia et al. study reflected a site that offered day-care and therefore admitted fewer people to hospital than would normally be admitted in clinical practice. The clinical expert stated that the Fonia et al. study describes a day unit that offered on‑site hotel accommodation to people. The committee noted that this option is much less costly than a hospital stay because it would not incur nursing and other hospital costs and, increasingly, is the model of care for people with psoriasis in the NHS. The committee also heard from the clinical experts that, in recent years, the number of people hospitalised for severe psoriasis has fallen, and that clinicians give best supportive care to people during their outpatient visits; therefore, hospitalisation costs associated with psoriasis have fallen, and are continuing to fall. The committee noted that after consultation, the company provided NHS hospital episode statistics data that showed that the average length of hospital stay associated with best supportive care was 3.5\xa0days. It heard from the company that in its view, these values underestimate actual length of NHS hospitalisation because they include people with different disease severities as well as people receiving concomitant medication and that, in patients who had received inpatient care, the average length of stay was 10.74\xa0days. The clinical experts agreed that the hospital episode statistics data underestimated length of hospitalisation. The committee agreed with this, but considered that the most plausible estimate would be lower than the ERG and company assumptions of 6.49\xa0and\xa026.6\xa0days per year. With respect to the proportion of people admitted to hospital, the clinical experts noted that the actual proportion is much lower than the 30% annual probability assumed by Fonia et al. (the lower of the 2\xa0estimates). The committee recognised the significant uncertainty in this model input, and agreed that the best supportive care costs are likely to be lower than in Fonia, and also noted that assuming a lower cost would increase the ICER. Additionally, the committee noted that costs associated with hospitalisation were consistently applied to all days in hospital. The committee, however, considered that it was reasonable to expect that the first few days in hospital would generate more expenses than later days; therefore the company may have overestimated the overall costs of best supportive care associated with hospitalisation in the model and accounting for this was likely to increase the ICERs presented. The committee recognised the considerable uncertainty and concluded that shortcomings exist among all sources of data for resource use, but that resource use for best supportive care is closer to Fonia et al. than to the estimates from NICE's guideline on psoriasis.\n\nThe committee went on to discuss the cost estimates for people whose disease does not respond to one systemic treatment and who then go on to get another one, during which time they need elements of best supportive care. The committee recognised this as a significant driver of cost-effectiveness results. The committee heard that the company had originally assumed that this resource would be lower than best supportive care costs and included an estimate of £460 per cycle, based on their preferred best supportive care costs from the NICE guideline on psoriasis (see section\xa04.11). The ERG instead based its preferred estimate on the study by Fonia et al. (2010) and also assumed that this additional resource is the same as for best supportive care, therefore including an estimate of £348 per cycle. After consultation, the company explored the effect on the cost‑effectiveness results of using the costs from Fonia et al. for the 12\xa0month period after patients start biological therapies. However the company noted that because it had already included costs for outpatients and systemic treatments in its model (also from Fonia et al.), it deducted these costs to avoid double counting, resulting in a cost for people whose condition does not respond of £45 per cycle. The committee agreed that avoiding double counting was appropriate, but also agreed with the ERG that using costs from the period after starting biological therapies includes costs for people whose condition responds, as well as costs for people whose condition does not respond to biological therapies; therefore underestimating the true costs. Instead, the committee preferred the ERG's inclusion of costs from Fonia et al. that reflect the 12\xa0month period before a person starts a biological therapy while at the same time reducing the costs of outpatient and systemic treatments (£225 per cycle). The company agreed during the second committee meeting that this estimate was plausible, but highlighted that the ERG applied this cost to all people starting a new biological therapy for the 16\xa0week 'trial' period, whereas a proportion of people on new treatments benefit immediately or at least quickly. The company acknowledged that there was uncertainty around the proportion of patients to which this 'non-responder' cost should apply. The clinical experts agreed that response varies among people who try new active treatments, and that it is unlikely that all people will incur the same 'non-responder' costs. The committee heard from the ERG that the costs from Fonia et al. include patients at different levels of response and therefore the model already accounted for variable non-responder costs during the period in which modelled patients try new drugs. The committee concluded that there was considerable uncertainty about the actual costs associated with starting a new therapy if a person's disease has previously not responded to another therapy in the model, but concluded that the ERG's estimate of £225 per cycle was the most plausible of those presented.\n\nThe committee considered the quality-of-life and utility values used in the company's original model. It was aware that the company did not use the baseline EQ‑5D data collected in the apremilast clinical trials. The committee heard that the company sourced the baseline utility value in the model (0.7) from previous technology appraisals, and noted that people in the apremilast clinical trials had a baseline utility value of\xa00.8. The company stated that the baseline EQ‑5D value in the apremilast trials differed from the baseline value in trials of biological therapies (although other key baseline characteristics such as PASI score were consistent across the trials). The ERG confirmed that changing the baseline utility value used in the model would not significantly affect the cost-effectiveness results because the model is driven by the incremental changes in utility score from baseline. The committee then discussed the company's approach to incorporating utility increments associated with a response to treatment in the model. The committee was concerned that the company had included trial-based EQ‑5D data in its model reflecting a DLQI score of 10\xa0or less but that, in the model reflecting a DLQI score of more than\xa010, the company had used a mapping algorithm instead of clinical trial data. The committee was also concerned that the company used etanercept data in the mapping algorithm instead of apremilast data. The company justified this on the basis that EQ‑5D data in the apremilast trials were subject to a ceiling effect. However, following the first committee meeting the company clarified that it had, in error, derived EQ‑5D data from US instead of UK tariffs. The company agreed that the updated trial-based EQ‑5D data was appropriate and presented revised results for the change in utility from baseline associated with the different PASI response categories in the model. The committee noted that the company's models did not take into account the disutility values associated with adverse events, but the ERG was unable to comment on how including these values would have affected the ICER. The committee concluded that the utility gains estimated from the company's revised model (for people with a DLQI score of more than\xa010) were plausible.\n\nThe committee discussed the assumption in the company model that apremilast is associated with fewer visits to a clinician than biological therapies (1\xa0annual visit for apremilast, compared with 4\xa0visits per year with biological therapies). The committee heard from the clinical experts that because apremilast is a new drug dermatologists would be cautious in allowing fewer visits to a clinician and therefore the number of clinician visits (including GP visits in 'shared care' arrangements) for apremilast and biological therapies would be the same initially, but, in the long term, the clinical experts expected that the number of monitoring visits would be lower for apremilast. The committee did not consider it realistic that people receiving apremilast would visit their clinician only once each year, and concluded that 4\xa0visits per year (including visits to GPs) is more appropriate (based on the company's assumption of 4\xa0visits for biological therapies). The clinical experts agreed with this, but noted that monitoring costs for apremilast were likely to be lower than for biological therapies. The clinical experts also confirmed that for treatment with apremilast GPs could monitor patients under shared care arrangements. However, the committee noted that the cost of monitoring people on apremilast in primary care should reflect the assumption of additional payments to GPs, similar to arrangements for monitoring methotrexate. The committee noted that if lower monitoring costs for apremilast were incorporated in the model, this would lower the ICERs presented, but acknowledged the lack of robust estimates available. Therefore, the committee concluded that the assumption of equal monitoring visits was appropriate. The committee discussed the potential for waste with apremilast. The clinical experts acknowledged that when people did not adhere to or withdrew from treatment, some tablets would be wasted. The committee considered that it would be reasonable to account for some treatment waste with apremilast. It noted the company's revised model, which included an assumption of 14\xa0days' wasted treatment; it heard from the ERG and experts that this was plausible. The company additionally stated that a waste assumption should be applied equally to biological therapies and apremilast. The ERG, however, considered that the waste for biological therapies in each arm of the model would cancel each other out but the company stated that would be true only if a lifetime horizon was assumed. The clinical experts also stated that while there will be waste with biological therapies, this is low because people get rigorous training before being prescribed biological therapies, in order to boost adherence. The committee concluded that the assumption of 14\xa0days' apremilast waste in the revised model was appropriate.\n\nThe committee discussed the company's assumption that the probability of response for each treatment was the same regardless of its position in the sequence. It heard from the company that clinical trials show that the efficacy of apremilast appears consistent across the positions in the treatment sequence. The company noted that the response was slightly lower if apremilast were positioned after biologicals, and that its model accounted for this reduced efficacy. The committee was satisfied that the company had included the efficacy of apremilast appropriately in its model.\n\nThe committee considered the other assumptions in the company model in light of its clinical discussion. It concluded that the model should include the possibility that psoriasis can improve with best supportive care (in contrast to the company's assumption of no effectiveness, see section\xa04.3). The committee agreed with the company's assumptions that withdrawal rates are similar for apremilast and biologicals (see section\xa04.9), and that response rates remain relatively constant over time (see section\xa04.7).\n\nThe committee discussed the ICERs for apremilast positioned before biological therapies in a population with a PASI score of 10\xa0or more and a DLQI score of more than\xa010.The committee considered the company's revised base-case results and the ERG's exploratory analyses. The committee concluded that the most plausible ICER available for decision-making was about £30,300 per quality-adjusted life year (QALY) gained and noted that this was above the range normally considered cost effective. However it noted that there was considerable uncertainty about key factors driving this ICER, such as monitoring costs (see section\xa04.13), amount of drug waste (see section\xa04.14), the likely costs associated with best supportive care (see section\xa04.11) and the costs associated with 'non-responders' (see section\xa04.12). The committee considered that these uncertainties could drive the ICERs in different directions and the magnitude of impact was uncertain. However, the committee recalled its consideration in section\xa04.11 that the costs associated with best supportive care are likely to be even lower than those estimated by the ERG from Fonia et al. (2010) and accounting for this would increase the ICER. Moreover, being mindful that apremilast was not as effective as biological therapies, the committee noted comments from consultation and from the patient expert that apremilast in a sequence before biological therapies could delay access to more effective treatment, and may therefore not be preferred. The committee heard from the patient expert that achieving clear skin in the shortest possible time is important to people and that a PASI\xa075 response shown with apremilast means that people are still affected by psoriasis. Together with the uncertainties in the economic modelling, the committee concluded that apremilast could not be recommended for severe psoriasis after the failure of conventional systemic therapy but before biological therapy.\n\nThe committee discussed the ICERs for apremilast positioned before biological therapies in a population with a PASI score of 10\xa0or more and a DLQI score of 10\xa0or less (moderate disease), and where best supportive care was the only comparator because patients with moderate disease are not offered biological therapies. At its first meeting, the committee concluded that the most plausible ICER for the apremilast sequence lay somewhere between £97,500 and £125,300 per QALY gained, taking into account its preferred assumptions. The committee noted that the company had not updated this analysis with the UK tariff-based utility values, and estimated, based on the original modelling, that the ICER in the less severely affected population could be twice that seen for the population with a PASI and DLQI of 10\xa0or more, that is, about £60,000 per QALY gained. The committee noted that the evidence base for apremilast did not include people with moderate disease as defined in UK clinical practice (a PASI score of 5\xa0to\xa09). Given that the company's model indicated that apremilast had a higher ICER in a less affected population (that is, people with a DLQI score of 10\xa0or less), the committee concluded that the ICER for apremilast for treating moderate psoriasis would not be within the range considered to be a cost-effective use of NHS resources.\n\nThe committee considered the company's cost-effectiveness results for apremilast positioned after biological therapies and before best supportive care. It noted that the sequence in which apremilast was positioned after biological therapy was dominated (provided fewer QALYs at a higher cost) by the sequence in which apremilast came before biological agents. Having already concluded that apremilast, as a treatment in a sequence before biological therapy, is not a cost-effective use of NHS resources (see section\xa04.17), the committee concluded that a treatment sequence that provides fewer QALYs but costs more could not be considered a cost-effective use of NHS resources.\n\nThe committee considered the company's cost-effectiveness results for apremilast as a replacement treatment for 1\xa0of the biological therapies in the sequence, even though the clinical experts stated that apremilast was unlikely to displace a biological agent in the treatment pathway. It noted that the sequences containing apremilast were cost saving – but less effective – than the comparator sequences, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £21,100 to £39,100 per QALY). The committee considered that the ICERs were based on uncertain assumptions and noted that that ICERs based on its preferred assumptions were not available. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The committee concluded that the ICERs for apremilast as a replacement for biological therapies for severe psoriasis were not within the range considered to be a cost-effective use of NHS resources.\n\nThe committee heard differing views about whether apremilast was innovative in its potential to make a significant and substantial impact on health-related benefits. It agreed that apremilast appeared to be innovative in its novel use of an existing mechanism of action, and agreed that it demonstrated innovation by providing an additional novel oral therapy. However, the committee recalled that some people with psoriasis prefer less frequent injectable treatments to more frequent oral ones (see section\xa04.4) and therefore the committee concluded that, in this respect, there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\nThe committee considered when appraising apremilast whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. The committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as an applicable consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view on the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was irrelevant for the consideration of cost effectiveness of apremilast.\n\nThe committee discussed whether the recommendations could be considered unfair because a small group of people are unable to take any biological therapies because of contraindications that could be associated with protected characteristics according to the Equality Act. The committee concluded that these patients would otherwise have best supportive care, and although the company did not present a revised ICER comparing apremilast with best supportive care for this group, the committee expected the ICER to be around £60,000 per QALY gained. Considering that this was much higher than what is normally accepted as good use of NHS resources, the committee concluded that to recommend apremilast for this group would not achieve the legitimate aim of providing advice on cost-effective treatments.\n\n# Rapid review\n\n## Population\n\nThe committee noted that the company's revised analyses focused on people with severe disease, but the marketing authorisation also included people with moderate disease. The committee recalled its discussions with clinical experts that the evidence base for apremilast did not include people with moderate disease as defined in UK clinical practice. The committee concluded that there was no evidence for clinical or cost effectiveness available to enable it to make a decision for people with moderate disease.\n\n## Key assumptions\n\nThe committee noted that the company included the preferred assumptions in NICE's original appraisal of apremilast in the revised economic modelling (see table\xa01).\n\n## Table 1 Company's preferred assumptions\n\nParameter\n\nCommittee's preferred inputs\n\nDiscussion reference\n\nCost of best supportive care per 28‑day cycle\n\n£348.22\n\nSection 4.14\n\nCost of non-response\n\n£225.00\n\nSection 4.15\n\nSource of utility estimates\n\nApremilast trial data\n\nSection 4.16\n\nEfficacy of best supportive care\n\nNational Clinical Guideline Centre model\n\nSection 4.3\n\nEfficacy of active treatments\n\nNetwork meta-analysis including PSOR‑010 study\n\nSection 4.9\n\nWastage of apremilast\n\nweeks\n\nNot applicable\n\nClinician visits\n\nSame number of visits for all active treatments\n\nSection 4.17\n\nEQ‑5D value set\n\nUK value set\n\nNot applicable\n\nThe ERG confirmed that the company did this appropriately, and the committee agreed that the company had presented results based on the committee's preferred inputs.\n\n## Stopping rule\n\nThe committee considered a stopping rule for apremilast. It heard during consultation of the rapid review appraisal document that NICE guidance for the biological therapies in psoriasis includes a stopping rule. The committee recognised that the summary of product characteristics states that 'if a patient shows no evidence of therapeutic benefit after 24\xa0weeks, treatment should be reconsidered'. The committee understood, however, that the analyses it considered had included a stopping rule at 16\xa0weeks. The committee recognised that NICE guidance for biological therapies for psoriasis defined 'no evidence of therapeutic benefit'; the committee did not hear anything during consultation or from the company during the appraisal of apremilast to change the criteria. The committee concluded that it was appropriate to include a stopping rule, and that this should be at 16\xa0weeks and be defined in the same way as in NICE guidance for biological therapies in psoriasis.\n\n## Treatment sequences\n\nThe committee was aware that apremilast would be used in clinical practice after all systemic therapies had failed, but could be used before, after or instead of biological therapies (see sections\xa04.4 to\xa04.7). The company's base case compared a sequence of apremilast positioned before biological therapies against a sequence without apremilast. The company's scenario analysis compared a sequence of apremilast positioned before biological therapies against a sequence of apremilast after biological therapies. The ERG stated that the company had not explored a full range of sequences, so the optimal position of apremilast in the treatment pathway could not be established. The company clarified that it did not intend to position apremilast as an option only before biological therapies. The ERG also identified problems with external validity of treatment sequences that included biological therapies. The ERG found that, when comparing each biological therapy with best supportive care, the ICERs generated were more than £30,000 per QALY gained. The committee noted that the results were unexpected because these biological therapies have been previously recommended by NICE as a cost-effective use of NHS resources. The committee understood that this difference was driven by the incorporation of the committee's preferred assumptions, particularly around the costs of best supportive care. It was outside the committee's current remit to appraise the cost effectiveness of biological therapies, so it did not explore this further. The committee agreed with the ERG that any treatment sequence including a biological therapy resulted in a lower ICER for the sequence that included apremilast compared with the sequence that did not include apremilast because apremilast up-front delayed giving biological therapies found to be cost ineffective in these analyses. The committee therefore agreed that it could not make a decision using ICERs based on these comparisons.\n\nThe company also presented results for sequences without biological therapies, defined as apremilast followed by best supportive care compared with best supportive care alone. The ERG considered this to be the only valid ICER available because the sequences did not include biological therapies (see section\xa04.26). The company's base-case ICER for apremilast followed by best supportive care was less than £30,000 per QALY gained compared with best supportive care alone (the precise ICER is commercial in confidence). The committee agreed that apremilast is a cost-effective use of NHS resources for people for whom best supportive care is the only option, that is, if biological therapies are not tolerated or after all biological therapies have failed.\n\nThe committee considered whether it could use the analyses of best supportive care to appraise apremilast for people with severe psoriasis for whom treatment with biological therapies was an option. The committee noted that apremilast was not as effective as biological therapies, and it was less costly. The committee agreed that it would have valued a direct comparison with biological therapies to understand the cost saved for each QALY lost, but recognised it had not been presented with this. The committee reiterated that the positioning of apremilast (either before or instead of biological therapy) would be driven largely by patient choice. The committee was aware that the results were comparable with the ICERs for biological therapies compared with best supportive care in previous NICE technology appraisals. The committee noted that patients value having a range of treatment options. It concluded that, because the ICER for apremilast was comparable to those estimated previously for biological therapies, it could recommend apremilast as an option for treating severe chronic plaque psoriasis that has not responded to all systemic therapies, or when systemic therapy is contraindicated or not tolerated. This recommendation applies only when the company provides apremilast with the discount agreed in the patient access scheme.\n\n# Summary of appraisal committee's key conclusions\n\nTA419\n\nAppraisal title: Apremilast for treating moderate to severe plaque psoriasis\n\nSection\n\nKey conclusion\n\nApremilast is recommended as an option for treating chronic plaque psoriasis in adults whose disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and ultraviolet‑A light), or when these treatments are contraindicated or not tolerated, only if:\n\n\n\nthe disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) of 10\xa0or more and a Dermatology Life Quality Index (DLQI) of more than\xa010\n\ntreatment is stopped if the psoriasis has not responded adequately at 16\xa0weeks; an adequate response is defined as:\n\n\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from start of treatment\n\n\n\nthe company provides apremilast with the discount agreed in the patient access scheme.\n\n\n\nApremilast was cost effective when compared with best supportive care.\n\n\n\nApremilast was less effective but also less costly than biological therapies. The cost-effectiveness analyses, which compared apremilast with biological therapies, included treatment sequences. These were not considered appropriate for decision-making because the biological therapies in the sequence were not in themselves cost effective, which biased the results. However, the incremental cost-effectiveness ratio (ICER) for apremilast compared with best supportive care was comparable to ICERs for biological therapies in previous NICE technology appraisals. The committee recognised that treatment choice will be largely driven by patient preference, and agreed apremilast was a cost-effective use of NHS resources.\n\nThere was no clinical- or cost-effectiveness evidence available to make a decision for people with moderate disease.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nSevere psoriasis has a significant psychosocial impact and substantially decreases quality of life. People with psoriasis have topical treatments as first-line treatment, followed by conventional (non‑biological) systemic therapies and phototherapy. If these treatments do not adequately control the psoriasis, people may have biological therapies. People with psoriasis will often try many alternative biological agents in a short timeframe and, for people whose disease has not responded to multiple biological agents, the only remaining treatment option is best supportive care. Although best supportive care can provide limited, short‑term benefits, it is associated with disutility because of the intensive time-consuming, inconvenient and unpleasant treatments.\n\n, 4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nApremilast provides a novel use of an existing mechanism of action, and an oral alternative to injectable biological therapies. However, some people with psoriasis prefer less frequent injectable treatments to more frequent oral ones. Another advantage of apremilast over biological agents is that apremilast is not contraindicated in people with tuberculosis.\n\n, 4.20\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe marketing authorisation for apremilast allows it to be positioned before, instead of, and after biological therapies. However, clinical experts did not consider that apremilast would displace a biological therapy in the treatment pathway, and agreed that the positioning of apremilast (either before or after biological therapy) would be largely driven by patient choice and intolerance or contraindications to biological therapy.\n\n\n\nAdverse reactions\n\nThe most common adverse events with apremilast are related to the gastrointestinal tract (including diarrhoea and nausea), but these would not preclude the use of apremilast because people are willing to tolerate gastrointestinal adverse effects if they are benefiting from the drug.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe clinical evidence for apremilast came from 4\xa0multicentre, placebo-controlled, double-blind randomised controlled trials in people with moderate to severe chronic plaque psoriasis. The trials were good quality and the treatment groups were generally similar at baseline. Because PSOR‑010 was not powered to compare apremilast with etanercept, and there were no other head-to-head trials comparing apremilast with any of the biological therapies recommended by NICE for psoriasis, the company did a network meta-analysis that included 24\xa0studies. The evidence review group (ERG) stated that the results from the company's network meta-analysis were likely to be reasonably reliable, but that the results of the company's sensitivity analysis should be interpreted with caution.\n\n\n\nRelevance to general clinical practice in the NHS\n\nNot everyone in the PSOR‑008 and PSOR‑009 trials had systemic therapies before starting the trial (a criterion of the UK marketing authorisation for apremilast). The ERG suggested that PSOR‑008 and PSOR‑009 might have overestimated the benefit of apremilast because some patients in the trial had no previous systemic treatment, so their disease would have been more likely to respond to apremilast because it was less severe than in people who had more treatments.\n\n\n\nUncertainties generated by the evidence\n\nThe evidence base for apremilast did not include people with moderate disease as defined in UK clinical practice (total PASI score between 5\xa0and\xa09).\n\n\n\nThe committee was uncertain about the longer-term effectiveness of apremilast, beyond the clinical trial data (beyond 1\xa0year).\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that apremilast is more effective than placebo but not as effective as biological therapies.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company's base-case model included a treatment sequence positioning apremilast before biological therapies (adalimumab and etanercept) and best supportive care, compared with a treatment sequence without apremilast. The company provided scenario analyses assessing the cost effectiveness of apremilast positioned after biological therapies (compared with a sequence with apremilast positioned before biological therapies) and apremilast as a replacement treatment for 1\xa0of the biological therapies in the sequence. Given that clinical experts suggested that apremilast would extend the treatment sequence (either before or after biological therapies), the committee concluded that, although the positions and comparisons modelled by the company differed from NICE's original scope for this appraisal, they were generally sufficient for decision-making.\n\n, 4.10\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee considered that the company's base-case results were based on uncertain assumptions about key factors driving the ICER, such as monitoring costs, amount of drug waste, the likely costs associated with best supportive care and the costs associated with non-response. The ERG addressed these uncertainties in their exploratory analyses.\n\n, 4.13, 4.14, 4.16, 4.17\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nFollowing the first committee meeting the company clarified that it had, in error, derived EQ‑5D data from US instead of UK tariffs. The company agreed that the updated trial-based EQ‑5D data was appropriate and presented revised results for the change in utility from baseline associated with the different PASI response categories in the model.\n\n\n\nThe committee noted that the company's models did not take into account the disutility values associated with adverse events, but the ERG was unable to comment on whether including these values would have affected the model results. The committee concluded that the utility gains estimated from the company's revised model (for people with a DLQI score of more than\xa010) were plausible.\n\nThere were no additional gains in health‑related quality of life over those already included in the quality-adjusted life year (QALY) calculations.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe ICERs were highly sensitive to the costs associated with best supportive care, and specifically whether the model included hospitalisation rates and costs from Fonia et al. (2010) or NICE's psoriasis guideline. The committee concluded that resource use for best supportive care is closer to Fonia et al. than to estimates from NICE's guideline.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee considered that the most plausible ICER available for the apremilast treatment sequence (in which apremilast was positioned before biological therapies) was about £30,300 per QALY gained. However it noted that there was considerable uncertainty about key factors driving this ICER, such as monitoring costs, amount of drug waste, the likely costs associated with best supportive care and the costs associated with non-response.\n\n, 4.18\n\nThe committee estimated that the ICER in the less severely affected population could be twice that for the population with severe disease; that is, about £60,000 per QALY gained for apremilast positioned before biological therapies in a population with a PASI score of 10\xa0or more and a DLQI score of 10\xa0or less (moderate disease), and where best supportive care was the only comparator.\n\n\n\nThe committee concluded that a treatment sequence in which apremilast is positioned after biological therapies would not be a cost-effective use of NHS resources because it is dominated by a sequence that was not considered cost effective (apremilast positioned before biological therapies).\n\nThe committee noted that the sequences in which apremilast replaced 1\xa0of the biological therapies were cost saving but less effective than the comparator sequences, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £21,100–£39,100 per QALY).\n\n\n\nRapid review reconsideration\n\nThe rapid review only considered severe disease.\n\n\n\nThe committee agreed it could not use ICERs based on comparisons of treatment sequences for decision-making. This was because biological therapies were not cost effective in these analyses, biasing the results.\n\n\n\nWith the patient access scheme included, the ICER for apremilast compared with best supportive care was under £30,000 per QALY gained (the precise ICER is commercial in confidence). The committee agreed that apremilast was cost effective after biological therapies had failed, when best supportive care is the only treatment option.\n\n\n\nThe committee recognised that apremilast was less effective than biological therapies, but that patient preference (mainly relating to method of administration) would influence whether it would be an appropriate treatment option. It noted that the ICERs compared with best supportive care were comparable to the ICERs for the biological therapies in the respective technology appraisals. The committee agreed that, for people for whom systemic therapies had failed and biological therapies were a treatment option, apremilast was a cost-effective use of NHS resources.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of apremilast. The level of the discount is commercial in confidence.\n\nEnd-of-life considerations\n\nNot applicable.\n\nEqualities considerations and social value judgements\n\nWhen using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate."}	https://www.nice.org.uk/guidance/ta419	Evidence-based recommendations on apremilast (Otezla) for treating moderate to severe plaque psoriasis in adults.
34c5b939f13594916995fe6d63fe392c36358436	nice	High-throughput non-invasive prenatal testing for fetal RHD genotype	High-throughput non-invasive prenatal testing for fetal RHD genotype Evidence-based recommendations on high-throughput non-invasive prenatal testing (NIPT) for fetal RHD genotype. # Recommendations High-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype is recommended as a cost-effective option to guide antenatal prophylaxis with anti‑D immunoglobulin, provided that the overall cost of testing is £24 or less. This will help reduce unnecessary use of a blood product in pregnant women, and conserve supplies by only using anti‑D immunoglobulin for those who need it. Cost savings associated with high-throughput NIPT for fetal RHD genotype are sensitive to the unit cost of the test, additional pathway costs and implementation costs. Trusts adopting NIPT should collect and monitor the costs and resource use associated with implementing testing to ensure that cost savings are achieved (see section 6.1).# Clinical need and practice # The problem addressed NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative recommends anti‑D immunoglobulin for all rhesus‑D (D) negative pregnant women who are not known to be sensitised to the D antigen, to reduce the risk of sensitisation. The British Committee for Standards in Haematology (BCSH) guideline on anti-D immunoglobulin to prevent haemolytic disease of the fetus and newborn also recommends that all D‑negative pregnant women who are not known to be sensitised to D antigen have anti‑D immunoglobulin after: potentially sensitising events birth, if the baby is confirmed to be D positive by cord blood typing. Anti‑D immunoglobulin is produced from the pooled plasma donated by large numbers of D‑negative people who have had a transfusion of D‑positive red cells to stimulate the production of D antibodies. It is a finite resource and, because there have been shortages in the past, it needs to be used carefully to maintain stocks. Anti‑D immunoglobulin is a blood product and may also carry the risks common to all blood products, including physiological reactions, processing errors and the potential future risk of unknown blood-borne viruses or prion diseases. Physiological reactions must be reported to the Medicines and Healthcare products Regulatory Agency and processing errors to the Serious Hazards of Transfusion Scheme. High-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype involves analysing cell-free fetal DNA in maternal blood and is intended for use in pregnant women who are D negative and are not sensitised to D antigen. It is a laboratory-developed test offered by the International Blood Group Reference Laboratory, Bristol. This laboratory is an accredited NHS Blood and Transplant Laboratory that is currently providing NIPT for RHD genotype for some NHS patients. High-throughput NIPT for fetal RHD genotype would allow D‑negative women who are carrying a D‑negative fetus to avoid unnecessary treatment with anti‑D immunoglobulin. High-throughput NIPT for fetal RHD genotype would allow D‑negative women to make an informed choice about whether to have treatment with anti‑D immunoglobulin. This may improve adherence to anti‑D immunoglobulin treatment, reduce the number of sensitisations and so reduce haemolytic disease of the fetus and newborn in later pregnancies. # The condition During pregnancy, small amounts of fetal blood can enter the maternal circulation (an event called fetomaternal haemorrhage). The presence of fetal D‑positive cells in the maternal circulation, after fetomaternal haemorrhage, can cause a mother who is D negative to produce antibodies against the D antigen on the fetal blood cells (anti‑D) – a process called sensitisation. Sensitisation can happen at any time during pregnancy, but is most common during the third trimester and delivery. It can follow events in pregnancy known to be associated with fetomaternal haemorrhage, such as medical interventions, terminations, late miscarriages, antepartum haemorrhage and abdominal trauma. These are called potentially sensitising events. The process of sensitisation has no adverse health effects for the mother and usually does not affect the pregnancy during which it occurs. However, if the mother is exposed to the D antigen from a D‑positive fetus during a later pregnancy, the immune response is quicker and much greater. The anti‑D produced by the mother can cross the placenta and cause haemolytic disease of the fetus and newborn. This can cause severe fetal anaemia, leading to fetal heart failure, fluid retention and swelling (hydrops), and intrauterine death. The risk of sensitisation can be reduced if D‑negative pregnant women have anti‑D immunoglobulin. Before anti‑D immunoglobulin was available, the incidence of sensitisation in D‑negative women after the birth of 2 D‑positive babies was about 16%. Haemolytic disease of the fetus and newborn, which occurred in about 1% of all births, was a significant cause of morbidity and mortality. After routine postpartum anti‑D prophylaxis was introduced, the incidence of D sensitisation dropped to about 2%. The sensitisation rate has further reduced since the introduction of routine antenatal anti‑D prophylaxis. In England, there were 646,904 births from April 2013 to March 2014, of which about 15% (97,036 births) were to D‑negative women. About 40% of these women carry a D‑negative fetus (around 39,000 per year) and so do not need to have anti‑D immunoglobulin. D‑negative status occurs in about 15% of people of white European family origin, about 3% to 5% of people of black African family origin, and is very rare in people of eastern Asian origin. Most D‑negative people of white European family origin have an RHD gene deletion; less than 1% have RHD gene variants. However, in D‑negative people of black African family origin, 66% have an inactive RHD gene (the RHD pseudogene), which mostly results from genes that contain D sequences but do not produce D antigen. # The diagnostic and care pathways ## Care for D‑negative pregnant women who are not sensitised to D antigen In current practice, babies born to women who are D negative and not sensitised to D antigen have their Rh blood group determined after birth, using cord blood typing. Testing to find out the RHD genotype of the fetus during pregnancy is not currently done in most centres in the NHS. The NICE guideline on antenatal care and the BCSH guideline on blood grouping and antibody testing in pregnancy recommend that women should be offered testing for ABO and Rh blood group in early pregnancy. All women identified as D‑negative would be tested for the presence of D antibodies, regardless of whether they are known to be sensitised or not. To prevent sensitisation in women identified as D‑negative but without D antibodies, anti‑D immunoglobulin is recommended, both as prophylaxis and after potentially sensitising events. The NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative recommends routine antenatal anti‑D prophylaxis (RAADP) as a treatment option for all pregnant women who are D negative and who are not known to be sensitised to the D antigen. RAADP can be given as 2 doses at weeks 28 and 34 of pregnancy, or as a single dose between 28 and 30 weeks. The guideline from the BCSH on using anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn recommends that all D‑negative pregnant women, who are not known to be sensitised to D antigen, have anti‑D immunoglobulin after: potentially sensitising events birth, if the baby is confirmed to be D positive by cord blood typing.The BCSH guideline also states that RAADP should be given regardless of, and in addition to, any anti-D immunoglobulin that may have been given for a potentially sensitising event. ## Care for D‑negative pregnant women who are sensitised to D antigen The Royal College of Obstetricians and Gynaecologists' (RCOG) guidance on managing women with red cell antibodies during pregnancy recommends that all women who are D negative and are sensitised to D antigen should: attend pre-pregnancy counselling with a clinician who has knowledge and expertise in managing this condition have their blood group and antibody status determined at the booking appointment (ideally by 10 weeks of gestation) and at 28 weeks of gestation be offered non‑invasive fetal RHD genotyping using maternal blood if maternal anti‑D is present.The NIPT offered to D-negative women who are sensitised to D antigen is different to the high-throughput NIPT for fetal RHD genotype assessed in this diagnostics guidance, and has different diagnostic accuracy. The RCOG guideline and the BCSH guideline on blood grouping and antibody testing in pregnancy also recommend that if a D‑positive fetus is identified, additional monitoring and treatment are needed during the pregnancy, which should include: measuring D‑antibody levels every 4 weeks up to 28 weeks of gestation and then every 2 weeks until delivery referral to a fetal medicine specialist if D‑antibody levels are rising or are at a level above a specific threshold, or ultrasound features suggest fetal anaemia weekly monitoring by ultrasound if D‑antibody levels rise above a specific threshold fetal blood sampling if ultrasound shows signs of fetal anaemia, and considering intrauterine transfusion considering early delivery of the baby, depending on antibody levels and whether any fetal therapy has been needed using continuous electronic fetal heart monitoring during labour. After the baby is born, the RCOG guideline recommends that assessments should include: a direct antiglobulin test to detect maternal antibodies adhering to the baby's red blood cells confirmation of the baby's blood group (using a cord blood sample) haemoglobin level measurement to test for anaemia bilirubin level measurement to test for jaundice clinical assessment of the baby's neurobehavioural state and observations for jaundice and anaemia. The NICE guideline on jaundice in newborn babies under 28 days gives recommendations on diagnosing and treating jaundice.# The diagnostic tests The assessment compared 1 intervention test with 1 comparator test. # The intervention High-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype is a laboratory developed test offered by the International Blood Group Reference Laboratory, Bristol (NHS Blood and Transplant). The test uses a real-time quantitative polymerase chain reaction (PCR) method for identifying fetal RHD genotype from fetal DNA in the plasma of rhesus‑D (D) negative women. The test analyses cell-free fetal DNA, in the form of small fragments of fetal extracellular DNA shed from the placenta and circulating freely in the maternal plasma. The level of cell-free fetal DNA in maternal blood increases throughout the pregnancy and rapidly falls after delivery. Most women who are D negative do not have copies of the RHD gene; therefore, the presence of the RHD gene in a D‑negative pregnant woman suggests a D‑positive fetus. High-throughput NIPT is carried out using 4 ml to 6 ml of maternal anti-coagulated blood. DNA extraction is done using an automated robotic platform (MDx BioRobot, Qiagen), which can rapidly process samples. The robotic platform is also used as a liquid handler to dispense samples and reagents. PCR is then done on an ABI Prism 7900HT analyser (Applied Biosystems). Primers and probes for exons 5 and 7 of the RHD gene are used, and the following controls are tested alongside the samples: RHD positive DNA; RHD negative DNA; RHD pseudogene positive DNA; and no DNA. The samples can be tested in batches of between 32 and 88 samples. The time to complete the test from sample receipt to report generation is 5 to 6 hours. The exon 5 assay amplifies the RHD gene, whereas the exon 7 assay amplifies both the RHD gene and the RHD pseudogene. A threshold value of less than 42 cycles is interpreted as a positive signal and an algorithm is used to determine the fetal RHD genotype. Results are reported as 'D‑positive', 'D‑negative' or 'indeterminate – treat as D‑positive'. The result would influence whether to offer routine antenatal anti‑D prophylaxis and anti‑D immunoglobulin to D‑negative women, who are not sensitised to D antigen, after potentially sensitising events. # The comparator The comparator in the assessment was cord blood typing, which is used to determine the Rh blood group of a baby after birth.# Evidence The diagnostics advisory committee (section 8) considered evidence on high-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype from several sources (section 9). Full details of all the evidence are in the committee papers. # Clinical effectiveness ## Assessment of test accuracy Eight studies reported the diagnostic accuracy of high-throughput NIPT for fetal RHD genotype, all of which were prospective studies carried out in European countries. Four studies were done in England, 3 of which were based in Bristol. Cord blood typing was the reference standard in all studies. Six studies were considered to be at low risk of bias and 2 studies (Akolekar et al. 2011; Thurik et al. 2015) were judged to be at high risk of bias. Except for 2 studies (Akolekar et al. 2001; Wikman et al. 2012), the results of the studies were considered broadly applicable to using high-throughput NIPT for fetal RHD genotype for nationwide testing in the UK. It is expected that, in the UK, women with inconclusive NIPT results will be treated as having a positive test with no further testing. Data on inconclusive results were not reported in 2 studies (Thurik et al. 2015; Grande et al. 2013). So, 4 approaches to the diagnostic accuracy analysis were considered: women with inconclusive tests were treated as test positive (including Thurik et al. 2015 and Grande et al. 2013) women with inconclusive tests were treated as test positive (excluding Thurik et al. 2015 and Grande et al. 2013) excluding all women with inconclusive test results including only studies done in Bristol. Results of the hierarchical bivariate meta-analyses are shown in table 1. In all analyses, women in whom NIPT was carried out at or before 11 weeks' gestation were excluded because the test is known to be less accurate before 11 weeks. NIPT for fetal RHD genotype is very accurate among women with a rhesus‑D (D) positive fetus; only 2 to 4 in 1,000 such women will have a negative test result and so be at risk of sensitisation because they would not be offered antenatal anti‑D immunoglobulin. NIPT for fetal RHD genotype is slightly less accurate among women with a D‑negative fetus; between 13 and 57 in 1,000 such women will have a positive test result and so be offered antenatal anti‑D immunoglobulin unnecessarily. Analysis case Number of studies False-negative rate (at risk of sensitisation) estimate (% ) False-positive rate (unnecessary anti D) estimate (% ) Inconclusive treated as test positive (including Thurik et al. and Grande et al.) Inconclusive treated as test positive (excluding Thurik et al. and Grande et al.) Excluding all inconclusive test results Studies only done in Bristol Abbreviation: CI, confidence interval. The analysis of the 3 Bristol studies gave a slightly lower false-negative rate (0.21%; 95% confidence interval 0.09 to 0.48) and a higher false-positive rate (5.73%; 95% CI 4.58 to 7.16) than analyses including other studies. This suggests that the Bristol high-throughput NIPT approach may use a different test threshold compared with the testing done in other studies; minimising false-negative findings, with a consequent increase in the false-positive rate. There was considerable variation in rates of inconclusive tests across studies, ranging from 0.4% to 14.3%. The most likely causes for this variability are differences in how the NIPT was done (such as different numbers and types of exons considered) and differences in characteristics of study populations (for example, different proportions of women of black African family origin). Based on a meta-analysis, the average rate of inconclusive test results was estimated to be 4.0% (95% CI 1.5 to 10.3) if all studies reporting inconclusive results were included, and 6.7% (95% CI 3.7 to 11.7) if only the Bristol studies were included. An analysis of the effect of the timing of high-throughput NIPT for fetal RHD genotype on diagnostic accuracy suggested that false-negative rates were higher before 11 weeks' gestation, and thereafter false-negative rates were consistent, irrespective of timing. The effect of the timing of high-throughput NIPT on the number of inconclusive test results suggested that the percentage of inconclusive results drops as the gestational age increases from 11 weeks. ## Assessment of clinical outcomes Seven studies reported the clinical effectiveness of NIPT for fetal RHD genotype, all of which were observational and carried out in European countries. The sample size of the studies ranged from 284 to 15,126 and most participants were of white European family origin. Only 2 studies compared women having NIPT for fetal RHD genotype with controls (Tiblad et al. 2013; Banch Clausen et al. 2014). Tiblad et al. (2013) was considered to be at serious risk of bias, and Banch Clausen et al. (2014) was considered to be at critical risk of bias. The generalisability of these 2 studies to NHS clinical practice was limited because participants in the control group did not have routine antenatal anti‑D prophylaxis (RAADP). The other 5 studies only reported non-comparative-effectiveness data for women having NIPT for fetal RHD genotype. Data from these studies were supplemented with data from a UK audit on anti‑D immunoglobulin use (National comparative audit of blood transfusion: 2013 audit of anti-D immunoglobulin prophylaxis) for a comparison with current practice. Tiblad et al. (2013) compared targeted RAADP in the first trimester with routine care (postpartum anti‑D prophylaxis only) in Sweden. They reported the incidence of D sensitisation in the cohort that had high-throughput NIPT for fetal RHD genotype as 0.26% (95% CI 0.15 to 0.36%; n=8347) compared with 0.46% (95% CI 0.37 to 0.56%; n=18,546) in the historical control cohort. High-throughput NIPT for fetal RHD genotype was associated with a significant risk reduction in sensitisation (unadjusted risk ratio 0.55; 95% CI 0.35 to 0.87) compared with historical controls. An updated analysis reported in a linked conference abstract (Neovius et al. 2015) found an adjusted odds ratio of 0.41 (95% CI 0.22 to 0.87). Seven studies reported uptake rates of NIPT for fetal RHD genotype. Uptake rates ranged from 70% to more than 95% across the studies. In a pilot study done by Soothill et al. (2015) in 3 maternity services in the south-west of England, only 70% of eligible women joined the study in the first 6 months. The larger English study done by Chitty et al. (2014) reported that 88% of the 3,069 participants consented to have NIPT for fetal RHD genotype. The only country that reported nationwide uptake data was the Netherlands, where more than 95% of eligible women had NIPT for fetal RHD genotype. The studies generally noted that uptake is likely to increase over time if a nationwide screening programme is implemented. The uptake of RAADP in women who accepted NIPT and had a positive result was reported in 4 studies and ranged from 86.0% to 96.1%. Of the larger studies, Van der Ploeg et al. (2015) reported nationwide data on women having NIPT for fetal RHD genotype in the Netherlands, where 96.1% of about 18,383 women with a positive test result had RAADP. Tiblad et al. (2013) reported a slightly lower rate, with 90% of 5,104 women with a positive NIPT result having RAADP. Data on the uptake of RAADP in women who had a negative test result, those who had an inconclusive test result, and those who refused NIPT for fetal RHD genotype, were limited. None of the studies reported whether all the women who had RAADP had the intended dosage at the intended time, or what proportion of women had additional anti‑D immunoglobulin because of a potentially sensitising event. The uptake of postpartum anti‑D prophylaxis in women who accepted NIPT for fetal RHD genotype and had a positive test result was reported in 3 studies. Van der Ploeg et al. (2015) reported nationwide data on women having NIPT for fetal RHD genotype in the Netherlands, where 92% of about 18,383 women had postpartum anti‑D prophylaxis. A subgroup analysis by Banch Clausen et al. (2014) found slightly higher uptake of postpartum anti‑D prophylaxis among women who had NIPT (99.7%, 353/354) compared with those who did not have NIPT (95.7%, 66/69). Damkjaer et al. (2012) reported a similar rate among women who had NIPT (99.3%, 151/152). None of the included studies reported whether all women who had postpartum anti‑D prophylaxis had the intended dosage at the intended time. Outcome measures relating to anti‑D immunoglobulin administration were reported in 3 non‑comparative studies. Soothill et al. (2015) reported a significant 6% reduction per month in anti‑D immunoglobulin administration (95% CI 4 to 8) over a 6‑month period in 3 maternity services in the south west of England. The total use of anti‑D immunoglobulin fell by about 29%, corresponding to 35% of D‑negative women not having anti‑D immunoglobulin in their pregnancy unnecessarily. Similar results were also seen by Banch Clausen et al. (2014), who reported that 37.1% of women avoided unnecessary anti‑D immunoglobulin within 2 years of the introduction of a programme of NIPT for fetal RHD genotype. Grande et al. (2013) reported that, of 95 women carrying a D‑negative fetus, 5 women requested anti‑D immunoglobulin; so, unnecessary anti‑D immunoglobulin was avoided in 95% of women carrying a D‑negative fetus. To better understand the likely consequences of implementing NIPT for fetal RHD genotype and basing antenatal anti‑D immunoglobulin administration on its results, the external assessment group did a simulation study. The following assumptions were made: When needed, antenatal anti‑D immunoglobulin is offered at around 28 weeks. Postpartum anti‑D prophylaxis is offered based on the result of cord blood typing. Cord blood typing is 100% accurate. There are no adverse consequences of giving anti‑D immunoglobulin. The results of the simulation study, summarised in table 2, showed that using NIPT for fetal RHD genotype leads to a substantial reduction in RAADP use, from 99% of D‑negative women to 65.9%. This decline is similar in size to that seen by Soothill et al. (2015). The decrease is because of the drop (from 39% to 5.7%) in women with D‑negative fetuses needlessly having anti‑D immunoglobulin. Using NIPT for fetal RHD genotype means that about 1.2% of women miss having possibly beneficial RAADP, compared with 0.6% when using a universal RAADP approach with no testing. Outcome Treatment approach Proportion of women Antenatal anti‑D given Universal anti‑D Antenatal anti‑D given Based on NIPT Unnecessary anti‑D given (D‑negative fetus) Universal anti‑D Unnecessary anti‑D given (D‑negative fetus) Based on NIPT Anti‑D not given (D‑positive fetus) Universal anti‑D Anti‑D not given (D‑positive fetus) Based on NIPT Treatment approach Proportion of women Postpartum and emergency anti‑D only Universal anti‑D Based on NIPT with postpartum anti‑D Based on NIPT with no postpartum anti‑D for women who test negative Treatment approach Proportion of women Postpartum and emergency anti‑D only Universal anti‑D Based on NIPT with postpartum anti‑D based on cord blood typing Based on NIPT with no postpartum anti‑D for women testing negative Abbreviation: NIPT, non invasive prenatal testing. Assuming all women still have postpartum cord blood typing and postpartum anti‑D prophylaxis if needed, the simulation study showed that NIPT would result in about 3 extra sensitisations per 100,000 women. If cord blood typing is not done, there would be about 13 extra sensitisations per 100,000 women. These increases are small compared with the total number of sensitisations because of anti‑D immunoglobulin failure and non‑adherence to anti‑D immunoglobulin treatment (around 281 per 100,000 women), and compared with not using RAADP at all (around 641 per 100,000). Results of the simulation study also showed that using NIPT for fetal RHD genotype is unlikely to have any meaningful effect on mortality in later pregnancies; if women with a negative NIPT result never have postpartum anti‑D prophylaxis, there would be about 5 extra fetal or neonatal deaths per 1 million D‑negative women. In current practice, there are an estimated 86 fetal or neonatal deaths per 1 million D‑negative women. ## Assessment of implementation issues Twelve studies were identified in a review of implementation of NIPT for fetal RHD genotype. Most studies reported that NIPT for fetal RHD genotype was feasible. Several studies reported potential issues relating to implementation, such as adherence to the anti‑D prophylaxis programme. Some studies highlighted the importance of short transport times for samples and effective management of transporting samples. The need for greater awareness of NIPT among physicians and midwives was also identified in some studies. A UK-based survey (Oxenford et al. 2013) showed that, although most of the women surveyed supported the implementation of NIPT, their current knowledge of Rh blood groups and anti‑D treatment was limited, which could be a barrier to implementation. # Cost effectiveness ## Review of economic evidence Seven studies were identified in a review of existing studies on the cost effectiveness of high-throughput NIPT to determine fetal RHD genotype in pregnant women who are D negative and are not sensitised to the D antigen. The quality of the included studies' findings was uncertain because they did not report the validity of the diagnostic accuracy outcomes used. The degree of uncertainty in the cost-effectiveness estimates was also difficult to establish. Results across the existing economic studies were conflicting. Only 1 study found NIPT for targeting RAADP to be cost saving compared with non‑targeted RAADP. Two studies reported that NIPT for fetal RHD genotype was cost saving compared with no RAADP, that is, compared with postpartum anti‑D prophylaxis only. Three studies reported that NIPT for fetal RHD genotype was not cost effective or was of no economic benefit. Only 1 study directly related to the UK (Szczepura et al. 2011). ## Modelling approach The external assessment group developed a de novo economic model designed to assess the cost effectiveness of high-throughput NIPT to determine fetal RHD genotype in pregnant women who are D negative and are not sensitised to D antigen. A decision tree cohort approach was developed to estimate the costs and health outcomes with and without high-throughput NIPT for fetal RHD genotype. The treatment part of the model was based closely on the economic model used in the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative, developed by researchers at the School of Health and Related Research (ScHARR). In the model, a pregnant woman enters after being identified as D negative and not sensitised to D antigen, based on testing at first contact with the doctor or midwife, or at the booking appointment (at 8 to 12 weeks' gestation). The first part of the model divides the cohort according to fetal RHD genotype and treatment. This determines when having RAADP is appropriate, inappropriate, or unnecessary, and when avoidance of RAADP is potentially harmful. Test performance, adherence to high-throughput NIPT for fetal RHD genotype and RAADP, and the effectiveness of RAADP all inform the estimation of the probability of sensitisation. The second part of the model considers the short- and long-term consequences of sensitisations, such as fetal or neonatal death, and minor or major fetal development problems in later pregnancies. Four alternative ways (see table 3) that using high-throughput NIPT may affect the existing postpartum care pathway were considered: Postpartum scenario 1 (PP1): postpartum cord blood typing and fetomaternal haemorrhage testing would continue to be done, based on current guidelines, in all women regardless of the fetal RHD genotype identified with high-throughput NIPT. Postpartum scenario 2 (PP2): postpartum cord blood typing and fetomaternal haemorrhage testing (and by implication anti‑D immunoglobulin) would be withheld if high-throughput NIPT for fetal RHD genotype identified a D‑negative fetus, but would continue to be done if high-throughput NIPT was inconclusive or had identified a D‑positive fetus. Postpartum scenario 3 (PP3): postpartum cord blood typing would be done if high-throughput NIPT for fetal RHD genotype identified a D‑negative fetus. Fetomaternal haemorrhage testing and post-delivery anti‑D immunoglobulin would be provided if high-throughput NIPT was inconclusive or identified a D‑positive fetus. Postpartum scenario 4 (PP4): postpartum cord blood typing would not be carried out in any women. Fetomaternal haemorrhage testing and post-delivery anti‑D immunoglobulin would be provided if high-throughput NIPT was inconclusive or had identified a D‑positive fetus. Scenario High-throughput NIPT result Cord blood typing FMH testing Postpartum anti‑D Postpartum scenario 1 Any Yes Yes if CBT+ As guided by CBT and FMH testing Postpartum scenario 2 Negative No No No Postpartum scenario 2 Positive or inconclusive Yes Yes if CBT+ As guided by CBT and FMH testing Postpartum scenario 3 Negative Yes Yes if CBT+ As guided by CBT and FMH testing Postpartum scenario 3 Positive or inconclusive No Yes Yes with additional dose per FMH test Postpartum scenario 4 Negative No No No Postpartum scenario 4 Positive or inconclusive No Yes Yes with additional dose per FMH test Abbreviations: CBT, cord blood typing; NIPT, non invasive prenatal testing; FMH, fetomaternal haemorrhage; +, positive. The annual number of pregnancies in D‑negative women in England was estimated to be 99,225. This represents a cross section of all pregnancies, and the proportions of first, second, third and later pregnancies are used to characterise the total fertility rate of a typical D‑negative woman. This estimate was based on a birth rate of 12.2 per 1,000 women per year and assumes that 15% of the population is D negative. The proportion of D‑positive babies born to women who are D negative was estimated as 61.6%. This rate was applied across all pregnancies, that is, the first and later pregnancies. The diagnostic accuracy of high-throughput NIPT for fetal RHD genotype and the proportion of inconclusive results were based on the meta-analyses done in the clinical-effectiveness assessment. The base case used the pooled results for the subgroup of UK (Bristol-based) studies in which inconclusive results were considered as test positive. These studies were considered the most relevant to NHS clinical practice. Sensitivity was 0.998 (95% CI 0.992 to 0.999), specificity was 0.942 (95% CI 0.920 to 0.959) and the rate of inconclusive results was 6.7%. For consistency, this diagnostics assessment used the clinical effectiveness of RAADP that was established in the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative. Evidence for the clinical effectiveness of postpartum anti‑D prophylaxis was taken from a Cochrane review (Crowther et al. 1997). The clinical-effectiveness estimates are presented in table 4. Outcome NICE guidance on routine antenatal anti‑D prophylaxis for women who are rhesus D negative Crowther et al. (1997; sensitisation 6 months after delivery) Odds ratio: sensitisation with RAADP (compared with no RAADP, conditional on having postpartum anti‑D prophylaxis) (95% CI) (0.21 to 0.65) Odds ratio: sensitisation at birth, follow-up up to 6 months, with postpartum anti‑D prophylaxis (compared with no postpartum anti‑D prophylaxis, conditional on no RAADP) (95% CI) (0.06 to 0.11) Sensitisation rate without RAADP (conditional on having postpartum anti‑D prophylaxis) (95% CI) (0.18 to 1.71) (0.18 to 1.71) Baseline sensitisation rate of no RAADP assumed the same Sensitisation rate with RAADP (95% CI) (0.29 to 0.40) Sensitisation rate without RAADP and without postpartum anti‑D prophylaxis (95% CI) (8.0 to 13.8) Abbreviations: CI, confidence interval; RAADP, routine antenatal anti‑D prophylaxis. The number of potentially sensitising events was taken from the recent UK audit on anti‑D immunoglobulin use (National comparative audit of blood transfusion: 2013 audit of anti-D immunoglobulin prophylaxis). The probability of women having at least 1 (reported) potentially sensitising event was estimated as 15.5%. Of these, 69.3% were estimated to have had a fetomaternal haemorrhage test and 95.8% were estimated to have had anti‑D immunoglobulin after the event. It was estimated that about 80% of these events happened after 20 weeks' gestation, and it was assumed that these events were treated with the minimum required dose of 500 IU anti‑D immunoglobulin. For the remaining 20% of events (before 20 weeks' gestation), it was assumed that women had the minimum required dose of 250 IU anti‑D immunoglobulin. The National comparative audit of blood transfusion: 2013 audit of anti‑D immunoglobulin prophylaxis was used to provide estimates of adherence to RAADP. It reported that, out of all eligible women: 99% had at least 1 RAADP injection; full adherence (that is the correct dose at the correct time) was better with the single-dose regimen (90%) compared with the 2‑dose regimen (59%); 98.4% had postpartum anti‑D prophylaxis; and 96% had anti‑D immunoglobulin for documented potentially sensitising events. Within the economic model, it was assumed that adherence to RAADP was 99.0% and that adherence to postpartum anti‑D prophylaxis was 98.4%. There was limited evidence on adherence to NIPT for fetal RHD genotype, so it was assumed that using NIPT has no additional effect on adherence to anti‑D prophylaxis. The effects of sensitisation on later pregnancies were taken from Finning et al. (2008) and the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative. The proportion of fetal or neonatal deaths was estimated to be 5%; and the proportion of babies affected with minor or major developmental problems was estimated to be 6% or 5% respectively. Minor developmental problems were estimated to last 16 years and the life expectancy for a person with major developmental problems was estimated to be 59.5 years. The estimated cost of high-throughput NIPT for fetal RHD genotype included consumables, staffing, equipment, and indirect and overhead costs. The estimated cost was based on testing at full capacity, that is, dealing with at least 100,000 samples per year. The unit cost per sample may vary, because it is a function of capacity and the annual predicted level of usage of each testing machine. Also, a royalty fee is under negotiation and will need to be added to the cost of the test. The cost of high-throughput NIPT for fetal RHD genotype remains commercial in confidence at the time of writing this diagnostics guidance. The cost of anti‑D immunoglobulin was taken from the British national formulary. Currently 2 brands (D‑Gam and Rhophylac) and 4 doses (250-, 500-, 1,500- and 2,500‑unit vials) are available. Weighted averages based on recommended dose regimens and market share were calculated. The estimated costs were: £31.69 for anti‑D immunoglobulin for potentially sensitising events; £41.58 for RAADP; and £35.69 for postpartum anti‑D prophylaxis. The cost of giving anti‑D immunoglobulin was set to £5. In current practice, cord blood typing is done to confirm the baby's Rh blood group, and maternal blood samples are tested for fetomaternal haemorrhage after birth. The costs, updated to 2015 prices, for cord blood typing (£4.18) and associated phlebotomy (£3.32) were taken from Szczepura et al. (2011). The cost of fetomaternal haemorrhage testing by flow cytometry was estimated to be £128.10. The relevant interventions for maternal and neonatal sensitisation were taken from the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative. Unit costs were taken from the NHS reference costs 2014/15. This resulted in an estimated average total cost per sensitisation of £3,167. The estimated annual costs for minor (£111) and major (£574) development problems were also assumed to be the same as in the NICE technology appraisal guidance (updated to 2015 prices). The following utilities were assumed in the model: minor developmental problems, 0.85; major developmental problems, 0.42; and general population, 0.88. These values are the same as those used in the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus negative. ## Base-case results Key assumptions made in the model were: Sensitisations do not affect the pregnancy in which they occur. Anti‑D immunoglobulin used within 1 pregnancy has no effect in reducing sensitisations during the next pregnancy. The proportion of D‑negative women is based on estimates from people of white European family origin. The proportion of D‑positive babies born to D‑negative women is assumed to be the same irrespective of pregnancy number. The number of D‑positive babies in the model is determined by combining the probability, in the general population of D‑negative women, of having a D‑positive baby (61.6%) with the sensitivity and specificity of NIPT (in which inconclusive results are treated as test positive). The probability of having a D‑positive baby in women with inconclusive test results is based on the pooled probability in the study populations used to inform the diagnostic accuracy estimate. All NIPT is assumed to be done early enough to determine the need for RAADP at 28 weeks' gestation. RAADP is only offered to women in whom the NIPT result indicates that their fetus is D positive or in whom the results are inconclusive. Women with an inconclusive NIPT result are treated the same as women who test positive in terms of RAADP, and tests and treatment after potentially sensitising events. Women offered RAADP will also be offered supplementary anti‑D immunoglobulin at the minimum dose needed for any potentially sensitising events. Potentially sensitising events that involve fetal death are assumed to be independent of previous sensitisation within the same pregnancy. Women with false-negative test results indicated by cord blood typing and who have postpartum anti‑D prophylaxis are assumed to have a sensitisation rate of 0.95%. Adherence to RAADP is assumed to be the same with and without NIPT; similarly, adherence to postpartum anti‑D prophylaxis is assumed to be the same with or without NIPT. There are no adverse health effects from using anti‑D immunoglobulin. Results show that all NIPT strategies cost less, but are less effective than the comparator, current clinical practice (table 5). Strategies PP1 and PP3 are associated with smaller quality-adjusted life year (QALY) losses than PP2 and PP4. This is because in both PP1 and PP3, cord blood typing is used to identify false-negative results, which would allow women who had been incorrectly identified as having a D‑negative baby, and so had not been offered RAADP, to have postpartum anti‑D prophylaxis. This would reduce the number of sensitisations, therefore reducing QALY losses. Strategies Total costs Total QALYs Incremental costs Incremental QALYs ICER (£ saved/ QALY lost) No test and RAADP (current practice) N/A N/A N/A Postpartum scenario 1 versus no test and RAADP Postpartum scenario 2 versus no test and RAADP Postpartum scenario 3 versus no test and RAADP Postpartum scenario 4 versus no test and RAADP Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; RAADP, routine antenatal anti D prophylaxis. The variations in costs between the 4 strategies were mainly driven by different postpartum testing costs and postpartum anti‑D prophylaxis costs. The added cost of managing sensitisations and their associated health consequences in later pregnancies was largest for the strategies with more sensitisations (PP2 and PP4), and was very small for strategies PP1 and PP3. In the fully incremental analysis of NIPT for fetal RHD genotype for the different postpartum testing strategies, PP3 and PP4 were dominated. Strategy PP4 was dominated by strategy PP2 because it had the same number of QALYs but was more expensive than PP2. Strategy PP3 was dominated by strategy PP1 because it had the same number of QALYs but was more expensive than PP1. The cost-effectiveness acceptability curve showed that PP1 had the highest probability of being cost effective, with 0.65 and 0.73 for maximum acceptable incremental cost-effectiveness ratio (ICER) values of £20,000 and £30,000 per QALY gained respectively. For the same maximum acceptable ICER values, the probability of PP2 being cost effective was 0.30 and 0.22 respectively. ## Sensitivity and scenario analyses Sensitivity analyses showed that the results of the economic model are robust to small changes in the clinical effectiveness of RAADP, the timing of testing (between 11 and 23 weeks) and adherence to anti‑D immunoglobulin treatment. A sensitivity analysis was done on the diagnostic accuracy of NIPT. When the diagnostic accuracy of NIPT was based on the meta-analysis of all studies rather than the Bristol studies alone, specificity increased by 2%, sensitivity decreased by 0.2%, the total cost across all NIPT strategies reduced, but total QALYs were only marginally affected. PP1 and PP3 remained the most cost-effective strategies. In a sensitivity analysis on the rates of inconclusive results, NIPT became less cost effective as the rate of inconclusive results increased, but strategies PP1 and PP3 always remained more cost effective than current practice. When the rate of inconclusive results was low, PP3 became the most cost-effective strategy. When the rate of inconclusive results was high, PP1 became the most cost-effective strategy. A 2‑way sensitivity analysis was done on test and treatment costs. The unit cost of NIPT is subject to uncertainty because it depends on throughput (the annual total number of samples analysed) and the level of the royalty fee. Similarly, the cost of anti‑D immunoglobulin may differ from the list price depending on negotiated discounts. The results of a 2‑way analysis on these unit costs showed that the base case is very sensitive to both the price of NIPT and the price of anti‑D immunoglobulin. A small increase in price of high-throughput NIPT or a small fall in the price of anti‑D immunoglobulin would result in current practice becoming more cost effective than NIPT strategies. The cost of high-throughput NIPT for fetal RHD genotype was uncertain when this diagnostics guidance was written because it is highly dependent on the number of tests processed. The external assessment group did a threshold analysis to identify the point at which the test would move from being considered cost effective to being considered not cost effective, using a maximum acceptable ICER of £20,000 per QALY gained. Results show that raising the cost for high-throughput NIPT to £24.64 or more would result in current practice becoming more cost effective than NIPT strategies. A sensitivity analysis was done on the cost of fetomaternal haemorrhage testing. Reducing the cost of a fetomaternal haemorrhage test to £3.17 (Szczepura et al. 2011; updated to 2015 prices) halved the estimated total costs of all strategies when compared with the total costs of the base-case scenarios, with total QALYs remaining similar to base-case results. When the cost of fetomaternal haemorrhage test was reduced, PP2 and PP4 became less cost effective than current practice, whereas PP1 and PP3 remained more cost effective compared with current practice. An alternative postpartum-testing strategy to those included in the scope was assessed. The strategy separated women in whom NIPT identified a D‑positive fetus from women in whom NIPT gave an inconclusive result (and were therefore treated as if the fetus was D‑positive). Cord blood typing was done for women identified as having either a D‑negative fetus by NIPT or who had an inconclusive NIPT result, but not done for women in whom NIPT indicated a D‑positive fetus, and resulted in total costs of £15,230,372 and £2,433,756 QALYs per 100,000 pregnancies. This postpartum approach dominated all other NIPT strategies, and the ICER for this strategy compared with current practice was £1,638,356 saved per QALY lost.# Committee discussion # Current practice The committee considered the current standard of care offered to pregnant women who are rhesus‑D (D) negative. It heard from clinical experts on the committee that current care for women who are not sensitised to the D antigen involves routine antenatal anti‑D prophylaxis, additional doses of anti‑D immunoglobulin if a woman has a potentially sensitising event, and postpartum testing of cord blood and anti‑D prophylaxis if cord blood typing shows the baby to be D positive. The committee noted that introducing these methods for preventing sensitisation of women to the D antigen has dramatically reduced the number of sensitisations and the rates of haemolytic disease of the fetus and newborn over the last 40 years. The committee also heard from a clinical expert that there are effective treatments for D‑negative women who are sensitised to D antigen, which means that deaths from severe haemolytic disease of the fetus and newborn are very rare. The committee considered whether there were any problems with the current care offered to pregnant women who are D negative and not sensitised to the D antigen. It heard from a clinical expert that errors do sometimes occur, for example, a small number of women at risk of sensitisation do not have anti‑D immunoglobulin, or do not receive the correct dose of anti‑D immunoglobulin at the correct time. The committee also heard from a clinical expert that many sensitisations result from clinically silent fetomaternal haemorrhage events – potentially sensitising events without a known cause or clinical symptoms. The committee further heard that cord blood typing to determine the Rh blood group of the baby after birth may be affected by errors, such as sampling the blood of the mother instead of the baby, or incorrect sample labelling. The committee concluded that although anti‑D prophylaxis is very effective for reducing sensitisations and therefore haemolytic disease of the fetus and newborn, it is not perfect because sensitisations do still happen. The committee considered the possible disadvantages of using anti‑D immunoglobulin. It heard from experts that there have previously been shortages of supply because it is a blood product and therefore a finite resource. The committee also considered the potential future risks from unknown prions or pathogens associated with using a blood product such as anti‑D immunoglobulin. The committee concluded that it would be beneficial to conserve supplies by only using anti‑D immunoglobulin for those in whom it is necessary. The committee heard from a patient expert that for some women, having anti‑D immunoglobulin may not be acceptable for personal, cultural or religious reasons. It noted that using high-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype would allow women whose fetus was identified as D negative to avoid having unnecessary anti‑D immunoglobulin, while women identified as having a D‑positive fetus would be able to make an informed decision about whether to have anti‑D immunoglobulin. # Clinical effectiveness The committee considered the diagnostic performance of high-throughput NIPT for fetal RHD genotype. It noted that good-quality evidence was available and that the test is accurate after 11 weeks of gestation. The committee then considered how the diagnostic accuracy of the test affected clinical effectiveness. It noted that there is a small increase in the false-negative rate for high-throughput NIPT to determine fetal RHD genotype (0.21%; 95% CI 0.09 to 0.48), compared with the current practice of postpartum cord blood typing. This means that some women with a D‑positive fetus would be incorrectly identified as having a D‑negative fetus and would not be offered routine antenatal anti‑D prophylaxis (RAADP) or anti‑D immunoglobulin after potentially sensitising events. Because of this, more women could become sensitised to the D antigen and may have complications in later pregnancies, although the committee heard from a clinical expert that the severity of these complications is hard to predict. The committee noted that the rate of sensitisations with current practice was estimated to be 281 per 100,000 D‑negative pregnancies. If offering RAADP and anti‑D immunoglobulin after potentially sensitising events was based on the results from NIPT for fetal RHD genotype, the rate of sensitisations would increase by 3, to 284 sensitisations per 100,000 D‑negative pregnancies. The committee considered that this relatively small increase in the number of sensitisations could be accepted in the context of other potential benefits of NIPT associated with avoiding unnecessary treatment with blood products. The committee considered the results of the economic model. It noted that the quality-adjusted life year (QALY) losses in the model were 0.46 per 100,000 pregnancies if the postpartum testing strategy stayed the same as current practice (cord blood typing for all D‑negative women regardless of the NIPT result). The committee noted that although this is a reduction in clinical effectiveness compared with current practice, the reduction is extremely small (0.0000046 QALYs per pregnancy). The committee therefore concluded that the clinical effectiveness of using high-throughput NIPT for fetal RHD genotype to guide antenatal anti‑D prophylaxis is comparable with offering antenatal anti‑D prophylaxis to all D‑negative women, provided that there are no changes to postpartum practice. # Cost effectiveness The committee considered the cost savings in the economic model. It noted that cost savings in the models were £583,538 per 100,000 pregnancies in D‑negative women if the postpartum testing strategy stayed the same as current practice (cord blood typing for all D‑negative women regardless of the NIPT result, referred to as postpartum scenario 1 in the economic analysis). The committee noted that the cost savings are relatively small, at £5.84 per pregnancy, and on their own might not justify the risks that could be associated with making substantial changes to current practice. The committee then considered the base-case incremental cost-effectiveness ratio (ICER) for PP1. It noted that although the ICER appears to be large, at £1,269,100 saved for each QALY lost, it is very sensitive to changes in the numerator (change in cost) or denominator (change in QALYs), and is therefore subject to substantial uncertainty. The committee concluded that the total costs for using high-throughput NIPT for fetal RHD genotype to guide antenatal anti‑D prophylaxis are not substantially different from the total costs for the current practice of offering antenatal anti‑D prophylaxis to all D‑negative women, provided that there are no changes to postpartum practice. The committee considered the different postpartum testing strategies presented in the diagnostics assessment report (see section 4.24). It noted that in the base-case analysis, NIPT using PP1 was the most cost-effective strategy compared with current practice. The committee heard from clinical experts that the postpartum care in PP1 is the same as used in current clinical practice. It also noted that with different assumptions on postpartum testing, other postpartum scenarios could be associated with greater cost savings, but increased QALY losses compared with PP1. The committee concluded that it is preferable to minimise the QALY losses. The committee considered the results of a scenario analysis that made different assumptions on postpartum testing (PP5). It noted that this postpartum scenario was associated with greater cost savings and equivalent QALY losses compared with PP1. The committee heard from clinical experts that postpartum testing involves taking a cord blood sample soon after the birth, and that although midwives are used to doing this they also have multiple other tasks to complete at this time. The committee was concerned that if midwives had to get the NIPT result and then make a decision on whether to take a cord blood sample in the period immediately after the delivery, errors could be made, for example, not taking a cord blood sample from a fetus predicted to be D negative. The committee concluded that although alternative postpartum strategies may potentially have greater cost savings, they would be complicated to implement in clinical practice and may result in errors, which could affect costs and clinical effectiveness. The committee also discussed an alternative approach in which cord blood samples would be taken from all babies born to D‑negative women and the laboratory would then decide whether to test the cord blood sample. The committee concluded that the postpartum testing of cord blood should not be changed from current practice. This is because without cord blood typing, false-negative NIPT results would not be identified and women with false-negative NIPT results would not have postpartum anti‑D prophylaxis. The committee noted the difficulties of taking a blood sample from the cord and that the consequences of a sampling error may include having to take repeat blood samples from a neonate. It decided that further research on the practicalities of implementing alternative postpartum testing strategies would be valuable (see section 6.2). The committee discussed the input used in the model for the cost of care of a pregnant woman who has been sensitised to the D antigen in an earlier pregnancy. It heard from a clinical expert that some women who are sensitised to the D antigen will be identified as having a D‑negative fetus, and others will be identified as having a D‑positive fetus, but will not experience problems during their pregnancy. These 2 groups of women would not need many extra appointments with a specialist obstetrician. A third group of sensitised women will be identified as having a D‑positive fetus and will experience problems during their pregnancy. These women will need more frequent surveillance and treatment for the baby before and after the birth. The committee concluded that if a weighted average is taken of the cost of care for these 3 groups of pregnant women, then an input of £3,167 per sensitised pregnancy is reasonable. The committee considered the cost of the test that was used in the economic model and noted that the cost did not include sample transport. It heard from the current provider of the test, the International Blood Group Reference Laboratory (IBGRL), that blood samples are transported around the country to their laboratory on a daily basis using the NHS Blood and Transplant (NHSBT) transport network. It heard further, that because of this established transport network, there should be no cost for sample transport. The committee was concerned that although there may be no cost for sample transport between the NHSBT units and the IBGRL, there may be a cost for transporting the sample from the maternity clinic to the NHSBT unit. It was also concerned about the length of time it may take to transport samples from rural areas to the IBGRL, and that longer sample transport times may result in increased rates of failed tests. The committee also heard from the IBGRL that the unit cost of the test depends on the expected annual sample throughput and on a royalty fee, which is currently under negotiation. The committee concluded that the test cost is uncertain. The committee considered whether there were any costs associated with implementing high-throughput NIPT for fetal RHD genotype that had not been included in the economic model. It noted that extra time to explain the test, take the blood sample, give the test results, and provide counselling, that could result in extra midwife appointments, were not included in the model. The committee heard from a clinical expert that in the south-west of England where high-throughput NIPT for fetal RHD genotype has been implemented, the blood sample for the test is normally taken at the routine 16‑week antenatal appointment; therefore, no additional appointments are needed. It also heard from the clinical expert that the main issue when implementing the test was educating midwives and other healthcare professionals so they understood the test and could explain it to women and their families. It noted that a patient information leaflet explaining the test and its results is available from NHSBT. The committee heard from the external assessment group that none of the studies in the review of implementation, included costs associated with implementation. The committee concluded that the costs associated with implementing high-throughput NIPT for fetal RHD genotype were uncertain. The committee considered a threshold analysis done by the external assessment group on the unit cost of the test. It noted that results show that the cost effectiveness of high-throughput NIPT for fetal RHD genotype is sensitive to small increases in costs associated with doing the test, for example, sample transport, the need for repeat tests, midwife time, or the cost of the test itself. The committee also noted that increasing the test cost to £24.64 or more per test would result in high-throughput NIPT for fetal RHD genotype no longer being cost effective compared with current practice, using a maximum acceptable ICER of £20,000 per QALY gained. The committee concluded that high-throughput NIPT for fetal RHD genotype has the potential to be cost effective, but that the cost savings are volatile with respect to the cost of the test (see section 5.11) and the costs associated with implementation (see section 5.12). The committee also concluded that the overall cost of testing below which high-throughput NIPT for fetal RHD genotype can be considered cost effective should not be stated to 2 decimal places in the recommendation. This is because there is substantial uncertainty about the results of the model. The committee decided that £24.64 should be rounded down to £24 rather than up to £25 to increase the chance of high-throughput NIPT for fetal RHD genotype being cost effective. # Other considerations The committee noted its conclusions on the comparable clinical effectiveness of high-throughput NIPT for fetal RHD genotype and current practice (see section 5.6), and the uncertainty about cost savings (see section 5.13). The committee also noted its conclusion that it would be beneficial to avoid inappropriate use of anti‑D immunoglobulin (see section 5.3). The committee decided that although the cost savings are potentially small, recommending high-throughput NIPT for fetal RHD genotype would be an effective way of reducing unnecessary use of anti‑D immunoglobulin, and that this reduction could affect a large number of women. The committee considered the effect that ethnicity has on NIPT results. They heard from the provider of the test, IBGRL, that D‑negative women of black African family origin are more likely to have an RHD pseudogene, and so are more likely to have an inconclusive or false-positive NIPT result compared with women from other ethnic family origins. The committee noted that women with an inconclusive or false-positive NIPT result would be offered antenatal anti‑D prophylaxis (that is, they would have the same care as they would have in current practice), and so would not be at a greater risk of sensitisation to the D antigen than women from other ethnic family origins. It noted further that although unnecessary anti‑D immunoglobulin use would be reduced in women of black African family origin, these women would be more likely to have unnecessary anti‑D immunoglobulin than women of white European family origin. The committee concluded that this is a proportionate means of achieving a reduction in anti‑D immunoglobulin use in the population as a whole. The committee considered the current level of interest in high-throughput NIPT for fetal RHD genotype. It heard from a clinical expert that there have been many enquiries about the test from healthcare professionals and women who would like to have the test but do not live in an area where it has been implemented. It also heard from another clinical expert that the level of knowledge and understanding of NIPT is growing because of the publicity around NIPT for Down's syndrome and other aneuploidies. The committee concluded that based on the current level of interest, the timing was right for making a recommendation of high-throughput NIPT for fetal RHD genotype, but noted that additional data collection from areas beginning to implement the test would help confirm the cost of implementing the test given the uncertainty about this.# Recommendation for further research Data collection and analysis of the costs and resource use associated with implementing high-throughput non‑invasive prenatal testing for fetal RHD genotype is recommended to show the overall cost of testing and to inform any future update of the guidance. This may include costs and resource use associated with: training for healthcare professionals explaining the test to women and their families test failures blood sampling, giving results and counselling when needed sample transport and management record keeping adherence to high-throughput non‑invasive prenatal testing and antenatal anti‑D prophylaxis. Further research is recommended on alternative postpartum testing strategies that do not include cord blood typing of all babies born to rhesus‑D (D) negative women. This may include: an audit of D results from cord blood typing compared with results from high-throughput NIPT for fetal RHD genotype research on the practicalities of implementing alternative postpartum testing strategies.	{'Recommendations': 'High-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype is recommended as a cost-effective option to guide antenatal prophylaxis with anti‑D immunoglobulin, provided that the overall cost of testing is £24 or less. This will help reduce unnecessary use of a blood product in pregnant women, and conserve supplies by only using anti‑D immunoglobulin for those who need it.\n\nCost savings associated with high-throughput NIPT for fetal RHD genotype are sensitive to the unit cost of the test, additional pathway costs and implementation costs. Trusts adopting NIPT should collect and monitor the costs and resource use associated with implementing testing to ensure that cost savings are achieved (see section\xa06.1).', 'Clinical need and practice': "# The problem addressed\n\nNICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative recommends anti‑D immunoglobulin for all rhesus‑D (D) negative pregnant women who are not known to be sensitised to the D\xa0antigen, to reduce the risk of sensitisation. The British Committee for Standards in Haematology (BCSH) guideline on anti-D immunoglobulin to prevent haemolytic disease of the fetus and newborn also recommends that all D‑negative pregnant women who are not known to be sensitised to D\xa0antigen have anti‑D immunoglobulin after:\n\npotentially sensitising events\n\nbirth, if the baby is confirmed to be D\xa0positive by cord blood typing.\n\nAnti‑D immunoglobulin is produced from the pooled plasma donated by large numbers of D‑negative people who have had a transfusion of D‑positive red cells to stimulate the production of D\xa0antibodies. It is a finite resource and, because there have been shortages in the past, it needs to be used carefully to maintain stocks. Anti‑D immunoglobulin is a blood product and may also carry the risks common to all blood products, including physiological reactions, processing errors and the potential future risk of unknown blood-borne viruses or prion diseases. Physiological reactions must be reported to the Medicines and Healthcare products Regulatory Agency and processing errors to the Serious Hazards of Transfusion Scheme.\n\nHigh-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype involves analysing cell-free fetal DNA in maternal blood and is intended for use in pregnant women who are D\xa0negative and are not sensitised to D\xa0antigen. It is a laboratory-developed test offered by the International Blood Group Reference Laboratory, Bristol. This laboratory is an accredited NHS Blood and Transplant Laboratory that is currently providing NIPT for RHD genotype for some NHS patients.\n\nHigh-throughput NIPT for fetal RHD genotype would allow D‑negative women who are carrying a D‑negative fetus to avoid unnecessary treatment with anti‑D immunoglobulin.\n\nHigh-throughput NIPT for fetal RHD genotype would allow D‑negative women to make an informed choice about whether to have treatment with anti‑D immunoglobulin. This may improve adherence to anti‑D immunoglobulin treatment, reduce the number of sensitisations and so reduce haemolytic disease of the fetus and newborn in later pregnancies.\n\n# The condition\n\nDuring pregnancy, small amounts of fetal blood can enter the maternal circulation (an event called fetomaternal haemorrhage). The presence of fetal D‑positive cells in the maternal circulation, after fetomaternal haemorrhage, can cause a mother who is D\xa0negative to produce antibodies against the D\xa0antigen on the fetal blood cells (anti‑D) – a process called sensitisation. Sensitisation can happen at any time during pregnancy, but is most common during the third trimester and delivery. It can follow events in pregnancy known to be associated with fetomaternal haemorrhage, such as medical interventions, terminations, late miscarriages, antepartum haemorrhage and abdominal trauma. These are called potentially sensitising events.\n\nThe process of sensitisation has no adverse health effects for the mother and usually does not affect the pregnancy during which it occurs. However, if the mother is exposed to the D\xa0antigen from a D‑positive fetus during a later pregnancy, the immune response is quicker and much greater. The anti‑D produced by the mother can cross the placenta and cause haemolytic disease of the fetus and newborn. This can cause severe fetal anaemia, leading to fetal heart failure, fluid retention and swelling (hydrops), and intrauterine death.\n\nThe risk of sensitisation can be reduced if D‑negative pregnant women have anti‑D immunoglobulin. Before anti‑D immunoglobulin was available, the incidence of sensitisation in D‑negative women after the birth of 2\xa0D‑positive babies was about 16%. Haemolytic disease of the fetus and newborn, which occurred in about 1% of all births, was a significant cause of morbidity and mortality. After routine postpartum anti‑D prophylaxis was introduced, the incidence of D\xa0sensitisation dropped to about 2%. The sensitisation rate has further reduced since the introduction of routine antenatal anti‑D prophylaxis.\n\nIn England, there were 646,904\xa0births from April 2013 to March 2014, of which about 15% (97,036\xa0births) were to D‑negative women. About 40% of these women carry a D‑negative fetus (around 39,000 per year) and so do not need to have anti‑D immunoglobulin. D‑negative status occurs in about 15% of people of white European family origin, about 3% to 5% of people of black African family origin, and is very rare in people of eastern Asian origin. Most D‑negative people of white European family origin have an RHD gene deletion; less than 1% have RHD gene variants. However, in D‑negative people of black African family origin, 66% have an inactive RHD gene (the RHD pseudogene), which mostly results from genes that contain D\xa0sequences but do not produce D\xa0antigen.\n\n# The diagnostic and care pathways\n\n## Care for D‑negative pregnant women who are not sensitised to D\xa0antigen\n\nIn current practice, babies born to women who are D\xa0negative and not sensitised to D\xa0antigen have their Rh\xa0blood group determined after birth, using cord blood typing. Testing to find out the RHD genotype of the fetus during pregnancy is not currently done in most centres in the NHS.\n\nThe NICE guideline on antenatal care and the BCSH guideline on blood grouping and antibody testing in pregnancy recommend that women should be offered testing for ABO and Rh\xa0blood group in early pregnancy. All women identified as D‑negative would be tested for the presence of D\xa0antibodies, regardless of whether they are known to be sensitised or not. To prevent sensitisation in women identified as D‑negative but without D\xa0antibodies, anti‑D immunoglobulin is recommended, both as prophylaxis and after potentially sensitising events.\n\nThe NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative recommends routine antenatal anti‑D prophylaxis (RAADP) as a treatment option for all pregnant women who are D\xa0negative and who are not known to be sensitised to the D\xa0antigen. RAADP can be given as 2\xa0doses at weeks\xa028 and\xa034 of pregnancy, or as a single dose between 28\xa0and 30\xa0weeks.\n\nThe guideline from the BCSH on using anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn recommends that all D‑negative pregnant women, who are not known to be sensitised to D\xa0antigen, have anti‑D immunoglobulin after:\n\npotentially sensitising events\n\nbirth, if the baby is confirmed to be D\xa0positive by cord blood typing.The BCSH guideline also states that RAADP should be given regardless of, and in addition to, any anti-D immunoglobulin that may have been given for a potentially sensitising event.\n\n## Care for D‑negative pregnant women who are sensitised to D\xa0antigen\n\nThe Royal College of Obstetricians and Gynaecologists' (RCOG) guidance on managing women with red cell antibodies during pregnancy recommends that all women who are D\xa0negative and are sensitised to D\xa0antigen should:\n\nattend pre-pregnancy counselling with a clinician who has knowledge and expertise in managing this condition\n\nhave their blood group and antibody status determined at the booking appointment (ideally by 10\xa0weeks of gestation) and at 28\xa0weeks of gestation\n\nbe offered non‑invasive fetal RHD genotyping using maternal blood if maternal anti‑D is present.The NIPT offered to D-negative women who are sensitised to D antigen is different to the high-throughput NIPT for fetal RHD genotype assessed in this diagnostics guidance, and has different diagnostic accuracy.\n\nThe RCOG guideline and the BCSH guideline on blood grouping and antibody testing in pregnancy also recommend that if a D‑positive fetus is identified, additional monitoring and treatment are needed during the pregnancy, which should include:\n\nmeasuring D‑antibody levels every 4\xa0weeks up to 28\xa0weeks of gestation and then every 2\xa0weeks until delivery\n\nreferral to a fetal medicine specialist if D‑antibody levels are rising or are at a level above a specific threshold, or ultrasound features suggest fetal anaemia\n\nweekly monitoring by ultrasound if D‑antibody levels rise above a specific threshold\n\nfetal blood sampling if ultrasound shows signs of fetal anaemia, and considering intrauterine transfusion\n\nconsidering early delivery of the baby, depending on antibody levels and whether any fetal therapy has been needed\n\nusing continuous electronic fetal heart monitoring during labour.\n\nAfter the baby is born, the RCOG guideline recommends that assessments should include:\n\na direct antiglobulin test to detect maternal antibodies adhering to the baby's red blood cells\n\nconfirmation of the baby's blood group (using a cord blood sample)\n\nhaemoglobin level measurement to test for anaemia\n\nbilirubin level measurement to test for jaundice\n\nclinical assessment of the baby's neurobehavioural state and observations for jaundice and anaemia.\n\nThe NICE guideline on jaundice in newborn babies under 28 days gives recommendations on diagnosing and treating jaundice.", 'The diagnostic tests': "The assessment compared 1\xa0intervention test with 1\xa0comparator test.\n\n# The intervention\n\nHigh-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype is a laboratory developed test offered by the International Blood Group Reference Laboratory, Bristol (NHS Blood and Transplant). The test uses a real-time quantitative polymerase chain reaction (PCR) method for identifying fetal RHD genotype from fetal DNA in the plasma of rhesus‑D (D) negative women. The test analyses cell-free fetal DNA, in the form of small fragments of fetal extracellular DNA shed from the placenta and circulating freely in the maternal plasma. The level of cell-free fetal DNA in maternal blood increases throughout the pregnancy and rapidly falls after delivery. Most women who are D\xa0negative do not have copies of the RHD gene; therefore, the presence of the RHD gene in a D‑negative pregnant woman suggests a D‑positive fetus.\n\nHigh-throughput NIPT is carried out using 4\xa0ml to 6\xa0ml of maternal anti-coagulated blood. DNA extraction is done using an automated robotic platform (MDx BioRobot, Qiagen), which can rapidly process samples. The robotic platform is also used as a liquid handler to dispense samples and reagents. PCR is then done on an ABI Prism 7900HT analyser (Applied Biosystems). Primers and probes for exons\xa05 and\xa07 of the RHD gene are used, and the following controls are tested alongside the samples: RHD positive DNA; RHD negative DNA; RHD pseudogene positive DNA; and no DNA. The samples can be tested in batches of between 32\xa0and 88\xa0samples. The time to complete the test from sample receipt to report generation is 5\xa0to 6\xa0hours.\n\nThe exon\xa05 assay amplifies the RHD gene, whereas the exon\xa07 assay amplifies both the RHD gene and the RHD pseudogene. A threshold value of less than 42\xa0cycles is interpreted as a positive signal and an algorithm is used to determine the fetal RHD genotype. Results are reported as 'D‑positive', 'D‑negative' or 'indeterminate – treat as D‑positive'. The result would influence whether to offer routine antenatal anti‑D prophylaxis and anti‑D immunoglobulin to D‑negative women, who are not sensitised to D\xa0antigen, after potentially sensitising events.\n\n# The comparator\n\nThe comparator in the assessment was cord blood typing, which is used to determine the Rh\xa0blood group of a baby after birth.", 'Evidence': "The diagnostics advisory committee (section\xa08) considered evidence on high-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype from several sources (section\xa09). Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\n## Assessment of test accuracy\n\nEight studies reported the diagnostic accuracy of high-throughput NIPT for fetal RHD genotype, all of which were prospective studies carried out in European countries. Four studies were done in England, 3 of which were based in Bristol. Cord blood typing was the reference standard in all studies. Six studies were considered to be at low risk of bias and 2\xa0studies (Akolekar et al. 2011; Thurik et al. 2015) were judged to be at high risk of bias. Except for 2\xa0studies (Akolekar et al. 2001; Wikman et al. 2012), the results of the studies were considered broadly applicable to using high-throughput NIPT for fetal RHD genotype for nationwide testing in the UK.\n\nIt is expected that, in the UK, women with inconclusive NIPT results will be treated as having a positive test with no further testing. Data on inconclusive results were not reported in 2\xa0studies (Thurik et al. 2015; Grande et al. 2013). So, 4\xa0approaches to the diagnostic accuracy analysis were considered:\n\nwomen with inconclusive tests were treated as test positive (including Thurik et al. 2015 and Grande et al. 2013)\n\nwomen with inconclusive tests were treated as test positive (excluding Thurik et al. 2015 and Grande et al. 2013)\n\nexcluding all women with inconclusive test results\n\nincluding only studies done in Bristol.\n\nResults of the hierarchical bivariate meta-analyses are shown in table\xa01. In all analyses, women in whom NIPT was carried out at or before 11\xa0weeks' gestation were excluded because the test is known to be less accurate before 11\xa0weeks. NIPT for fetal RHD genotype is very accurate among women with a rhesus‑D (D) positive fetus; only 2\xa0to\xa04 in 1,000 such women will have a negative test result and so be at risk of sensitisation because they would not be offered antenatal anti‑D immunoglobulin. NIPT for fetal RHD genotype is slightly less accurate among women with a D‑negative fetus; between 13 and 57 in 1,000\xa0such women will have a positive test result and so be offered antenatal anti‑D immunoglobulin unnecessarily.\n\nAnalysis case\n\n\n\nNumber of studies\n\nFalse-negative rate (at risk of sensitisation) estimate (% [95% CI])\n\nFalse-positive rate (unnecessary anti D) estimate (%\xa0[95%\xa0CI])\n\nInconclusive treated as test positive (including Thurik et al. and Grande et al.)\n\n\n\n(0.15–0.76)\n\n(2.54–5.82)\n\nInconclusive treated as test positive (excluding Thurik et al. and Grande et al.)\n\n\n\n(0.15–0.94)\n\n(2.79–6.78)\n\nExcluding all inconclusive test results\n\n\n\n(0.15–0.82)\n\n(0.87–1.83)\n\nStudies only done in Bristol\n\n\n\n(0.09–0.48)\n\n(4.58–7.16)\n\nAbbreviation: CI, confidence interval.\n\nThe analysis of the 3\xa0Bristol studies gave a slightly lower false-negative rate (0.21%; 95% confidence interval [CI]\xa00.09 to\xa00.48) and a higher false-positive rate (5.73%; 95% CI\xa04.58 to\xa07.16) than analyses including other studies. This suggests that the Bristol high-throughput NIPT approach may use a different test threshold compared with the testing done in other studies; minimising false-negative findings, with a consequent increase in the false-positive rate.\n\nThere was considerable variation in rates of inconclusive tests across studies, ranging from 0.4% to 14.3%. The most likely causes for this variability are differences in how the NIPT was done (such as different numbers and types of exons considered) and differences in characteristics of study populations (for example, different proportions of women of black African family origin). Based on a meta-analysis, the average rate of inconclusive test results was estimated to be 4.0% (95% CI\xa01.5 to\xa010.3) if all studies reporting inconclusive results were included, and 6.7% (95% CI\xa03.7 to\xa011.7) if only the Bristol studies were included.\n\nAn analysis of the effect of the timing of high-throughput NIPT for fetal RHD genotype on diagnostic accuracy suggested that false-negative rates were higher before 11\xa0weeks' gestation, and thereafter false-negative rates were consistent, irrespective of timing. The effect of the timing of high-throughput NIPT on the number of inconclusive test results suggested that the percentage of inconclusive results drops as the gestational age increases from 11\xa0weeks.\n\n## Assessment of clinical outcomes\n\nSeven studies reported the clinical effectiveness of NIPT for fetal RHD genotype, all of which were observational and carried out in European countries. The sample size of the studies ranged from 284 to 15,126 and most participants were of white European family origin. Only 2\xa0studies compared women having NIPT for fetal RHD genotype with controls (Tiblad et al. 2013; Banch Clausen et al. 2014). Tiblad et al. (2013) was considered to be at serious risk of bias, and Banch Clausen et al. (2014) was considered to be at critical risk of bias. The generalisability of these 2\xa0studies to NHS clinical practice was limited because participants in the control group did not have routine antenatal anti‑D prophylaxis (RAADP). The other 5\xa0studies only reported non-comparative-effectiveness data for women having NIPT for fetal RHD genotype. Data from these studies were supplemented with data from a UK audit on anti‑D immunoglobulin use (National comparative audit of blood transfusion: 2013 audit of anti-D immunoglobulin prophylaxis) for a comparison with current practice.\n\nTiblad et al. (2013) compared targeted RAADP in the first trimester with routine care (postpartum anti‑D prophylaxis only) in Sweden. They reported the incidence of D\xa0sensitisation in the cohort that had high-throughput NIPT for fetal RHD genotype as 0.26% (95% CI\xa00.15 to\xa00.36%; n=8347) compared with 0.46% (95% CI\xa00.37 to\xa00.56%; n=18,546) in the historical control cohort. High-throughput NIPT for fetal RHD genotype was associated with a significant risk reduction in sensitisation (unadjusted risk ratio [RR] 0.55; 95% CI\xa00.35 to\xa00.87) compared with historical controls. An updated analysis reported in a linked conference abstract (Neovius et al. 2015) found an adjusted odds ratio of 0.41 (95% CI\xa00.22 to\xa00.87).\n\nSeven studies reported uptake rates of NIPT for fetal RHD genotype. Uptake rates ranged from 70% to more than 95% across the studies. In a pilot study done by Soothill et al. (2015) in 3\xa0maternity services in the south-west of England, only 70% of eligible women joined the study in the first 6\xa0months. The larger English study done by Chitty et al. (2014) reported that 88% of the 3,069\xa0participants consented to have NIPT for fetal RHD genotype. The only country that reported nationwide uptake data was the Netherlands, where more than 95% of eligible women had NIPT for fetal RHD genotype. The studies generally noted that uptake is likely to increase over time if a nationwide screening programme is implemented.\n\nThe uptake of RAADP in women who accepted NIPT and had a positive result was reported in 4\xa0studies and ranged from 86.0% to 96.1%. Of the larger studies, Van der Ploeg et al. (2015) reported nationwide data on women having NIPT for fetal RHD genotype in the Netherlands, where 96.1% of about 18,383\xa0women with a positive test result had RAADP. Tiblad et al. (2013) reported a slightly lower rate, with 90% of 5,104\xa0women with a positive NIPT result having RAADP. Data on the uptake of RAADP in women who had a negative test result, those who had an inconclusive test result, and those who refused NIPT for fetal RHD genotype, were limited. None of the studies reported whether all the women who had RAADP had the intended dosage at the intended time, or what proportion of women had additional anti‑D immunoglobulin because of a potentially sensitising event.\n\nThe uptake of postpartum anti‑D prophylaxis in women who accepted NIPT for fetal RHD genotype and had a positive test result was reported in 3\xa0studies. Van der Ploeg et al. (2015) reported nationwide data on women having NIPT for fetal RHD genotype in the Netherlands, where 92% of about 18,383\xa0women had postpartum anti‑D prophylaxis. A subgroup analysis by Banch Clausen et al. (2014) found slightly higher uptake of postpartum anti‑D prophylaxis among women who had NIPT (99.7%, 353/354) compared with those who did not have NIPT (95.7%, 66/69). Damkjaer et al. (2012) reported a similar rate among women who had NIPT (99.3%, 151/152). None of the included studies reported whether all women who had postpartum anti‑D prophylaxis had the intended dosage at the intended time.\n\nOutcome measures relating to anti‑D immunoglobulin administration were reported in 3\xa0non‑comparative studies. Soothill et al. (2015) reported a significant 6% reduction per month in anti‑D immunoglobulin administration (95% CI\xa04 to\xa08) over a 6‑month period in 3\xa0maternity services in the south west of England. The total use of anti‑D immunoglobulin fell by about 29%, corresponding to 35% of D‑negative women not having anti‑D immunoglobulin in their pregnancy unnecessarily. Similar results were also seen by Banch Clausen et al. (2014), who reported that 37.1% of women avoided unnecessary anti‑D immunoglobulin within 2\xa0years of the introduction of a programme of NIPT for fetal RHD genotype. Grande et al. (2013) reported that, of 95\xa0women carrying a D‑negative fetus, 5\xa0women requested anti‑D immunoglobulin; so, unnecessary anti‑D immunoglobulin was avoided in 95% of women carrying a D‑negative fetus.\n\nTo better understand the likely consequences of implementing NIPT for fetal RHD genotype and basing antenatal anti‑D immunoglobulin administration on its results, the external assessment group did a simulation study. The following assumptions were made:\n\nWhen needed, antenatal anti‑D immunoglobulin is offered at around 28\xa0weeks.\n\nPostpartum anti‑D prophylaxis is offered based on the result of cord blood typing.\n\nCord blood typing is 100% accurate.\n\nThere are no adverse consequences of giving anti‑D immunoglobulin.\n\nThe results of the simulation study, summarised in table\xa02, showed that using NIPT for fetal RHD genotype leads to a substantial reduction in RAADP use, from 99% of D‑negative women to 65.9%. This decline is similar in size to that seen by Soothill et al. (2015). The decrease is because of the drop (from 39% to 5.7%) in women with D‑negative fetuses needlessly having anti‑D immunoglobulin. Using NIPT for fetal RHD genotype means that about 1.2% of women miss having possibly beneficial RAADP, compared with 0.6% when using a universal RAADP approach with no testing.\n\nOutcome\n\nTreatment approach\n\nProportion of women\n\nAntenatal anti‑D given\n\nUniversal anti‑D\n\n%\n\nAntenatal anti‑D given\n\nBased on NIPT\n\n%\n\nUnnecessary anti‑D given (D‑negative fetus)\n\nUniversal anti‑D\n\n%\n\nUnnecessary anti‑D given (D‑negative fetus)\n\nBased on NIPT\n\n%\n\nAnti‑D not given (D‑positive fetus)\n\nUniversal anti‑D\n\n%\n\nAnti‑D not given (D‑positive fetus)\n\nBased on NIPT\n\n%\n\nTreatment approach\n\nProportion of women\n\nPostpartum and emergency anti‑D only\n\n%\n\nUniversal anti‑D\n\n%\n\nBased on NIPT with postpartum anti‑D\n\n%\n\nBased on NIPT with no postpartum anti‑D for women who test negative\n\n%\n\nTreatment approach\n\nProportion of women\n\nPostpartum and emergency anti‑D only\n\n%\n\nUniversal anti‑D\n\n%\n\nBased on NIPT with postpartum anti‑D based on cord blood typing\n\n%\n\nBased on NIPT with no postpartum anti‑D for women testing negative\n\n%\n\nAbbreviation: NIPT, non invasive prenatal testing.\n\nAssuming all women still have postpartum cord blood typing and postpartum anti‑D prophylaxis if needed, the simulation study showed that NIPT would result in about 3\xa0extra sensitisations per 100,000 women. If cord blood typing is not done, there would be about 13\xa0extra sensitisations per 100,000\xa0women. These increases are small compared with the total number of sensitisations because of anti‑D immunoglobulin failure and non‑adherence to anti‑D immunoglobulin treatment (around 281\xa0per 100,000\xa0women), and compared with not using RAADP at all (around 641\xa0per 100,000).\n\nResults of the simulation study also showed that using NIPT for fetal RHD genotype is unlikely to have any meaningful effect on mortality in later pregnancies; if women with a negative NIPT result never have postpartum anti‑D prophylaxis, there would be about 5\xa0extra fetal or neonatal deaths per 1\xa0million D‑negative women. In current practice, there are an estimated 86\xa0fetal or neonatal deaths per 1\xa0million D‑negative women.\n\n## Assessment of implementation issues\n\nTwelve studies were identified in a review of implementation of NIPT for fetal RHD genotype. Most studies reported that NIPT for fetal RHD genotype was feasible. Several studies reported potential issues relating to implementation, such as adherence to the anti‑D prophylaxis programme. Some studies highlighted the importance of short transport times for samples and effective management of transporting samples. The need for greater awareness of NIPT among physicians and midwives was also identified in some studies.\n\nA UK-based survey (Oxenford et al. 2013) showed that, although most of the women surveyed supported the implementation of NIPT, their current knowledge of Rh\xa0blood groups and anti‑D treatment was limited, which could be a barrier to implementation.\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nSeven studies were identified in a review of existing studies on the cost effectiveness of high-throughput NIPT to determine fetal RHD genotype in pregnant women who are D\xa0negative and are not sensitised to the D\xa0antigen. The quality of the included studies' findings was uncertain because they did not report the validity of the diagnostic accuracy outcomes used. The degree of uncertainty in the cost-effectiveness estimates was also difficult to establish.\n\nResults across the existing economic studies were conflicting. Only 1\xa0study found NIPT for targeting RAADP to be cost saving compared with non‑targeted RAADP. Two studies reported that NIPT for fetal RHD genotype was cost saving compared with no RAADP, that is, compared with postpartum anti‑D prophylaxis only. Three studies reported that NIPT for fetal RHD genotype was not cost effective or was of no economic benefit. Only 1\xa0study directly related to the UK (Szczepura et al. 2011).\n\n## Modelling approach\n\nThe external assessment group developed a de novo economic model designed to assess the cost effectiveness of high-throughput NIPT to determine fetal RHD genotype in pregnant women who are D\xa0negative and are not sensitised to D\xa0antigen.\n\nA decision tree cohort approach was developed to estimate the costs and health outcomes with and without high-throughput NIPT for fetal RHD genotype. The treatment part of the model was based closely on the economic model used in the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative, developed by researchers at the School of Health and Related Research (ScHARR).\n\nIn the model, a pregnant woman enters after being identified as D\xa0negative and not sensitised to D\xa0antigen, based on testing at first contact with the doctor or midwife, or at the booking appointment (at 8\xa0to 12\xa0weeks' gestation). The first part of the model divides the cohort according to fetal RHD genotype and treatment. This determines when having RAADP is appropriate, inappropriate, or unnecessary, and when avoidance of RAADP is potentially harmful. Test performance, adherence to high-throughput NIPT for fetal RHD genotype and RAADP, and the effectiveness of RAADP all inform the estimation of the probability of sensitisation. The second part of the model considers the short- and long-term consequences of sensitisations, such as fetal or neonatal death, and minor or major fetal development problems in later pregnancies.\n\nFour alternative ways (see table\xa03) that using high-throughput NIPT may affect the existing postpartum care pathway were considered:\n\nPostpartum scenario\xa01 (PP1): postpartum cord blood typing and fetomaternal haemorrhage testing would continue to be done, based on current guidelines, in all women regardless of the fetal RHD genotype identified with high-throughput NIPT.\n\nPostpartum scenario\xa02 (PP2): postpartum cord blood typing and fetomaternal haemorrhage testing (and by implication anti‑D immunoglobulin) would be withheld if high-throughput NIPT for fetal RHD genotype identified a D‑negative fetus, but would continue to be done if high-throughput NIPT was inconclusive or had identified a D‑positive fetus.\n\nPostpartum scenario\xa03 (PP3): postpartum cord blood typing would be done if high-throughput NIPT for fetal RHD genotype identified a D‑negative fetus. Fetomaternal haemorrhage testing and post-delivery anti‑D immunoglobulin would be provided if high-throughput NIPT was inconclusive or identified a D‑positive fetus.\n\nPostpartum scenario\xa04 (PP4): postpartum cord blood typing would not be carried out in any women. Fetomaternal haemorrhage testing and post-delivery anti‑D immunoglobulin would be provided if high-throughput NIPT was inconclusive or had identified a D‑positive fetus.\n\nScenario\n\nHigh-throughput NIPT result\n\nCord blood typing\n\nFMH testing\n\nPostpartum anti‑D\n\nPostpartum scenario\xa01\n\nAny\n\nYes\n\nYes if CBT+\n\nAs guided by CBT and FMH testing\n\nPostpartum scenario\xa02\n\nNegative\n\nNo\n\nNo\n\nNo\n\nPostpartum scenario\xa02\n\nPositive or inconclusive\n\nYes\n\nYes if CBT+\n\nAs guided by CBT and FMH testing\n\nPostpartum scenario\xa03\n\nNegative\n\nYes\n\nYes if CBT+\n\nAs guided by CBT and FMH testing\n\nPostpartum scenario\xa03\n\nPositive or inconclusive\n\nNo\n\nYes\n\nYes with additional dose per FMH test\n\nPostpartum scenario\xa04\n\nNegative\n\nNo\n\nNo\n\nNo\n\nPostpartum scenario\xa04\n\nPositive or inconclusive\n\nNo\n\nYes\n\nYes with additional dose per FMH test\n\nAbbreviations: CBT, cord blood typing; NIPT, non invasive prenatal testing; FMH, fetomaternal haemorrhage; +, positive.\n\nThe annual number of pregnancies in D‑negative women in England was estimated to be 99,225. This represents a cross section of all pregnancies, and the proportions of first, second, third and later pregnancies are used to characterise the total fertility rate of a typical D‑negative woman. This estimate was based on a birth rate of 12.2 per 1,000 women per year and assumes that 15% of the population is D\xa0negative. The proportion of D‑positive babies born to women who are D\xa0negative was estimated as 61.6%. This rate was applied across all pregnancies, that is, the first and later pregnancies.\n\nThe diagnostic accuracy of high-throughput NIPT for fetal RHD genotype and the proportion of inconclusive results were based on the meta-analyses done in the clinical-effectiveness assessment. The base case used the pooled results for the subgroup of UK (Bristol-based) studies in which inconclusive results were considered as test positive. These studies were considered the most relevant to NHS clinical practice. Sensitivity was 0.998 (95% CI\xa00.992 to\xa00.999), specificity was 0.942 (95% CI\xa00.920 to\xa00.959) and the rate of inconclusive results was 6.7%.\n\nFor consistency, this diagnostics assessment used the clinical effectiveness of RAADP that was established in the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative. Evidence for the clinical effectiveness of postpartum anti‑D prophylaxis was taken from a Cochrane review (Crowther et al. 1997). The clinical-effectiveness estimates are presented in table\xa04.\n\nOutcome\n\nNICE guidance on routine antenatal anti‑D prophylaxis for women who are rhesus D negative\n\nCrowther et al. (1997; sensitisation 6\xa0months after delivery)\n\nOdds ratio: sensitisation with RAADP (compared with no RAADP, conditional on having postpartum anti‑D prophylaxis) (95% CI)\n\n\n\n(0.21 to 0.65)\n\n-\n\nOdds ratio: sensitisation at birth, follow-up up to 6\xa0months, with postpartum anti‑D prophylaxis (compared with no postpartum anti‑D prophylaxis, conditional on no RAADP) (95% CI)\n\n-\n\n(0.06 to 0.11)\n\nSensitisation rate without RAADP (conditional on having postpartum anti‑D prophylaxis) (95% CI)\n\n(0.18 to 1.71)\n\n(0.18\xa0to\xa01.71) Baseline sensitisation rate of no RAADP assumed the same\n\nSensitisation rate with RAADP (95% CI)\n\n(0.29 to 0.40)\n\n-\n\nSensitisation rate without RAADP and without postpartum anti‑D prophylaxis (95% CI)\n\n-\n\n(8.0 to 13.8)\n\nAbbreviations: CI, confidence interval; RAADP, routine antenatal anti‑D prophylaxis.\n\nThe number of potentially sensitising events was taken from the recent UK audit on anti‑D immunoglobulin use (National comparative audit of blood transfusion: 2013 audit of anti-D immunoglobulin prophylaxis). The probability of women having at least\xa01 (reported) potentially sensitising event was estimated as 15.5%. Of these, 69.3% were estimated to have had a fetomaternal haemorrhage test and 95.8% were estimated to have had anti‑D immunoglobulin after the event. It was estimated that about 80% of these events happened after 20\xa0weeks' gestation, and it was assumed that these events were treated with the minimum required dose of 500\xa0IU anti‑D immunoglobulin. For the remaining 20% of events (before 20\xa0weeks' gestation), it was assumed that women had the minimum required dose of 250\xa0IU anti‑D immunoglobulin.\n\nThe National comparative audit of blood transfusion: 2013 audit of anti‑D immunoglobulin prophylaxis was used to provide estimates of adherence to RAADP. It reported that, out of all eligible women: 99% had at least 1\xa0RAADP injection; full adherence (that is the correct dose at the correct time) was better with the single-dose regimen (90%) compared with the 2‑dose regimen (59%); 98.4% had postpartum anti‑D prophylaxis; and 96% had anti‑D immunoglobulin for documented potentially sensitising events. Within the economic model, it was assumed that adherence to RAADP was 99.0% and that adherence to postpartum anti‑D prophylaxis was 98.4%. There was limited evidence on adherence to NIPT for fetal RHD genotype, so it was assumed that using NIPT has no additional effect on adherence to anti‑D prophylaxis.\n\nThe effects of sensitisation on later pregnancies were taken from Finning et al. (2008) and the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative. The proportion of fetal or neonatal deaths was estimated to be 5%; and the proportion of babies affected with minor or major developmental problems was estimated to be 6% or 5% respectively. Minor developmental problems were estimated to last 16\xa0years and the life expectancy for a person with major developmental problems was estimated to be 59.5\xa0years.\n\nThe estimated cost of high-throughput NIPT for fetal RHD genotype included consumables, staffing, equipment, and indirect and overhead costs. The estimated cost was based on testing at full capacity, that is, dealing with at least 100,000 samples per year. The unit cost per sample may vary, because it is a function of capacity and the annual predicted level of usage of each testing machine. Also, a royalty fee is under negotiation and will need to be added to the cost of the test. The cost of high-throughput NIPT for fetal RHD genotype remains commercial in confidence at the time of writing this diagnostics guidance.\n\nThe cost of anti‑D immunoglobulin was taken from the British national formulary. Currently 2\xa0brands (D‑Gam and Rhophylac) and 4\xa0doses (250-, 500-, 1,500- and 2,500‑unit vials) are available. Weighted averages based on recommended dose regimens and market share were calculated. The estimated costs were: £31.69 for anti‑D immunoglobulin for potentially sensitising events; £41.58 for RAADP; and £35.69 for postpartum anti‑D prophylaxis. The cost of giving anti‑D immunoglobulin was set to £5.\n\nIn current practice, cord blood typing is done to confirm the baby's Rh\xa0blood group, and maternal blood samples are tested for fetomaternal haemorrhage after birth. The costs, updated to 2015 prices, for cord blood typing (£4.18) and associated phlebotomy (£3.32) were taken from Szczepura et al. (2011). The cost of fetomaternal haemorrhage testing by flow cytometry was estimated to be £128.10.\n\nThe relevant interventions for maternal and neonatal sensitisation were taken from the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus D negative. Unit costs were taken from the NHS reference costs 2014/15. This resulted in an estimated average total cost per sensitisation of £3,167. The estimated annual costs for minor (£111) and major (£574) development problems were also assumed to be the same as in the NICE technology appraisal guidance (updated to 2015 prices).\n\nThe following utilities were assumed in the model: minor developmental problems, 0.85; major developmental problems, 0.42; and general population, 0.88. These values are the same as those used in the NICE technology appraisal guidance on routine antenatal anti-D prophylaxis for women who are rhesus negative.\n\n## Base-case results\n\nKey assumptions made in the model were:\n\nSensitisations do not affect the pregnancy in which they occur.\n\nAnti‑D immunoglobulin used within 1\xa0pregnancy has no effect in reducing sensitisations during the next pregnancy.\n\nThe proportion of D‑negative women is based on estimates from people of white European family origin.\n\nThe proportion of D‑positive babies born to D‑negative women is assumed to be the same irrespective of pregnancy number.\n\nThe number of D‑positive babies in the model is determined by combining the probability, in the general population of D‑negative women, of having a D‑positive baby (61.6%) with the sensitivity and specificity of NIPT (in which inconclusive results are treated as test positive).\n\nThe probability of having a D‑positive baby in women with inconclusive test results is based on the pooled probability in the study populations used to inform the diagnostic accuracy estimate.\n\nAll NIPT is assumed to be done early enough to determine the need for RAADP at 28\xa0weeks' gestation.\n\nRAADP is only offered to women in whom the NIPT result indicates that their fetus is D\xa0positive or in whom the results are inconclusive.\n\nWomen with an inconclusive NIPT result are treated the same as women who test positive in terms of RAADP, and tests and treatment after potentially sensitising events.\n\nWomen offered RAADP will also be offered supplementary anti‑D immunoglobulin at the minimum dose needed for any potentially sensitising events.\n\nPotentially sensitising events that involve fetal death are assumed to be independent of previous sensitisation within the same pregnancy.\n\nWomen with false-negative test results indicated by cord blood typing and who have postpartum anti‑D prophylaxis are assumed to have a sensitisation rate of 0.95%.\n\nAdherence to RAADP is assumed to be the same with and without NIPT; similarly, adherence to postpartum anti‑D prophylaxis is assumed to be the same with or without NIPT.\n\nThere are no adverse health effects from using anti‑D immunoglobulin.\n\nResults show that all NIPT strategies cost less, but are less effective than the comparator, current clinical practice (table\xa05). Strategies PP1 and PP3 are associated with smaller quality-adjusted life year (QALY) losses than PP2 and PP4. This is because in both PP1 and PP3, cord blood typing is used to identify false-negative results, which would allow women who had been incorrectly identified as having a D‑negative baby, and so had not been offered RAADP, to have postpartum anti‑D prophylaxis. This would reduce the number of sensitisations, therefore reducing QALY losses.\n\nStrategies\n\nTotal costs\n\nTotal QALYs\n\nIncremental costs\n\nIncremental QALYs\n\nICER\n\n(£ saved/ QALY lost)\n\nNo test and RAADP (current practice)\n\n£15,983,725\n\n,433,756\n\nN/A\n\nN/A\n\nN/A\n\nPostpartum scenario\xa01 versus no test and RAADP\n\n£15,400,187\n\n,433,756\n\n−£583,538\n\n−0.46\n\n£1,269,050\n\nPostpartum scenario\xa02 versus no test and RAADP\n\n£15,312,630\n\n,433,737\n\n−£671,095\n\n−19.13\n\n£35,087\n\nPostpartum scenario\xa03 versus no test and RAADP\n\n£15,498,942\n\n,433,756\n\n−£484,783\n\n−0.46\n\n£1,054,281\n\nPostpartum scenario\xa04 versus no test and RAADP\n\n£15,410,610\n\n,433,737\n\n−£573,114\n\n−19.13\n\n£29,964\n\nAbbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; RAADP, routine antenatal anti D prophylaxis.\n\nThe variations in costs between the 4\xa0strategies were mainly driven by different postpartum testing costs and postpartum anti‑D prophylaxis costs. The added cost of managing sensitisations and their associated health consequences in later pregnancies was largest for the strategies with more sensitisations (PP2 and PP4), and was very small for strategies PP1 and PP3.\n\nIn the fully incremental analysis of NIPT for fetal RHD genotype for the different postpartum testing strategies, PP3 and PP4 were dominated. Strategy PP4 was dominated by strategy PP2 because it had the same number of QALYs but was more expensive than PP2. Strategy PP3 was dominated by strategy PP1 because it had the same number of QALYs but was more expensive than PP1.\n\nThe cost-effectiveness acceptability curve showed that PP1 had the highest probability of being cost effective, with 0.65 and 0.73 for maximum acceptable incremental cost-effectiveness ratio (ICER) values of £20,000 and £30,000 per QALY gained respectively. For the same maximum acceptable ICER values, the probability of PP2 being cost effective was 0.30 and 0.22 respectively.\n\n## Sensitivity and scenario analyses\n\nSensitivity analyses showed that the results of the economic model are robust to small changes in the clinical effectiveness of RAADP, the timing of testing (between 11\xa0and 23\xa0weeks) and adherence to anti‑D immunoglobulin treatment.\n\nA sensitivity analysis was done on the diagnostic accuracy of NIPT. When the diagnostic accuracy of NIPT was based on the meta-analysis of all studies rather than the Bristol studies alone, specificity increased by 2%, sensitivity decreased by 0.2%, the total cost across all NIPT strategies reduced, but total QALYs were only marginally affected. PP1 and PP3 remained the most cost-effective strategies.\n\nIn a sensitivity analysis on the rates of inconclusive results, NIPT became less cost effective as the rate of inconclusive results increased, but strategies PP1 and PP3 always remained more cost effective than current practice. When the rate of inconclusive results was low, PP3 became the most cost-effective strategy. When the rate of inconclusive results was high, PP1 became the most cost-effective strategy.\n\nA 2‑way sensitivity analysis was done on test and treatment costs. The unit cost of NIPT is subject to uncertainty because it depends on throughput (the annual total number of samples analysed) and the level of the royalty fee. Similarly, the cost of anti‑D immunoglobulin may differ from the list price depending on negotiated discounts. The results of a 2‑way analysis on these unit costs showed that the base case is very sensitive to both the price of NIPT and the price of anti‑D immunoglobulin. A small increase in price of high-throughput NIPT or a small fall in the price of anti‑D immunoglobulin would result in current practice becoming more cost effective than NIPT strategies.\n\nThe cost of high-throughput NIPT for fetal RHD genotype was uncertain when this diagnostics guidance was written because it is highly dependent on the number of tests processed. The external assessment group did a threshold analysis to identify the point at which the test would move from being considered cost effective to being considered not cost effective, using a maximum acceptable ICER of £20,000 per QALY gained. Results show that raising the cost for high-throughput NIPT to £24.64 or more would result in current practice becoming more cost effective than NIPT strategies.\n\nA sensitivity analysis was done on the cost of fetomaternal haemorrhage testing. Reducing the cost of a fetomaternal haemorrhage test to £3.17 (Szczepura et al. 2011; updated to 2015 prices) halved the estimated total costs of all strategies when compared with the total costs of the base-case scenarios, with total QALYs remaining similar to base-case results. When the cost of fetomaternal haemorrhage test was reduced, PP2 and PP4 became less cost effective than current practice, whereas PP1 and PP3 remained more cost effective compared with current practice.\n\nAn alternative postpartum-testing strategy to those included in the scope was assessed. The strategy separated women in whom NIPT identified a D‑positive fetus from women in whom NIPT gave an inconclusive result (and were therefore treated as if the fetus was D‑positive). Cord blood typing was done for women identified as having either a D‑negative fetus by NIPT or who had an inconclusive NIPT result, but not done for women in whom NIPT indicated a D‑positive fetus, and resulted in total costs of £15,230,372 and £2,433,756 QALYs per 100,000 pregnancies. This postpartum approach dominated all other NIPT strategies, and the ICER for this strategy compared with current practice was £1,638,356 saved per QALY lost.", 'Committee discussion': "# Current practice\n\nThe committee considered the current standard of care offered to pregnant women who are rhesus‑D (D) negative. It heard from clinical experts on the committee that current care for women who are not sensitised to the D\xa0antigen involves routine antenatal anti‑D prophylaxis, additional doses of anti‑D immunoglobulin if a woman has a potentially sensitising event, and postpartum testing of cord blood and anti‑D prophylaxis if cord blood typing shows the baby to be D\xa0positive. The committee noted that introducing these methods for preventing sensitisation of women to the D\xa0antigen has dramatically reduced the number of sensitisations and the rates of haemolytic disease of the fetus and newborn over the last 40\xa0years. The committee also heard from a clinical expert that there are effective treatments for D‑negative women who are sensitised to D\xa0antigen, which means that deaths from severe haemolytic disease of the fetus and newborn are very rare.\n\nThe committee considered whether there were any problems with the current care offered to pregnant women who are D\xa0negative and not sensitised to the D\xa0antigen. It heard from a clinical expert that errors do sometimes occur, for example, a small number of women at risk of sensitisation do not have anti‑D immunoglobulin, or do not receive the correct dose of anti‑D immunoglobulin at the correct time. The committee also heard from a clinical expert that many sensitisations result from clinically silent fetomaternal haemorrhage events – potentially sensitising events without a known cause or clinical symptoms. The committee further heard that cord blood typing to determine the Rh\xa0blood group of the baby after birth may be affected by errors, such as sampling the blood of the mother instead of the baby, or incorrect sample labelling. The committee concluded that although anti‑D prophylaxis is very effective for reducing sensitisations and therefore haemolytic disease of the fetus and newborn, it is not perfect because sensitisations do still happen.\n\nThe committee considered the possible disadvantages of using anti‑D immunoglobulin. It heard from experts that there have previously been shortages of supply because it is a blood product and therefore a finite resource. The committee also considered the potential future risks from unknown prions or pathogens associated with using a blood product such as anti‑D immunoglobulin. The committee concluded that it would be beneficial to conserve supplies by only using anti‑D immunoglobulin for those in whom it is necessary.\n\nThe committee heard from a patient expert that for some women, having anti‑D immunoglobulin may not be acceptable for personal, cultural or religious reasons. It noted that using high-throughput non‑invasive prenatal testing (NIPT) for fetal RHD genotype would allow women whose fetus was identified as D\xa0negative to avoid having unnecessary anti‑D immunoglobulin, while women identified as having a D‑positive fetus would be able to make an informed decision about whether to have anti‑D immunoglobulin.\n\n# Clinical effectiveness\n\nThe committee considered the diagnostic performance of high-throughput NIPT for fetal RHD genotype. It noted that good-quality evidence was available and that the test is accurate after 11\xa0weeks of gestation. The committee then considered how the diagnostic accuracy of the test affected clinical effectiveness. It noted that there is a small increase in the false-negative rate for high-throughput NIPT to determine fetal RHD genotype (0.21%; 95% CI [confidence interval]\xa00.09 to\xa00.48), compared with the current practice of postpartum cord blood typing. This means that some women with a D‑positive fetus would be incorrectly identified as having a D‑negative fetus and would not be offered routine antenatal anti‑D prophylaxis (RAADP) or anti‑D immunoglobulin after potentially sensitising events. Because of this, more women could become sensitised to the D\xa0antigen and may have complications in later pregnancies, although the committee heard from a clinical expert that the severity of these complications is hard to predict. The committee noted that the rate of sensitisations with current practice was estimated to be 281 per 100,000 D‑negative pregnancies. If offering RAADP and anti‑D immunoglobulin after potentially sensitising events was based on the results from NIPT for fetal RHD genotype, the rate of sensitisations would increase by 3, to 284\xa0sensitisations per 100,000 D‑negative pregnancies. The committee considered that this relatively small increase in the number of sensitisations could be accepted in the context of other potential benefits of NIPT associated with avoiding unnecessary treatment with blood products.\n\nThe committee considered the results of the economic model. It noted that the quality-adjusted life year (QALY) losses in the model were 0.46 per 100,000 pregnancies if the postpartum testing strategy stayed the same as current practice (cord blood typing for all D‑negative women regardless of the NIPT result). The committee noted that although this is a reduction in clinical effectiveness compared with current practice, the reduction is extremely small (0.0000046 QALYs per pregnancy). The committee therefore concluded that the clinical effectiveness of using high-throughput NIPT for fetal RHD genotype to guide antenatal anti‑D prophylaxis is comparable with offering antenatal anti‑D prophylaxis to all D‑negative women, provided that there are no changes to postpartum practice.\n\n# Cost effectiveness\n\nThe committee considered the cost savings in the economic model. It noted that cost savings in the models were £583,538 per 100,000 pregnancies in D‑negative women if the postpartum testing strategy stayed the same as current practice (cord blood typing for all D‑negative women regardless of the NIPT result, referred to as postpartum scenario\xa01 [PP1] in the economic analysis). The committee noted that the cost savings are relatively small, at £5.84 per pregnancy, and on their own might not justify the risks that could be associated with making substantial changes to current practice. The committee then considered the base-case incremental cost-effectiveness ratio (ICER) for PP1. It noted that although the ICER appears to be large, at £1,269,100 saved for each QALY lost, it is very sensitive to changes in the numerator (change in cost) or denominator (change in QALYs), and is therefore subject to substantial uncertainty. The committee concluded that the total costs for using high-throughput NIPT for fetal RHD genotype to guide antenatal anti‑D prophylaxis are not substantially different from the total costs for the current practice of offering antenatal anti‑D prophylaxis to all D‑negative women, provided that there are no changes to postpartum practice.\n\nThe committee considered the different postpartum testing strategies presented in the diagnostics assessment report (see section\xa04.24). It noted that in the base-case analysis, NIPT using PP1 was the most cost-effective strategy compared with current practice. The committee heard from clinical experts that the postpartum care in PP1 is the same as used in current clinical practice. It also noted that with different assumptions on postpartum testing, other postpartum scenarios could be associated with greater cost savings, but increased QALY losses compared with PP1. The committee concluded that it is preferable to minimise the QALY losses.\n\nThe committee considered the results of a scenario analysis that made different assumptions on postpartum testing (PP5). It noted that this postpartum scenario was associated with greater cost savings and equivalent QALY losses compared with PP1. The committee heard from clinical experts that postpartum testing involves taking a cord blood sample soon after the birth, and that although midwives are used to doing this they also have multiple other tasks to complete at this time. The committee was concerned that if midwives had to get the NIPT result and then make a decision on whether to take a cord blood sample in the period immediately after the delivery, errors could be made, for example, not taking a cord blood sample from a fetus predicted to be D\xa0negative. The committee concluded that although alternative postpartum strategies may potentially have greater cost savings, they would be complicated to implement in clinical practice and may result in errors, which could affect costs and clinical effectiveness. The committee also discussed an alternative approach in which cord blood samples would be taken from all babies born to D‑negative women and the laboratory would then decide whether to test the cord blood sample. The committee concluded that the postpartum testing of cord blood should not be changed from current practice. This is because without cord blood typing, false-negative NIPT results would not be identified and women with false-negative NIPT results would not have postpartum anti‑D prophylaxis. The committee noted the difficulties of taking a blood sample from the cord and that the consequences of a sampling error may include having to take repeat blood samples from a neonate. It decided that further research on the practicalities of implementing alternative postpartum testing strategies would be valuable (see section\xa06.2).\n\nThe committee discussed the input used in the model for the cost of care of a pregnant woman who has been sensitised to the D\xa0antigen in an earlier pregnancy. It heard from a clinical expert that some women who are sensitised to the D\xa0antigen will be identified as having a D‑negative fetus, and others will be identified as having a D‑positive fetus, but will not experience problems during their pregnancy. These 2\xa0groups of women would not need many extra appointments with a specialist obstetrician. A third group of sensitised women will be identified as having a D‑positive fetus and will experience problems during their pregnancy. These women will need more frequent surveillance and treatment for the baby before and after the birth. The committee concluded that if a weighted average is taken of the cost of care for these 3\xa0groups of pregnant women, then an input of £3,167 per sensitised pregnancy is reasonable.\n\nThe committee considered the cost of the test that was used in the economic model and noted that the cost did not include sample transport. It heard from the current provider of the test, the International Blood Group Reference Laboratory (IBGRL), that blood samples are transported around the country to their laboratory on a daily basis using the NHS Blood and Transplant (NHSBT) transport network. It heard further, that because of this established transport network, there should be no cost for sample transport. The committee was concerned that although there may be no cost for sample transport between the NHSBT units and the IBGRL, there may be a cost for transporting the sample from the maternity clinic to the NHSBT unit. It was also concerned about the length of time it may take to transport samples from rural areas to the IBGRL, and that longer sample transport times may result in increased rates of failed tests. The committee also heard from the IBGRL that the unit cost of the test depends on the expected annual sample throughput and on a royalty fee, which is currently under negotiation. The committee concluded that the test cost is uncertain.\n\nThe committee considered whether there were any costs associated with implementing high-throughput NIPT for fetal RHD genotype that had not been included in the economic model. It noted that extra time to explain the test, take the blood sample, give the test results, and provide counselling, that could result in extra midwife appointments, were not included in the model. The committee heard from a clinical expert that in the south-west of England where high-throughput NIPT for fetal RHD genotype has been implemented, the blood sample for the test is normally taken at the routine 16‑week antenatal appointment; therefore, no additional appointments are needed. It also heard from the clinical expert that the main issue when implementing the test was educating midwives and other healthcare professionals so they understood the test and could explain it to women and their families. It noted that a patient information leaflet explaining the test and its results is available from NHSBT. The committee heard from the external assessment group that none of the studies in the review of implementation, included costs associated with implementation. The committee concluded that the costs associated with implementing high-throughput NIPT for fetal RHD genotype were uncertain.\n\nThe committee considered a threshold analysis done by the external assessment group on the unit cost of the test. It noted that results show that the cost effectiveness of high-throughput NIPT for fetal RHD genotype is sensitive to small increases in costs associated with doing the test, for example, sample transport, the need for repeat tests, midwife time, or the cost of the test itself. The committee also noted that increasing the test cost to £24.64 or more per test would result in high-throughput NIPT for fetal RHD genotype no longer being cost effective compared with current practice, using a maximum acceptable ICER of £20,000 per QALY gained. The committee concluded that high-throughput NIPT for fetal RHD genotype has the potential to be cost effective, but that the cost savings are volatile with respect to the cost of the test (see section\xa05.11) and the costs associated with implementation (see section\xa05.12). The committee also concluded that the overall cost of testing below which high-throughput NIPT for fetal RHD genotype can be considered cost effective should not be stated to 2\xa0decimal places in the recommendation. This is because there is substantial uncertainty about the results of the model. The committee decided that £24.64 should be rounded down to £24 rather than up to £25 to increase the chance of high-throughput NIPT for fetal RHD genotype being cost effective.\n\n# Other considerations\n\nThe committee noted its conclusions on the comparable clinical effectiveness of high-throughput NIPT for fetal RHD genotype and current practice (see section\xa05.6), and the uncertainty about cost savings (see section\xa05.13). The committee also noted its conclusion that it would be beneficial to avoid inappropriate use of anti‑D immunoglobulin (see section\xa05.3). The committee decided that although the cost savings are potentially small, recommending high-throughput NIPT for fetal RHD genotype would be an effective way of reducing unnecessary use of anti‑D immunoglobulin, and that this reduction could affect a large number of women.\n\nThe committee considered the effect that ethnicity has on NIPT results. They heard from the provider of the test, IBGRL, that D‑negative women of black African family origin are more likely to have an RHD pseudogene, and so are more likely to have an inconclusive or false-positive NIPT result compared with women from other ethnic family origins. The committee noted that women with an inconclusive or false-positive NIPT result would be offered antenatal anti‑D prophylaxis (that is, they would have the same care as they would have in current practice), and so would not be at a greater risk of sensitisation to the D\xa0antigen than women from other ethnic family origins. It noted further that although unnecessary anti‑D immunoglobulin use would be reduced in women of black African family origin, these women would be more likely to have unnecessary anti‑D immunoglobulin than women of white European family origin. The committee concluded that this is a proportionate means of achieving a reduction in anti‑D immunoglobulin use in the population as a whole.\n\nThe committee considered the current level of interest in high-throughput NIPT for fetal RHD genotype. It heard from a clinical expert that there have been many enquiries about the test from healthcare professionals and women who would like to have the test but do not live in an area where it has been implemented. It also heard from another clinical expert that the level of knowledge and understanding of NIPT is growing because of the publicity around NIPT for Down's syndrome and other aneuploidies. The committee concluded that based on the current level of interest, the timing was right for making a recommendation of high-throughput NIPT for fetal RHD genotype, but noted that additional data collection from areas beginning to implement the test would help confirm the cost of implementing the test given the uncertainty about this.", 'Recommendation for further research': 'Data collection and analysis of the costs and resource use associated with implementing high-throughput non‑invasive prenatal testing for fetal RHD genotype is recommended to show the overall cost of testing and to inform any future update of the guidance. This may include costs and resource use associated with:\n\ntraining for healthcare professionals\n\nexplaining the test to women and their families\n\ntest failures\n\nblood sampling, giving results and counselling when needed\n\nsample transport and management\n\nrecord keeping\n\nadherence to high-throughput non‑invasive prenatal testing and antenatal anti‑D prophylaxis.\n\nFurther research is recommended on alternative postpartum testing strategies that do not include cord blood typing of all babies born to rhesus‑D (D) negative women. This may include:\n\nan audit of D\xa0results from cord blood typing compared with results from high-throughput NIPT for fetal RHD genotype\n\nresearch on the practicalities of implementing alternative postpartum testing strategies.'}	https://www.nice.org.uk/guidance/dg25	Evidence-based recommendations on high-throughput non-invasive prenatal testing (NIPT) for fetal RHD genotype.
7c1fff358aac53b231a5c2e01dc2101d9efba3e4	nice	Physical health of people in prison	Physical health of people in prison This guideline covers assessing, diagnosing and managing physical health problems of people in prison. It aims to improve health and wellbeing in the prison population by promoting more coordinated care and more effective approaches to prescribing, dispensing and supervising medicines. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Assessing health ## First-stage health assessment at reception into prison At first reception into prison, a healthcare professional (or trained healthcare assistant under the supervision of a registered nurse) should carry out a health assessment for every person. Do this before the person is allocated to their cell. As part of the assessment, identify: any issues that may affect the person's immediate health and safety before the second-stage health assessment priority health needs to be addressed at the next clinical opportunity. Ensure continuity of care for people transferring from one custodial setting to another (including court, the receiving prison or during escort periods) by, for example: accessing relevant information from the patient clinical record, prisoner escort record and cell sharing risk assessment checking medicines and any outstanding medical appointments. Take into account any communication needs or difficulties the person has (including reading and writing ability), and follow the principles in NICE's guideline on patient experience in adult NHS services. The first-stage health assessment should include the questions and actions in table 1. It should cover: physical health alcohol use substance misuse mental health self-harm and suicide risk. Topic Questions Actions Prison sentence . Has the person committed murder, manslaughter or another offence with a long sentence? Yes: refer the person for mental health assessment by the prison mental health in-reach team if necessary. No: record no action needed. Prescribed medicines . Is the person taking any prescribed medicines (for example, insulin) or over-the-counter medicines (such as creams or drops)? If so: what are they what are they for how do they take them? Yes: document any current medicines being taken and generate a medicine chart. Refer the person to the prescriber for appropriate medicines to be prescribed, to ensure continuity of medicines. If medicines are being taken, ensure that the next dose has been provided (see recommendations 1.7.10 and 1.7.11 in the section on continuity of medicines). Let the person know that medicines reconciliation will take place before the second-stage health assessment. No: record no action needed. Physical injuries . Has the person received any physical injuries over the past few days, and if so: what were they how were they treated? Yes: assess severity of injury, any treatment received and record any significant head, abdominal injuries or fractures. Document any bruises or lacerations observed on a body map. In very severe cases, or after GP assessment, the person may need to be transferred to an external hospital. Liaise with prison staff to transfer the person to the hospital emergency department by ambulance. If the person has made any allegations of assault, record negative observations as well (for example, 'no physical evidence of injury'). No: record no action needed. Other health conditions . Does the person have any of the following: allergies, asthma, diabetes, epilepsy or history of seizures chest pain, heart disease chronic obstructive pulmonary disease tuberculosis, sickle cell disease hepatitis B or C virus, HIV, other sexually transmitted infections learning disabilities neurodevelopmental disorders physical disabilities? Ask about each condition listed. Yes: make short notes on any details of the person's condition or management. For example, 'Asthma – on Ventolin 1 puff daily'. Make appointments with relevant clinics or specialist nurses if specific needs have been identified. No: record no action needed. Other health conditions . Are there any other health problems the person is aware of that have not been reported? Yes: record the details and check with the person that no other physical health complaint has been overlooked. No: record no action needed. Other health conditions . Are there any other concerns about the person's health? Yes: make a note of any other concerns about physical health. This should include any health-related observations about the person's physical appearance (for example, weight, pallor, jaundice, gait or frailty). Refer the person to the GP or relevant clinic. No: note 'Nil'. Additional question for women . Does the woman have reason to think she is pregnant, or would she like a pregnancy test? If the woman is pregnant, refer to the GP and midwife. If there is reason to think the woman is pregnant, or would like a pregnancy test: provide a pregnancy test. Record the outcome. If positive, make an appointment for the woman to see the GP and midwife. No: record response. Living arrangements, mobility and diet . Does the person need help to live independently? Yes: note any needs. Liaise with the prison disability lead in reception about: the location of the person's cell further disability assessments the prison may need to carry out. No: record response. Living arrangements, mobility and diet . Do they use any equipment or aids (for example, walking stick, hearing aid, glasses, dentures, continence aids or stoma)? Yes: remind prison staff that all special equipment and aids the person uses should follow them from reception to their cell. No: record response. Living arrangements, mobility and diet . Do they need a special medical diet? Yes: confirm the need for a special medical diet. Note the medical diet the person needs and send a request to catering. Refer to appropriate clinic for ongoing monitoring. No: record response. Past or future medical appointments . Has the person seen a doctor or other healthcare professional in the past few months? If so, what this was for? Yes: note details of any recent medical contact. Arrange a contact letter to get further information from the person's doctor or specialist clinic. Note any ongoing treatment the person needs and make appointments with relevant clinics, specialist nurses, GP or other healthcare staff. No: record no action needed. Past or future medical appointments . Does the person have any outstanding medical appointments? If so, who are they with, and when? Yes: note future appointment dates. Ask healthcare administrative staff to manage these appointments or arrange for new dates and referral letters to be sent if the person's current hospital is out of the local area. No: record no action needed. Alcohol and substance misuse . Does the person drink alcohol, and if so: how much do they normally drink? how much did they drink in the week before coming into custody? Urgently refer the person to the GP or an alternative suitable healthcare professional if: they drink more than 15 units of alcohol daily or they are showing signs of withdrawal or they have been given medication for withdrawal in police or court cells. No: record response. Alcohol and substance misuse . Has the person used street drugs in the last month? If so, how frequently? When did they last use: heroin methadone benzodiazepines amphetamine cocaine or crack novel psychoactive substances cannabis anabolic steroids performance and image enhancing drugs? Yes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. Take into account whether: they have taken drugs intravenously they have a positive urine test for drugs their answers suggest that they use drugs more than once a week they have been given medication for withdrawal in police or court cells. If the person has used intravenous drugs, check them for injection sites. Refer them to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. No: record response. Problematic use of prescription medicines . Has the person used prescription or over-the-counter medicines in the past month: that were not prescribed or recommended for them or for purposes or at doses that were not prescribed? If so, what was the medicine and how did they use it (frequency and dose)? Yes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. No: record response. Mental health . Has the person ever seen a healthcare professional or service about a mental health problem (including a psychiatrist, GP, psychologist, counsellor, community mental health services, alcohol or substance misuse services or learning disability services)? If so, who did they see and what was the nature of the problem? Yes: refer the person for a mental health assessment if they have previously seen a mental health professional in any service setting. No: record response. Mental health . Has the person ever been admitted to a psychiatric hospital, and if so: when was their most recent discharge what is the name of the hospital what is the name of their consultant? Yes: refer the person for a mental health assessment. No: record response. Mental health . Has the person ever been prescribed medicine for any mental health problems? If so: what was the medicine when did they receive it when did they take the last dose what is the current dose (if they are still taking it) when did they stop taking it? Yes: refer the person for a mental health assessment if they have taken medicine for mental health problems. No: record response Self-harm and suicide risk . Is the person: feeling hopeless or currently thinking about or planning to harm themselves or attempt suicide? Yes: refer the person for an urgent mental health assessment. Open an Assessment, Care in Custody and Teamwork (ACCT) plan if: there are serious concerns raised in response to questions about self-harm, including thoughts, intentions or plans, or observations (for example, the patient is very withdrawn or agitated) or the person has a history of previous suicide attempts. Be aware and record details of the impact of the sentence on the person, changes in legal status and first imprisonment, and the nature of the offence (for example, murder, manslaughter, offence against the person and sexual offences). No: record response. Self-harm and suicide risk . Has the person ever tried to harm themselves, and if so: do they have a history of suicide attempts was this inside or outside prison when was the most recent incident what was the most serious incident? Yes: refer the person for a mental health assessment if they have ever tried to harm themselves. No: record response. ## Following the first-stage health assessment Give the person advice about how to contact prison health services and book GP appointments in the future. Ask the person for consent to transfer their medical records from their GP to the prison healthcare service (see the section on continuity of healthcare on entry to prison for more information about transfer of medical records). Enter in the person's medical record: all answers to the reception health assessment questions health-related observations, including those about behaviour and mental state (including eye contact, body language, rapid, slow or strange speech, poor hygiene, strange thoughts) details of any action taken. Carry out a medicines reconciliation (in line with NICE's guideline on medicines optimisation) before the second-stage health assessment. See recommendation 1.4.1 in the section on access to medicines and recommendation 1.7.10 in the section on continuity of medicines for recommendations on risk assessments for in-possession medicines and ensuring continuity of medicine. ## Tuberculosis screening within 48 hours The recommendations in this section have been adapted from the NICE guideline on tuberculosis (TB). Healthcare professionals in prisons should ensure people coming into prison are screened for TB within 48 hours of arrival. Report all suspected and confirmed TB cases to the local multidisciplinary TB team within 1 working day. If a case of TB is confirmed: Arrange for the local multidisciplinary TB team to visit within 5 working days. Contact the local Public Health England unit and multidisciplinary TB team to arrange a contact investigations exercise. They should also consider using mobile X‑ray to check for further cases. Put contingency, liaison and handover plans in place to ensure continuity of care before a person being treated for TB is transferred between prisons or released. Any other agencies working with the person should also be involved in this planning. ## Second-stage health assessment within 7 days A healthcare professional (for example, a registered general nurse) should carry out a second-stage health assessment for every person in prison. Do this within 7 days of the first-stage health assessment, and include as a minimum: reviewing the actions and outcomes from the first-stage health assessment asking the person about: any previous misuse of alcohol, use of drugs or improper use of prescription medicine if they have ever suffered a head injury or lost consciousness, and if so: how many times this has happened whether they have ever been unconscious for more than 20 minutes whether they have any problems with their memory or concentration smoking history the date of their last sexual health screen any history of serious illness in their family (for example, heart disease, diabetes, epilepsy, cancer or chronic conditions) their expected release date, and if less than 1 month plan a pre-release health assessment: see recommendation 1.7.5 in the section on before release from prison whether they have ever had a screening test (for example, a cervical screening test or mammogram) whether they have, or have had, any gynaecological problems measuring and recording the person's height, weight, pulse, blood pressure and temperature, and carrying out a urinalysis. Review the person's first- and second-stage health assessment records, medical history, GP and vaccination records and: Refer the person to the GP or a relevant clinic if further assessment is needed. See, for example, recommendations on identifying people for full formal risk assessment in the NICE guideline on cardiovascular disease or the recommendation on risk assessment in NICE's guideline on type 2 diabetes. Arrange a follow-up appointment if needed. Consider using the Correctional Mental Health Screen for Men (CMHS‑M) or Women (CMHS‑W) to identify possible mental health problems if: the person's history, presentation or behaviour suggests they may have a mental health problem the person's responses to the first-stage health assessment suggest they may have a mental health problem the person has a chronic physical health problem with associated functional impairment concerns have been raised by other agencies about the person's abilities to participate in the criminal justice process. When using the CMHS‑M or CMHS‑W with a transgender person, use the measure that is in line with their preferred gender identity. If there is other evidence supporting the likelihood of mental health problems, or a man scores 6 or more on the CMHS‑M, or a woman scores 4 or more on the CMHS‑W: a practitioner who is trained to perform an assessment of mental health problems should conduct further assessment or a practitioner who is not trained to perform an assessment of mental health problems should refer the person to an appropriately trained professional for further assessment. Offer people tailored health advice based on their responses to the assessment questions. This should be in a variety of formats (including face-to-face). It should include advice on: alcohol (see NICE's guideline on alcohol-use disorders) substance misuse (see NICE's guideline on drug misuse in over 16s) exercise (see recommendations on exercise in the section on promoting health and wellbeing) diet (see recommendation 1.3.5 on diet in the section on promoting health and wellbeing) stopping smoking (see recommendation 1.3.6 on stopping smoking in the section on promoting health and wellbeing) sexual health (see recommendations 1.3.7 and 1.3.8 on sexual health in the section on promoting health and wellbeing). Offer the person advice, with supporting literature if appropriate, on: how to contact prison health services and book GP appointments or other clinics, for example, dental, optician, chiropodist, substance misuse and recovery services where to find health information that is accessible and understandable how to attend or get a referral to attend any health-promoting activities in the future (see the section on promoting health and wellbeing) medicines adherence (see recommendation 1.4.7 in the section on access to medicines). Enter in the person's medical record: all answers to the second-stage health assessment questions health-related observations details of any action taken. Plan a follow-up healthcare review at a suitable time based on clinical judgement, taking into account the age of the person and length of their sentence. For people who may be in prison for less than 1 month, see recommendation 1.7.5 in the section on before release from prison. ## Health checks and screening Ensure that there is a system and processes in place to carry out and refer to other assessments in line with recommendations in NICE guidelines. The recommendations in this section have been adapted from the NICE guideline on hepatitis B and C testing. Prison healthcare services (working with the NHS lead for hepatitis) should ensure that: all people are offered a hepatitis B vaccination when entering prison (for the vaccination schedule, refer to the Green Book) all people are offered access to confidential testing for hepatitis B and C when entering prison and during their detention people who test for hepatitis B or C receive the results of the test, regardless of their location, when they become available results from hepatitis B and C testing are provided to the person's community-based GP, if consent is given. The recommendations in this section have been adapted from the NICE guideline on HIV testing. Offer all people HIV testing when entering prison. Primary care providers should ensure annual HIV testing is part of the integrated healthcare offered to men who are known to have sex with men. Provide information on HIV testing and discuss why it is recommended (including to those who indicate that they may wish to decline the test). Conduct post-test discussions, including giving positive test results and delivering post-test and general health promotion interventions. Recognise illnesses that may signify primary HIV infection and clinical indicator diseases that often coexist with HIV. The recommendations in this section have been adapted from the NICE guideline on sexually transmitted infections. Identify people at high risk of STIs using their sexual history. Opportunities for risk assessment may arise during consultations on contraception, pregnancy or abortion, and when carrying out a cervical smear test or offering an STI test. Risk assessment could also be carried out during routine care or when a new patient registers. Have structured, one-to-one discussions with people at high risk of STIs (if trained in sexual health), or arrange for these discussions to take place with a trained practitioner. Offer people equivalent health checks to those offered in the community, for example: the NHS health check programme learning disabilities annual health check relevant NHS screening programmes, such as those for abdominal aortic aneurysm and bowel, breast and cervical cancer. # Communication and coordination Ensure that the different teams (including prison staff) that manage a person's care in prison communicate with one another to coordinate care. Share information with other health and social care staff, offender supervisors and probation providers who are involved in the person's care in prison if necessary for the person's care. Ensure that people with complex health and social care needs have a lead care coordinator responsible for managing their care. Ensure that the person and all healthcare and prison staff know who this is. Share relevant information about people with complex needs with prison staff using prison record systems in line with legislation and national guidance. This should include information about any high-level risks, such as: risk of self-harm risk to others communicable diseases epilepsy diabetes allergies deteriorating health conditions learning disabilities. Review people in prison with complex health and social care needs. Ensure that if a person is supported by a multidisciplinary team, the teams meet regularly to plan and coordinate ongoing management. These should be facilitated by primary care. Document all health and social care patient interactions and any information related to health and social care in the person's primary care patient record. # Promoting health and wellbeing ## General health advice Consider using peer support and mentoring to help promote a healthy lifestyle while in prison. Offer people in prison tailored health information in a variety of formats, including face-to-face. Include advice about: exercise diet stopping smoking sexual health personal hygiene, including oral hygiene. ## Exercise Encourage people to be physically active. Offer them information about: the benefits of exercise what exercise facilities are provided, where they are and how they can use them, for example: going to the gym using the exercise yard exercises that can be done in the cell. Offer people information and advice in line with recommendations in the NICE guidelines on: physical activity: brief advice for adults in primary care physical activity: exercise referral schemes preventing excess weight gain -besity: identification, assessment and management (section 1.6 on physical activity). ## Diet Offer people information about: the benefits of a healthy diet healthier food options available in the prison.See the section on dietary advice in the NICE guideline on obesity: identification, assessment and management. ## Stopping smoking Offer people in prison information about: the risks of smoking support available to stop as part of smoking cessation services (for example, nicotine patches and motivational support). See the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. ## Sexual health Offer people in prison information about sexually transmitted infections and available sexual health services. Ensure that people in prison have discreet access to condoms, dental dams and water-based lubricants without the need to ask for them. # Managing medicines ## Access to medicines Carry out an individual risk assessment to determine if the person can hold their medicines in-possession. Allow people in prison to hold all medicine in-possession unless the person does not pass the risk assessment. Directly observe the administration of all schedule 2 and 3 medicines (also see NICE's guideline on controlled drugs) and medicines for tuberculosis (see NICE guideline on tuberculosis). Directly observe the administration of any medicine that is not in-possession. Work with prison staff to ensure a system is in place to: supervise the administering of medicines not held in-possession to maximise adherence allow timings of medicines doses to align with the prescribed dose regime reduce diversion (passing medicines on to other people) protect confidentiality. See the section on supporting adherence in the NICE guideline on medicines adherence. Review and (if necessary) repeat a person's risk assessment for in-possession medicine if the person's circumstances change. Involve a multidisciplinary team if needed, including prison staff and the person. Examples of when the risk assessment should be repeated include: if carrying out a medicines review if a person is considered able to manage their own medicines after a period of having medicines not in-possession if there is a medicine safety incident, including evidence of self-harm if someone has raised security concerns (for example, about bullying, diversion or hoarding) if the person has not been taking their prescribed medicines if there is concern about the person's ability to self-medicate when following the Assessment Care in Custody and Teamwork care planning approach if the person is transferred to or from a segregation unit. Consider providing storage for in-possession medicine in prison cells, for example, a lockable cupboard. Give people in prison information and education about medicines adherence (see the section on patient involvement in decisions about medicines in the NICE guideline on medicines adherence). # Monitoring chronic conditions Monitor people with chronic conditions in accordance with the following NICE guidelines: chronic heart failure chronic kidney disease chronic obstructive pulmonary disease epilepsies hypertension acute coronary syndromes type 1 diabetes and type 2 diabetes.See also the NICE quality standard on asthma. Monitor people with chronic conditions that need specialist management in line with relevant NICE guidelines (for example, the NICE guideline on hepatitis B (chronic) and colorectal cancer). Consider more frequent monitoring for older people and people with chronic conditions (such as diabetes) who are serving longer prison sentences. # Managing deteriorating health and health emergencies Ensure a local protocol is available for responding to and managing situations in which a person's health quickly deteriorates, or in a health emergency. This could include, for example: essential training for front-line prison staff, including the first person likely to be on the scene in an emergency processes to enable healthcare staff to reach a person in prison quickly, such as how to gain access to their cell processes to ensure a person can be quickly seen by a healthcare professional if their health deteriorates quickly availability of emergency equipment, such as emergency grab bags recording the actions and observations taken by prison and healthcare staff when assessing people with rapidly deteriorating health or in an emergency situation, such as: updating a person's care plan or recommendations for immediate follow-up a clear care plan for supporting people with rapidly deteriorating health guidance on sharing information between prison staff and healthcare staff, such as details on standardised clinical handovers and follow-up. Ensure prison and healthcare staff are made aware of people who have underlying chronic conditions and allergies: if the person agrees (in line with the local information-sharing policies) in emergencies, in line with the duty of healthcare staff to share relevant confidential patient data. # Continuity of healthcare ## On entry into prison Arrange for the person's medical records to be transferred from primary and secondary care to the prison healthcare team on the person's entry to prison (see recommendation 1.1.6 in the section on following the first-stage health assessment). Primary and secondary care services should provide information from the person's medical records to the prison healthcare team that is: relevant in the person's best interests. ## Transit between custodial settings Ensure continuity of care between custodial settings, including court, the receiving prison or during escort periods by, for example: providing access to relevant information from the patient record providing any medicines (including controlled drugs) – see also the section on continuity of medicines issuing an FP10 prescription. ## Before release from prison Carry out a pre-release health assessment for people with complex needs. This should be led by primary healthcare and involve multidisciplinary team members and the person. It should take place at least 1 month before the date the person is expected to be released. For people who may be in prison for less than 1 month, plan pre-release health assessments during the second-stage health assessment (see recommendation 1.1.13 in the section on second-stage health assessment within 7 days for details of this assessment). Include the following in the care summary and post-release action plan for all people: any significant health events that affected the person while they were in prison, for example: new diagnoses hospital admissions instances of self-harm any health or social care provided in prison details of any ongoing health and social care needs, including: medicines they are taking (see also recommendations 1.7.12 to 1.7.14 in the section on continuity of medicines) mental health or substance misuse future health and social care appointments, including appointments with: secondary and tertiary care mental health services substance misuse and recovery services social services. Give the person a copy of the care summary and post-release plan. Help people who are being released from prison to find and register with a community GP if they were not previously registered with one. Before the person is released, liaise with services that will be providing care and support to them after they leave prison. This should include (as needed): primary care secondary and tertiary specialist services (for example, HIV, TB, oncology) mental health or learning disability services substance misuse services National Probation Service community rehabilitation company (CRC) social services family or carers external agencies such as home care. ## Continuity of medicines Ensure the person can keep taking their medicines after coming into prison. Give critical medicines in a timely way to prevent harm from missed or delayed doses. Use the examples of critical medicines in table 2 in conjunction with clinical judgement and any safety alerts. Area Medicines Cardiovascular system Anticoagulants Nitrates Respiratory system Adrenoceptor agonists Antimuscarinic bronchodilators Adrenaline for allergic emergencies Central nervous system Anti-epileptic drugs Drugs used in psychoses and related disorders Drugs used in parkinsonism and related disorders Drugs used to treat substance misuse Infections As clinically indicated, such as anti-infectives or anti-retrovirals Endocrine system Corticosteroids Drugs used in diabetes Obstetrics, gynaecology and urinary tract disorders Emergency contraceptives Malignant disease and immunosuppression Drugs affecting the immune response Sex hormones and hormone antagonists in malignant disease – depot preparations Nutrition and blood Parenteral vitamins B and C Eye Corticosteroids and other anti-inflammatory preparations Local anaesthetics Mydriatics and cycloplegics Glaucoma treatment Based on UKMi NPSA Rapid Response Report: Reducing harm from omitted and delayed medicines in hospital. Revised January 2016. This table contains examples only and should be used in conjunction with clinical judgement. It is important to assess each person on an individual basis. Hold a one-to-one discussion with the person to agree a plan for how they will take their medicine after their release from prison. This should include education about taking prescribed medicines. Consider carrying out a medicines review for people who are assessed as needing extra support to manage their medicines on release or transfer from prison. For example: people with TB, HIV, diabetes, substance misuse or mental health problems people with neurodevelopmental disorders or learning disabilities people receiving end of life care -lder people people serving long-term sentences. When a person is discharged or transferred from prison, give them a minimum of 7 days' prescribed medicines or an FP10 prescription, based on a risk assessment. Set up a process to ensure that people being discharged or transferred at short notice from prison are given a supply of their medicines or an FP10 prescription. For recommendations on care for people moving from prison to another care setting, see the section on medicines-related communication systems in the NICE guideline on medicines optimisation. # Terms used in this guideline ## Body map A diagram of the body on which physical injuries can be recorded. ## Diversion The transfer of any prescription medicines from the person for whom they were prescribed to another person for misuse. ## FP10 A prescription form. People who are released from prison unexpectedly can take an FP10 to a community pharmacy to receive their medicines free of charge until they can arrange to see their GP or register with a new GP. ## Grab bags Medical emergency bags containing equipment and medication for dealing with common medical emergencies. The equipment may include dressings, automated external defibrillator and oxygen. It may also include medicine, for example, for treating allergic reactions (anaphylaxis). ## In-possession Medicine is said to be held in-possession if a person (usually in a prison or other secure setting) is responsible for holding and taking it themselves. ## Medicines reconciliation The process of identifying an accurate list of a person's current medicines and comparing them with the current list in use, recognising any discrepancies, and documenting any changes, thereby resulting in a complete list of medicines, accurately communicated. Adapted from definition by the Institute for Healthcare Improvement. ## Multidisciplinary team A group of professionals from different disciplines who each provide specific support to a person, working as a team. In prison settings, a multidisciplinary team may include physical and mental health professionals, prison staff, National Probation Service and/or community rehabilitation company (CRC) representatives, chaplains and staff from other agencies, such as immigration services and social care staff. ## Prison Her Majesty's prison establishments, including young offender institutions. ## Street drugs Substances taken for a non-medical purpose (for example, mood-altering, stimulant or sedative effects).# Context In April 2013 NHS England became responsible for commissioning all health services for people in prison in England. Healthcare in prison has a very important role in identifying significant health needs, maintaining health and detecting chronic conditions. This guideline supports equivalence of healthcare in prisons, a principle whereby health services for people in prisons are provided to the same standard, quality and specification as for patients in the wider NHS. Providing equivalence of care aims to address health needs, reduce health inequalities, prevent deterioration, reduce deaths from natural causes and ultimately assist rehabilitation and reduce reoffending. The guideline population includes adults over 18 in prisons or young offender institutions. The prison population includes highly vulnerable groups such as: people with learning disabilities who find it difficult to understand the prison regime and what is happening to them -lder people and those serving longer sentences whose physical health often deteriorates or is exacerbated by previous lifestyle choices during imprisonment people serving short sentences, making it difficult for prison healthcare staff to achieve any sustainable change in their health people who have particular healthcare needs, such as: people with physical disabilities people with a history of substance misuse pregnant women. Since 2006 there have been considerable changes in prison health services. But barriers to delivering health services in custodial settings still exist. These barriers make providing healthcare equivalent to what is available in the community a significant challenge. There are many recognised areas that the prison and healthcare systems need to address to manage the overall safety of people in prison. Key areas of focus for this guideline include: The initial reception assessment and subsequent general health assessments. This includes liaison and communication with external health organisations for the benefit of people's care while in prison or hospital, between establishments and on release. Continuity of healthcare for those moving around the prison estate, including continuity of medicine, a coordinated approach between prison health services, and visiting health services and prison staff. Effective communication between teams, in particular when dealing with complex needs and sharing information to support people's care in the wider prison. Managing emergency situations, which can include high levels of complex needs within the prison population, the staff skills needed to work with this client group and the large numbers of people in prison moving across the prison estate. Procedures and methods to support people in transit between custodial settings or on release to the community. This guidance should be read together with the NICE guideline on the mental health of adults in contact with the criminal justice system. People in prison often have a mix of physical and mental health issues during their sentence. Healthcare professionals working in prisons need a range of skills to assess, diagnose and manage physical health, mental health and addiction problems, as well as underlying complex social and behavioural issues.# Recommendations for research The guideline committee has made the following recommendations for research. # Subsequent health assessment When should subsequent health assessments be carried out in prison for people serving long-term sentences? ## Why this is important Case management of chronic conditions in prison is difficult, and opportunities for self-care may be limited. The number of older people and people serving long sentences in prison is increasing. There is emerging anecdotal evidence that long-term incarceration exacerbates chronic ill health and causes early onset of conditions associated with old age. Research on this topic would help inform whether additional health checks may be needed to prevent potential health deterioration and quickly identify any new health-related conditions. # Chronic conditions What is the prevalence of disease in the UK prison population? ## Why this is important At the time this guideline was published (November 2016), it was estimated that there were around 90,000 people in prison in the UK with an annual throughput of around 180,000. To date, there is little clear evidence of the prevalence of disease among people in prison. This was highlighted by our reviews of chronic conditions (for which there was no disease prevalence data) and when searching for prevalence data for the health economic model. Systems are now in place that will allow the relevant data to be gathered to inform a longitudinal study. Such a study would provide a useful starting point for a better understanding of how to shape healthcare provided to people in prison, both in terms of: meeting the needs of the prison population and providing commissioners with priority areas for developing and delivering health services. # Promoting health and wellbeing What is the most effective method for delivering health promotion activities and who should lead them (peers or professionals)? ## Why this is important There are few data on how health promotion interventions should be delivered and who is best to deliver them. People in prison sometimes find it challenging to use services provided by people they think are in positions of authority, such as prison officers and healthcare professionals. This is acknowledged in the qualitative review in this area. There are many examples of health promotion activities, ranging from information leaflets to one-to-one sessions and group-based learning. If it can be shown which methods of health promotion are more effective, then both the NHS and prisons could better target their resources to inform, educate and support people to take a more active role in looking after themselves. This would lead to greater equivalence of service, a better experience of health promotion activities and more confidence in overall health provision. # Assessment tools for health promotion What are the most effective tools to determine the health promotion needs of people in prison? ## Why this is important Health promotion in prison can vary and may not be seen as a priority by healthcare staff. But people in prison are entitled to an equivalent standard of healthcare to that which they would receive in the community. Prison offers an ideal opportunity to help people who perhaps have not previously attended health services. The prison population is known to have a high prevalence of smoking, often a poor diet and difficulties in accessing exercise programmes or information on sexual health. All of these may exacerbate existing health conditions or lead to poor health or infection. No evidence was identified for health promotion needs assessment and a study would inform future recommendations in this area. An effective, valid assessment tool for identifying health promotion needs would ensure that people received care that met their needs. It may also identify specific healthcare needs more quickly so people can be given information and advice about self-care, both in prison and after release. # Access to medicines Does the use of directly observed supply of named high-risk medicines (that is, not supplying the medicines to people to hold in-possession), reduce diversion, abuse and non-adherence? ## Why this is important Since 2003 self-administration of medicines by people in prison (known as holding medicines 'in-possession') has been encouraged. Directly observed administration is reserved for high-risk medicines and vulnerable patients. But different medicines are categorised as high risk by different prisons so the approach has been inconsistent. This is influenced by local factors including capacity. Delivering directly observed medicines is labour-intensive and difficult to include in the daily schedules of people in prison. There is no evidence base underpinning which medicines should be administered under observation. This research would provide evidence to inform the development of a more consistent list of high-risk medicines that need direct observation to improve safety. The research would also inform commissioners of health and offender management services about the need to provide the workforce and operational capacity to administer high-risk medicines safely.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessing health\n\n## First-stage health assessment at reception into prison\n\nAt first reception into prison, a healthcare professional (or trained healthcare assistant under the supervision of a registered nurse) should carry out a health assessment for every person. Do this before the person is allocated to their cell. As part of the assessment, identify:\n\nany issues that may affect the person's immediate health and safety before the second-stage health assessment\n\npriority health needs to be addressed at the next clinical opportunity.\n\nEnsure continuity of care for people transferring from one custodial setting to another (including court, the receiving prison or during escort periods) by, for example:\n\naccessing relevant information from the patient clinical record, prisoner escort record and cell sharing risk assessment\n\nchecking medicines and any outstanding medical appointments.\n\nTake into account any communication needs or difficulties the person has (including reading and writing ability), and follow the principles in NICE's guideline on patient experience in adult NHS services.\n\nThe first-stage health assessment should include the questions and actions in table\xa01. It should cover:\n\nphysical health\n\nalcohol use\n\nsubstance misuse\n\nmental health\n\nself-harm and suicide risk.\n\nTopic\n\nQuestions\n\nActions\n\nPrison sentence\n\n. Has the person committed murder, manslaughter or another offence with a long sentence?\n\nYes: refer the person for mental health assessment by the prison mental health in-reach team if necessary.\n\nNo: record no action needed.\n\nPrescribed medicines\n\n. Is the person taking any prescribed medicines (for example, insulin) or over-the-counter medicines (such as creams or drops)? If so:\n\nwhat are they\n\nwhat are they for\n\nhow do they take them?\n\nYes: document any current medicines being taken and generate a medicine chart.\n\nRefer the person to the prescriber for appropriate medicines to be prescribed, to ensure continuity of medicines.\n\nIf medicines are being taken, ensure that the next dose has been provided (see recommendations 1.7.10 and 1.7.11 in the section on continuity of medicines).\n\nLet the person know that medicines reconciliation will take place before the second-stage health assessment.\n\nNo: record no action needed.\n\nPhysical injuries\n\n. Has the person received any physical injuries over the past few days, and if so:\n\nwhat were they\n\nhow were they treated?\n\nYes: assess severity of injury, any treatment received and record any significant head, abdominal injuries or fractures.\n\nDocument any bruises or lacerations observed on a body map.\n\nIn very severe cases, or after GP assessment, the person may need to be transferred to an external hospital. Liaise with prison staff to transfer the person to the hospital emergency department by ambulance.\n\nIf the person has made any allegations of assault, record negative observations as well (for example, 'no physical evidence of injury').\n\nNo: record no action needed.\n\nOther health conditions\n\n. Does the person have any of the following:\n\nallergies, asthma, diabetes, epilepsy or history of seizures\n\nchest pain, heart disease\n\nchronic obstructive pulmonary disease\n\ntuberculosis, sickle cell disease\n\nhepatitis\xa0B or\xa0C virus, HIV, other sexually transmitted infections\n\nlearning disabilities\n\nneurodevelopmental disorders\n\nphysical disabilities?\n\nAsk about each condition listed.\n\nYes: make short notes on any details of the person's condition or management. For example, 'Asthma – on Ventolin 1\xa0puff daily'.\n\nMake appointments with relevant clinics or specialist nurses if specific needs have been identified.\n\nNo: record no action needed.\n\n\n\nOther health conditions\n\n. Are there any other health problems the person is aware of that have not been reported?\n\nYes: record the details and check with the person that no other physical health complaint has been overlooked.\n\nNo: record no action needed.\n\nOther health conditions\n\n. Are there any other concerns about the person's health?\n\nYes: make a note of any other concerns about physical health. This should include any health-related observations about the person's physical appearance (for example, weight, pallor, jaundice, gait or frailty).\n\nRefer the person to the GP or relevant clinic.\n\nNo: note 'Nil'.\n\nAdditional question for women\n\n. Does the woman have reason to think she is pregnant, or would she like a pregnancy test?\n\nIf the woman is pregnant, refer to the GP and midwife.\n\nIf there is reason to think the woman is pregnant, or would like a pregnancy test: provide a pregnancy test. Record the outcome. If positive, make an appointment for the woman to see the GP and midwife.\n\nNo: record response.\n\nLiving arrangements, mobility and diet\n\n. Does the person need help to live independently?\n\n\n\nYes: note any needs. Liaise with the prison disability lead in reception about:\n\nthe location of the person's cell\n\nfurther disability assessments the prison may need to carry out.\n\nNo: record response.\n\nLiving arrangements, mobility and diet\n\n. Do they use any equipment or aids (for example, walking stick, hearing aid, glasses, dentures, continence aids or stoma)?\n\nYes: remind prison staff that all special equipment and aids the person uses should follow them from reception to their cell.\n\nNo: record response.\n\nLiving arrangements, mobility and diet\n\n. Do they need a special medical diet?\n\n\n\nYes: confirm the need for a special medical diet. Note the medical diet the person needs and send a request to catering. Refer to appropriate clinic for ongoing monitoring.\n\nNo: record response.\n\nPast or future medical appointments\n\n. Has the person seen a doctor or other healthcare professional in the past few months? If so, what this was for?\n\n\n\nYes: note details of any recent medical contact. Arrange a contact letter to get further information from the person's doctor or specialist clinic. Note any ongoing treatment the person needs and make appointments with relevant clinics, specialist nurses, GP or other healthcare staff.\n\nNo: record no action needed.\n\nPast or future medical appointments\n\n. Does the person have any outstanding medical appointments? If so, who are they with, and when?\n\nYes: note future appointment dates. Ask healthcare administrative staff to manage these appointments or arrange for new dates and referral letters to be sent if the person's current hospital is out of the local area.\n\nNo: record no action needed.\n\nAlcohol and substance misuse\n\n. Does the person drink alcohol, and if so:\n\nhow much do they normally drink?\n\nhow much did they drink in the week before coming into custody?\n\nUrgently refer the person to the GP or an alternative suitable healthcare professional if:\n\nthey drink more than 15\xa0units of alcohol daily or\n\nthey are showing signs of withdrawal or\n\nthey have been given medication for withdrawal in police or court cells.\n\nNo: record response.\n\nAlcohol and substance misuse\n\n. Has the person used street drugs in the last month? If so, how frequently?\n\nWhen did they last use:\n\nheroin\n\nmethadone\n\nbenzodiazepines\n\namphetamine\n\ncocaine or crack\n\nnovel psychoactive substances\n\ncannabis\n\nanabolic steroids\n\nperformance and image enhancing drugs?\n\nYes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support. Take into account whether:\n\nthey have taken drugs intravenously\n\nthey have a positive urine test for drugs\n\ntheir answers suggest that they use drugs more than once a week\n\nthey have been given medication for withdrawal in police or court cells.\n\nIf the person has used intravenous drugs, check them for injection sites. Refer them to substance misuse services if there are concerns about their immediate clinical management and they need immediate support.\n\nNo: record response.\n\nProblematic use of prescription medicines\n\n. Has the person used prescription or over-the-counter medicines in the past month:\n\nthat were not prescribed or recommended for them or\n\nfor purposes or at doses that were not prescribed?\n\nIf so, what was the medicine and how did they use it (frequency and dose)?\n\nYes: refer the person to substance misuse services if there are concerns about their immediate clinical management and they need immediate support.\n\nNo: record response.\n\nMental health\n\n. Has the person ever seen a healthcare professional or service about a mental health problem (including a psychiatrist, GP, psychologist, counsellor, community mental health services, alcohol or substance misuse services or learning disability services)?\n\nIf so, who did they see and what was the nature of the problem?\n\nYes: refer the person for a mental health assessment if they have previously seen a mental health professional in any service setting.\n\nNo: record response.\n\nMental health\n\n. Has the person ever been admitted to a psychiatric hospital, and if so:\n\nwhen was their most recent discharge\n\nwhat is the name of the hospital\n\nwhat is the name of their consultant?\n\nYes: refer the person for a mental health assessment.\n\nNo: record response.\n\nMental health\n\n. Has the person ever been prescribed medicine for any mental health problems? If so:\n\nwhat was the medicine\n\nwhen did they receive it\n\nwhen did they take the last dose\n\nwhat is the current dose (if they are still taking it)\n\nwhen did they stop taking it?\n\nYes: refer the person for a mental health assessment if they have taken medicine for mental health problems.\n\nNo: record response\n\nSelf-harm and suicide risk\n\n. Is the person:\n\nfeeling hopeless or\n\ncurrently thinking about or planning to harm themselves or attempt suicide?\n\nYes: refer the person for an urgent mental health assessment. Open an Assessment, Care in Custody and Teamwork (ACCT) plan if:\n\nthere are serious concerns raised in response to questions about self-harm, including thoughts, intentions or plans, or observations (for example, the patient is very withdrawn or agitated) or\n\nthe person has a history of previous suicide attempts.\n\nBe aware and record details of the impact of the sentence on the person, changes in legal status and first imprisonment, and the nature of the offence (for example, murder, manslaughter, offence against the person and sexual offences).\n\nNo: record response.\n\nSelf-harm and suicide risk\n\n. Has the person ever tried to harm themselves, and if so:\n\ndo they have a history of suicide attempts\n\nwas this inside or outside prison\n\nwhen was the most recent incident\n\nwhat was the most serious incident?\n\nYes: refer the person for a mental health assessment if they have ever tried to harm themselves.\n\nNo: record response.\n\n\n\n## Following the first-stage health assessment\n\nGive the person advice about how to contact prison health services and book GP appointments in the future.\n\nAsk the person for consent to transfer their medical records from their GP to the prison healthcare service (see the section on continuity of healthcare on entry to prison for more information about transfer of medical records).\n\nEnter in the person's medical record:\n\nall answers to the reception health assessment questions\n\nhealth-related observations, including those about behaviour and mental state (including eye contact, body language, rapid, slow or strange speech, poor hygiene, strange thoughts)\n\ndetails of any action taken.\n\nCarry out a medicines reconciliation (in line with NICE's guideline on medicines optimisation) before the second-stage health assessment. See recommendation 1.4.1 in the section on access to medicines and recommendation 1.7.10 in the section on continuity of medicines for recommendations on risk assessments for in-possession medicines and ensuring continuity of medicine.\n\n## Tuberculosis screening within 48\xa0hours\n\nThe recommendations in this section have been adapted from the NICE guideline on tuberculosis (TB).\n\nHealthcare professionals in prisons should ensure people coming into prison are screened for TB within 48\xa0hours of arrival.\n\nReport all suspected and confirmed TB cases to the local multidisciplinary TB team within 1\xa0working day.\n\nIf a case of TB is confirmed:\n\nArrange for the local multidisciplinary TB team to visit within 5\xa0working days.\n\nContact the local Public Health England unit and multidisciplinary TB team to arrange a contact investigations exercise. They should also consider using mobile X‑ray to check for further cases.\n\nPut contingency, liaison and handover plans in place to ensure continuity of care before a person being treated for TB is transferred between prisons or released. Any other agencies working with the person should also be involved in this planning.\n\n## Second-stage health assessment within 7\xa0days\n\nA healthcare professional (for example, a registered general nurse) should carry out a second-stage health assessment for every person in prison. Do this within 7\xa0days of the first-stage health assessment, and include as a minimum:\n\nreviewing the actions and outcomes from the first-stage health assessment\n\nasking the person about:\n\n\n\nany previous misuse of alcohol, use of drugs or improper use of prescription medicine\n\nif they have ever suffered a head injury or lost consciousness, and if so:\n\n\n\nhow many times this has happened\n\nwhether they have ever been unconscious for more than 20\xa0minutes\n\nwhether they have any problems with their memory or concentration\n\n\n\nsmoking history\n\nthe date of their last sexual health screen\n\nany history of serious illness in their family (for example, heart disease, diabetes, epilepsy, cancer or chronic conditions)\n\ntheir expected release date, and if less than 1\xa0month plan a pre-release health assessment: see recommendation 1.7.5 in the section on before release from prison\n\nwhether they have ever had a screening test (for example, a cervical screening test or mammogram)\n\nwhether they have, or have had, any gynaecological problems\n\n\n\nmeasuring and recording the person's height, weight, pulse, blood pressure and temperature, and carrying out a urinalysis.\n\nReview the person's first- and second-stage health assessment records, medical history, GP and vaccination records and:\n\nRefer the person to the GP or a relevant clinic if further assessment is needed. See, for example, recommendations on identifying people for full formal risk assessment in the NICE guideline on cardiovascular disease or the recommendation on risk assessment in NICE's guideline on type 2 diabetes.\n\nArrange a follow-up appointment if needed.\n\nConsider using the Correctional Mental Health Screen for Men (CMHS‑M) or Women (CMHS‑W) to identify possible mental health problems if:\n\nthe person's history, presentation or behaviour suggests they may have a mental health problem\n\nthe person's responses to the first-stage health assessment suggest they may have a mental health problem\n\nthe person has a chronic physical health problem with associated functional impairment\n\nconcerns have been raised by other agencies about the person's abilities to participate in the criminal justice process.\n\nWhen using the CMHS‑M or CMHS‑W with a transgender person, use the measure that is in line with their preferred gender identity.\n\nIf there is other evidence supporting the likelihood of mental health problems, or a man scores 6\xa0or more on the CMHS‑M, or a woman scores 4\xa0or more on the CMHS‑W:\n\na practitioner who is trained to perform an assessment of mental health problems should conduct further assessment or\n\na practitioner who is not trained to perform an assessment of mental health problems should refer the person to an appropriately trained professional for further assessment.\n\nOffer people tailored health advice based on their responses to the assessment questions. This should be in a variety of formats (including face-to-face). It should include advice on:\n\nalcohol (see\xa0NICE's guideline on alcohol-use disorders)\n\nsubstance misuse (see\xa0NICE's guideline on drug misuse in over\xa016s)\n\nexercise (see recommendations on exercise in the section on promoting health and wellbeing)\n\ndiet (see recommendation 1.3.5 on diet in the section on promoting health and wellbeing)\n\nstopping smoking (see recommendation 1.3.6 on stopping smoking in the section on promoting health and wellbeing)\n\nsexual health (see recommendations 1.3.7 and 1.3.8 on sexual health in the section on promoting health and wellbeing).\n\nOffer the person advice, with supporting literature if appropriate, on:\n\nhow to contact prison health services and book GP appointments or other clinics, for example, dental, optician, chiropodist, substance misuse and recovery services\n\nwhere to find health information that is accessible and understandable\n\nhow to attend or get a referral to attend any health-promoting activities in the future (see the section on promoting health and wellbeing)\n\nmedicines adherence (see recommendation 1.4.7 in the section on access to medicines).\n\nEnter in the person's medical record:\n\nall answers to the second-stage health assessment questions\n\nhealth-related observations\n\ndetails of any action taken.\n\nPlan a follow-up healthcare review at a suitable time based on clinical judgement, taking into account the age of the person and length of their sentence. For people who may be in prison for less than 1\xa0month, see recommendation 1.7.5 in the section on before release from prison.\n\n## Health checks and screening\n\nEnsure that there is a system and processes in place to carry out and refer to other assessments in line with recommendations in NICE guidelines.\n\nThe recommendations in this section have been adapted from the NICE guideline on hepatitis B and C testing.\n\nPrison healthcare services (working with the NHS lead for hepatitis) should ensure that:\n\nall people are offered a hepatitis B vaccination when entering prison (for the vaccination schedule, refer to the Green Book)\n\nall people are offered access to confidential testing for hepatitis\xa0B and\xa0C when entering prison and during their detention\n\npeople who test for hepatitis\xa0B or\xa0C receive the results of the test, regardless of their location, when they become available\n\nresults from hepatitis\xa0B and\xa0C testing are provided to the person's community-based GP, if consent is given.\n\nThe recommendations in this section have been adapted from the NICE guideline on HIV testing.\n\nOffer all people HIV testing when entering prison.\n\nPrimary care providers should ensure annual HIV testing is part of the integrated healthcare offered to men who are known to have sex with men.\n\nProvide information on HIV testing and discuss why it is recommended (including to those who indicate that they may wish to decline the test).\n\nConduct post-test discussions, including giving positive test results and delivering post-test and general health promotion interventions.\n\nRecognise illnesses that may signify primary HIV infection and clinical indicator diseases that often coexist with HIV.\n\nThe recommendations in this section have been adapted from the NICE guideline on sexually transmitted infections.\n\nIdentify people at high risk of STIs using their sexual history. Opportunities for risk assessment may arise during consultations on contraception, pregnancy or abortion, and when carrying out a cervical smear test or offering an STI test. Risk assessment could also be carried out during routine care or when a new patient registers.\n\nHave structured, one-to-one discussions with people at high risk of STIs (if trained in sexual health), or arrange for these discussions to take place with a trained practitioner.\n\nOffer people equivalent health checks to those offered in the community, for example:\n\nthe NHS health check programme\n\nlearning disabilities annual health check\n\nrelevant NHS screening programmes, such as those for abdominal aortic aneurysm and bowel, breast and cervical cancer.\n\n# Communication and coordination\n\nEnsure that the different teams (including prison staff) that manage a person's care in prison communicate with one another to coordinate care.\n\nShare information with other health and social care staff, offender supervisors and probation providers who are involved in the person's care in prison if necessary for the person's care.\n\nEnsure that people with complex health and social care needs have a lead care coordinator responsible for managing their care. Ensure that the person and all healthcare and prison staff know who this is.\n\nShare relevant information about people with complex needs with prison staff using prison record systems in line with legislation and national guidance. This should include information about any high-level risks, such as:\n\nrisk of self-harm\n\nrisk to others\n\ncommunicable diseases\n\nepilepsy\n\ndiabetes\n\nallergies\n\ndeteriorating health conditions\n\nlearning disabilities.\n\nReview people in prison with complex health and social care needs. Ensure that if a person is supported by a multidisciplinary team, the teams meet regularly to plan and coordinate ongoing management. These should be facilitated by primary care.\n\nDocument all health and social care patient interactions and any information related to health and social care in the person's primary care patient record.\n\n# Promoting health and wellbeing\n\n## General health advice\n\nConsider using peer support and mentoring to help promote a healthy lifestyle while in prison.\n\nOffer people in prison tailored health information in a variety of formats, including face-to-face. Include advice about:\n\nexercise\n\ndiet\n\nstopping smoking\n\nsexual health\n\npersonal hygiene, including oral hygiene.\n\n## Exercise\n\nEncourage people to be physically active. Offer them information about:\n\nthe benefits of exercise\n\nwhat exercise facilities are provided, where they are and how they can use them, for example:\n\n\n\ngoing to the gym\n\nusing the exercise yard\n\n\n\nexercises that can be done in the cell.\n\nOffer people information and advice in line with recommendations in the NICE guidelines on:\n\nphysical activity: brief advice for adults in primary care\n\nphysical activity: exercise referral schemes\n\npreventing excess weight gain\n\nobesity: identification, assessment and management (section\xa01.6 on physical activity).\n\n## Diet\n\nOffer people information about:\n\nthe benefits of a healthy diet\n\nhealthier food options available in the prison.See the section\xa0on dietary advice in the NICE guideline on obesity: identification, assessment and management.\n\n## Stopping smoking\n\nOffer people in prison information about:\n\nthe risks of smoking\n\nsupport available to stop as part of smoking cessation services (for example, nicotine patches and motivational support). See the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence.\n\n## Sexual health\n\nOffer people in prison information about sexually transmitted infections and available sexual health services.\n\nEnsure that people in prison have discreet access to condoms, dental dams and water-based lubricants without the need to ask for them.\n\n# Managing medicines\n\n## Access to medicines\n\nCarry out an individual risk assessment to determine if the person can hold their medicines in-possession. Allow people in prison to hold all medicine in-possession unless the person does not pass the risk assessment.\n\nDirectly observe the administration of all schedule\xa02 and\xa03 medicines (also see NICE's guideline on controlled drugs) and medicines for tuberculosis (see NICE guideline on tuberculosis).\n\nDirectly observe the administration of any medicine that is not in-possession.\n\nWork with prison staff to ensure a system is in place to:\n\nsupervise the administering of medicines not held in-possession to maximise adherence\n\nallow timings of medicines doses to align with the prescribed dose regime\n\nreduce diversion (passing medicines on to other people)\n\nprotect confidentiality. See the section on supporting adherence in the NICE guideline on medicines adherence.\n\nReview and (if necessary) repeat a person's risk assessment for in-possession medicine if the person's circumstances change. Involve a multidisciplinary team if needed, including prison staff and the person. Examples of when the risk assessment should be repeated include:\n\nif carrying out a medicines review\n\nif a person is considered able to manage their own medicines after a period of having medicines not in-possession\n\nif there is a medicine safety incident, including evidence of self-harm\n\nif someone has raised security concerns (for example, about bullying, diversion or hoarding)\n\nif the person has not been taking their prescribed medicines\n\nif there is concern about the person's ability to self-medicate\n\nwhen following the Assessment Care in Custody and Teamwork care planning approach\n\nif the person is transferred to or from a segregation unit.\n\nConsider providing storage for in-possession medicine in prison cells, for example, a lockable cupboard.\n\nGive people in prison information and education about medicines adherence (see the section on patient involvement in decisions about medicines in the NICE guideline on medicines adherence).\n\n# Monitoring chronic conditions\n\nMonitor people with chronic conditions in accordance with the following NICE guidelines:\n\nchronic heart failure\n\nchronic kidney disease\n\nchronic obstructive pulmonary disease\n\nepilepsies\n\nhypertension\n\nacute coronary syndromes\n\ntype\xa01 diabetes and type\xa02 diabetes.See also the NICE quality standard on asthma.\n\nMonitor people with chronic conditions that need specialist management in line with relevant NICE guidelines (for example, the NICE guideline on hepatitis\xa0B (chronic) and colorectal cancer).\n\nConsider more frequent monitoring for older people and people with chronic conditions (such as diabetes) who are serving longer prison sentences.\n\n# Managing deteriorating health and health emergencies\n\nEnsure a local protocol is available for responding to and managing situations in which a person's health quickly deteriorates, or in a health emergency. This could include, for example:\n\nessential training for front-line prison staff, including the first person likely to be on the scene in an emergency\n\nprocesses to enable healthcare staff to reach a person in prison quickly, such as how to gain access to their cell\n\nprocesses to ensure a person can be quickly seen by a healthcare professional if their health deteriorates quickly\n\navailability of emergency equipment, such as emergency grab bags\n\nrecording the actions and observations taken by prison and healthcare staff when assessing people with rapidly deteriorating health or in an emergency situation, such as:\n\n\n\nupdating a person's care plan or\n\nrecommendations for immediate follow-up\n\n\n\na clear care plan for supporting people with rapidly deteriorating health\n\nguidance on sharing information between prison staff and healthcare staff, such as details on standardised clinical handovers and follow-up.\n\nEnsure prison and healthcare staff are made aware of people who have underlying chronic conditions and allergies:\n\nif the person agrees (in line with the local information-sharing policies)\n\nin emergencies, in line with the duty of healthcare staff to share relevant confidential patient data.\n\n# Continuity of healthcare\n\n## On entry into prison\n\nArrange for the person's medical records to be transferred from primary and secondary care to the prison healthcare team on the person's entry to prison (see recommendation 1.1.6 in the section on following the first-stage health assessment).\n\nPrimary and secondary care services should provide information from the person's medical records to the prison healthcare team that is:\n\nrelevant\n\nin the person's best interests.\n\n## Transit between custodial settings\n\nEnsure continuity of care between custodial settings, including court, the receiving prison or during escort periods by, for example:\n\nproviding access to relevant information from the patient record\n\nproviding any medicines (including controlled drugs) – see also the section on continuity of medicines\n\nissuing an FP10 prescription.\n\n## Before release from prison\n\nCarry out a pre-release health assessment for people with complex needs. This should be led by primary healthcare and involve multidisciplinary team members and the person. It should take place at least 1\xa0month before the date the person is expected to be released.\n\nFor people who may be in prison for less than 1\xa0month, plan pre-release health assessments during the second-stage health assessment (see recommendation 1.1.13 in the section on second-stage health assessment within 7 days for details of this assessment).\n\nInclude the following in the care summary and post-release action plan for all people:\n\nany significant health events that affected the person while they were in prison, for example:\n\n\n\nnew diagnoses\n\nhospital admissions\n\ninstances of self-harm\n\n\n\nany health or social care provided in prison\n\ndetails of any ongoing health and social care needs, including:\n\n\n\nmedicines they are taking (see also recommendations 1.7.12 to 1.7.14 in the section on continuity of medicines)\n\nmental health or substance misuse\n\n\n\nfuture health and social care appointments, including appointments with:\n\n\n\nsecondary and tertiary care\n\nmental health services\n\nsubstance misuse and recovery services\n\n\n\nsocial services.\n\nGive the person a copy of the care summary and post-release plan.\n\nHelp people who are being released from prison to find and register with a community GP if they were not previously registered with one.\n\nBefore the person is released, liaise with services that will be providing care and support to them after they leave prison. This should include (as needed):\n\nprimary care\n\nsecondary and tertiary specialist services (for example, HIV, TB, oncology)\n\nmental health or learning disability services\n\nsubstance misuse services\n\nNational Probation Service\n\ncommunity rehabilitation company (CRC)\n\nsocial services\n\nfamily or carers\n\nexternal agencies such as home care.\n\n## Continuity of medicines\n\nEnsure the person can keep taking their medicines after coming into prison.\n\nGive critical medicines in a timely way to prevent harm from missed or delayed doses. Use the examples of critical medicines in table\xa02 in conjunction with clinical judgement and any safety alerts.\n\nArea\n\nMedicines\n\nCardiovascular system\n\nAnticoagulants\n\nNitrates\n\nRespiratory system\n\nAdrenoceptor agonists\n\nAntimuscarinic bronchodilators\n\nAdrenaline for allergic emergencies\n\nCentral nervous system\n\nAnti-epileptic drugs\n\nDrugs used in psychoses and related disorders\n\nDrugs used in parkinsonism and related disorders\n\nDrugs used to treat substance misuse\n\nInfections\n\nAs clinically indicated, such as anti-infectives or anti-retrovirals\n\nEndocrine system\n\nCorticosteroids\n\nDrugs used in diabetes\n\nObstetrics, gynaecology and urinary tract disorders\n\nEmergency contraceptives\n\nMalignant disease and immunosuppression\n\nDrugs affecting the immune response\n\nSex hormones and hormone antagonists in malignant disease – depot preparations\n\nNutrition and blood\n\nParenteral vitamins B and C\n\nEye\n\nCorticosteroids and other anti-inflammatory preparations\n\nLocal anaesthetics\n\nMydriatics and cycloplegics\n\nGlaucoma treatment\n\n\n\nBased on UKMi NPSA Rapid Response Report: Reducing harm from omitted and delayed medicines in hospital. Revised January 2016.\n\nThis table contains examples only and should be used in conjunction with clinical judgement. It is important to assess each person on an individual basis.\n\nHold a one-to-one discussion with the person to agree a plan for how they will take their medicine after their release from prison. This should include education about taking prescribed medicines.\n\nConsider carrying out a medicines review for people who are assessed as needing extra support to manage their medicines on release or transfer from prison. For example:\n\npeople with TB, HIV, diabetes, substance misuse or mental health problems\n\npeople with neurodevelopmental disorders or learning disabilities\n\npeople receiving end of life care\n\nolder people\n\npeople serving long-term sentences.\n\nWhen a person is discharged or transferred from prison, give them a minimum of 7\xa0days' prescribed medicines or an FP10 prescription, based on a risk assessment.\n\nSet up a process to ensure that people being discharged or transferred at short notice from prison are given a supply of their medicines or an FP10 prescription.\n\nFor recommendations on care for people moving from prison to another care setting, see the section on medicines-related communication systems in the NICE guideline on medicines optimisation.\n\n# Terms used in this guideline\n\n## Body map\n\nA diagram of the body on which physical injuries can be recorded.\n\n## Diversion\n\nThe transfer of any prescription medicines from the person for whom they were prescribed to another person for misuse.\n\n## FP10\n\nA prescription form. People who are released from prison unexpectedly can take an FP10 to a community pharmacy to receive their medicines free of charge until they can arrange to see their GP or register with a new GP.\n\n## Grab bags\n\nMedical emergency bags containing equipment and medication for dealing with common medical emergencies. The equipment may include dressings, automated external defibrillator and oxygen. It may also include medicine, for example, for treating allergic reactions (anaphylaxis).\n\n## In-possession\n\nMedicine is said to be held in-possession if a person (usually in a prison or other secure setting) is responsible for holding and taking it themselves.\n\n## Medicines reconciliation\n\nThe process of identifying an accurate list of a person's current medicines and comparing them with the current list in use, recognising any discrepancies, and documenting any changes, thereby resulting in a complete list of medicines, accurately communicated. Adapted from definition by the Institute for Healthcare Improvement.\n\n## Multidisciplinary team\n\nA group of professionals from different disciplines who each provide specific support to a person, working as a team. In prison settings, a multidisciplinary team may include physical and mental health professionals, prison staff, National Probation Service and/or community rehabilitation company (CRC) representatives, chaplains and staff from other agencies, such as immigration services and social care staff.\n\n## Prison\n\nHer Majesty's prison establishments, including young offender institutions.\n\n## Street drugs\n\nSubstances taken for a non-medical purpose (for example, mood-altering, stimulant or sedative effects).", 'Context': "In April 2013 NHS England became responsible for commissioning all health services for people in prison in England. Healthcare in prison has a very important role in identifying significant health needs, maintaining health and detecting chronic conditions. This guideline supports equivalence of healthcare in prisons, a principle whereby health services for people in prisons are provided to the same standard, quality and specification as for patients in the wider NHS. Providing equivalence of care aims to address health needs, reduce health inequalities, prevent deterioration, reduce deaths from natural causes and ultimately assist rehabilitation and reduce reoffending.\n\nThe guideline population includes adults over\xa018 in prisons or young offender institutions. The prison population includes highly vulnerable groups such as:\n\npeople with learning disabilities who find it difficult to understand the prison regime and what is happening to them\n\nolder people and those serving longer sentences whose physical health often deteriorates or is exacerbated by previous lifestyle choices during imprisonment\n\npeople serving short sentences, making it difficult for prison healthcare staff to achieve any sustainable change in their health\n\npeople who have particular healthcare needs, such as:\n\n\n\npeople with physical disabilities\n\npeople with a history of substance misuse\n\npregnant women.\n\n\n\nSince 2006 there have been considerable changes in prison health services. But barriers to delivering health services in custodial settings still exist. These barriers make providing healthcare equivalent to what is available in the community a significant challenge. There are many recognised areas that the prison and healthcare systems need to address to manage the overall safety of people in prison. Key areas of focus for this guideline include:\n\nThe initial reception assessment and subsequent general health assessments. This includes liaison and communication with external health organisations for the benefit of people's care while in prison or hospital, between establishments and on release.\n\nContinuity of healthcare for those moving around the prison estate, including continuity of medicine, a coordinated approach between prison health services, and visiting health services and prison staff.\n\nEffective communication between teams, in particular when dealing with complex needs and sharing information to support people's care in the wider prison.\n\nManaging emergency situations, which can include high levels of complex needs within the prison population, the staff skills needed to work with this client group and the large numbers of people in prison moving across the prison estate.\n\nProcedures and methods to support people in transit between custodial settings or on release to the community.\n\nThis guidance should be read together with the NICE guideline on the mental health of adults in contact with the criminal justice system. People in prison often have a mix of physical and mental health issues during their sentence. Healthcare professionals working in prisons need a range of skills to assess, diagnose and manage physical health, mental health and addiction problems, as well as underlying complex social and behavioural issues.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Subsequent health assessment\n\nWhen should subsequent health assessments be carried out in prison for people serving long-term sentences?\n\n## Why this is important\n\nCase management of chronic conditions in prison is difficult, and opportunities for self-care may be limited. The number of older people and people serving long sentences in prison is increasing. There is emerging anecdotal evidence that long-term incarceration exacerbates chronic ill health and causes early onset of conditions associated with old age. Research on this topic would help inform whether additional health checks may be needed to prevent potential health deterioration and quickly identify any new health-related conditions.\n\n# Chronic conditions\n\nWhat is the prevalence of disease in the UK prison population?\n\n## Why this is important\n\nAt the time this guideline was published (November 2016), it was estimated that there were around 90,000\xa0people in prison in the UK with an annual throughput of around 180,000. To date, there is little clear evidence of the prevalence of disease among people in prison. This was highlighted by our reviews of chronic conditions (for which there was no disease prevalence data) and when searching for prevalence data for the health economic model.\n\nSystems are now in place that will allow the relevant data to be gathered to inform a longitudinal study. Such a study would provide a useful starting point for a better understanding of how to shape healthcare provided to people in prison, both in terms of:\n\nmeeting the needs of the prison population and\n\nproviding commissioners with priority areas for developing and delivering health services.\n\n# Promoting health and wellbeing\n\nWhat is the most effective method for delivering health promotion activities and who should lead them (peers or professionals)?\n\n## Why this is important\n\nThere are few data on how health promotion interventions should be delivered and who is best to deliver them. People in prison sometimes find it challenging to use services provided by people they think are in positions of authority, such as prison officers and healthcare professionals. This is acknowledged in the qualitative review in this area.\n\nThere are many examples of health promotion activities, ranging from information leaflets to one-to-one sessions and group-based learning. If it can be shown which methods of health promotion are more effective, then both the NHS and prisons could better target their resources to inform, educate and support people to take a more active role in looking after themselves. This would lead to greater equivalence of service, a better experience of health promotion activities and more confidence in overall health provision.\n\n# Assessment tools for health promotion\n\nWhat are the most effective tools to determine the health promotion needs of people in prison?\n\n## Why this is important\n\nHealth promotion in prison can vary and may not be seen as a priority by healthcare staff. But people in prison are entitled to an equivalent standard of healthcare to that which they would receive in the community. Prison offers an ideal opportunity to help people who perhaps have not previously attended health services. The prison population is known to have a high prevalence of smoking, often a poor diet and difficulties in accessing exercise programmes or information on sexual health. All of these may exacerbate existing health conditions or lead to poor health or infection.\n\nNo evidence was identified for health promotion needs assessment and a study would inform future recommendations in this area. An effective, valid assessment tool for identifying health promotion needs would ensure that people received care that met their needs. It may also identify specific healthcare needs more quickly so people can be given information and advice about self-care, both in prison and after release.\n\n# Access to medicines\n\nDoes the use of directly observed supply of named high-risk medicines (that is, not supplying the medicines to people to hold in-possession), reduce diversion, abuse and non-adherence?\n\n## Why this is important\n\nSince 2003 self-administration of medicines by people in prison (known as holding medicines 'in-possession') has been encouraged. Directly observed administration is reserved for high-risk medicines and vulnerable patients. But different medicines are categorised as high risk by different prisons so the approach has been inconsistent. This is influenced by local factors including capacity. Delivering directly observed medicines is labour-intensive and difficult to include in the daily schedules of people in prison.\n\nThere is no evidence base underpinning which medicines should be administered under observation. This research would provide evidence to inform the development of a more consistent list of high-risk medicines that need direct observation to improve safety. The research would also inform commissioners of health and offender management services about the need to provide the workforce and operational capacity to administer high-risk medicines safely."}	https://www.nice.org.uk/guidance/ng57	This guideline covers assessing, diagnosing and managing physical health problems of people in prison. It aims to improve health and wellbeing in the prison population by promoting more coordinated care and more effective approaches to prescribing, dispensing and supervising medicines.
ed55137435b9c28085d73441e25d52497b141ee7	nice	Elbasvir–grazoprevir for treating chronic hepatitis C	Elbasvir–grazoprevir for treating chronic hepatitis C Evidence-based recommendations on elbasvir–grazoprevir (Zepatier) for treating genotype 1 or 4 chronic hepatitis C in adults. # Recommendations Elbasvir–grazoprevir is recommended, within its marketing authorisation, as an option for treating genotype 1 or 4 chronic hepatitis C in adults, as specified in table 1, only if the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit. Table 1 Elbasvir–grazoprevir for treating chronic hepatitis C in adults Genotype Treatment and duration a Elbasvir–grazoprevir for 12 weeks. Consider elbasvir–grazoprevir plus ribavirin for 16 weeks in people with a baseline hepatitis C virus RNA level of more than 800,000 IU/ml or specific NS5A polymorphisms causing at least a 5‑fold reduction in activity of elbasvir. b Elbasvir–grazoprevir for 12 weeks. Elbasvir–grazoprevir for 12 weeks. Consider elbasvir‑grazoprevir plus ribavirin for 16 weeks in people with a baseline hepatitis C virus RNA level of more than 800,000 IU/ml. It is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.# The technology Description of the technology Elbasvir–grazoprevir (Zepatier, Merck Sharp & Dohme) is a fixed-dose combination drug. Elbasvir inhibits hepatitis C virus (HCV) non‑structural viral protein NS5A and grazoprevir inhibits HCV NS3/4A protease. Marketing authorisation Elbasvir–grazoprevir has a marketing authorisation in the UK for treating chronic hepatitis C in adults. The recommendations in the marketing authorisation for the specific genotypes are listed below: genotype 1a: 12 weeks (16 weeks plus ribavirin should be considered in patients with baseline HCV RNA level >800,000 IU/ml or the presence of specific NS5A polymorphisms causing at least a 5‑fold reduction in activity of elbasvir to minimise the risk of treatment failure) genotype 1b: 12 weeks genotype 4: 12 weeks (16 weeks plus ribavirin should be considered in patients with baseline HCV RNA level >800,000 IU/ml to minimise the risk of treatment failure). Adverse reactions The summary of product characteristics includes headache and fatigue as very common adverse reactions, and nausea as a common reaction. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule It is taken orally. The recommended dose of elbasvir–grazoprevir is 1 tablet once daily. Each tablet contains 50 mg elbasvir and 100 mg grazoprevir. Price Elbasvir–grazoprevir costs £12,166.67 per 28‑day pack. The total cost of a 12‑week treatment course is £36,500. The company has agreed a nationally available price reduction for elbasvir–grazoprevir with the Commercial Medicines Unit. The contract prices agreed through the framework are commercial in confidence.# Evidence The appraisal committee (section 6) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of elbasvir–grazoprevir, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of elbasvir–grazoprevir by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical need and practice The committee heard from the clinical and patient experts that people who have chronic hepatitis C are a disadvantaged population and often have to cope with stigma and discrimination because people associate hepatitis C with drug use. The clinical experts stated that because of the introduction of the newer direct-acting antivirals, treatment with peginterferon alpha plus ribavirin is gradually diminishing in clinical practice, particularly for genotypes 1 and 4. However, they highlighted that some of these newer treatments are given in combination with peginterferon alpha or ribavirin. The committee heard from the patient experts that having treatment options that are free from peginterferon alpha with or without ribavirin is important to people with chronic hepatitis C because of the associated adverse reactions. The clinical experts stated that people with renal disease are an important group whose condition is difficult to treat because there are few treatment regimens without ribavirin, especially for people who also have compensated cirrhosis. The committee heard that elbasvir–grazoprevir does not have to be used with ribavirin, an important advantage for improved tolerability in people with renal disease. The committee also heard that elbasvir–grazoprevir provided another alternative to the existing oral treatment combinations for people with genotype 1 and 4 hepatitis C virus (HCV). Therefore the committee recognised the importance of having an additional effective and tolerable treatment for people with chronic hepatitis C and concluded that elbasvir–grazoprevir could be a valuable option for genotype 1 and 4 HCV. The committee discussed the relevant comparators for elbasvir–grazoprevir given the changes in managing chronic hepatitis C. It noted that the company did not include boceprevir and telaprevir as comparators because they are no longer used in clinical practice, although the NICE scope included them. The committee also noted that the company included peginterferon alpha plus ribavirin as a comparator alongside the newer treatments, although it has been less commonly used since new direct-acting antivirals were introduced. The committee questioned whether it was appropriate to keep peginterferon alpha plus ribavirin as a comparator, given the argument for excluding boceprevir and telaprevir. It heard from a clinical expert that peginterferon alpha plus ribavirin is associated with toxicities and these were worsened by adding other toxic treatments, such as boceprevir or telaprevir, which is why boceprevir and telaprevir are no longer used. The clinical expert stated that although treatment with peginterferon plus ribavirin for genotype 1 and 4 HCV is rapidly diminishing, its use in clinical practice has not completely stopped. The clinical experts confirmed that the new direct-acting antivirals would be the most relevant comparators for elbasvir–grazoprevir. The committee accepted the views of the clinical experts and concluded that the most relevant comparators are the new direct-acting antivirals and acknowledged that peginterferon alpha plus ribavirin may be used for a small number of people. # Clinical effectiveness The committee considered the clinical evidence for elbasvir–grazoprevir, which came from 8 clinical trials. It noted that 4 of these trials had a comparator arm (3 placebo-controlled trials and 1 active-controlled trial with sofosbuvir plus peginterferon alpha plus ribavirin), but the rest did not. The committee was aware that the evidence review group (ERG) agreed with the company's assessment that the risk of bias in the trials was generally low. The committee noted that the results of the clinical trials showed high sustained virological response (SVR) at 12 weeks for elbasvir–grazoprevir; ranging from 67% (for genotype 4 in some of the trials) to over 90% in most of the trials and up to 100% in some cases, irrespective of genotype, cirrhosis stage or treatment experience. The committee also noted that the SVR rates for elbasvir–grazoprevir and sofosbuvir plus peginterferon alpha plus ribavirin were comparable in people with genotype 1a HCV, but higher for elbasvir–grazoprevir than sofosbuvir plus peginterferon alpha plus ribavirin in genotype 1b HCV. Having noted the high SVR rates as well as the ERG and the company's comments that the risk of bias in the trials was generally low, the committee concluded that the trials showed that elbasvir–grazoprevir was effective in people with genotype 1 and 4 HCV. The committee noted that the company submitted a network meta-analysis to provide comparative estimates of SVR and safety outcomes for elbasvir–grazoprevir and the relevant comparators included in the scope (except boceprevir and telaprevir) for 12 subpopulations (that is, genotype 1a, 1b and 4, further divided according to treatment history, and cirrhosis status). The committee was aware that the company used genotype 1 HCV data as a proxy for genotype 4 HCV. The committee and clinical experts considered this assumption valid given the limited data available for people with genotype 4 HCV, in line with previous NICE technology appraisals for chronic hepatitis C. The committee also noted the ERG's concern about the serious limitations of the network meta-analysis results, given the lack of connected trial networks and the imputation of missing treatment arms using peginterferon alpha plus ribavirin as a control arm. The committee was aware that the company also submitted a naive comparison, which was not discussed because it was considered to be the least robust method of comparing treatments across trials. The committee noted that the results of the network meta-analysis showed no significant differences in SVR rates between elbasvir–grazoprevir and the other all-direct-acting antiviral regimens (ledipasvir‑sofosbuvir, ombitasvir‑paritaprevir‑ritonavir with dasabuvir, and daclatasvir‑sofosbuvir) in any of the 12 subgroups. However, the results did show differences in SVR rates between elbasvir–grazoprevir and the peginterferon alpha plus ribavirin-containing regimens (except sofosbuvir plus peginterferon alpha plus ribavirin) in some subgroups. The committee heard from the clinical experts that these new all-direct-acting antiviral regimens were interchangeable for efficacy and tolerability, and treatment decisions would mostly be guided by cost. Although the committee recognised that there were limitations in the network meta-analysis, it concluded that elbasvir–grazoprevir was similar in efficacy to the other all-direct-acting antiviral regimens. The committee considered the safety data included in the company's submission and was aware that the most commonly reported adverse events were headache, fatigue and nausea. The committee noted that the results showed that elbasvir–grazoprevir had a relatively favourable safety and tolerability profile, irrespective of cirrhosis stage and treatment experience, especially when compared with the peginterferon alpha plus ribavirin-containing regimen. It also heard from the clinical experts that elbasvir–grazoprevir had a similar safety profile to all-direct-acting antiviral regimens. The committee concluded that the adverse events associated with elbasvir–grazoprevir were generally tolerable. # Cost effectiveness The committee considered the company's economic model, the assumptions underlying the values of the parameters, and the critique and exploratory analyses from the ERG. The committee noted that the structure of the model showing the natural history of the disease was similar to models submitted for other NICE technology appraisals for chronic hepatitis C. The committee considered the ERG's comment that a dynamic model would have better captured the health benefits of more effective treatments for preventing transmission of HCV. The committee had highlighted this as a concern in the previous hepatitis C appraisals. Although the committee would have preferred the company to explore further the effect of future transmission, it acknowledged that this would have needed a different (and potentially more complex) model structure. The committee agreed that not using a dynamic model introduces uncertainty in the cost-effectiveness estimates because of potential benefits not being captured, but concluded that the structure of the model was acceptable for decision-making. The committee noted that unlike some of the previous hepatitis C appraisals, the company's model allowed for re-infection after getting an SVR. The committee considered this to be a good approach that will improve the robustness of the results. However it noted the ERG's concerns that the model allows people who become re-infected to go back to health state F0 (that is, no fibrosis), which assumes that liver damage caused by hepatitis C is fully reversible. The committee did not consider this assumption to be plausible and was aware that the ERG's base-case revision assumes that people who become re-infected after getting an SVR return to their pre-SVR fibrosis health state instead. The clinical experts agreed that the ERG's assumption was reasonable and better reflects clinical practice. The committee was satisfied with the company's approach of including re-infection but concluded that the ERG's assumption on re-infection was more reasonable. The committee discussed the population included in the company's model. It noted that the company presented separate analyses according to the 12 subpopulations covered by the marketing authorisation (see section 4.4). The committee was satisfied with the company's approach of assessing these groups separately. The committee noted the ERG's comment that the company's model does not account for the genotype 1a and 4 groups, for whom 16 weeks of elbasvir–grazoprevir treatment is recommended in line with the marketing authorisation. The committee understood that this could have cost implications as well as higher SVR rates for elbasvir–grazoprevir. It heard from the company and the clinical experts that only a few people could potentially have treatment for 16 weeks. The committee heard from the ERG that the balance between the cost of an extra period of treatment and the benefits of getting an improved SVR rate and utility led to uncertainty in determining the cost effectiveness of this strategy. The committee noted the comments from the company and those from the stakeholders in the previous appraisals that people with HIV co-infection would be expected to be treated similarly to those with HCV infection alone. The clinical experts commented that people with HIV co-infection have more comorbidities and faster disease progression than those with HCV infection alone. The committee considered that this could mean that the newer treatments become associated with more health gains in people with HIV co-infection than in those with HCV alone. Without any evidence to support this assertion, it could not come to a conclusion on this. Therefore the committee concluded that it would not consider HIV co-infection separately. The committee considered the clinical inputs in the model. It noted that the company used the network meta-analysis to estimate the SVR, treatment discontinuation and adverse-event rates in the base case. The committee recalled its previous conclusion that there were limitations with the network meta-analysis, but accepted that this was the best source of evidence available for estimating the clinical inputs for model. The committee noted that the company used outcome data from genotype 1 as a proxy for genotype 4 in the base case, and recalled that it had accepted this approach for previous hepatitis C appraisals. It was aware that using genotype 4-specific data in the scenario analysis did not have a large effect on the incremental cost-effectiveness ratios (ICERs) for genotype 4. Taking into account the comments from the clinical experts (see section 4.4), the committee concluded that the company's approach to estimating the model's clinical inputs was acceptable. The committee discussed the transition probabilities used in the model. It was aware that the company used the same sources for the non-treatment-specific transition probabilities as those used in previous appraisals. The committee was generally satisfied with this approach. However it noted that the company and the ERG used the study by Grishchenko et al. (2009) to estimate age-dependent transition probabilities across fibrosis health states F0–F3 (no cirrhosis health states) in scenario analyses, rather than the study by Thien et al. (2008) as used in the base case. When then ERG and the company did this, some of the ICERs increased above £20,000 per quality-adjusted life year (QALY) gained using the list price of elbasvir–grazoprevir. The committee noted that this was because of the slower progression rates using Grishchenko et al. It heard from the ERG that there was no particular preference because both the Grishchenko and Thien studies were published at a similar time. The committee considered that although Grishchenko et al. included UK patients, Thien et al. was a meta-analysis of several studies and included people from other countries. Without any clear rationale for preferring 1 study over the other, the committee concluded that the cost-effectiveness analyses using both studies should be considered. The committee discussed how health-related quality of life was incorporated into the economic model. It noted that the company used utility data from the literature (Wright et al. 2006) in line with the previous NICE technology appraisals for chronic hepatitis C. The committee noted that the company collected utility data in some of the clinical trials using the EQ‑5D, but that no UK patients were included in the studies. It was aware that 1 of the company's scenario analyses and the ERG's preferred base case used the SVR-related utility increment from the European subgroup of the clinical trials. The committee noted that the average SVR-related utility increment from Wright et al. was 0.05, which was larger than that reported in the European subgroup of the elbasvir–grazoprevir trials (0.03). The committee was aware that higher utility benefits from Wright et al. (0.05) and Vera-Llonch et al. (2013; 0.04) had been accepted in previous NICE technology appraisals for chronic hepatitis C. It emphasised that where available, it prefers utility values collected from the clinical trials used to inform the effectiveness of the intervention under evaluation to those estimated from other sources. Therefore, the committee concluded that the values from elbasvir–grazoprevir's clinical trials would be used to inform its decision for this appraisal, but it was aware that this assumption had little effect on the results. The committee also noted the ERG's comment that the company's approach of including age-based utility decrements could lead to double-counting. The ERG stated that utility values used in the model already incorporate the effect of ageing, because they were based on average utility data from Wright et al. that included people with a wide range of ages. The committee agreed that there would be some double-counting at first, but in the later stages of a life-time model, utility decrements would need to be accounted for separately. The committee was aware that including age-based utility decrements had very little effect on the ICERs and it concluded that both the company's and the ERG's approach would be taken into account in the decision-making. The committee considered the costs used in the company's model. It noted that list prices of elbasvir–grazoprevir and the comparators were used in the company's base case. The committee noted from the company submission that elbasvir–grazoprevir has a confidential reduced price based on contract pricing arrangements between the company and the Commercial Medicines Unit. It also noted that confidential reduced contract prices for the comparators were included in the analyses carried out by the ERG, where known and important to the committee's decision-making. The committee understood that the contract prices were the prices that the NHS pays for these treatments. The committee noted that NICE's guide to the methods of technology appraisal prefers using nationally available price reductions in the reference-case analysis to reflect the price relevant to the NHS. The committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision. The committee considered the cost effectiveness of elbasvir–grazoprevir. It noted that all ICERs were below £20,000 per QALY gained, regardless of genotype, treatment history or cirrhosis status. The committee noted that this applied to the different analyses presented (that is, those of the company compared with the ERG; base case compared with scenario analyses; and pairwise compared with fully incremental results). It concluded that elbasvir–grazoprevir was a cost-effective use of NHS resources. The committee also noted that accounting for the few patients who could have up to 16 weeks of elbasvir–grazoprevir did not change the conclusion on the cost effectiveness of elbasvir‑grazoprevir. The committee therefore recommended elbasvir–grazoprevir within its marketing authorisation for treating genotype 1a, 1b and 4 HCV. The committee was aware of NHS England's ongoing concerns about the increase in investment and capacity needed to make these new oral treatments for hepatitis C available. The committee heard that the capacity to treat all eligible persons with hepatitis C in the NHS according to the NICE's recommendation is still constrained. It recalled that treatment decisions are influenced by clinical characteristics including HCV genotype, level of liver damage, comorbidities, and treatment history. With these factors in mind, people with chronic hepatitis C may accept treatment being prioritised for those with the highest unmet clinical need (including some people without cirrhosis), as determined by multidisciplinary teams. # Innovation The committee agreed with the company that there is significant unmet need in people with chronic hepatitis C complicated by severe renal disease. The committee noted that like some of the newer treatments for chronic hepatitis C, the dose of elbasvir–grazoprevir does not need to be adjusted for any stage of renal impairment. The committee also recognised the additional value of elbasvir–grazoprevir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, were likely to decrease the ICERs. However, the committee noted that it had taken these potential benefits into account when considering the cost effectiveness of elbasvir–grazoprevir and concluded that its recommendations for each population remained unchanged. # Equality issues The committee noted the potential equality issues raised by the company and a professional organisation that there are proportionately more people from black, Asian and minority ethnic groups and people with HIV co-infection in the genotype 4 population than in the genotype 1 population. The committee also noted from the company that people who have hepatitis C and chronic kidney disease can feel stigmatised because they must have dialysis treatment in a separate room. The company also commented that people with HIV co-infection are more likely to disclose their HIV status than their hepatitis C status because of the perceived stigma around hepatitis C as a result of the lack of awareness about the condition. However, having decided that elbasvir–grazoprevir should be recommended for genotype 1 and 4, the committee concluded that no further consideration of these potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment. # Summary of appraisal committee's key conclusions TA413 Appraisal title: Elbasvir–grazoprevir for treating chronic hepatitis C Section Key conclusion Elbasvir–grazoprevir is recommended, within its marketing authorisation, as an option for treating genotype 1 or 4 chronic hepatitis C in adults), only if the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit. The committee concluded that the trials showed that elbasvir–grazoprevir was effective in people with genotype 1 and 4 hepatitis C virus (HCV) and that the network meta-analysis showed elbasvir–grazoprevir to be similar in efficacy to the other all-direct-acting antiviral regimens. The committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision. The committee noted that all incremental cost-effectiveness ratios (ICERs) for elbasvir–grazoprevir compared with other treatments were below £20,000 per quality-adjusted life year (QALY) gained regardless of genotype, treatment history or cirrhosis status. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard from the clinical and patient experts that some of the newer treatments are given in combination with peginterferon alpha or ribavirin, and that having treatment options that are free from peginterferon alpha with or without ribavirin is important to people with HCV because of the associated adverse reactions. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee noted that elbasvir–grazoprevir does not have to be used with ribavirin, an important advantage for improved tolerability in people with renal disease. The committee recognised the additional value of elbasvir–grazoprevir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV), but noted that it had taken these potential benefits into account when considering the cost effectiveness of elbasvir–grazoprevir. What is the position of the treatment in the pathway of care for the condition? The committee also heard that elbasvir–grazoprevir provided another alternative to the existing oral treatment combinations for people with genotype 1 and 4 HCV. Adverse reactions The committee concluded that the adverse events associated with elbasvir–grazoprevir were generally tolerable and elbasvir–grazoprevir has a similar safety profile to all-direct-acting antiviral regimens. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee noted that 4 out of the 8 clinical trials for elbasvir–grazoprevir had a comparator arm (3 placebo-controlled trials and 1 active-controlled trial with sofosbuvir plus peginterferon alpha plus ribavirin). It also noted that the risk of bias in the trials was generally low. The committee noted the limited available evidence in people with genotype 4 HCV. The company also submitted a network meta-analysis to provide comparative estimates of sustained virological response and safety outcomes for elbasvir–grazoprevir and the relevant comparators included in the scope (except boceprevir and telaprevir). Uncertainties generated by the evidence The committee noted the evidence review group's (ERG) concern about the serious limitations of the network meta-analysis results, given the lack of connected trial networks and the imputation of missing treatment arms using peginterferon alpha plus ribavirin as a control arm. The committee noted that there was limited evidence available in people with genotype 4 HCV, therefore genotype 1 data was used as a proxy for genotype 4. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee recommended elbasvir–grazoprevir for all subgroups in line with the marketing authorisation. Estimate of the size of the clinical effectiveness including strength of supporting evidence Having noted the high sustained virological response rates as well as the ERG and the company's comments that the risk of bias in the trials was generally low, the committee concluded that the trials showed that elbasvir–grazoprevir was effective in people with genotype 1 and 4 HCV. Although the committee recognised that there were limitations in the network meta-analysis, it concluded that elbasvir–grazoprevir was similar in efficacy to the other all-direct-acting antiviral regimens. Evidence for cost effectiveness Availability and nature of evidence The committee noted that the structure of the model showing the natural history of the disease was similar to models submitted for other NICE technology appraisals for chronic hepatitis C. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee agreed that not using a dynamic model to capture the effect of future transmission introduces uncertainty in the cost-effectiveness estimates because of potential benefits not being captured, but concluded that the structure of the model was acceptable for decision-making. The committee was aware that there were limitations with the network meta-analysis, but concluded that this was the best source of evidence available for estimating the clinical inputs for model. The committee was aware that the company used the same sources for non-treatment-specific transition probabilities as those used in previous appraisals, although using a different source increased the ICERs above £20,000 per QALY gained. Without any clear rationale for preferring 1 study over the other, the committee concluded that the cost-effectiveness analyses using both studies should be considered. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee noted that utility values collected from the clinical trials used to inform the effectiveness of the intervention under evaluation have been preferred to those estimated from other sources. The committee also noted the company's approach of including age-based utility decrements could lead to double-counting. However, the committee was aware that this assumption had little effect on the results. The committee recognised the additional value of elbasvir–grazoprevir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV), but noted that it had taken these potential benefits into account when considering the cost effectiveness of elbasvir–grazoprevir. Are there specific groups of people for whom the technology is particularly cost effective? The committee recommended the elbasvir–grazoprevir for all subgroups in line with the marketing authorisation. What are the key drivers of cost effectiveness? The prices of the drugs and the non-treatment-transition probabilities were the key drivers of the cost-effectiveness results. Most likely cost-effectiveness estimate (given as an ICER) The committee noted that all ICERs for elbasvir–grazoprevir compared with other treatments were below £20,000 per QALY gained, regardless of genotype, treatment history or cirrhosis status. Additional factors taken into account Patient access schemes The company has agreed a nationally available price reduction for elbasvir–grazoprevir with the Commercial Medicines Unit. Confidential reduced contract prices for the comparators were included in the analyses carried out by the ERG, where known and important to the committee's decision-making. The contract prices used in this appraisal are confidential and cannot be disclosed. Pharmaceutical Price Regulation Scheme (PPRS) 2014 Not applicable. End-of-life considerations Not applicable. Equalities considerations and social value judgements Having decided that elbasvir–grazoprevir should be recommended for all the groups specified in the marketing authorisation, the committee concluded that no further consideration of the potential equality issues raised by consultees was needed to meet NICE's obligation to promote equality of access to treatment.	{'Recommendations': 'Elbasvir–grazoprevir is recommended, within its marketing authorisation, as an option for treating genotype\xa01 or\xa04 chronic hepatitis\xa0C in adults, as specified in table\xa01, only if the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit.\n\nTable\xa01 Elbasvir–grazoprevir for treating chronic hepatitis\xa0C in adults\n\nGenotype\n\nTreatment and duration\n\na\n\nElbasvir–grazoprevir for 12\xa0weeks.\n\nConsider elbasvir–grazoprevir plus ribavirin for 16\xa0weeks in people with a baseline hepatitis\xa0C virus RNA level of more than 800,000\xa0IU/ml or specific NS5A polymorphisms causing at least a 5‑fold reduction in activity of elbasvir.\n\nb\n\nElbasvir–grazoprevir for 12\xa0weeks.\n\n\n\nElbasvir–grazoprevir for 12\xa0weeks.\n\nConsider elbasvir‑grazoprevir plus ribavirin for 16\xa0weeks in people with a baseline hepatitis\xa0C virus RNA level of more than 800,000\xa0IU/ml.\n\nIt is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.', 'The technology ': 'Description of the technology\n\nElbasvir–grazoprevir (Zepatier, Merck Sharp & Dohme) is a fixed-dose combination drug. Elbasvir inhibits hepatitis\xa0C virus (HCV) non‑structural viral protein NS5A and grazoprevir inhibits HCV NS3/4A protease.\n\nMarketing authorisation\n\nElbasvir–grazoprevir has a marketing authorisation in the UK for treating chronic hepatitis\xa0C in adults.\n\nThe recommendations in the marketing authorisation for the specific genotypes are listed below:\n\ngenotype\xa01a: 12\xa0weeks (16\xa0weeks plus ribavirin should be considered in patients with baseline HCV RNA level >800,000 IU/ml or the presence of specific NS5A polymorphisms causing at least a 5‑fold reduction in activity of elbasvir to minimise the risk of treatment failure)\n\ngenotype\xa01b: 12\xa0weeks\n\ngenotype\xa04: 12\xa0weeks (16\xa0weeks plus ribavirin should be considered in patients with baseline HCV RNA level >800,000\xa0IU/ml to minimise the risk of treatment failure).\n\nAdverse reactions\n\nThe summary of product characteristics includes headache and fatigue as very common adverse reactions, and nausea as a common reaction. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nIt is taken orally. The recommended dose of elbasvir–grazoprevir is 1\xa0tablet once daily. Each tablet contains 50\xa0mg elbasvir and 100\xa0mg grazoprevir.\n\nPrice\n\nElbasvir–grazoprevir costs £12,166.67 per 28‑day pack. The total cost of a 12‑week treatment course is £36,500.\n\nThe company has agreed a nationally available price reduction for elbasvir–grazoprevir with the Commercial Medicines Unit. The contract prices agreed through the framework are commercial in confidence.', 'Evidence': 'The appraisal committee (section 6) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of elbasvir–grazoprevir, having considered evidence on the nature of chronic hepatitis\xa0C and the value placed on the benefits of elbasvir–grazoprevir by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and practice\n\nThe committee heard from the clinical and patient experts that people who have chronic hepatitis\xa0C are a disadvantaged population and often have to cope with stigma and discrimination because people associate hepatitis\xa0C with drug use. The clinical experts stated that because of the introduction of the newer direct-acting antivirals, treatment with peginterferon alpha plus ribavirin is gradually diminishing in clinical practice, particularly for genotypes\xa01 and\xa04. However, they highlighted that some of these newer treatments are given in combination with peginterferon alpha or ribavirin. The committee heard from the patient experts that having treatment options that are free from peginterferon alpha with or without ribavirin is important to people with chronic hepatitis\xa0C because of the associated adverse reactions. The clinical experts stated that people with renal disease are an important group whose condition is difficult to treat because there are few treatment regimens without ribavirin, especially for people who also have compensated cirrhosis. The committee heard that elbasvir–grazoprevir does not have to be used with ribavirin, an important advantage for improved tolerability in people with renal disease. The committee also heard that elbasvir–grazoprevir provided another alternative to the existing oral treatment combinations for people with genotype\xa01 and\xa04 hepatitis\xa0C virus (HCV). Therefore the committee recognised the importance of having an additional effective and tolerable treatment for people with chronic hepatitis\xa0C and concluded that elbasvir–grazoprevir could be a valuable option for genotype\xa01 and\xa04 HCV.\n\nThe committee discussed the relevant comparators for elbasvir–grazoprevir given the changes in managing chronic hepatitis\xa0C. It noted that the company did not include boceprevir and telaprevir as comparators because they are no longer used in clinical practice, although the NICE scope included them. The committee also noted that the company included peginterferon alpha plus ribavirin as a comparator alongside the newer treatments, although it has been less commonly used since new direct-acting antivirals were introduced. The committee questioned whether it was appropriate to keep peginterferon alpha plus ribavirin as a comparator, given the argument for excluding boceprevir and telaprevir. It heard from a clinical expert that peginterferon alpha plus ribavirin is associated with toxicities and these were worsened by adding other toxic treatments, such as boceprevir or telaprevir, which is why boceprevir and telaprevir are no longer used. The clinical expert stated that although treatment with peginterferon plus ribavirin for genotype\xa01 and\xa04 HCV is rapidly diminishing, its use in clinical practice has not completely stopped. The clinical experts confirmed that the new direct-acting antivirals would be the most relevant comparators for elbasvir–grazoprevir. The committee accepted the views of the clinical experts and concluded that the most relevant comparators are the new direct-acting antivirals and acknowledged that peginterferon alpha plus ribavirin may be used for a small number of people.\n\n# Clinical effectiveness\n\nThe committee considered the clinical evidence for elbasvir–grazoprevir, which came from 8\xa0clinical trials. It noted that 4\xa0of these trials had a comparator arm (3\xa0placebo-controlled trials and 1\xa0active-controlled trial with sofosbuvir plus peginterferon alpha plus ribavirin), but the rest did not. The committee was aware that the evidence review group (ERG) agreed with the company's assessment that the risk of bias in the trials was generally low. The committee noted that the results of the clinical trials showed high sustained virological response (SVR) at 12\xa0weeks for elbasvir–grazoprevir; ranging from 67% (for genotype\xa04 in some of the trials) to over 90% in most of the trials and up to 100% in some cases, irrespective of genotype, cirrhosis stage or treatment experience. The committee also noted that the SVR rates for elbasvir–grazoprevir and sofosbuvir plus peginterferon alpha plus ribavirin were comparable in people with genotype\xa01a HCV, but higher for elbasvir–grazoprevir than sofosbuvir plus peginterferon alpha plus ribavirin in genotype\xa01b HCV. Having noted the high SVR rates as well as the ERG and the company's comments that the risk of bias in the trials was generally low, the committee concluded that the trials showed that elbasvir–grazoprevir was effective in people with genotype\xa01 and\xa04 HCV.\n\nThe committee noted that the company submitted a network meta-analysis to provide comparative estimates of SVR and safety outcomes for elbasvir–grazoprevir and the relevant comparators included in the scope (except boceprevir and telaprevir) for 12\xa0subpopulations (that is, genotype\xa01a, 1b\xa0and\xa04, further divided according to treatment history, and cirrhosis status). The committee was aware that the company used genotype\xa01 HCV data as a proxy for genotype\xa04 HCV. The committee and clinical experts considered this assumption valid given the limited data available for people with genotype\xa04 HCV, in line with previous NICE technology appraisals for chronic hepatitis\xa0C. The committee also noted the ERG's concern about the serious limitations of the network meta-analysis results, given the lack of connected trial networks and the imputation of missing treatment arms using peginterferon alpha plus ribavirin as a control arm. The committee was aware that the company also submitted a naive comparison, which was not discussed because it was considered to be the least robust method of comparing treatments across trials. The committee noted that the results of the network meta-analysis showed no significant differences in SVR rates between elbasvir–grazoprevir and the other all-direct-acting antiviral regimens (ledipasvir‑sofosbuvir, ombitasvir‑paritaprevir‑ritonavir with dasabuvir, and daclatasvir‑sofosbuvir) in any of the 12\xa0subgroups. However, the results did show differences in SVR rates between elbasvir–grazoprevir and the peginterferon alpha plus ribavirin-containing regimens (except sofosbuvir plus peginterferon alpha plus ribavirin) in some subgroups. The committee heard from the clinical experts that these new all-direct-acting antiviral regimens were interchangeable for efficacy and tolerability, and treatment decisions would mostly be guided by cost. Although the committee recognised that there were limitations in the network meta-analysis, it concluded that elbasvir–grazoprevir was similar in efficacy to the other all-direct-acting antiviral regimens.\n\nThe committee considered the safety data included in the company's submission and was aware that the most commonly reported adverse events were headache, fatigue and nausea. The committee noted that the results showed that elbasvir–grazoprevir had a relatively favourable safety and tolerability profile, irrespective of cirrhosis stage and treatment experience, especially when compared with the peginterferon alpha plus ribavirin-containing regimen. It also heard from the clinical experts that elbasvir–grazoprevir had a similar safety profile to all-direct-acting antiviral regimens. The committee concluded that the adverse events associated with elbasvir–grazoprevir were generally tolerable.\n\n# Cost effectiveness\n\nThe committee considered the company's economic model, the assumptions underlying the values of the parameters, and the critique and exploratory analyses from the ERG. The committee noted that the structure of the model showing the natural history of the disease was similar to models submitted for other NICE technology appraisals for chronic hepatitis\xa0C. The committee considered the ERG's comment that a dynamic model would have better captured the health benefits of more effective treatments for preventing transmission of HCV. The committee had highlighted this as a concern in the previous hepatitis\xa0C appraisals. Although the committee would have preferred the company to explore further the effect of future transmission, it acknowledged that this would have needed a different (and potentially more complex) model structure. The committee agreed that not using a dynamic model introduces uncertainty in the cost-effectiveness estimates because of potential benefits not being captured, but concluded that the structure of the model was acceptable for decision-making.\n\nThe committee noted that unlike some of the previous hepatitis\xa0C appraisals, the company's model allowed for re-infection after getting an SVR. The committee considered this to be a good approach that will improve the robustness of the results. However it noted the ERG's concerns that the model allows people who become re-infected to go back to health state F0 (that is, no fibrosis), which assumes that liver damage caused by hepatitis\xa0C is fully reversible. The committee did not consider this assumption to be plausible and was aware that the ERG's base-case revision assumes that people who become re-infected after getting an SVR return to their pre-SVR fibrosis health state instead. The clinical experts agreed that the ERG's assumption was reasonable and better reflects clinical practice. The committee was satisfied with the company's approach of including re-infection but concluded that the ERG's assumption on re-infection was more reasonable.\n\nThe committee discussed the population included in the company's model. It noted that the company presented separate analyses according to the 12\xa0subpopulations covered by the marketing authorisation (see section\xa04.4). The committee was satisfied with the company's approach of assessing these groups separately. The committee noted the ERG's comment that the company's model does not account for the genotype\xa01a and 4\xa0groups, for whom 16\xa0weeks of elbasvir–grazoprevir treatment is recommended in line with the marketing authorisation. The committee understood that this could have cost implications as well as higher SVR rates for elbasvir–grazoprevir. It heard from the company and the clinical experts that only a few people could potentially have treatment for 16\xa0weeks. The committee heard from the ERG that the balance between the cost of an extra period of treatment and the benefits of getting an improved SVR rate and utility led to uncertainty in determining the cost effectiveness of this strategy. The committee noted the comments from the company and those from the stakeholders in the previous appraisals that people with HIV co-infection would be expected to be treated similarly to those with HCV infection alone. The clinical experts commented that people with HIV co-infection have more comorbidities and faster disease progression than those with HCV infection alone. The committee considered that this could mean that the newer treatments become associated with more health gains in people with HIV co-infection than in those with HCV alone. Without any evidence to support this assertion, it could not come to a conclusion on this. Therefore the committee concluded that it would not consider HIV co-infection separately.\n\nThe committee considered the clinical inputs in the model. It noted that the company used the network meta-analysis to estimate the SVR, treatment discontinuation and adverse-event rates in the base case. The committee recalled its previous conclusion that there were limitations with the network meta-analysis, but accepted that this was the best source of evidence available for estimating the clinical inputs for model. The committee noted that the company used outcome data from genotype\xa01 as a proxy for genotype\xa04 in the base case, and recalled that it had accepted this approach for previous hepatitis\xa0C appraisals. It was aware that using genotype\xa04-specific data in the scenario analysis did not have a large effect on the incremental cost-effectiveness ratios (ICERs) for genotype\xa04. Taking into account the comments from the clinical experts (see section\xa04.4), the committee concluded that the company's approach to estimating the model's clinical inputs was acceptable.\n\nThe committee discussed the transition probabilities used in the model. It was aware that the company used the same sources for the non-treatment-specific transition probabilities as those used in previous appraisals. The committee was generally satisfied with this approach. However it noted that the company and the ERG used the study by Grishchenko et al. (2009) to estimate age-dependent transition probabilities across fibrosis health states F0–F3 (no cirrhosis health states) in scenario analyses, rather than the study by Thien et al. (2008) as used in the base case. When then ERG and the company did this, some of the ICERs increased above £20,000 per quality-adjusted life year (QALY) gained using the list price of elbasvir–grazoprevir. The committee noted that this was because of the slower progression rates using Grishchenko et al. It heard from the ERG that there was no particular preference because both the Grishchenko and Thien studies were published at a similar time. The committee considered that although Grishchenko et al. included UK patients, Thien et al. was a meta-analysis of several studies and included people from other countries. Without any clear rationale for preferring 1\xa0study over the other, the committee concluded that the cost-effectiveness analyses using both studies should be considered.\n\nThe committee discussed how health-related quality of life was incorporated into the economic model. It noted that the company used utility data from the literature (Wright et al. 2006) in line with the previous NICE technology appraisals for chronic hepatitis\xa0C. The committee noted that the company collected utility data in some of the clinical trials using the EQ‑5D, but that no UK patients were included in the studies. It was aware that 1\xa0of the company's scenario analyses and the ERG's preferred base case used the SVR-related utility increment from the European subgroup of the clinical trials. The committee noted that the average SVR-related utility increment from Wright et al. was 0.05, which was larger than that reported in the European subgroup of the elbasvir–grazoprevir trials (0.03). The committee was aware that higher utility benefits from Wright et al. (0.05) and Vera-Llonch et al. (2013; 0.04) had been accepted in previous NICE technology appraisals for chronic hepatitis\xa0C. It emphasised that where available, it prefers utility values collected from the clinical trials used to inform the effectiveness of the intervention under evaluation to those estimated from other sources. Therefore, the committee concluded that the values from elbasvir–grazoprevir's clinical trials would be used to inform its decision for this appraisal, but it was aware that this assumption had little effect on the results. The committee also noted the ERG's comment that the company's approach of including age-based utility decrements could lead to double-counting. The ERG stated that utility values used in the model already incorporate the effect of ageing, because they were based on average utility data from Wright et al. that included people with a wide range of ages. The committee agreed that there would be some double-counting at first, but in the later stages of a life-time model, utility decrements would need to be accounted for separately. The committee was aware that including age-based utility decrements had very little effect on the ICERs and it concluded that both the company's and the ERG's approach would be taken into account in the decision-making.\n\nThe committee considered the costs used in the company's model. It noted that list prices of elbasvir–grazoprevir and the comparators were used in the company's base case. The committee noted from the company submission that elbasvir–grazoprevir has a confidential reduced price based on contract pricing arrangements between the company and the Commercial Medicines Unit. It also noted that confidential reduced contract prices for the comparators were included in the analyses carried out by the ERG, where known and important to the committee's decision-making. The committee understood that the contract prices were the prices that the NHS pays for these treatments. The committee noted that NICE's guide to the methods of technology appraisal prefers using nationally available price reductions in the reference-case analysis to reflect the price relevant to the NHS. The committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision.\n\nThe committee considered the cost effectiveness of elbasvir–grazoprevir. It noted that all ICERs were below £20,000 per QALY gained, regardless of genotype, treatment history or cirrhosis status. The committee noted that this applied to the different analyses presented (that is, those of the company compared with the ERG; base case compared with scenario analyses; and pairwise compared with fully incremental results). It concluded that elbasvir–grazoprevir was a cost-effective use of NHS resources. The committee also noted that accounting for the few patients who could have up to 16\xa0weeks of elbasvir–grazoprevir did not change the conclusion on the cost effectiveness of elbasvir‑grazoprevir. The committee therefore recommended elbasvir–grazoprevir within its marketing authorisation for treating genotype\xa01a, 1b\xa0and\xa04 HCV.\n\nThe committee was aware of NHS England's ongoing concerns about the increase in investment and capacity needed to make these new oral treatments for hepatitis\xa0C available. The committee heard that the capacity to treat all eligible persons with hepatitis\xa0C in the NHS according to the NICE's recommendation is still constrained. It recalled that treatment decisions are influenced by clinical characteristics including HCV genotype, level of liver damage, comorbidities, and treatment history. With these factors in mind, people with chronic hepatitis\xa0C may accept treatment being prioritised for those with the highest unmet clinical need (including some people without cirrhosis), as determined by multidisciplinary teams.\n\n# Innovation\n\nThe committee agreed with the company that there is significant unmet need in people with chronic hepatitis\xa0C complicated by severe renal disease. The committee noted that like some of the newer treatments for chronic hepatitis\xa0C, the dose of elbasvir–grazoprevir does not need to be adjusted for any stage of renal impairment. The committee also recognised the additional value of elbasvir–grazoprevir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, were likely to decrease the ICERs. However, the committee noted that it had taken these potential benefits into account when considering the cost effectiveness of elbasvir–grazoprevir and concluded that its recommendations for each population remained unchanged.\n\n# Equality issues\n\nThe committee noted the potential equality issues raised by the company and a professional organisation that there are proportionately more people from black, Asian and minority ethnic groups and people with HIV co-infection in the genotype\xa04 population than in the genotype\xa01 population. The committee also noted from the company that people who have hepatitis\xa0C and chronic kidney disease can feel stigmatised because they must have dialysis treatment in a separate room. The company also commented that people with HIV co-infection are more likely to disclose their HIV status than their hepatitis\xa0C status because of the perceived stigma around hepatitis\xa0C as a result of the lack of awareness about the condition. However, having decided that elbasvir–grazoprevir should be recommended for genotype\xa01 and\xa04, the committee concluded that no further consideration of these potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment.\n\n# Summary of appraisal committee's key conclusions\n\nTA413\n\nAppraisal title: Elbasvir–grazoprevir for treating chronic hepatitis\xa0C\n\nSection\n\nKey conclusion\n\nElbasvir–grazoprevir is recommended, within its marketing authorisation, as an option for treating genotype\xa01 or\xa04 chronic hepatitis\xa0C in adults), only if the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit.\n\nThe committee concluded that the trials showed that elbasvir–grazoprevir was effective in people with genotype\xa01 and\xa04 hepatitis C\xa0virus (HCV) and that the network meta-analysis showed elbasvir–grazoprevir to be similar in efficacy to the other all-direct-acting antiviral regimens.\n\nThe committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision.\n\nThe committee noted that all incremental cost-effectiveness ratios (ICERs) for elbasvir–grazoprevir compared with other treatments were below £20,000 per quality-adjusted life year (QALY) gained regardless of genotype, treatment history or cirrhosis status.\n\n, 4.3, 4.4, 4.12, 4.13\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the clinical and patient experts that some of the newer treatments are given in combination with peginterferon alpha or ribavirin, and that having treatment options that are free from peginterferon alpha with or without ribavirin is important to people with HCV because of the associated adverse reactions.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee noted that elbasvir–grazoprevir does not have to be used with ribavirin, an important advantage for improved tolerability in people with renal disease.\n\nThe committee recognised the additional value of elbasvir–grazoprevir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV), but noted that it had taken these potential benefits into account when considering the cost effectiveness of elbasvir–grazoprevir.\n\n, 4.15\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee also heard that elbasvir–grazoprevir provided another alternative to the existing oral treatment combinations for people with genotype\xa01 and\xa04 HCV.\n\n\n\nAdverse reactions\n\nThe committee concluded that the adverse events associated with elbasvir–grazoprevir were generally tolerable and elbasvir–grazoprevir has a similar safety profile to all-direct-acting antiviral regimens.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee noted that 4\xa0out of the 8\xa0clinical trials for elbasvir–grazoprevir had a comparator arm (3\xa0placebo-controlled trials and 1\xa0active-controlled trial with sofosbuvir plus peginterferon alpha plus ribavirin). It also noted that the risk of bias in the trials was generally low.\n\nThe committee noted the limited available evidence in people with genotype 4\xa0HCV.\n\nThe company also submitted a network meta-analysis to provide comparative estimates of sustained virological response and safety outcomes for elbasvir–grazoprevir and the relevant comparators included in the scope (except boceprevir and telaprevir).\n\n, 4.4\n\nUncertainties generated by the evidence\n\nThe committee noted the evidence review group's (ERG) concern about the serious limitations of the network meta-analysis results, given the lack of connected trial networks and the imputation of missing treatment arms using peginterferon alpha plus ribavirin as a control arm. The committee noted that there was limited evidence available in people with genotype\xa04 HCV, therefore genotype\xa01 data was used as a proxy for genotype\xa04.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee recommended elbasvir–grazoprevir for all subgroups in line with the marketing authorisation.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nHaving noted the high sustained virological response rates as well as the ERG and the company's comments that the risk of bias in the trials was generally low, the committee concluded that the trials showed that elbasvir–grazoprevir was effective in people with genotype\xa01 and 4\xa0HCV.\n\nAlthough the committee recognised that there were limitations in the network meta-analysis, it concluded that elbasvir–grazoprevir was similar in efficacy to the other all-direct-acting antiviral regimens.\n\n, 4.4\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee noted that the structure of the model showing the natural history of the disease was similar to models submitted for other NICE technology appraisals for chronic hepatitis\xa0C.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee agreed that not using a dynamic model to capture the effect of future transmission introduces uncertainty in the cost-effectiveness estimates because of potential benefits not being captured, but concluded that the structure of the model was acceptable for decision-making.\n\nThe committee was aware that there were limitations with the network meta-analysis, but concluded that this was the best source of evidence available for estimating the clinical inputs for model.\n\nThe committee was aware that the company used the same sources for non-treatment-specific transition probabilities as those used in previous appraisals, although using a different source increased the ICERs above £20,000 per QALY gained. Without any clear rationale for preferring 1\xa0study over the other, the committee concluded that the cost-effectiveness analyses using both studies should be considered.\n\n, 4.9, 4.10\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that utility values collected from the clinical trials used to inform the effectiveness of the intervention under evaluation have been preferred to those estimated from other sources. The committee also noted the company's approach of including age-based utility decrements could lead to double-counting. However, the committee was aware that this assumption had little effect on the results.\n\nThe committee recognised the additional value of elbasvir–grazoprevir as an interferon- and ribavirin-free treatment but concluded that these health gains are likely to have been included in the QALY calculations. The committee agreed that there were other wider benefits to society (for example, reduced transmission of HCV), but noted that it had taken these potential benefits into account when considering the cost effectiveness of elbasvir–grazoprevir.\n\n, 4.15\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee recommended the elbasvir–grazoprevir for all subgroups in line with the marketing authorisation.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe prices of the drugs and the non-treatment-transition probabilities were the key drivers of the cost-effectiveness results.\n\n, 4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee noted that all ICERs for elbasvir–grazoprevir compared with other treatments were below £20,000 per QALY gained, regardless of genotype, treatment history or cirrhosis status.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes\n\nThe company has agreed a nationally available price reduction for elbasvir–grazoprevir with the Commercial Medicines Unit.\n\nConfidential reduced contract prices for the comparators were included in the analyses carried out by the ERG, where known and important to the committee's decision-making.\n\nThe contract prices used in this appraisal are confidential and cannot be disclosed.\n\n, 4.12\n\nPharmaceutical Price Regulation Scheme (PPRS) 2014\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nHaving decided that elbasvir–grazoprevir should be recommended for all the groups specified in the marketing authorisation, the committee concluded that no further consideration of the potential equality issues raised by consultees was needed to meet NICE's obligation to promote equality of access to treatment.\n\n\n\n"}	https://www.nice.org.uk/guidance/ta413	Evidence-based recommendations on elbasvir–grazoprevir (Zepatier) for treating genotype 1 or 4 chronic hepatitis C in adults.
8c3fd9550919067227d3d67a7370c14e51761a79	nice	Cobimetinib in combination with vemurafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma	Cobimetinib in combination with vemurafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma Evidence-based recommendations on cobimetinib (Cotellic) with vemurafenib (Zelboraf) for treating unresectable or metastatic melanoma in adults with a BRAF V600 mutation. # Recommendations Cobimetinib in combination with vemurafenib is not recommended within its marketing authorisation for treating unresectable or metastatic melanoma in adults with a BRAF V600 mutation. This guidance is not intended to affect the position of patients whose treatment with cobimetinib in combination with vemurafenib was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Cobimetinib (Cotellic, Roche) is an inhibitor of MEK 1 and MEK 2 kinases. Vemurafenib (Zelboraf, Roche) is an inhibitor of the BRAF protein. Both are taken as tablets. The BRAF protein and MEK 1 and 2 kinases are part of the same cell-signalling pathway. Inhibiting these proteins stops proliferation and survival of melanoma cells. Marketing authorisation Cobimetinib in combination with vemurafenib is indicated for the treatment of unresectable or metastatic melanoma in adults with a BRAF V600 mutation. Vemurafenib has a marketing authorisation for use as monotherapy for this indication. Cobimetinib does not have a marketing authorisation for use as monotherapy. Adverse reactions The following common adverse reactions affect more than 1 in 5 people: diarrhoea, rash, nausea, vomiting, fever, light sensitivity reaction, abnormal liver function tests, and abnormal results for an enzyme related to muscle breakdown (creatine phosphokinase). Less common adverse reactions include swelling of the retina (retinopathy) or effects on cardiac function (reduced left ventricular ejection fraction). People taking cobimetinib plus vemurafenib should be monitored for new and worsening visual disturbances, and for heart function. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Cobimetinib: 3 tablets per day for 21 days followed by a 7‑day break (days 22 to 28) before the next cycle is started. Vemurafenib: 960 mg (4 tablets of 240 mg) twice daily (equivalent to a total daily dose of 1,920 mg). Price The company has stated that the cost of cobimetinib (excluding VAT) is £4,275.67 for a 63‑tablet pack of 20 mg tablets. The company has agreed a patient access scheme with the Department of Health for vemurafenib as monotherapy. It is provided to the NHS with a simple discount to the list price of vemurafenib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS. If cobimetinib with vemurafenib had been recommended, the company would have provided vemurafenib for use in combination with cobimetinib with the same discount as that agreed for vemurafenib as monotherapy. Costs may vary in different settings because of negotiated procurement discounts.# Evidence The appraisal committee (section 5) considered evidence submitted by the company and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of cobimetinib in combination with vemurafenib, having considered evidence on the nature of advanced (unresectable or metastatic) BRAF V600 mutation-positive melanoma and the value placed on the benefits of cobimetinib plus vemurafenib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical management of advanced melanoma The committee discussed the clinical need of people with advanced BRAF V600 mutation-positive melanoma. It heard from the patient expert that the symptoms of advanced melanoma vary, partly depending on the sites of metastases, but they can be severe and wide ranging. Symptoms such as pain can have a major effect on quality of life. The patient expert explained that having a choice of effective treatments to switch to if there are side effects is greatly valued by people. However, prolonging survival is of such importance to people that many would be willing to accept considerable side effects if their chance of survival is improved. The committee concluded that the symptoms and effect on quality of life vary between people with advanced melanoma, and that people welcome having a choice of life-extending treatment options available to them. The committee noted that people with BRAF V600 mutation-positive advanced melanoma could have an immunotherapy agent (ipilimumab, pembrolizumab or nivolumab) or a targeted BRAF inhibitor (vemurafenib or dabrafenib). The clinical expert stated that about 70% of people with BRAF V600 mutation-positive disease have immunotherapy first line because of the long-term benefit that has been shown in trials. BRAF inhibitors would usually be used first line only for people with rapidly progressing disease, high disease burden or elevated LDH (lactate dehydrogenase) levels, when a rapid onset of action is needed. BRAF inhibitors are considered to be equally effective whether given before or after immunotherapy. The committee concluded that most people with BRAF V600 mutation-positive melanoma would have a targeted therapy at some point in their treatment. ## Comparators The clinical expert stated that the 2 comparators listed in the scope, vemurafenib and dabrafenib, are considered to have similar clinical effectiveness but some people will experience adverse reactions with either drug. The clinical expert noted that photosensitivity and rashes are more common with vemurafenib than dabrafenib, so dabrafenib tends to be prescribed more often, although the clinical expert also stated that fevers are less common with vemurafenib than dabrafenib. Because it is not possible to predict who will have adverse reactions with either drug before starting treatment, it is valuable to have 2 BRAF inhibitors available for patients. The committee noted that NICE recently recommended another combination treatment (trametinib, a MEK inhibitor, in combination with dabrafenib), which has a similar mechanism of action to cobimetinib plus vemurafenib. However, it noted that the final guidance had not yet been issued and this treatment combination could not be considered established practice. The clinical expert stated that if the NHS routinely funded a combination of a BRAF inhibitor plus a MEK inhibitor this would be preferred over BRAF-inhibitor monotherapy, because of the longer survival shown in trials. The committee recognised that the treatment options for melanoma are likely to increase in the near future but concluded that, at present, the comparators in the scope issued by NICE were appropriate for its decision-making. # Clinical effectiveness ## Evidence from the coBRIM trial The committee discussed the generalisability of the clinical evidence from the coBRIM trial that compared cobimetinib plus vemurafenib with vemurafenib plus placebo. It noted that most patients in coBRIM had not previously had an immunotherapy agent, and in this regard the population in coBRIM was different to the population who would have cobimetinib plus vemurafenib in clinical practice in England. However, the committee took into account the comments from the clinical expert that the clinical effectiveness of cobimetinib plus vemurafenib is not expected to differ if it is taken before or after an immunotherapy agent. It was therefore satisfied that the clinical-effectiveness evidence from coBRIM is generalisable to melanoma that has or has not been treated with immunotherapy. The committee examined the results of coBRIM. It noted that, at the time of the latest data cut-off in the company's submission, the combination of cobimetinib plus vemurafenib increased overall survival by 4.9 months compared with vemurafenib alone (median survival 22.3 months and 17.4 months respectively). The committee concluded that cobimetinib plus vemurafenib is clinically effective compared with vemurafenib alone. ## Company's network meta-analyses The committee considered the company's indirect comparison of cobimetinib plus vemurafenib with dabrafenib alone, noting that there were no direct head-to-head clinical trials comparing cobimetinib plus vemurafenib with dabrafenib. It agreed with the evidence review group (ERG) that the rationale and methods for the indirect comparison were appropriate. The committee noted the ERG's comments that the trials in the network were broadly comparable, based on selected characteristics, but the potential heterogeneity of the trials in the network had not been fully explored in the company's submission. The committee noted that the trials comparing dabrafenib with dacarbazine (BREAK‑3) and vemurafenib with dacarbazine (BRIM‑3), which were included in the meta-analysis, included similar populations to coBRIM but there were differences in the trial designs. For example, BREAK‑3 and BRIM‑3 allowed crossover from the dacarbazine arm to the dabrafenib or vemurafenib arm, but coBRIM did not allow crossover between treatment arms. The committee noted, and the company confirmed, that crossover had not been adjusted for in the network meta-analysis. The committee agreed with the ERG that the clinical effectiveness of dabrafenib and vemurafenib as monotherapies may have been underestimated in the network. The committee also noted that there was only 1 trial for each comparator in the network, which increased its uncertainty in the results. It concluded that taking into account the unexplored potential heterogeneity between the trials, and the limited number of trials in the network, the indirect comparison of cobimetinib plus vemurafenib with dabrafenib was associated with considerable uncertainty. Given the uncertainty surrounding the indirect comparison, the committee discussed whether it would be more appropriate to assume that the BRAF inhibitors (dabrafenib and vemurafenib) were sufficiently similar in clinical effectiveness to be considered clinically interchangeable. In response to the appraisal consultation document, the company stated that it considered that the results from the indirect comparison were more robust for the comparison with dabrafenib than an assumption of clinical equivalence between the 2 drugs. The committee agreed that there may be some differences in the tolerability of the 2 drugs, but noted that in the company's modelled base case, the total estimated life years and the total quality-adjusted life years (QALYs) for cobimetinib plus vemurafenib compared with vemurafenib or dabrafenib alone were similar (3.392 life years for vemurafenib compared with 3.281 for dabrafenib, and 2.489 QALYs for vemurafenib compared with 2.417 for dabrafenib). The committee considered that the company's modelling did not contradict the committee's preferred assumption of similar efficacy of vemurafenib and dabrafenib monotherapies, and this was also consistent with what the committee had heard from the clinical expert (see section 4.3). The committee therefore concluded that the most robust comparative data on which to base its decision were from the coBRIM trial of cobimetinib plus vemurafenib compared with vemurafenib alone, and that it would be reasonable to assume that a comparison of cobimetinib plus vemurafenib with dabrafenib alone gives similar results. # Cost effectiveness ## The company's model The committee noted that the 3‑state partitioned model used by the company was similar to the structure of models used in previous appraisals of technologies for treating melanoma, and met the NICE reference case. The committee also considered that the time horizon of 30 years was appropriate. The committee concluded that the model was in line with accepted NICE methods and appropriate for its decision-making. ## Utility values The company used 2 approaches to convert EQ‑5D‑5L data from coBRIM into utility values for the progression-free-survival health state. The committee accepted the company's rationale for choosing between these 2 approaches; that is, the company used the method that produced lower utility values, which were more plausible than the alternative approach that produced utility values above those for people without melanoma. The committee accepted that because the company had not been able to collect EQ‑5D‑5L data from many people after their melanoma had progressed, the utility values derived from the trial may not reflect quality of life for people with progressed disease. The committee noted that the company's preferred alternative came from a study (Beusterien et al. 2009) that did not meet the NICE reference case, and which reported that quality of life would be much worse in the first 5 years of progressed disease (0.590) than if a person survived for more than 5 years with progressed disease (0.770). The committee considered that this may be plausible but noted that the difference between the 2 values was large. The committee was aware that several approaches to calculating utility values had been used in previous melanoma appraisals, without uniform agreement on the most appropriate method. The ERG's alternative utility value for the progressed-disease state (0.73) was the same as that used in NICE's technology appraisal guidance on nivolumab for treating advanced (unresectable or metastatic) melanoma. The committee considered that there was uncertainty surrounding the most appropriate utility value, especially for people with progressed disease, because of data limitations. It noted that the patient expert had highlighted that the extent to which melanoma affects quality of life may vary (see section 4.1). The committee concluded that there was uncertainty surrounding utility values and it was appropriate to take into account the effect of a range of utility values, provided by sensitivity analyses, in its decision-making. ## Assumptions The company used different model inputs when comparing cobimetinib plus vemurafenib with vemurafenib alone, than it did for cobimetinib plus vemurafenib compared with dabrafenib. The committee noted the following differences: Cobimetinib plus vemurafenib compared with vemurafenib alone: extrapolating progression-free-survival and overall-survival data from coBRIM data; the same extrapolation distribution was used for each treatment arm extrapolating time on treatment from coBRIM data; different extrapolation distributions were used to extrapolate the trial data over the long term for each treatment arm estimating the drug dosages using data from coBRIM, in which people could have dose reductions. Cobimetinib plus vemurafenib compared with dabrafenib: extrapolating progression-free-survival and overall-survival data from coBRIM for cobimetinib plus vemurafenib, but from the network meta-analysis for dabrafenib monotherapy; the same extrapolation distribution was used for each treatment arm assuming that time on treatment was the same as progression-free survival for cobimetinib plus vemurafenib and for dabrafenib; the same extrapolation distribution was used to extrapolate progression-free-survival data for each treatment arm estimating the drug dosages using data from coBRIM for cobimetinib plus vemurafenib, and using the licensed dose for dabrafenib (with no adjustments for drug dose reductions).The company's rationale for using different assumptions for each comparison was that it did not have access to the patient-level data needed to model time on treatment and dose modifications for dabrafenib. The committee accepted this, but noted that the costs for dabrafenib may have been overestimated because the company did not account for dose modifications of dabrafenib. The committee considered that using progression-free survival as a proxy measure for time on treatment would overestimate time on treatment and consequently drug costs, because people may stop treatment before disease progression. The committee noted that the total costs for cobimetinib plus vemurafenib in the company's base case were higher when using assumptions from the comparison of cobimetinib plus vemurafenib with dabrafenib, than using those for the comparison with vemurafenib. The higher costs seemed to be due to using progression-free survival as a surrogate for time on treatment in the comparison with dabrafenib. The committee concluded that the differences in modelling assumptions had a substantial effect on costs, but only a marginal effect on the QALY estimates. The committee noted that the ERG had presented results using the same assumptions for each modelled treatment arm and a different utility value for the progressed-disease health state. The committee agreed with the ERG that where possible modelling assumptions should be consistent between treatment arms. However, it noted that to do this the ERG had to use data from the network meta-analysis and make further adjustments for possible changes in doses of dabrafenib; it therefore considered that the ERG's modelling was based on less robust data than the company's comparison of cobimetinib plus vemurafenib with vemurafenib. The committee concluded that it preferred: using data for cobimetinib plus vemurafenib compared with vemurafenib alone to inform its decision-making, given the lack of patient-level data available for dabrafenib and the uncertainties in the network meta-analysis for the indirect comparison of cobimetinib plus vemurafenib with dabrafenib alone adjusting the drug costs for dose modifications using data on doses taken by patients in clinical trials using time on treatment seen in clinical trials to estimate duration of drug treatment in clinical practice considering sensitivity analyses that reflect the range of utility values presented for other melanoma treatments appraised by NICE, and the potential variation in quality of life experienced by people with advanced melanoma, in its decision-making. ## Estimates of cost effectiveness The cost-effectiveness estimates provided by the company and the ERG used the list prices for both drugs or used the patient access scheme prices for vemurafenib and dabrafenib. These produced incremental cost-effectiveness ratios (ICERs) that were over £100,000 per QALY gained. This is substantially above the range usually considered a cost-effective use of NHS resources. The company already provides vemurafenib to the NHS at a discounted price as part of a patient access scheme, but no patient access scheme for cobimetinib in combination with vemurafenib has been agreed with the Department of Health for the current appraisal. The committee noted comments received from consultation stating that with combination treatment significantly fewer excisions by a dermatologist, with the associated costs, are needed for squamous cell carcinomas and keratoacanthomas. The committee noted that the difference in excisions, in favour of the combination treatment, had been included in the base case but had not been explored in any scenario analyses. However, the committee concluded that the cost savings associated with fewer outpatient procedures under local anaesthetic would not have a major impact on the ICERs. # End-of-life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the median survival of people having vemurafenib monotherapy in coBRIM was around 17 months. The committee noted that in its recent appraisal guidance on trametinib plus dabrafenib it had agreed that life expectancy in people with advanced BRAF V600 mutation-positive melanoma was likely to be under 24 months. There was no evidence to suggest that life expectancy has changed since that decision because the recommendations from that appraisal have not yet become established practice. However, the treatment pathway for advanced melanoma is changing as new treatments become available so life expectancy of this patient population is expected to improve. The committee accepted that results from coBRIM showed that cobimetinib plus vemurafenib extended life by more than 3 months compared with vemurafenib monotherapy. The committee concluded that cobimetinib plus vemurafenib met the end-of-life criteria and that this should be taken into account in its decision-making. The committee noted that even taking into account end-of-life considerations, the cost-effectiveness estimates for cobimetinib plus vemurafenib compared with vemurafenib or dabrafenib alone were above the range considered to be a cost-effective use of NHS resources. The committee considered the company's statement that even if it provided cobimetinib free of charge, the ICER would remain above this range so there was no price at which it could offer cobimetinib that would allow it to be recommended. The committee noted that this assertion was made using the list prices for both products, but there was already a patient access scheme for vemurafenib and therefore this statement, although factually correct, did not apply to routine NHS commissioning in the presence of an agreed patient access scheme. The company had itself presented a scenario showing that a price of zero for cobimetinib would not be needed for the combination to result in an ICER within a similar range to previous melanoma appraisals, in which those technologies had been recommended. The committee was not convinced that there was no price for cobimetinib, taken in combination with vemurafenib, which had the potential to be considered a cost-effective combination. Cobimetinib is not licensed for use as a monotherapy and must be taken with vemurafenib. Therefore the committee stated that the combined drug costs for both cobimetinib and vemurafenib compared with BRAF-inhibitor monotherapy were relevant for its cost-effectiveness analysis. The committee noted the company's comments received in consultation that a scenario of a positive price is possible but it would need a very large discount, and that these scenarios are neither sustainable for companies nor supportive of expanding patient access to innovative technologies. The committee accepted that not submitting a patient access scheme for cobimetinib in combination with vemurafenib was a commercial decision for the company. It concluded that it could not recommend cobimetinib in combination with vemurafenib as a cost-effective use of NHS resources. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA414 Appraisal title: Cobimetinib in combination with vemurafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma Section Key conclusion Cobimetinib in combination with vemurafenib is not recommended within its marketing authorisation for treating unresectable or metastatic melanoma in adults with a BRAF V600 mutation. In all of the analyses presented to the appraisal committee, the incremental cost-effectiveness ratios (ICERs) were over £100,000 per quality-adjusted life year (QALY) gained. This is substantially over the range usually considered a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments There are numerous treatment options available and more treatments that improve survival are either becoming available or are likely to be available to people in the near future. People value life-extending treatment options but also value having various options available, because some people will experience side effects and need to switch treatment. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The combination of cobimetinib plus vemurafenib improves survival compared with a BRAF inhibitor (vemurafenib or dabrafenib) taken alone. Cobimetinib plus vemurafenib is the second MEK inhibitor taken in combination with a BRAF inhibitor to be licensed for use in England. Trametinib plus dabrafenib has been licensed for the same patient population. What is the position of the treatment in the pathway of care for the condition? For most people with BRAF V600 mutation-positive melanoma, the combination of cobimetinib plus vemurafenib will be taken after an immunotherapy agent and as an alternative treatment option to a BRAF inhibitor (vemurafenib or dabrafenib). Adverse reactions The summary of product characteristics notes that people taking a combination of cobimetinib plus vemurafenib should be monitored for visual disturbances and cardiac function. Evidence for clinical effectiveness Availability, nature and quality of evidence Data from the coBRIM trial (comparing cobimetinib plus vemurafenib with vemurafenib alone) were considered to be the most robust clinical data for decision-making. This was because there were no head-to-head data comparing cobimetinib plus vemurafenib with dabrafenib, the company's indirect comparison was based on a network with a small number of trials, and potential differences between the trials had not been fully explored. Relevance to general clinical practice in the NHS Clinical-effectiveness evidence from coBRIM was generalisable to clinical practice in England. Uncertainties generated by the evidence The relative clinical effectiveness of cobimetinib plus vemurafenib compared with dabrafenib was uncertain because no trials had directly compared these treatment options. However, the relative clinical effectiveness of cobimetinib plus vemurafenib compared with dabrafenib was expected to be similar to the clinical effectiveness of cobimetinib plus vemurafenib compared with vemurafenib because the committee had heard that vemurafenib and dabrafenib monotherapies are considered to be of similar clinical effectiveness. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No. Estimate of the size of the clinical effectiveness including strength of supporting evidence Cobimetinib plus vemurafenib extends overall survival by 4.9 months compared with vemurafenib alone. Evidence for cost effectiveness Availability and nature of evidence The company used a model that has a structure consistent with those used in previous melanoma technology appraisals. Uncertainties around and plausibility of assumptions and inputs in the economic model The company used different assumptions for comparing cobimetinib plus vemurafenib with vemurafenib alone than for cobimetinib plus vemurafenib compared with dabrafenib because some trial data for dabrafenib were not available to it. The committee preferred the assumptions for cobimetinib plus vemurafenib compared with vemurafenib alone, and thought that the clinical data used to inform these assumptions in the modelling were robust. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? Utility values for people whose disease had not progressed were derived from coBRIM trial data. Less trial data on quality of life were available for people with progressed disease and the company and ERG presented different estimates for the utility value for these people. The committee thought it was appropriate that a range of utility values should be considered in its decision-making because it had heard from the clinical expert that the quality of life of people with advanced melanoma may vary. Are there specific groups of people for whom the technology is particularly cost effective? No. What are the key drivers of cost effectiveness? The costs of cobimetinib plus vemurafenib and its comparators. The duration of treatment and associated drug costs. Most likely cost-effectiveness estimate (given as an ICER) Over £100,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) Vemurafenib and dabrafenib have patient access schemes agreed with the Department of Health. These are simple discounts to the list price for vemurafenib and dabrafenib. The levels of these discounts are confidential. End-of-life considerations Cobimetinib plus vemurafenib met the end-of-life criteria and the committee took this into account in its decision-making. Equalities considerations and social value judgements No equality issues were raised.	{'Recommendations': 'Cobimetinib in combination with vemurafenib is not recommended within its marketing authorisation for treating unresectable or metastatic melanoma in adults with a BRAF\xa0V600 mutation.\n\nThis guidance is not intended to affect the position of patients whose treatment with cobimetinib in combination with vemurafenib was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': 'Description of the technology\n\nCobimetinib (Cotellic, Roche) is an inhibitor of MEK\xa01 and MEK\xa02 kinases. Vemurafenib (Zelboraf, Roche) is an inhibitor of the BRAF protein. Both are taken as tablets. The BRAF protein and MEK\xa01 and\xa02 kinases are part of the same cell-signalling pathway. Inhibiting these proteins stops proliferation and survival of melanoma cells.\n\nMarketing authorisation\n\nCobimetinib in combination with vemurafenib is indicated for the treatment of unresectable or metastatic melanoma in adults with a BRAF\xa0V600 mutation. Vemurafenib has a marketing authorisation for use as monotherapy for this indication. Cobimetinib does not have a marketing authorisation for use as monotherapy.\n\nAdverse reactions\n\nThe following common adverse reactions affect more than 1\xa0in 5\xa0people: diarrhoea, rash, nausea, vomiting, fever, light sensitivity reaction, abnormal liver function tests, and abnormal results for an enzyme related to muscle breakdown (creatine phosphokinase). Less common adverse reactions include swelling of the retina (retinopathy) or effects on cardiac function (reduced left ventricular ejection fraction). People taking cobimetinib plus vemurafenib should be monitored for new and worsening visual disturbances, and for heart function. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nCobimetinib: 3\xa0tablets per day for 21\xa0days followed by a 7‑day break (days\xa022 to\xa028) before the next cycle is started.\n\nVemurafenib: 960\xa0mg (4\xa0tablets of 240\xa0mg) twice daily (equivalent to a total daily dose of 1,920\xa0mg).\n\nPrice\n\nThe company has stated that the cost of cobimetinib (excluding VAT) is £4,275.67 for a 63‑tablet pack of 20\xa0mg tablets.\n\nThe company has agreed a patient access scheme with the Department of Health for vemurafenib as monotherapy. It is provided to the NHS with a simple discount to the list price of vemurafenib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.\n\nIf cobimetinib with vemurafenib had been recommended, the company would have provided vemurafenib for use in combination with cobimetinib with the same discount as that agreed for vemurafenib as monotherapy. Costs may vary in different settings because of negotiated procurement discounts.', 'Evidence': 'The appraisal committee (section\xa05) considered evidence submitted by the company and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of cobimetinib in combination with vemurafenib, having considered evidence on the nature of advanced (unresectable or metastatic) BRAF\xa0V600 mutation-positive melanoma and the value placed on the benefits of cobimetinib plus vemurafenib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management of advanced melanoma\n\nThe committee discussed the clinical need of people with advanced BRAF\xa0V600 mutation-positive melanoma. It heard from the patient expert that the symptoms of advanced melanoma vary, partly depending on the sites of metastases, but they can be severe and wide ranging. Symptoms such as pain can have a major effect on quality of life. The patient expert explained that having a choice of effective treatments to switch to if there are side effects is greatly valued by people. However, prolonging survival is of such importance to people that many would be willing to accept considerable side effects if their chance of survival is improved. The committee concluded that the symptoms and effect on quality of life vary between people with advanced melanoma, and that people welcome having a choice of life-extending treatment options available to them.\n\nThe committee noted that people with BRAF\xa0V600 mutation-positive advanced melanoma could have an immunotherapy agent (ipilimumab, pembrolizumab or nivolumab) or a targeted BRAF inhibitor (vemurafenib or dabrafenib). The clinical expert stated that about 70% of people with BRAF\xa0V600 mutation-positive disease have immunotherapy first line because of the long-term benefit that has been shown in trials. BRAF inhibitors would usually be used first line only for people with rapidly progressing disease, high disease burden or elevated LDH (lactate dehydrogenase) levels, when a rapid onset of action is needed. BRAF inhibitors are considered to be equally effective whether given before or after immunotherapy. The committee concluded that most people with BRAF\xa0V600 mutation-positive melanoma would have a targeted therapy at some point in their treatment.\n\n## Comparators\n\nThe clinical expert stated that the 2\xa0comparators listed in the scope, vemurafenib and dabrafenib, are considered to have similar clinical effectiveness but some people will experience adverse reactions with either drug. The clinical expert noted that photosensitivity and rashes are more common with vemurafenib than dabrafenib, so dabrafenib tends to be prescribed more often, although the clinical expert also stated that fevers are less common with vemurafenib than dabrafenib. Because it is not possible to predict who will have adverse reactions with either drug before starting treatment, it is valuable to have 2\xa0BRAF inhibitors available for patients. The committee noted that NICE recently recommended another combination treatment (trametinib, a MEK inhibitor, in combination with dabrafenib), which has a similar mechanism of action to cobimetinib plus vemurafenib. However, it noted that the final guidance had not yet been issued and this treatment combination could not be considered established practice. The clinical expert stated that if the NHS routinely funded a combination of a BRAF inhibitor plus a MEK inhibitor this would be preferred over BRAF-inhibitor monotherapy, because of the longer survival shown in trials. The committee recognised that the treatment options for melanoma are likely to increase in the near future but concluded that, at present, the comparators in the scope issued by NICE were appropriate for its decision-making.\n\n# Clinical effectiveness\n\n## Evidence from the coBRIM trial\n\nThe committee discussed the generalisability of the clinical evidence from the coBRIM trial that compared cobimetinib plus vemurafenib with vemurafenib plus placebo. It noted that most patients in coBRIM had not previously had an immunotherapy agent, and in this regard the population in coBRIM was different to the population who would have cobimetinib plus vemurafenib in clinical practice in England. However, the committee took into account the comments from the clinical expert that the clinical effectiveness of cobimetinib plus vemurafenib is not expected to differ if it is taken before or after an immunotherapy agent. It was therefore satisfied that the clinical-effectiveness evidence from coBRIM is generalisable to melanoma that has or has not been treated with immunotherapy.\n\nThe committee examined the results of coBRIM. It noted that, at the time of the latest data cut-off in the company's submission, the combination of cobimetinib plus vemurafenib increased overall survival by 4.9\xa0months compared with vemurafenib alone (median survival 22.3\xa0months and 17.4\xa0months respectively). The committee concluded that cobimetinib plus vemurafenib is clinically effective compared with vemurafenib alone.\n\n## Company's network meta-analyses\n\nThe committee considered the company's indirect comparison of cobimetinib plus vemurafenib with dabrafenib alone, noting that there were no direct head-to-head clinical trials comparing cobimetinib plus vemurafenib with dabrafenib. It agreed with the evidence review group (ERG) that the rationale and methods for the indirect comparison were appropriate. The committee noted the ERG's comments that the trials in the network were broadly comparable, based on selected characteristics, but the potential heterogeneity of the trials in the network had not been fully explored in the company's submission. The committee noted that the trials comparing dabrafenib with dacarbazine (BREAK‑3) and vemurafenib with dacarbazine (BRIM‑3), which were included in the meta-analysis, included similar populations to coBRIM but there were differences in the trial designs. For example, BREAK‑3 and BRIM‑3 allowed crossover from the dacarbazine arm to the dabrafenib or vemurafenib arm, but coBRIM did not allow crossover between treatment arms. The committee noted, and the company confirmed, that crossover had not been adjusted for in the network meta-analysis. The committee agreed with the ERG that the clinical effectiveness of dabrafenib and vemurafenib as monotherapies may have been underestimated in the network. The committee also noted that there was only 1\xa0trial for each comparator in the network, which increased its uncertainty in the results. It concluded that taking into account the unexplored potential heterogeneity between the trials, and the limited number of trials in the network, the indirect comparison of cobimetinib plus vemurafenib with dabrafenib was associated with considerable uncertainty.\n\nGiven the uncertainty surrounding the indirect comparison, the committee discussed whether it would be more appropriate to assume that the BRAF inhibitors (dabrafenib and vemurafenib) were sufficiently similar in clinical effectiveness to be considered clinically interchangeable. In response to the appraisal consultation document, the company stated that it considered that the results from the indirect comparison were more robust for the comparison with dabrafenib than an assumption of clinical equivalence between the 2\xa0drugs. The committee agreed that there may be some differences in the tolerability of the 2\xa0drugs, but noted that in the company's modelled base case, the total estimated life years and the total quality-adjusted life years (QALYs) for cobimetinib plus vemurafenib compared with vemurafenib or dabrafenib alone were similar (3.392\xa0life years for vemurafenib compared with 3.281 for dabrafenib, and 2.489 QALYs for vemurafenib compared with 2.417 for dabrafenib). The committee considered that the company's modelling did not contradict the committee's preferred assumption of similar efficacy of vemurafenib and dabrafenib monotherapies, and this was also consistent with what the committee had heard from the clinical expert (see section\xa04.3). The committee therefore concluded that the most robust comparative data on which to base its decision were from the coBRIM trial of cobimetinib plus vemurafenib compared with vemurafenib alone, and that it would be reasonable to assume that a comparison of cobimetinib plus vemurafenib with dabrafenib alone gives similar results.\n\n# Cost effectiveness\n\n## The company's model\n\nThe committee noted that the 3‑state partitioned model used by the company was similar to the structure of models used in previous appraisals of technologies for treating melanoma, and met the NICE reference case. The committee also considered that the time horizon of 30\xa0years was appropriate. The committee concluded that the model was in line with accepted NICE methods and appropriate for its decision-making.\n\n## Utility values\n\nThe company used 2\xa0approaches to convert EQ‑5D‑5L data from coBRIM into utility values for the progression-free-survival health state. The committee accepted the company's rationale for choosing between these 2\xa0approaches; that is, the company used the method that produced lower utility values, which were more plausible than the alternative approach that produced utility values above those for people without melanoma. The committee accepted that because the company had not been able to collect EQ‑5D‑5L data from many people after their melanoma had progressed, the utility values derived from the trial may not reflect quality of life for people with progressed disease. The committee noted that the company's preferred alternative came from a study (Beusterien et al. 2009) that did not meet the NICE reference case, and which reported that quality of life would be much worse in the first 5\xa0years of progressed disease (0.590) than if a person survived for more than 5\xa0years with progressed disease (0.770). The committee considered that this may be plausible but noted that the difference between the 2\xa0values was large. The committee was aware that several approaches to calculating utility values had been used in previous melanoma appraisals, without uniform agreement on the most appropriate method. The ERG's alternative utility value for the progressed-disease state (0.73) was the same as that used in NICE's technology appraisal guidance on nivolumab for treating advanced (unresectable or metastatic) melanoma. The committee considered that there was uncertainty surrounding the most appropriate utility value, especially for people with progressed disease, because of data limitations. It noted that the patient expert had highlighted that the extent to which melanoma affects quality of life may vary (see section\xa04.1). The committee concluded that there was uncertainty surrounding utility values and it was appropriate to take into account the effect of a range of utility values, provided by sensitivity analyses, in its decision-making.\n\n## Assumptions\n\nThe company used different model inputs when comparing cobimetinib plus vemurafenib with vemurafenib alone, than it did for cobimetinib plus vemurafenib compared with dabrafenib. The committee noted the following differences:\n\nCobimetinib plus vemurafenib compared with vemurafenib alone:\n\n\n\nextrapolating progression-free-survival and overall-survival data from coBRIM data; the same extrapolation distribution was used for each treatment arm\n\nextrapolating time on treatment from coBRIM data; different extrapolation distributions were used to extrapolate the trial data over the long term for each treatment arm\n\nestimating the drug dosages using data from coBRIM, in which people could have dose reductions.\n\n\n\nCobimetinib plus vemurafenib compared with dabrafenib:\n\n\n\nextrapolating progression-free-survival and overall-survival data from coBRIM for cobimetinib plus vemurafenib, but from the network meta-analysis for dabrafenib monotherapy; the same extrapolation distribution was used for each treatment arm\n\nassuming that time on treatment was the same as progression-free survival for cobimetinib plus vemurafenib and for dabrafenib; the same extrapolation distribution was used to extrapolate progression-free-survival data for each treatment arm\n\nestimating the drug dosages using data from coBRIM for cobimetinib plus vemurafenib, and using the licensed dose for dabrafenib (with no adjustments for drug dose reductions).The company's rationale for using different assumptions for each comparison was that it did not have access to the patient-level data needed to model time on treatment and dose modifications for dabrafenib. The committee accepted this, but noted that the costs for dabrafenib may have been overestimated because the company did not account for dose modifications of dabrafenib. The committee considered that using progression-free survival as a proxy measure for time on treatment would overestimate time on treatment and consequently drug costs, because people may stop treatment before disease progression. The committee noted that the total costs for cobimetinib plus vemurafenib in the company's base case were higher when using assumptions from the comparison of cobimetinib plus vemurafenib with dabrafenib, than using those for the comparison with vemurafenib. The higher costs seemed to be due to using progression-free survival as a surrogate for time on treatment in the comparison with dabrafenib. The committee concluded that the differences in modelling assumptions had a substantial effect on costs, but only a marginal effect on the QALY estimates.\n\n\n\nThe committee noted that the ERG had presented results using the same assumptions for each modelled treatment arm and a different utility value for the progressed-disease health state. The committee agreed with the ERG that where possible modelling assumptions should be consistent between treatment arms. However, it noted that to do this the ERG had to use data from the network meta-analysis and make further adjustments for possible changes in doses of dabrafenib; it therefore considered that the ERG's modelling was based on less robust data than the company's comparison of cobimetinib plus vemurafenib with vemurafenib. The committee concluded that it preferred:\n\nusing data for cobimetinib plus vemurafenib compared with vemurafenib alone to inform its decision-making, given the lack of patient-level data available for dabrafenib and the uncertainties in the network meta-analysis for the indirect comparison of cobimetinib plus vemurafenib with dabrafenib alone\n\nadjusting the drug costs for dose modifications using data on doses taken by patients in clinical trials\n\nusing time on treatment seen in clinical trials to estimate duration of drug treatment in clinical practice\n\nconsidering sensitivity analyses that reflect the range of utility values presented for other melanoma treatments appraised by NICE, and the potential variation in quality of life experienced by people with advanced melanoma, in its decision-making.\n\n## Estimates of cost effectiveness\n\nThe cost-effectiveness estimates provided by the company and the ERG used the list prices for both drugs or used the patient access scheme prices for vemurafenib and dabrafenib. These produced incremental cost-effectiveness ratios (ICERs) that were over £100,000 per QALY gained. This is substantially above the range usually considered a cost-effective use of NHS resources. The company already provides vemurafenib to the NHS at a discounted price as part of a patient access scheme, but no patient access scheme for cobimetinib in combination with vemurafenib has been agreed with the Department of Health for the current appraisal. The committee noted comments received from consultation stating that with combination treatment significantly fewer excisions by a dermatologist, with the associated costs, are needed for squamous cell carcinomas and keratoacanthomas. The committee noted that the difference in excisions, in favour of the combination treatment, had been included in the base case but had not been explored in any scenario analyses. However, the committee concluded that the cost savings associated with fewer outpatient procedures under local anaesthetic would not have a major impact on the ICERs.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the median survival of people having vemurafenib monotherapy in coBRIM was around 17\xa0months. The committee noted that in its recent appraisal guidance on trametinib plus dabrafenib it had agreed that life expectancy in people with advanced BRAF\xa0V600 mutation-positive melanoma was likely to be under 24\xa0months. There was no evidence to suggest that life expectancy has changed since that decision because the recommendations from that appraisal have not yet become established practice. However, the treatment pathway for advanced melanoma is changing as new treatments become available so life expectancy of this patient population is expected to improve. The committee accepted that results from coBRIM showed that cobimetinib plus vemurafenib extended life by more than 3\xa0months compared with vemurafenib monotherapy. The committee concluded that cobimetinib plus vemurafenib met the end-of-life criteria and that this should be taken into account in its decision-making.\n\nThe committee noted that even taking into account end-of-life considerations, the cost-effectiveness estimates for cobimetinib plus vemurafenib compared with vemurafenib or dabrafenib alone were above the range considered to be a cost-effective use of NHS resources. The committee considered the company's statement that even if it provided cobimetinib free of charge, the ICER would remain above this range so there was no price at which it could offer cobimetinib that would allow it to be recommended. The committee noted that this assertion was made using the list prices for both products, but there was already a patient access scheme for vemurafenib and therefore this statement, although factually correct, did not apply to routine NHS commissioning in the presence of an agreed patient access scheme. The company had itself presented a scenario showing that a price of zero for cobimetinib would not be needed for the combination to result in an ICER within a similar range to previous melanoma appraisals, in which those technologies had been recommended. The committee was not convinced that there was no price for cobimetinib, taken in combination with vemurafenib, which had the potential to be considered a cost-effective combination. Cobimetinib is not licensed for use as a monotherapy and must be taken with vemurafenib. Therefore the committee stated that the combined drug costs for both cobimetinib and vemurafenib compared with BRAF-inhibitor monotherapy were relevant for its cost-effectiveness analysis. The committee noted the company's comments received in consultation that a scenario of a positive price is possible but it would need a very large discount, and that these scenarios are neither sustainable for companies nor supportive of expanding patient access to innovative technologies. The committee accepted that not submitting a patient access scheme for cobimetinib in combination with vemurafenib was a commercial decision for the company. It concluded that it could not recommend cobimetinib in combination with vemurafenib as a cost-effective use of NHS resources.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA414\n\nAppraisal title: Cobimetinib in combination with vemurafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma\n\nSection\n\nKey conclusion\n\nCobimetinib in combination with vemurafenib is not recommended within its marketing authorisation for treating unresectable or metastatic melanoma in adults with a BRAF\xa0V600 mutation.\n\nIn all of the analyses presented to the appraisal committee, the incremental cost-effectiveness ratios (ICERs) were over £100,000 per quality-adjusted life year (QALY) gained. This is substantially over the range usually considered a cost-effective use of NHS resources.\n\n, 4.12\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThere are numerous treatment options available and more treatments that improve survival are either becoming available or are likely to be available to people in the near future. People value life-extending treatment options but also value having various options available, because some people will experience side effects and need to switch treatment.\n\n–4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe combination of cobimetinib plus vemurafenib improves survival compared with a BRAF inhibitor (vemurafenib or dabrafenib) taken alone.\n\nCobimetinib plus vemurafenib is the second MEK inhibitor taken in combination with a BRAF inhibitor to be licensed for use in England. Trametinib plus dabrafenib has been licensed for the same patient population.\n\n, 4.3\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nFor most people with BRAF\xa0V600 mutation-positive melanoma, the combination of cobimetinib plus vemurafenib will be taken after an immunotherapy agent and as an alternative treatment option to a BRAF inhibitor (vemurafenib or dabrafenib).\n\n, 4.3\n\nAdverse reactions\n\nThe summary of product characteristics notes that people taking a combination of cobimetinib plus vemurafenib should be monitored for visual disturbances and cardiac function.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nData from the coBRIM trial (comparing cobimetinib plus vemurafenib with vemurafenib alone) were considered to be the most robust clinical data for decision-making. This was because there were no head-to-head data comparing cobimetinib plus vemurafenib with dabrafenib, the company's indirect comparison was based on a network with a small number of trials, and potential differences between the trials had not been fully explored.\n\n, 4.6, 4.7\n\nRelevance to general clinical practice in the NHS\n\nClinical-effectiveness evidence from coBRIM was generalisable to clinical practice in England.\n\n\n\nUncertainties generated by the evidence\n\nThe relative clinical effectiveness of cobimetinib plus vemurafenib compared with dabrafenib was uncertain because no trials had directly compared these treatment options. However, the relative clinical effectiveness of cobimetinib plus vemurafenib compared with dabrafenib was expected to be similar to the clinical effectiveness of cobimetinib plus vemurafenib compared with vemurafenib because the committee had heard that vemurafenib and dabrafenib monotherapies are considered to be of similar clinical effectiveness.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nCobimetinib plus vemurafenib extends overall survival by 4.9\xa0months compared with vemurafenib alone.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company used a model that has a structure consistent with those used in previous melanoma technology appraisals.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe company used different assumptions for comparing cobimetinib plus vemurafenib with vemurafenib alone than for cobimetinib plus vemurafenib compared with dabrafenib because some trial data for dabrafenib were not available to it. The committee preferred the assumptions for cobimetinib plus vemurafenib compared with vemurafenib alone, and thought that the clinical data used to inform these assumptions in the modelling were robust.\n\n, 4.11\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nUtility values for people whose disease had not progressed were derived from coBRIM trial data. Less trial data on quality of life were available for people with progressed disease and the company and ERG presented different estimates for the utility value for these people. The committee thought it was appropriate that a range of utility values should be considered in its decision-making because it had heard from the clinical expert that the quality of life of people with advanced melanoma may vary.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe costs of cobimetinib plus vemurafenib and its comparators. The duration of treatment and associated drug costs.\n\n–\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nOver £100,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nVemurafenib and dabrafenib have patient access schemes agreed with the Department of Health. These are simple discounts to the list price for vemurafenib and dabrafenib. The levels of these discounts are confidential.\n\n\n\nEnd-of-life considerations\n\nCobimetinib plus vemurafenib met the end-of-life criteria and the committee took this into account in its decision-making.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised.\n\n–"}	https://www.nice.org.uk/guidance/ta414	Evidence-based recommendations on cobimetinib (Cotellic) with vemurafenib (Zelboraf) for treating unresectable or metastatic melanoma in adults with a BRAF V600 mutation.
6258f3c99bca60183282c0a5e6f0f00682e3f95a	nice	Jaundice in newborn babies under 28 days	Jaundice in newborn babies under 28 days This guideline covers diagnosing and treating jaundice, which is caused by increased levels of bilirubin in the blood, in newborn babies (neonates). It aims to help detect or prevent very high levels of bilirubin, which can be harmful if not treated. # Context Jaundice is one of the most common conditions needing medical attention in newborn babies. Jaundice refers to the yellow colouration of the skin and the sclerae (whites of the eyes) caused by the accumulation of bilirubin in the skin and mucous membranes. It is caused by a raised level of bilirubin in the body, a condition known as hyperbilirubinaemia. Approximately 60% of term and 80% of preterm babies develop jaundice in the first week of life, and about 10% of breastfed babies are still jaundiced at 1 month. For most babies, jaundice is not an indication of an underlying disease, and this early jaundice (termed 'physiological jaundice') is usually harmless. Breastfed babies are more likely than bottle‑fed babies to develop physiological jaundice within the first week of life. Prolonged jaundice – that is, jaundice persisting beyond the first 14 days – is also seen more commonly in breastfed babies. Prolonged jaundice is usually harmless, but can sometimes be an indication of serious liver disease. Jaundice has many possible causes, including blood group incompatibility (most commonly rhesus or ABO incompatibility), other causes of haemolysis (breaking down of red blood cells), sepsis (infection), liver disease, bruising and metabolic disorders. Deficiency of a particular enzyme, glucose‑6‑phosphate‑dehydrogenase, can cause severe neonatal jaundice. Glucose‑6‑phosphate‑dehydrogenase deficiency is more common in certain ethnic groups and runs in families. Bilirubin is mainly produced from the breakdown of red blood cells. Red cell breakdown produces unconjugated (or 'indirect') bilirubin, which circulates mostly bound to albumin although some is 'free' and hence able to enter the brain. Unconjugated bilirubin is metabolised in the liver to produce conjugated (or 'direct') bilirubin which then passes into the gut and is largely excreted in stool. The terms direct and indirect refer to the way the laboratory tests measure the different forms. Some tests measure total bilirubin and do not distinguish between the two forms. In young babies, unconjugated bilirubin can penetrate the membrane that lies between the brain and the blood (the blood–brain barrier). Unconjugated bilirubin is potentially toxic to neural tissue (brain and spinal cord). Entry of unconjugated bilirubin into the brain can cause both short‑term and long‑term neurological dysfunction (bilirubin encephalopathy). The term kernicterus is used to denote the clinical features of acute or chronic bilirubin encephalopathy, as well as the yellow staining in the brain associated with the former. The risk of kernicterus is increased in babies with extremely high bilirubin levels. Kernicterus is also known to occur at lower levels of bilirubin in term babies who have risk factors, and in preterm babies. Clinical recognition and assessment of jaundice can be difficult, particularly in babies with darker skin tones. Once jaundice is recognised, there is uncertainty about when to treat, and there is widespread variation in the use of phototherapy and exchange transfusion. There is a need for more uniform, evidence‑based practice and for consensus‑based practice where such evidence is lacking. This guideline provides guidance regarding the recognition, assessment and treatment of neonatal jaundice. The advice is based on evidence where this is available and on consensus‑based practice where it is not. In 2016, we reviewed the evidence on tests for recognising neonatal jaundice, bilirubin thresholds for retesting, and the type and procedure for phototherapy. New and updated recommendations have been added on bilirubin thresholds for retesting and the type of phototherapy to use.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Threshold table Note that there is variability between assays from different manufacturers in reported bilirubin measurement. Healthcare professionals should consult their local pathology laboratory when interpreting threshold tables. Age (hours) Bilirubin measurement (micromol/litre) Action Start phototherapy Perform an exchange transfusion unless the bilirubin level falls below threshold while the treatment is being prepared # Information for parents or carers Offer parents or carers information about neonatal jaundice that is tailored to their needs and expressed concerns. This information should be provided through verbal discussion backed up by written information. Care should be taken to avoid causing unnecessary anxiety to parents or carers. Information should include: factors that influence the development of significant hyperbilirubinaemia how to check the baby for jaundice what to do if they suspect jaundice the importance of recognising jaundice in the first 24 hours and of seeking urgent medical advice the importance of checking the baby's nappies for dark urine or pale chalky stools the fact that neonatal jaundice is common, and reassurance that it is usually transient and harmless reassurance that breastfeeding can usually continue. # Care for all babies Identify babies as being more likely to develop significant hyperbilirubinaemia if they have any of the following factors: gestational age under 38 weeks a previous sibling with neonatal jaundice requiring phototherapy mother's intention to breastfeed exclusively visible jaundice in the first 24 hours of life. Ensure that adequate support is offered to all women who intend to breastfeed exclusively. For information on breastfeeding support, see NICE's guideline on postnatal care. In all babies: check whether there are factors associated with an increased likelihood of developing significant hyperbilirubinaemia soon after birth examine the baby for jaundice at every opportunity especially in the first 72 hours. Parents, carers and healthcare professionals should all look for jaundice (visual inspection) in babies. When looking for jaundice (visual inspection): check the naked baby in bright and preferably natural light examine the sclerae and gums, and press lightly on the skin to check for signs of jaundice in 'blanched' skin. Do not rely on visual inspection alone to estimate the bilirubin level in a baby with suspected jaundice. Do not measure bilirubin levels routinely in babies who are not visibly jaundiced. Do not use any of the following to predict significant hyperbilirubinaemia: umbilical cord blood bilirubin level end‑tidal carbon monoxide (ETCOc) measurement umbilical cord blood direct antiglobulin test (DAT) (Coombs' test). ## Additional care Ensure babies with factors associated with an increased likelihood of developing significant hyperbilirubinaemia receive an additional visual inspection by a healthcare professional during the first 48 hours of life. ## Urgent additional care for babies with visible jaundice in the first 24 hours In all babies with suspected or obvious jaundice in the first 24 hours of life, measure and record the serum bilirubin level urgently (within 2 hours). In all babies with suspected or obvious jaundice in the first 24 hours of life, continue to measure the serum bilirubin level every 6 hours until the level is both: below the treatment threshold stable and/or falling. Arrange a referral to ensure that an urgent medical review is conducted (as soon as possible and within 6 hours) for babies with suspected or obvious jaundice in the first 24 hours of life to exclude pathological causes of jaundice. Interpret bilirubin levels according to the baby's postnatal age in hours and manage hyperbilirubinaemia according to the threshold table and the treatment threshold graphs. ## Care for babies more than 24 hours old Measure and record the bilirubin level urgently (within 6 hours) in all babies more than 24 hours old with suspected or obvious jaundice. ## How to measure the bilirubin level Use serum bilirubin measurement for babies: in the first 24 hours of life or who have a gestational age of less than 35 weeks. In babies who have a gestational age of 35 weeks or more and who are over 24 hours old: use a transcutaneous bilirubinometer to measure the bilirubin level if a transcutaneous bilirubinometer is not available, measure the serum bilirubin if a transcutaneous bilirubinometer measurement indicates a bilirubin level greater than 250 micromol/litre, measure the serum bilirubin to check the result use serum bilirubin measurement if bilirubin levels are at or above the relevant treatment thresholds for their age, and for all subsequent measurements. Do not use an icterometer to measure bilirubin levels in babies. # Management and treatment of hyperbilirubinaemia ## Information for parents or carers on treatment Offer parents or carers information about treatment for hyperbilirubinaemia, including: anticipated duration of treatment reassurance that breastfeeding, nappy‑changing and cuddles can usually continue. Encourage mothers of breastfed babies with jaundice to breastfeed frequently, and to wake the baby for feeds if necessary. Provide lactation/feeding support to breastfeeding mothers whose baby is visibly jaundiced. ## How to manage hyperbilirubinaemia Note that there is variability between assays from different manufacturers in reported bilirubin measurement. Healthcare professionals should consult their local pathology laboratory when interpreting threshold tables. Use the bilirubin level to determine the management of hyperbilirubinaemia in all babies (see the threshold table and the treatment threshold graphs). Do not use the albumin/bilirubin ratio when making decisions about the management of hyperbilirubinaemia. Do not subtract conjugated bilirubin from total serum bilirubin when making decisions about the management of hyperbilirubinaemia (see management thresholds in the threshold table and the treatment threshold graphs). # Measuring and monitoring bilirubin thresholds before and during phototherapy ## Before starting phototherapy In babies who are clinically well, have a gestational age of 38 weeks or more and are more than 24 hours old, and who have a bilirubin level that is below the phototherapy threshold but within 50 micromol/litre of the threshold (see the threshold table and the treatment threshold graphs), repeat bilirubin measurement as follows: within 18 hours for babies with risk factors for neonatal jaundice (those with a sibling who had neonatal jaundice that needed phototherapy or a mother who intends to exclusively breastfeed) within 24 hours for babies without risk factors. In babies who are clinically well, have a gestational age of 38 weeks or more and are more than 24 hours old, and who have a bilirubin level that is below the phototherapy threshold by more than 50 micromol/litre (see the threshold table and the treatment threshold graphs), do not routinely repeat bilirubin measurement. Do not use phototherapy in babies whose bilirubin does not exceed the phototherapy threshold levels in the threshold table and the treatment threshold graphs. ## During phototherapy During phototherapy: repeat serum bilirubin measurement 4–6 hours after initiating phototherapy repeat serum bilirubin measurement every 6–12 hours when the serum bilirubin level is stable or falling. ## Stopping phototherapy Stop phototherapy once serum bilirubin has fallen to a level at least 50 micromol/litre below the phototherapy threshold (see threshold table and the treatment threshold graphs). Check for rebound of significant hyperbilirubinaemia with a repeat serum bilirubin measurement 12–18 hours after stopping phototherapy. Babies do not necessarily have to remain in hospital for this to be done. ## Type of phototherapy to use Do not use sunlight as treatment for hyperbilirubinaemia. Use phototherapy (phototherapy given using an artificial light source with an appropriate spectrum and irradiance. This can be delivered using light-emitting diode , fibreoptic or fluorescent lamps, tubes or bulbs) to treat significant hyperbilirubinaemia (see the threshold table and the treatment threshold graphs) in babies. Consider intensified phototherapy (phototherapy that is given with an increased level of irradiance with an appropriate spectrum. Phototherapy can be intensified by adding another light source or increasing the irradiance of the initial light source used) to treat significant hyperbilirubinaemia in babies if any of the following apply : the serum bilirubin level is rising rapidly (more than 8.5 micromol/litre per hour) the serum bilirubin is at a level within 50 micromol/litre below the threshold for which exchange transfusion is indicated after 72 hours or more since birth (see threshold table and the treatment threshold graphs) the bilirubin level fails to respond to initial phototherapy (that is, the level of serum bilirubin continues to rise, or does not fall, within 6 hours of starting phototherapy). If the serum bilirubin level falls during intensified phototherapy to a level 50 micromol/litre below the threshold for which exchange transfusion is indicated reduce the intensity of phototherapy. ## Information for parents or carers on phototherapy Offer parents or carers verbal and written information on phototherapy including all of the following: why phototherapy is being considered why phototherapy may be needed to treat significant hyperbilirubinaemia the possible adverse effects of phototherapy the need for eye protection and routine eye care reassurance that short breaks for feeding, nappy changing and cuddles will be encouraged what might happen if phototherapy fails rebound jaundice potential long‑term adverse effects of phototherapy potential impact on breastfeeding and how to minimise this. ## General care of the baby during phototherapy During phototherapy: place the baby in a supine position unless other clinical conditions prevent this ensure treatment is applied to the maximum area of skin monitor the baby's temperature and ensure the baby is kept in an environment that will minimise energy expenditure (thermoneutral environment) monitor hydration by daily weighing of the baby and assessing wet nappies support parents and carers and encourage them to interact with the baby. Give the baby eye protection and routine eye care during phototherapy. Use tinted headboxes as an alternative to eye protection in babies with a gestational age of 37 weeks or more undergoing phototherapy. ## Monitoring the baby during phototherapy During phototherapy: using clinical judgement, encourage short breaks (of up to 30 minutes) for breastfeeding, nappy changing and cuddles continue lactation/feeding support do not give additional fluids to babies who are breastfed. Maternal expressed milk is the additional feed of choice if available, and when additional feeds are indicated. During intensified phototherapy: do not interrupt phototherapy for feeding but continue administering intravenous/enteral feeds continue lactation/feeding support so that breastfeeding can start again when treatment stops.Maternal expressed milk is the additional feed of choice if available, and when additional feeds are indicated. ## Phototherapy equipment Ensure all phototherapy equipment is maintained and used according to the manufacturers' guidelines. Use incubators or bassinets according to clinical need and availability. Do not use white curtains routinely with phototherapy as they may impair observation of the baby. # Factors that influence the risk of kernicterus Identify babies with hyperbilirubinaemia as being at increased risk of developing kernicterus if they have any of the following: a serum bilirubin level greater than 340 micromol/litre in babies with a gestational age of 37 weeks or more a rapidly rising bilirubin level of greater than 8.5 micromol/litre per hour clinical features of acute bilirubin encephalopathy. # Formal assessment for underlying disease In addition to a full clinical examination by a suitably trained healthcare professional, carry out all of the following tests in babies with significant hyperbilirubinaemia as part of an assessment for underlying disease (see threshold table and the treatment threshold graphs): serum bilirubin (for baseline level to assess response to treatment) blood packed cell volume blood group (mother and baby) DAT (Coombs' test). Interpret the result taking account of the strength of reaction, and whether mother received prophylactic anti‑D immunoglobulin during pregnancy. When assessing the baby for underlying disease, consider whether the following tests are clinically indicated: full blood count and examination of blood film blood glucose‑6‑phosphate dehydrogenase levels, taking account of ethnic origin microbiological cultures of blood, urine and/or cerebrospinal fluid (if infection is suspected). # Care of babies with prolonged jaundice In babies with a gestational age of 37 weeks or more with jaundice lasting more than 14 days, and in babies with a gestational age of less than 37 weeks and jaundice lasting more than 21 days: look for pale chalky stools and/or dark urine that stains the nappy measure the conjugated bilirubin carry out a full blood count carry out a blood group determination (mother and baby) and DAT (Coombs' test). Interpret the result taking account of the strength of reaction, and whether mother received prophylactic anti‑D immunoglobulin during pregnancy carry out a urine culture ensure that routine metabolic screening (including screening for congenital hypothyroidism) has been performed. Follow expert advice about care for babies with a conjugated bilirubin level greater than 25 micromol/litre because this may indicate serious liver disease. # Intravenous immunoglobulin Use intravenous immunoglobulin (IVIG) (500 mg/kg over 4 hours) as an adjunct to continuous intensified phototherapy in cases of rhesus haemolytic disease or ABO haemolytic disease when the serum bilirubin continues to rise by more than 8.5 micromol/litre per hour. Offer parents or carers information on IVIG including: why IVIG is being considered why IVIG may be needed to treat significant hyperbilirubinaemia the possible adverse effects of IVIG when it will be possible for parents or carers to see and hold the baby. # Exchange transfusion Offer parents or carers information on exchange transfusion including: the fact that exchange transfusion requires that the baby be admitted to an intensive care bed why an exchange transfusion is being considered why an exchange transfusion may be needed to treat significant hyperbilirubinaemia the possible adverse effects of exchange transfusions when it will be possible for parents or carers to see and hold the baby after the exchange transfusion. Use a double‑volume exchange transfusion to treat babies: whose serum bilirubin level indicates its necessity (see threshold table and the treatment threshold graphs) and/or with clinical features and signs of acute bilirubin encephalopathy. During exchange transfusion do not: stop continuous intensified phototherapy perform a single‑volume exchange use albumin priming routinely administer intravenous calcium. Following exchange transfusion: maintain continuous intensified phototherapy measure serum bilirubin level within 2 hours and manage according to the threshold table and the treatment threshold graphs. # Other therapies Do not use any of the following to treat hyperbilirubinaemia: agar albumin barbiturates charcoal cholestyramine clofibrate D‑penicillamine glycerin manna metalloporphyrins riboflavin traditional Chinese medicine acupuncture homeopathy. # Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Recommendations for research In 2010, the guideline committee made the 5 recommendations for research. As part of the 2016 update, the standing committee made an additional recommendation for research on parent and healthcare professional experience of phototherapy. # Breastfeeding and hyperbilirubinaemia What are the factors that underlie the association between breastfeeding and jaundice? ## Why this is important Breastfeeding has been shown to be a factor in significant hyperbilirubinaemia. The reasons for this association have not yet been fully elucidated. This question should be answered by studying infants in the first 28 days of life receiving different feeding types (breast milk, formula feeds or mixed feeds). Infants who do not develop significant hyperbilirubinaemia should be compared with infants with significant hyperbilirubinaemia. The outcomes chosen should include maternal factors, neonatal factors and blood analyses. # Transcutaneous bilirubin screening and risk factors What is the comparative effectiveness and cost‑effectiveness of universal pre‑discharge transcutaneous bilirubin screening alone or combined with a risk assessment in reducing jaundice‑related neonatal morbidity and hospital readmission? ## Why this is important There is good evidence that a risk assessment that combines the result of a timed transcutaneous bilirubin level with risk factors for significant hyperbilirubinaemia is effective at preventing later significant hyperbilirubinaemia. This question should be answered by studying the effects of timed pre‑discharge transcutaneous bilirubin levels and timed pre‑discharge transcutaneous bilirubin levels combined with risk assessment. The study population should consist of babies in the first 28 days of life, with subgroups including near‑term babies and babies with dark skin tones. The interventions should be compared with standard care (discharge without timed transcutaneous bilirubin level), and the outcomes chosen should include significant hyperbilirubinaemia, cost‑effectiveness and parental anxiety. # Transcutaneous bilirubinometers What is the comparative accuracy of the Minolta JM‑103 and the BiliChek when compared to serum bilirubin levels in all babies? ## Why this is important The accuracy of transcutaneous bilirubinometers (Minolta JM‑103 and BiliChek) has been adequately demonstrated in term babies below treatment levels (bilirubin less than 250 micromol/litre). New research is needed to evaluate the accuracy of different transcutaneous bilirubinometers in comparison to serum bilirubin levels in all babies. This question should be answered by comparing bilirubin levels taken using different transcutaneous bilirubinometers with bilirubin levels assessed using serum (blood) tests. The study population should comprise babies in the first 28 days of life, with subgroups including preterm babies, babies with dark skin tones, babies with high levels of bilirubin and babies after phototherapy. The outcomes chosen should include diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value), parental anxiety, staff and parental satisfaction with test and cost effectiveness. # Interruptions during phototherapy How frequently and for how long can phototherapy be interrupted without adversely effecting clinical outcomes? ## Why this is important The effectiveness and tolerability of intermittent phototherapy has been adequately demonstrated in term babies at low treatment levels (bilirubin less than 250 micromol/litre). New research is needed to evaluate the effectiveness and tolerability of different frequencies of interruptions of different durations. The study population should comprise babies in the first 28 days of life in phototherapy. Interruptions of 45 or 60 minutes would be made either on demand, every hour or every 2 hours, and compared with interruptions of up to 30 minutes every 3 hours. The outcomes chosen should include effectiveness in terms of the mean decrease in bilirubin levels and the mean duration of phototherapy. Extra outcomes could include adverse effects, parental bonding and parental anxiety, staff and parental satisfaction with treatment and cost effectiveness. # National registries National registries are needed of cases of significant hyperbilirubinaemia, kernicterus and exchange transfusions. ## Why this is important There is good evidence that prospective surveys in the UK and data from a national kernicterus register in the US can help to identify root causes of kernicterus and acute bilirubin encephalopathy. The study population should comprise all children with a peak bilirubin level greater than 450 micromol/litre, which is the threshold for an exchange transfusion recommended by NICE. The intervention would be maternal, prenatal, perinatal and neonatal factors. The outcomes chosen should be shortcomings in clinical and service provision to prevent recurring themes in kernicterus cases. # Parent and healthcare professional experience of phototherapy What is the experience and acceptability of phototherapy from the perspective of parents and healthcare professionals? ## Why this is important There is a gap in the evidence about parental and healthcare professional experience and acceptability of phototherapy. The committee agreed that the need for this research should be supported, especially given the greater awareness of the crucial importance of close and early skin contact between babies and their carers. The study should be a qualitative study of newborn babies (term and preterm) with a diagnosis of jaundice but who are otherwise well. Outcomes should include both parental and staff experience, including access for bonding and breastfeeding.	{'Context': "Jaundice is one of the most common conditions needing medical attention in newborn babies. Jaundice refers to the yellow colouration of the skin and the sclerae (whites of the eyes) caused by the accumulation of bilirubin in the skin and mucous membranes. It is caused by a raised level of bilirubin in the body, a condition known as hyperbilirubinaemia.\n\nApproximately 60% of term and 80% of preterm babies develop jaundice in the first week of life, and about 10% of breastfed babies are still jaundiced at 1\xa0month. For most babies, jaundice is not an indication of an underlying disease, and this early jaundice (termed 'physiological jaundice') is usually harmless.\n\nBreastfed babies are more likely than bottle‑fed babies to develop physiological jaundice within the first week of life. Prolonged jaundice – that is, jaundice persisting beyond the first 14\xa0days – is also seen more commonly in breastfed babies. Prolonged jaundice is usually harmless, but can sometimes be an indication of serious liver disease.\n\nJaundice has many possible causes, including blood group incompatibility (most commonly rhesus or ABO incompatibility), other causes of haemolysis (breaking down of red blood cells), sepsis (infection), liver disease, bruising and metabolic disorders. Deficiency of a particular enzyme, glucose‑6‑phosphate‑dehydrogenase, can cause severe neonatal jaundice. Glucose‑6‑phosphate‑dehydrogenase deficiency is more common in certain ethnic groups and runs in families.\n\nBilirubin is mainly produced from the breakdown of red blood cells. Red cell breakdown produces unconjugated (or 'indirect') bilirubin, which circulates mostly bound to albumin although some is 'free' and hence able to enter the brain. Unconjugated bilirubin is metabolised in the liver to produce conjugated (or 'direct') bilirubin which then passes into the gut and is largely excreted in stool. The terms direct and indirect refer to the way the laboratory tests measure the different forms. Some tests measure total bilirubin and do not distinguish between the two forms.\n\nIn young babies, unconjugated bilirubin can penetrate the membrane that lies between the brain and the blood (the blood–brain barrier). Unconjugated bilirubin is potentially toxic to neural tissue (brain and spinal cord). Entry of unconjugated bilirubin into the brain can cause both short‑term and long‑term neurological dysfunction (bilirubin encephalopathy). The term kernicterus is used to denote the clinical features of acute or chronic bilirubin encephalopathy, as well as the yellow staining in the brain associated with the former. The risk of kernicterus is increased in babies with extremely high bilirubin levels. Kernicterus is also known to occur at lower levels of bilirubin in term babies who have risk factors, and in preterm babies.\n\nClinical recognition and assessment of jaundice can be difficult, particularly in babies with darker skin tones. Once jaundice is recognised, there is uncertainty about when to treat, and there is widespread variation in the use of phototherapy and exchange transfusion. There is a need for more uniform, evidence‑based practice and for consensus‑based practice where such evidence is lacking. This guideline provides guidance regarding the recognition, assessment and treatment of neonatal jaundice. The advice is based on evidence where this is available and on consensus‑based practice where it is not.\n\nIn 2016, we reviewed the evidence on tests for recognising neonatal jaundice, bilirubin thresholds for retesting, and the type and procedure for phototherapy. New and updated recommendations have been added on bilirubin thresholds for retesting and the type of phototherapy to use.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Threshold table\n\nNote that there is variability between assays from different manufacturers in reported bilirubin measurement. Healthcare professionals should consult their local pathology laboratory when interpreting threshold tables.\n\nAge (hours)\n\nBilirubin measurement (micromol/litre)\n\n\n\n>100\n\n>100\n\n\n\n>125\n\n>150\n\n\n\n>150\n\n>200\n\n\n\n>175\n\n>250\n\n\n\n>200\n\n>300\n\n\n\n>212\n\n>350\n\n\n\n>225\n\n>400\n\n\n\n>237\n\n>450\n\n\n\n>250\n\n>450\n\n\n\n>262\n\n>450\n\n\n\n>275\n\n>450\n\n\n\n>287\n\n>450\n\n\n\n>300\n\n>450\n\n\n\n>312\n\n>450\n\n\n\n>325\n\n>450\n\n\n\n>337\n\n>450\n\n+\n\n>350\n\n>450\n\nAction\n\n\n\nStart phototherapy\n\nPerform an exchange transfusion unless the bilirubin level falls below threshold while the treatment is being prepared\n\n# Information for parents or carers\n\nOffer parents or carers information about neonatal jaundice that is tailored to their needs and expressed concerns. This information should be provided through verbal discussion backed up by written information. Care should be taken to avoid causing unnecessary anxiety to parents or carers. Information should include:\n\nfactors that influence the development of significant hyperbilirubinaemia\n\nhow to check the baby for jaundice\n\nwhat to do if they suspect jaundice\n\nthe importance of recognising jaundice in the first 24\xa0hours and of seeking urgent medical advice\n\nthe importance of checking the baby's nappies for dark urine or pale chalky stools\n\nthe fact that neonatal jaundice is common, and reassurance that it is usually transient and harmless\n\nreassurance that breastfeeding can usually continue. \n\n# Care for all babies\n\nIdentify babies as being more likely to develop significant hyperbilirubinaemia if they have any of the following factors:\n\ngestational age under 38\xa0weeks\n\na previous sibling with neonatal jaundice requiring phototherapy\n\nmother's intention to breastfeed exclusively\n\nvisible jaundice in the first 24\xa0hours of life. \n\nEnsure that adequate support is offered to all women who intend to breastfeed exclusively. For information on breastfeeding support, see NICE's guideline on postnatal care. \n\nIn all babies:\n\ncheck whether there are factors associated with an increased likelihood of developing significant hyperbilirubinaemia soon after birth\n\nexamine the baby for jaundice at every opportunity especially in the first 72\xa0hours. \n\nParents, carers and healthcare professionals should all look for jaundice (visual inspection) in babies. \n\nWhen looking for jaundice (visual inspection):\n\ncheck the naked baby in bright and preferably natural light\n\nexamine the sclerae and gums, and press lightly on the skin to check for signs of jaundice in 'blanched' skin. \n\nDo not rely on visual inspection alone to estimate the bilirubin level in a baby with suspected jaundice. \n\nDo not measure bilirubin levels routinely in babies who are not visibly jaundiced. \n\nDo not use any of the following to predict significant hyperbilirubinaemia:\n\numbilical cord blood bilirubin level\n\nend‑tidal carbon monoxide (ETCOc) measurement\n\numbilical cord blood direct antiglobulin test (DAT) (Coombs' test). \n\n## Additional care\n\nEnsure babies with factors associated with an increased likelihood of developing significant hyperbilirubinaemia receive an additional visual inspection by a healthcare professional during the first 48\xa0hours of life. \n\n## Urgent additional care for babies with visible jaundice in the first 24\xa0hours\n\nIn all babies with suspected or obvious jaundice in the first 24\xa0hours of life, measure and record the serum bilirubin level urgently (within 2\xa0hours). \n\nIn all babies with suspected or obvious jaundice in the first 24\xa0hours of life, continue to measure the serum bilirubin level every 6\xa0hours until the level is both:\n\nbelow the treatment threshold\n\nstable and/or falling. \n\nArrange a referral to ensure that an urgent medical review is conducted (as soon as possible and within 6\xa0hours) for babies with suspected or obvious jaundice in the first 24\xa0hours of life to exclude pathological causes of jaundice. \n\nInterpret bilirubin levels according to the baby's postnatal age in hours and manage hyperbilirubinaemia according to the threshold table and the treatment threshold graphs. \n\n## Care for babies more than 24\xa0hours old\n\nMeasure and record the bilirubin level urgently (within 6\xa0hours) in all babies more than 24\xa0hours old with suspected or obvious jaundice. \n\n## How to measure the bilirubin level\n\nUse serum bilirubin measurement for babies:\n\nin the first 24\xa0hours of life or\n\nwho have a gestational age of less than 35\xa0weeks. \n\nIn babies who have a gestational age of 35\xa0weeks or more and who are over 24\xa0hours old:\n\nuse a transcutaneous bilirubinometer to measure the bilirubin level\n\nif a transcutaneous bilirubinometer is not available, measure the serum bilirubin\n\nif a transcutaneous bilirubinometer measurement indicates a bilirubin level greater than 250\xa0micromol/litre, measure the serum bilirubin to check the result\n\nuse serum bilirubin measurement if bilirubin levels are at or above the relevant treatment thresholds for their age, and for all subsequent measurements. \n\nDo not use an icterometer to measure bilirubin levels in babies. \n\n# Management and treatment of hyperbilirubinaemia\n\n## Information for parents or carers on treatment\n\nOffer parents or carers information about treatment for hyperbilirubinaemia, including:\n\nanticipated duration of treatment\n\nreassurance that breastfeeding, nappy‑changing and cuddles can usually continue. \n\nEncourage mothers of breastfed babies with jaundice to breastfeed frequently, and to wake the baby for feeds if necessary. \n\nProvide lactation/feeding support to breastfeeding mothers whose baby is visibly jaundiced. \n\n## How to manage hyperbilirubinaemia\n\nNote that there is variability between assays from different manufacturers in reported bilirubin measurement. Healthcare professionals should consult their local pathology laboratory when interpreting threshold tables.\n\nUse the bilirubin level to determine the management of hyperbilirubinaemia in all babies (see the threshold table and the treatment threshold graphs). \n\nDo not use the albumin/bilirubin ratio when making decisions about the management of hyperbilirubinaemia. \n\nDo not subtract conjugated bilirubin from total serum bilirubin when making decisions about the management of hyperbilirubinaemia (see management thresholds in the threshold table and the treatment threshold graphs). \n\n# Measuring and monitoring bilirubin thresholds before and during phototherapy\n\n## Before starting phototherapy\n\nIn babies who are clinically well, have a gestational age of 38\xa0weeks or more and are more than 24\xa0hours old, and who have a bilirubin level that is below the phototherapy threshold but within 50\xa0micromol/litre of the threshold (see the threshold table and the treatment threshold graphs), repeat bilirubin measurement as follows:\n\nwithin 18\xa0hours for babies with risk factors for neonatal jaundice (those with a sibling who had neonatal jaundice that needed phototherapy or a mother who intends to exclusively breastfeed)\n\nwithin 24\xa0hours for babies without risk factors. [new 2016]\n\nIn babies who are clinically well, have a gestational age of 38\xa0weeks or more and are more than 24\xa0hours old, and who have a bilirubin level that is below the phototherapy threshold by more than 50\xa0micromol/litre (see the threshold table and the treatment threshold graphs), do not routinely repeat bilirubin measurement. [new 2016]\n\nDo not use phototherapy in babies whose bilirubin does not exceed the phototherapy threshold levels in the threshold table and the treatment threshold graphs. \n\n## During phototherapy\n\nDuring phototherapy:\n\nrepeat serum bilirubin measurement 4–6\xa0hours after initiating phototherapy\n\nrepeat serum bilirubin measurement every 6–12\xa0hours when the serum bilirubin level is stable or falling. \n\n## Stopping phototherapy\n\nStop phototherapy once serum bilirubin has fallen to a level at least 50\xa0micromol/litre below the phototherapy threshold (see threshold table and the treatment threshold graphs). \n\nCheck for rebound of significant hyperbilirubinaemia with a repeat serum bilirubin measurement 12–18\xa0hours after stopping phototherapy. Babies do not necessarily have to remain in hospital for this to be done. \n\n## Type of phototherapy to use\n\nDo not use sunlight as treatment for hyperbilirubinaemia. \n\nUse phototherapy (phototherapy given using an artificial light source with an appropriate spectrum and irradiance. This can be delivered using light-emitting diode [LED], fibreoptic or fluorescent lamps, tubes or bulbs) to treat significant hyperbilirubinaemia (see the threshold table and the treatment threshold graphs) in babies. [new 2016]\n\nConsider intensified phototherapy (phototherapy that is given with an increased level of irradiance with an appropriate spectrum. Phototherapy can be intensified by adding another light source or increasing the irradiance of the initial light source used) to treat significant hyperbilirubinaemia in babies if any of the following apply [new 2016]:\n\nthe serum bilirubin level is rising rapidly (more than 8.5\xa0micromol/litre per hour)\n\nthe serum bilirubin is at a level within 50\xa0micromol/litre below the threshold for which exchange transfusion is indicated after 72\xa0hours or more since birth (see threshold table and the treatment threshold graphs)\n\nthe bilirubin level fails to respond to initial phototherapy (that is, the level of serum bilirubin continues to rise, or does not fall, within 6\xa0hours of starting phototherapy). \n\nIf the serum bilirubin level falls during intensified phototherapy to a level 50\xa0micromol/litre below the threshold for which exchange transfusion is indicated reduce the intensity of phototherapy. \n\n## Information for parents or carers on phototherapy\n\nOffer parents or carers verbal and written information on phototherapy including all of the following:\n\nwhy phototherapy is being considered\n\nwhy phototherapy may be needed to treat significant hyperbilirubinaemia\n\nthe possible adverse effects of phototherapy\n\nthe need for eye protection and routine eye care\n\nreassurance that short breaks for feeding, nappy changing and cuddles will be encouraged\n\nwhat might happen if phototherapy fails\n\nrebound jaundice\n\npotential long‑term adverse effects of phototherapy\n\npotential impact on breastfeeding and how to minimise this. \n\n## General care of the baby during phototherapy\n\nDuring phototherapy:\n\nplace the baby in a supine position unless other clinical conditions prevent this\n\nensure treatment is applied to the maximum area of skin\n\nmonitor the baby's temperature and ensure the baby is kept in an environment that will minimise energy expenditure (thermoneutral environment)\n\nmonitor hydration by daily weighing of the baby and assessing wet nappies\n\nsupport parents and carers and encourage them to interact with the baby. \n\nGive the baby eye protection and routine eye care during phototherapy. \n\nUse tinted headboxes as an alternative to eye protection in babies with a gestational age of 37\xa0weeks or more undergoing phototherapy. \n\n## Monitoring the baby during phototherapy\n\nDuring phototherapy:\n\nusing clinical judgement, encourage short breaks (of up to 30\xa0minutes) for breastfeeding, nappy changing and cuddles\n\ncontinue lactation/feeding support\n\ndo not give additional fluids to babies who are breastfed. Maternal expressed milk is the additional feed of choice if available, and when additional feeds are indicated. \n\nDuring intensified phototherapy:\n\ndo not interrupt phototherapy for feeding but continue administering intravenous/enteral feeds\n\ncontinue lactation/feeding support so that breastfeeding can start again when treatment stops.Maternal expressed milk is the additional feed of choice if available, and when additional feeds are indicated. \n\n## Phototherapy equipment\n\nEnsure all phototherapy equipment is maintained and used according to the manufacturers' guidelines. \n\nUse incubators or bassinets according to clinical need and availability. \n\nDo not use white curtains routinely with phototherapy as they may impair observation of the baby. \n\n# Factors that influence the risk of kernicterus\n\nIdentify babies with hyperbilirubinaemia as being at increased risk of developing kernicterus if they have any of the following:\n\na serum bilirubin level greater than 340\xa0micromol/litre in babies with a gestational age of 37\xa0weeks or more\n\na rapidly rising bilirubin level of greater than 8.5\xa0micromol/litre per hour\n\nclinical features of acute bilirubin encephalopathy. \n\n# Formal assessment for underlying disease\n\nIn addition to a full clinical examination by a suitably trained healthcare professional, carry out all of the following tests in babies with significant hyperbilirubinaemia as part of an assessment for underlying disease (see threshold table and the treatment threshold graphs):\n\nserum bilirubin (for baseline level to assess response to treatment)\n\nblood packed cell volume\n\nblood group (mother and baby)\n\nDAT (Coombs' test). Interpret the result taking account of the strength of reaction, and whether mother received prophylactic anti‑D immunoglobulin during pregnancy. \n\nWhen assessing the baby for underlying disease, consider whether the following tests are clinically indicated:\n\nfull blood count and examination of blood film\n\nblood glucose‑6‑phosphate dehydrogenase levels, taking account of ethnic origin\n\nmicrobiological cultures of blood, urine and/or cerebrospinal fluid (if infection is suspected). \n\n# Care of babies with prolonged jaundice\n\nIn babies with a gestational age of 37\xa0weeks or more with jaundice lasting more than 14\xa0days, and in babies with a gestational age of less than 37\xa0weeks and jaundice lasting more than 21\xa0days:\n\nlook for pale chalky stools and/or dark urine that stains the nappy\n\nmeasure the conjugated bilirubin\n\ncarry out a full blood count\n\ncarry out a blood group determination (mother and baby) and DAT (Coombs' test). Interpret the result taking account of the strength of reaction, and whether mother received prophylactic anti‑D immunoglobulin during pregnancy\n\ncarry out a urine culture\n\nensure that routine metabolic screening (including screening for congenital hypothyroidism) has been performed. \n\nFollow expert advice about care for babies with a conjugated bilirubin level greater than 25\xa0micromol/litre because this may indicate serious liver disease. \n\n# Intravenous immunoglobulin\n\nUse intravenous immunoglobulin (IVIG) (500\xa0mg/kg over 4\xa0hours) as an adjunct to continuous intensified phototherapy in cases of rhesus haemolytic disease or ABO haemolytic disease when the serum bilirubin continues to rise by more than 8.5\xa0micromol/litre per hour. \n\nOffer parents or carers information on IVIG including:\n\nwhy IVIG is being considered\n\nwhy IVIG may be needed to treat significant hyperbilirubinaemia\n\nthe possible adverse effects of IVIG\n\nwhen it will be possible for parents or carers to see and hold the baby. \n\n# Exchange transfusion\n\nOffer parents or carers information on exchange transfusion including:\n\nthe fact that exchange transfusion requires that the baby be admitted to an intensive care bed\n\nwhy an exchange transfusion is being considered\n\nwhy an exchange transfusion may be needed to treat significant hyperbilirubinaemia\n\nthe possible adverse effects of exchange transfusions\n\nwhen it will be possible for parents or carers to see and hold the baby after the exchange transfusion. \n\nUse a double‑volume exchange transfusion to treat babies:\n\nwhose serum bilirubin level indicates its necessity (see threshold table and the treatment threshold graphs) and/or\n\nwith clinical features and signs of acute bilirubin encephalopathy. \n\nDuring exchange transfusion do not:\n\nstop continuous intensified phototherapy\n\nperform a single‑volume exchange\n\nuse albumin priming\n\nroutinely administer intravenous calcium. \n\nFollowing exchange transfusion:\n\nmaintain continuous intensified phototherapy\n\nmeasure serum bilirubin level within 2\xa0hours and manage according to the threshold table and the treatment threshold graphs. \n\n# Other therapies\n\nDo not use any of the following to treat hyperbilirubinaemia:\n\nagar\n\nalbumin\n\nbarbiturates\n\ncharcoal\n\ncholestyramine\n\nclofibrate\n\nD‑penicillamine\n\nglycerin\n\nmanna\n\nmetalloporphyrins\n\nriboflavin\n\ntraditional Chinese medicine\n\nacupuncture\n\nhomeopathy. ", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Recommendations for research': 'In 2010, the guideline committee made the 5\xa0recommendations for research. As part of the 2016 update, the standing committee made an additional recommendation for research on parent and healthcare professional experience of phototherapy.\n\n# Breastfeeding and hyperbilirubinaemia\n\nWhat are the factors that underlie the association between breastfeeding and jaundice?\n\n## Why this is important\n\nBreastfeeding has been shown to be a factor in significant hyperbilirubinaemia. The reasons for this association have not yet been fully elucidated.\n\nThis question should be answered by studying infants in the first 28\xa0days of life receiving different feeding types (breast milk, formula feeds or mixed feeds). Infants who do not develop significant hyperbilirubinaemia should be compared with infants with significant hyperbilirubinaemia. The outcomes chosen should include maternal factors, neonatal factors and blood analyses.\n\n# Transcutaneous bilirubin screening and risk factors\n\nWhat is the comparative effectiveness and cost‑effectiveness of universal pre‑discharge transcutaneous bilirubin screening alone or combined with a risk assessment in reducing jaundice‑related neonatal morbidity and hospital readmission?\n\n## Why this is important\n\nThere is good evidence that a risk assessment that combines the result of a timed transcutaneous bilirubin level with risk factors for significant hyperbilirubinaemia is effective at preventing later significant hyperbilirubinaemia.\n\nThis question should be answered by studying the effects of timed pre‑discharge transcutaneous bilirubin levels and timed pre‑discharge transcutaneous bilirubin levels combined with risk assessment. The study population should consist of babies in the first 28\xa0days of life, with subgroups including near‑term babies and babies with dark skin tones. The interventions should be compared with standard care (discharge without timed transcutaneous bilirubin level), and the outcomes chosen should include significant hyperbilirubinaemia, cost‑effectiveness and parental anxiety.\n\n# Transcutaneous bilirubinometers\n\nWhat is the comparative accuracy of the Minolta JM‑103 and the BiliChek when compared to serum bilirubin levels in all babies?\n\n## Why this is important\n\nThe accuracy of transcutaneous bilirubinometers (Minolta JM‑103 and BiliChek) has been adequately demonstrated in term babies below treatment levels (bilirubin less than 250\xa0micromol/litre). New research is needed to evaluate the accuracy of different transcutaneous bilirubinometers in comparison to serum bilirubin levels in all babies.\n\nThis question should be answered by comparing bilirubin levels taken using different transcutaneous bilirubinometers with bilirubin levels assessed using serum (blood) tests. The study population should comprise babies in the first 28\xa0days of life, with subgroups including preterm babies, babies with dark skin tones, babies with high levels of bilirubin and babies after phototherapy. The outcomes chosen should include diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value), parental anxiety, staff and parental satisfaction with test and cost effectiveness.\n\n# Interruptions during phototherapy\n\nHow frequently and for how long can phototherapy be interrupted without adversely effecting clinical outcomes?\n\n## Why this is important\n\nThe effectiveness and tolerability of intermittent phototherapy has been adequately demonstrated in term babies at low treatment levels (bilirubin less than 250\xa0micromol/litre). New research is needed to evaluate the effectiveness and tolerability of different frequencies of interruptions of different durations.\n\nThe study population should comprise babies in the first 28\xa0days of life in phototherapy. Interruptions of 45\xa0or 60\xa0minutes would be made either on demand, every hour or every 2\xa0hours, and compared with interruptions of up to 30\xa0minutes every 3\xa0hours. The outcomes chosen should include effectiveness in terms of the mean decrease in bilirubin levels and the mean duration of phototherapy. Extra outcomes could include adverse effects, parental bonding and parental anxiety, staff and parental satisfaction with treatment and cost effectiveness.\n\n# National registries\n\nNational registries are needed of cases of significant hyperbilirubinaemia, kernicterus and exchange transfusions.\n\n## Why this is important\n\nThere is good evidence that prospective surveys in the UK and data from a national kernicterus register in the US can help to identify root causes of kernicterus and acute bilirubin encephalopathy.\n\nThe study population should comprise all children with a peak bilirubin level greater than 450\xa0micromol/litre, which is the threshold for an exchange transfusion recommended by NICE. The intervention would be maternal, prenatal, perinatal and neonatal factors. The outcomes chosen should be shortcomings in clinical and service provision to prevent recurring themes in kernicterus cases.\n\n# Parent and healthcare professional experience of phototherapy\n\nWhat is the experience and acceptability of phototherapy from the perspective of parents and healthcare professionals?\n\n## Why this is important\n\nThere is a gap in the evidence about parental and healthcare professional experience and acceptability of phototherapy. The committee agreed that the need for this research should be supported, especially given the greater awareness of the crucial importance of close and early skin contact between babies and their carers. The study should be a qualitative study of newborn babies (term and preterm) with a diagnosis of jaundice but who are otherwise well. Outcomes should include both parental and staff experience, including access for bonding and breastfeeding.'}	https://www.nice.org.uk/guidance/cg98	This guideline covers diagnosing and treating jaundice, which is caused by increased levels of bilirubin in the blood, in newborn babies (neonates). It aims to help detect or prevent very high levels of bilirubin, which can be harmful if not treated.
0ab76169041b5953a2523875b13955e43e7e46b2	nice	Psychosis and schizophrenia in children and young people: recognition and management	Psychosis and schizophrenia in children and young people: recognition and management This guideline covers recognising and managing psychosis and schizophrenia in children and young people. It aims to improve early recognition of psychosis and schizophrenia so that children and young people can be offered the treatment and care they need to live with the condition. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. All recommendations relate to children and young people (younger than 18 years) unless otherwise specified. # General principles of care ## Working safely and effectively with children and young people Health and social care professionals working with children and young people with psychosis or schizophrenia should be trained and competent to work with children and young people with mental health problems of all levels of learning ability, cognitive capacity, emotional maturity and development. See also NICE's guideline on babies, children and young people's experience of healthcare. Health and social care professionals should ensure that they: can assess capacity and competence, including 'Gillick competence', in children and young people of all ages, and understand how to apply legislation, including the Children Act (1989; amended 2004), the Mental Health Act (1983; amended 1995 and 2007; including the Code of Practice: Mental Health Act 1983) and the Mental Capacity Act (2005), in the care and treatment of children and young people. Consider children and young people with psychosis or schizophrenia for assessment according to local safeguarding procedures if there are concerns regarding exploitation or self‑care, or if they have been in contact with the criminal justice system. Health and social care providers should ensure that children and young people with psychosis or schizophrenia: can routinely receive care and treatment from a single multidisciplinary community team are not passed from one team to another unnecessarily do not undergo multiple assessments unnecessarily. Help the child or young person to continue their education. Contact the school or college, subject to consent, to ask for additional educational support if their performance has been affected by their condition. ## Establishing relationships with children and young people and their parents or carers Work in partnership with children and young people with psychosis or schizophrenia of an appropriate developmental level, emotional maturity and cognitive capacity and parents or carers. Offer help, treatment and care in an atmosphere of hope and optimism. Take time to build trusting, supportive, empathic and non‑judgemental relationships as an essential part of care. When working with children and young people with psychosis or schizophrenia: aim to foster autonomy, promote active participation in treatment decisions, and support self‑management and access to peer support in children and young people of an appropriate developmental level, emotional maturity and cognitive capacity maintain continuity of individual therapeutic relationships wherever possible -ffer access to a trained advocate. When working with children and young people with psychosis or schizophrenia and their parents or carers: make sure that discussions take place in settings in which confidentiality, privacy and dignity are respected be clear with the child or young person and their parents or carers about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others). Discuss with young people with psychosis or schizophrenia of an appropriate developmental level, emotional maturity and cognitive capacity how they want their parents or carers to be involved in their care. Such discussions should take place at intervals to take account of any changes in circumstances, including developmental level, and should not happen only once. Advise parents and carers about their right to a formal carer's assessment of their own physical and mental health needs, and explain how to access this. ## Communication and information Health and social care professionals working with children and young people with psychosis or schizophrenia should be trained and skilled in: negotiating and working with parents and carers, and managing issues relating to information sharing and confidentiality as these apply to children and young people. If a young person is 'Gillick competent' ask them what information can be shared before discussing their condition and treatment with their parents or carers. When communicating with children and young people with psychosis or schizophrenia and their parents or carers: take into account the child or young person's developmental level, emotional maturity and cognitive capacity including any learning disabilities, sight or hearing problems or delays in language development use plain language where possible and clearly explain any clinical language check that the child or young person and their parents or carers understand what is being said use communication aids (such as pictures, symbols, large print, braille, different languages or sign language) if needed. Provide children and young people with psychosis or schizophrenia and their parents or carers, comprehensive written information about: the nature of, and interventions for, psychosis and schizophrenia (including biomedical and psychosocial perspectives on causes and treatment) in an appropriate language or format, including any relevant 'Information for the public' booklets support groups, such as third sector, including voluntary, organisations. Ensure that you are: familiar with local and national sources (organisations and websites) of information and/or support for children and young people with psychosis or schizophrenia and their parents or carers able to discuss and advise how to access these resources able to discuss and actively support children and young people and their parents or carers to engage with these resources. When communicating with a child or young person with psychosis or schizophrenia, use diverse media, including letters, phone calls, emails or text messages, according to their preference. Copy all written communications with other health or social care professionals to the child or young person and/or their parents or carers at the address of their choice, unless this is declined. ## Culture, ethnicity and social inclusion When working with children and young people with psychosis or schizophrenia and their parents or carers: take into account that stigma and discrimination are often associated with using mental health services be respectful of and sensitive to children and young people's gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability be aware of possible variations in the presentation of mental health problems in children and young people of different genders, ages, cultural, ethnic, religious or other diverse backgrounds. When working with children and young people and their parents or carers who have difficulties speaking or reading English: provide and work proficiently with interpreters if needed -ffer a list of local education providers who can provide English language teaching. Health and social care professionals working with children and young people with psychosis or schizophrenia and their parents or carers should have competence in: assessment skills for people from diverse ethnic and cultural backgrounds using explanatory models of illness for people from diverse ethnic and cultural backgrounds explaining the possible causes of psychosis and schizophrenia and treatment options addressing cultural and ethnic differences in treatment expectations and adherence addressing cultural and ethnic differences in beliefs regarding biological, social and family influences on the possible causes of mental health problems conflict management and conflict resolution. Health and social care professionals inexperienced in working with children and young people with psychosis or schizophrenia from diverse ethnic and cultural backgrounds, and their parents or carers, should seek advice and supervision from healthcare professionals who are experienced in working transculturally. Local mental health services should work with primary care, other secondary care and local third sector, including voluntary, organisations to ensure that: all children and young people with psychosis or schizophrenia have equal access to services based on clinical need and irrespective of gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability services are culturally appropriate. Mental health services should work with local voluntary black and minority ethnic groups to jointly ensure that culturally appropriate psychological and psychosocial treatment, consistent with this guideline and delivered by competent practitioners, is provided to children and young people from diverse ethnic and cultural backgrounds. ## Transfer and discharge Anticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in children and young people with psychosis or schizophrenia and their parents or carers. Ensure that: such changes, especially discharge and transfer from CAMHS to adult services, or to primary care, are discussed and planned carefully beforehand with the child or young person and their parents or carers, and are structured and phased the care plan supports effective collaboration with social care and other care providers during endings and transitions, and includes details of how to access services in times of crisis when referring a child or young person for an assessment in other services (including for psychological interventions), they are supported during the referral period and arrangements for support are agreed beforehand with them. # Possible psychosis ## Referral from primary care When a child or young person experiences transient or attenuated psychotic symptoms or other experiences suggestive of possible psychosis, refer for assessment without delay to a specialist mental health service such as CAMHS or an early intervention in psychosis service (14 years or over). ## Assessment in specialist mental health services Carry out an assessment of the child or young person with possible psychosis, ensuring that: assessments in CAMHS include a consultant psychiatrist assessments in early intervention in psychosis services are multidisciplinary where there is considerable uncertainty about the diagnosis, or concern about underlying neurological illness, there is an assessment by a consultant psychiatrist with training in child and adolescent mental health. If a clear diagnosis of psychosis cannot be made, monitor regularly for further changes in symptoms and functioning for up to 3 years. Determine the frequency and duration of monitoring by: the severity and frequency of symptoms the level of impairment and/or distress in the child or young person, and the degree of family disruption or concern. If discharge from the service is requested, offer follow‑up appointments and the option to self‑refer at a later date. Ask the GP to continue monitoring changes in mental state. ## Treatment options for symptoms not sufficient for a diagnosis of psychosis or schizophrenia When transient or attenuated psychotic symptoms or other mental state changes associated with distress, impairment or help‑seeking behaviour are not sufficient for a diagnosis of psychosis or schizophrenia: consider individual cognitive behavioural therapy (CBT) (delivered as set out in recommendation 1.3.29) with or without family intervention (delivered as set out in recommendation 1.3.28), and -ffer treatments recommended in NICE guidance for children and young people with any of the anxiety disorders, depression, emerging personality disorder or substance misuse. Do not offer antipsychotic medication: for psychotic symptoms or mental state changes that are not sufficient for a diagnosis of psychosis or schizophrenia, or with the aim of decreasing the risk of psychosis. # First episode psychosis ## Referral from primary care Urgently refer all children and young people with a first presentation of sustained psychotic symptoms (lasting 4 weeks or more) to a specialist mental health service, either CAMHS (up to 17 years) or an early intervention in psychosis service (14 years or over), which includes a consultant psychiatrist with training in child and adolescent mental health. Antipsychotic medication in children and young people with a first presentation of sustained psychotic symptoms should not be started in primary care unless it is done in consultation with a consultant psychiatrist with training in child and adolescent mental health. ## Assessment and care planning in secondary care When carrying out an assessment: ensure there is enough time for: the child or young person and their parents or carers to describe and discuss their problems summarising the conclusions of the assessment and for discussion, with questions and answers explain and give written material in an accessible format about any diagnosis given give information about different treatment options, including pharmacological and psychological interventions, and their benefits and side effects, to promote discussion and shared understanding -ffer support after the assessment, particularly if sensitive issues, such as childhood trauma, have been discussed. Ensure that children and young people with first episode psychosis receive a comprehensive multidisciplinary assessment. The assessment should address the following domains: psychiatric (mental health problems, risk of harm to self or others, alcohol consumption and prescribed and non‑prescribed drug history) medical, including medical history and full physical examination to identify physical illness (including organic brain disorders) and prescribed drug treatments that may result in psychosis psychological and psychosocial, including social networks, relationships and history of trauma developmental (social, cognitive and motor development and skills, including coexisting neurodevelopmental conditions) physical health and wellbeing (including weight and height, and information about smoking, diet and exercise, and sexual health) social (accommodation, culture and ethnicity, leisure activities and recreation, carer responsibilities ) educational and occupational (attendance at school or college, educational attainment, employment and functional activity) economic (family's economic status). Routinely monitor for other coexisting mental health problems, including depression and anxiety, and substance misuse, particularly in the early phases of treatment. Develop a care plan with the parents or carers of younger children, or jointly with the young person and their parents or carers, as soon as possible, and: include activities that promote physical health and social inclusion, especially education, but also employment, volunteering and other occupations such as leisure activities provide support to help the child or young person and their parents or carers realise the plan give an up-to-date written copy of the care plan to the young person and their parents or carers if the young person agrees to this; give a copy of the care plan to the parents or carers of younger children; agree a suitable time to review it send a copy to the primary healthcare professional who made the referral. Support children and young people to develop strategies, including risk- and self‑management plans, to promote and maintain independence and self‑efficacy, wherever possible. Incorporate these strategies into the care plan. If the child or young person is at risk of crisis, develop a crisis plan with the parents or carers of younger children, or jointly with the young person and their parents or carers, and with their care coordinator. The plan should be respected and implemented, incorporated into the care plan and include: possible early warning signs of a crisis and coping strategies support available to help prevent hospitalisation where the child or young person would like to be admitted in the event of hospitalisation definitions of the roles of primary and secondary care professionals and the degree to which parents or carers are involved information about 24‑hour access to services the names of key clinical contacts. For children and young people with first episode psychosis who are unable to attend mainstream school or college, facilitate alternative educational input in line with their capacity to engage with educational activity and according to their individual needs, with an ultimate goal of returning to mainstream education, training or employment. If the child or young person and/or their parent or carer is unhappy about the assessment, diagnosis or care plan, give them time to discuss this and offer them the opportunity for a second opinion. ## Treatment options for first episode psychosis For children and young people with first episode psychosis offer: -ral antipsychotic medication (see recommendations 1.3.14 to 1.3.26) in conjunction with psychological interventions (family intervention with individual CBT, delivered as set out in recommendations 1.3.27 to 1.3.33). In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. If the child or young person and their parents or carers wish to try psychological interventions (family intervention with individual CBT) alone without antipsychotic medication, advise that psychological interventions are more effective when delivered in conjunction with antipsychotic medication. If the child or young person and their parents or carers still wish to try psychological interventions alone, then offer family intervention with individual CBT. Agree a time limit (1 month or less) for reviewing treatment options, including introducing antipsychotic medication. Continue to monitor symptoms, level of distress, impairment and level of functioning, including educational engagement and achievement, regularly. If the child or young person shows symptoms and behaviour sufficient for a diagnosis of an affective psychosis or disorder, including bipolar disorder and unipolar psychotic depression, follow the recommendations in NICE's guidelines on bipolar disorder: assessment and management or depression in children and young people: identification and management. ## Choice of antipsychotic medication The choice of antipsychotic medication should be made by the parents or carers of younger children, or jointly with the young person and their parents or carers, and healthcare professionals. Provide age‑appropriate information and discuss the likely benefits and possible side effects of each drug including: metabolic (including weight gain and diabetes) extrapyramidal (including akathisia, dyskinesia and dystonia) cardiovascular (including prolonging the QT interval) hormonal (including increasing plasma prolactin) -ther (including unpleasant subjective experiences).In May 2016, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. When choosing between olanzapine and other 'second generation' antipsychotic medications, discuss with the young person and their parents or carers the increased likelihood of greater weight gain with olanzapine.Inform them that this effect is likely to happen soon after starting treatment. In May 2016, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. ## How to use oral antipsychotic medication Before starting antipsychotic medication, undertake and record the following baseline investigations (see supplementary information for a table of baseline investigations and monitoring for children and young people who are prescribed antipsychotic medication ): weight and height (both plotted on a growth chart) waist and hip circumference pulse and blood pressure fasting blood glucose or glycosylated haemoglobin (HbA1c) blood lipid profile and prolactin levels assessment of any movement disorders assessment of nutritional status, diet and level of physical activity. In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. Before starting antipsychotic medication, offer the child or young person an electrocardiogram (ECG) if: specified in the SPC for adults and/or children a physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure) there is a personal history of cardiovascular disease there is a family history of cardiovascular disease such as premature sudden cardiac death or prolonged QT interval, or the child or young person is being admitted as an inpatient. Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following: From a discussion with the child or young person and their parent or carer, record the side effects the child or young person is most and least willing to tolerate. Record the indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects. At the start of treatment give a dose below the lower end of the licensed range for adults if the drug is not licensed for children and young people and at the lower end of the licensed range if the drug is licensed for children and young people; slowly titrate upwards within the dose range given in the British national formulary (BNF), the British national formulary for children (BNFC) or the SPC. Justify and record reasons for dosages above the range given in the BNF, BNFC or SPC. Record the rationale for continuing, changing or stopping medication, and the effects of such changes. Carry out a trial of the medication at optimum dosage for 4–6 weeks. In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. Monitor and record the following regularly and systematically throughout treatment, but especially during titration (see supplementary information for a table of baseline investigations and monitoring for children and young people who are prescribed antipsychotic medication ): efficacy, including changes in symptoms and behaviour side effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia (for example, the overlap between akathisia and agitation or anxiety) the emergence of movement disorders weight, weekly for the first 6 weeks, then at 12 weeks and then every 6 months (plotted on a growth chart) height every 6 months (plotted on a growth chart) waist circumference every 6 months (plotted on a percentile chart) pulse and blood pressure (plotted on a percentile chart) at 12 weeks and then every 6 months fasting blood glucose or HbA1c, and blood lipid and prolactin levels at 12 weeks and then every 6 months adherence physical health.The secondary care team should maintain responsibility for monitoring physical health and the effects of antipsychotic medication in children and young people for at least the first 12 months or until their condition has stabilised. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared care arrangements. Discuss any non-prescribed therapies that children or young people, or their parents or carers, wish to use (including complementary therapies) with them. Discuss the safety and efficacy of the therapies, and possible interference with the therapeutic effects of prescribed medication and psychological interventions. Discuss the use of alcohol, tobacco, prescription and non‑prescription medication and illicit drugs with the child or young person, and their parents or carers where this has been agreed. Discuss their possible interference with the therapeutic effects of prescribed medication and psychological interventions and the potential of illicit drugs to exacerbate psychotic symptoms. 'As required' (p.r.n.) prescriptions of antipsychotic medication should be made as described in recommendation 1.3.18. Review clinical indications, frequency of administration, therapeutic benefits and side effects at least weekly. Check whether 'p.r.n.' prescriptions have led to a dosage above the maximum specified in the BNF, BNFC or SPC. Do not use a loading dose of antipsychotic medication (often referred to as 'rapid neuroleptisation'). Do not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication). If prescribing chlorpromazine, warn of its potential to cause skin photosensitivity. Advise using sunscreen if necessary. Review antipsychotic medication annually, including observed benefits and any side effects. ## How to deliver psychological interventions When delivering psychological interventions for children and young people with psychosis or schizophrenia, take into account their developmental level, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems or delays in language development. Family intervention should: include the child or young person with psychosis or schizophrenia if practical be carried out for between 3 months and 1 year include at least 10 planned sessions take account of the whole family's preference for either single‑family intervention or multi‑family group intervention take account of the relationship between the parent or carer and the child or young person with psychosis or schizophrenia have a specific supportive, educational or treatment function and include negotiated problem solving or crisis management work. CBT should be delivered on a one‑to‑one basis over at least 16 planned sessions (although longer may be needed) and: follow a treatment manual so that: children and young people can establish links between their thoughts, feelings or actions and their current or past symptoms, and/or functioning the re-evaluation of the child or young person's perceptions, beliefs or reasoning relates to the target symptoms also include at least one of the following components: normalising, leading to understanding and acceptability of their experience children and young people monitoring their own thoughts, feelings or behaviours with respect to their symptoms or recurrence of symptoms promoting alternative ways of coping with the target symptom reducing distress improving functioning. Treatment manuals that have evidence for their efficacy from clinical trials are preferred. If developed for adults, the approach should be adapted to suit the age and developmental level of the child or young person. ## Monitoring and reviewing psychological interventions When providing psychological interventions, routinely and systematically monitor a range of outcomes across relevant areas, including the child or young person's satisfaction and, if appropriate, parents' or carers' satisfaction. Healthcare teams working with children and young people with psychosis or schizophrenia should identify a lead healthcare professional within the team whose responsibility is to monitor and review: access to and engagement with psychological interventions decisions to offer psychological interventions and equality of access across different ethnic groups. ## Competencies for delivering psychological interventions Healthcare professionals delivering psychological interventions should: have an appropriate level of competence in delivering the intervention to children and young people with psychosis or schizophrenia be regularly supervised during psychological therapy by a competent therapist and supervisor. Trusts should provide access to training that equips healthcare professionals with the competencies required to deliver the psychological interventions for children and young people recommended in this guideline. # Subsequent acute episodes of psychosis or schizophrenia For children and young people with an acute exacerbation or recurrence of psychosis or schizophrenia offer: -ral antipsychotic medication in conjunction with psychological interventions (family intervention with individual CBT). In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. ## Pharmacological interventions For children or young people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer oral antipsychotic medication or review existing medication. The choice of drug should be influenced by the same criteria recommended for starting treatment (see recommendations 1.3.14 to 1.3.26). Take into account the clinical response to and side effects associated with current and previous medication, and monitor as described in recommendation 1.3.19.In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. Aripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17 years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone. ## Psychological and psychosocial interventions Offer family intervention (delivered as set out in recommendation 1.3.28) to all families of children and young people with psychosis or schizophrenia, particularly for preventing and reducing relapse. This can be started either during the acute phase or later, including in inpatient settings. Offer CBT (delivered as set out in recommendation 1.3.29) to all children and young people with psychosis or schizophrenia, particularly for symptom reduction. This can be started either during the acute phase or later, including in inpatient settings. Consider arts therapies (for example, dance movement, music or art therapy or dramatherapy) for all children and young people with psychosis or schizophrenia, particularly for the alleviation of negative symptoms. This can be started either during the acute phase or later, including in inpatient settings. If arts therapies are considered, they should be provided by Health Professions Council (HPC) registered arts therapists, with experience of working with children and young people with psychosis or schizophrenia. The intervention should be provided in groups unless difficulties with acceptability and access and engagement indicate otherwise. Arts therapies should combine psychotherapeutic techniques with activity aimed at promoting creative expression, which is often unstructured and led by the child or young person. Aims of arts therapies should include: enabling children and young people with psychosis or schizophrenia to experience themselves differently and to develop new ways of relating to others helping children and young people to express themselves and to organise their experience into a satisfying aesthetic form helping children and young people to accept and understand feelings that may have emerged during the creative process (including, in some cases, how they came to have these feelings) at a pace suited to them. Do not routinely offer counselling and supportive psychotherapy (as specific interventions) to children and young people with psychosis or schizophrenia. However, take the child or young person's and their parents' or carers' preferences into account, especially if other more efficacious psychological interventions, such as CBT, family intervention and arts therapies, are not available locally. Do not offer adherence therapy (as a specific intervention) to children and young people with psychosis or schizophrenia. Do not routinely offer social skills training (as a specific intervention) to children and young people with psychosis or schizophrenia. When psychological interventions, including arts therapies, are started in the acute phase (including in inpatient settings), the full course should be continued after discharge without unnecessary interruption. # Referral in crisis and challenging behaviour When a child or young person is referred in crisis they should be seen by specialist mental health secondary care services within 4 hours of referral. To avoid admission, aim to: explore with the child or young person and their parents or carers what support systems they have, including other family members and friends support a child or young person in crisis and their parents or carers in their home environment make early plans to help the child or young person maintain their day‑to‑day activities, including education, work, voluntary work, and other occupations and leisure activities, wherever possible. At the end of a crisis assessment, ensure that the decision to start home treatment depends not on the diagnosis, but on: the level of distress the severity of the problems the vulnerability of the child or young person and issues of safety and support at home the child or young person's cooperation with treatment. Consider the support and care needs of parents or carers of children or young people in crisis. Where needs are identified, ensure they are met when it is safe and practicable to do so. Follow the recommendations in NICE's guideline on self-harm: assessment, management and preventing recurrence when managing acts of self‑harm in children and young people with psychosis or schizophrenia who are 8 years or over. ## Hospital care If a child or young person needs hospital care, this should be in a setting appropriate to their age and developmental level. Before referral for hospital care, think about the impact on the child or young person and their parents, carers and other family members, especially when the inpatient unit is a long way from where they live. Consider alternative care within the community wherever possible. If hospital admission is unavoidable, provide support for parents or carers when the child or young person is admitted. Give verbal and written information to children and young people with psychosis or schizophrenia admitted to hospital, and their parents or carers, about: the hospital and the ward in which the child or young person will stay treatments, activities and services available expected contact from health and social care professionals rules of the ward (including substance misuse policy) their rights, responsibilities and freedom to move around the ward and outside meal times visiting arrangements.Make sure there is enough time for the child or young person and their parents or carers to ask questions. Undertake shared decision-making routinely with children or young people in hospital who are of an appropriate developmental level, emotional maturity and cognitive capacity, including, whenever possible, those who are subject to the Mental Health Act (1983; amended 1995 and 2007). Include their parents or carers if appropriate. Ensure that children and young people of compulsory school age have access to a full educational programme while in hospital. The programme should meet the National Curriculum, be matched to the child or young person's developmental level and educational attainment, and should take account of their illness and degree of impairment. Ensure that children and young people in hospital continue to have access to a wide range of meaningful and culturally appropriate occupations and activities 7 days per week, and not restricted to 9am to 5pm. These should include creative and leisure activities, exercise, self‑care and community access activities (where appropriate). Activities should be facilitated by appropriately trained educational, health or social care professionals. Children and young people receiving community care before hospital admission should be routinely visited while in hospital by the health and social care professionals responsible for their community care. Promote good physical health, including healthy eating, exercise and smoking cessation. ## Rapid tranquillisation and restraint Healthcare professionals undertaking rapid tranquillisation and/or restraint in children and young people with psychosis or schizophrenia should be trained and competent in undertaking these procedures in children and young people. Occasionally children and young people with psychosis or schizophrenia pose an immediate risk to themselves or others during an acute episode and may need rapid tranquillisation. Be particularly cautious when considering high‑potency antipsychotic medication (such as haloperidol) in children and young people, especially those who have not taken antipsychotic medication before, because of the increased risk of acute dystonic reactions in that age group. After rapid tranquillisation, offer the child or young person the opportunity to discuss their experiences. Provide them with a clear explanation of the decision to use urgent sedation. Record this in their notes. # Early post-acute period In the early period of recovery following an acute episode, reflect upon the episode and its impact with the child or young person and their parents or carers, and make plans for recovery and possible future care. Inform the child or young person and their parents or carers that there is a high risk of relapse if medication is stopped in the 1 to 2 years following an acute episode. If withdrawing antipsychotic medication, undertake gradually and monitor regularly for signs and symptoms of relapse. After withdrawal from antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2 years. # Promoting recovery and providing possible future care in primary care Develop and use practice case registers to monitor the physical and mental health of children and young people with psychosis or schizophrenia in primary care. GPs and other primary healthcare professionals should monitor the physical health of children and young people with psychosis or schizophrenia at least once a year. They should bear in mind that people with schizophrenia are at higher risk of cardiovascular disease than the general population. Identify children and young people with psychosis or schizophrenia who smoke or who have high blood pressure, raised lipid levels or increased waist measurement at the earliest opportunity and monitor for the emergence of cardiovascular disease and diabetes. Treat children and young people with psychosis or schizophrenia who have diabetes and/or cardiovascular disease in primary care. Use the appropriate NICE guidance for children and young people where available. (See NICE's guideline on diabetes (type 1 and type 2) in children and young people: diagnosis and management.) Healthcare professionals in secondary care should ensure, as part of the care programme approach (CPA) in England and care and treatment plans in Wales, that children and young people with psychosis or schizophrenia receive physical healthcare from primary care as described in recommendations 1.7.2 to 1.7.4. Healthcare professionals in secondary care should continue to maintain responsibility for monitoring and managing any side effects of antipsychotic medication. When a child or young person with a diagnosis of psychosis or schizophrenia presents with a suspected relapse (for example, with increased psychotic symptoms or a significant increase in the use of alcohol or other substances) and is still receiving treatment, primary healthcare professionals should refer to the crisis section of the care plan. Consider referral to the key clinician or care coordinator identified in the crisis plan. For a child or young person with psychosis or schizophrenia being cared for in primary care, consider referral to secondary care again if there is: poor response to treatment non-adherence to medication intolerable side effects from medication or the child or young person or their parents or carers request a review of side effects the child or young person or their parents or carers request psychological interventions not available in primary care comorbid substance misuse risk to self or others. # Promoting recovery and providing possible future care in secondary care Children and young people with psychosis or schizophrenia who are being treated in an early intervention in psychosis service should have access to that service for up to 3 years (or until their 18th birthday, whichever is longer) whatever the age of onset of psychosis or schizophrenia. ## Psychological interventions Offer family intervention to families of children and young people with psychosis or schizophrenia to promote recovery. Deliver family intervention as described in recommendation 1.3.28. Consider family intervention particularly for families of children and young people with psychosis or schizophrenia who have: recently relapsed or are at risk of relapse persisting symptoms. Offer CBT to assist in promoting recovery in children and young people with persisting positive and negative symptoms and for those in remission. Deliver CBT as described in recommendation 1.3.29. Consider arts therapies (see recommendation 1.4.7) to assist in promoting recovery, particularly in children and young people with negative symptoms. ## Pharmacological interventions The choice of drug should be influenced by the same criteria recommended for starting treatment (see recommendations 1.3.14 to 1.3.26). In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. Do not use targeted, intermittent dosage maintenance strategies routinely. However, consider them for children and young people with psychosis or schizophrenia who are unwilling to accept a continuous maintenance regimen or if there is another contraindication to maintenance therapy, such as side‑effect sensitivity. Dosage maintenance strategies are defined as the use of antipsychotic medication only during periods of incipient relapse or symptom exacerbation rather than continuously. ## Interventions for children and young people whose illness has not responded adequately to treatment In January 2013, recommendations 1.8.8 to 1.8.10 were an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. For children and young people with psychosis or schizophrenia whose illness has not responded adequately to pharmacological or psychological interventions: review the diagnosis establish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct duration review engagement with and use of psychological interventions and ensure that these have been offered according to this guideline; if family intervention has been undertaken suggest CBT; if CBT has been undertaken suggest family intervention for children and young people in close contact with their families consider other causes of non‑response, such as comorbid substance misuse (including alcohol), the concurrent use of other prescribed medication or physical illness. Offer clozapine to children and young people with schizophrenia whose illness has not responded adequately to pharmacological treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs each used for 6 to 8 weeks. For children and young people whose illness has not responded adequately to clozapine at an optimised dose, consider a multidisciplinary review, and recommendation 1.8.8 (including measuring therapeutic drug levels) before adding a second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8 to 10 weeks. Choose a drug that does not compound the common side effects of clozapine. ## Education, employment and occupational activities for children and young people with psychosis and schizophrenia For children and young people of compulsory school age, liaise with the child or young person's school and educational authority, subject to consent, to ensure that ongoing education is provided. Liaise with the child or young person's school and with their parents or carers, subject to consent, to determine whether a special educational needs assessment is necessary. If it is agreed that this is needed, explain to parents or carers how to apply for an assessment and offer support throughout the process. Provide supported employment programmes for those young people with psychosis or schizophrenia above compulsory school age who wish to return to work or find employment. Consider other work‑related activities and programmes when individuals are unable to work or are unsuccessful in their attempts to find employment. Mental health services should work in partnership with local stakeholders, including those representing black and minority ethnic groups, to enable young people with psychosis or schizophrenia to access local employment and educational opportunities. This should be sensitive to the young person's needs and skill level and is likely to involve working with agencies such as Jobcentre Plus, disability employment advisers and non‑statutory providers. Routinely record the daytime activities of children and young people with psychosis or schizophrenia in their care plans, including educational and occupational outcomes. # Context This guideline is concerned with the recognition and management of psychosis and schizophrenia in children and young people up to the age of 18. The term 'psychosis' is used in this guideline to refer to the group of psychotic disorders that includes schizophrenia, schizoaffective disorder, schizophreniform disorder and delusional disorder. This guideline also addresses those children and young people considered clinically to be at high risk or prodromal for psychosis and schizophrenia. The recognition, treatment and management of affective psychoses (such as bipolar disorder or unipolar psychotic depression) are covered by other NICE guidelines. Psychosis and the specific diagnosis of schizophrenia in children and young people represent a major psychiatric disorder, or cluster of disorders that alters a person's perception, thoughts, mood and behaviour. The symptoms of psychosis are usually divided into 'positive symptoms', including hallucinations (perception in the absence of any stimulus) and delusions (fixed or falsely held beliefs), and 'negative symptoms' (such as emotional apathy, lack of drive, poverty of speech, social withdrawal and self‑neglect). Children and young people who develop psychosis will have their own unique combination of symptoms and experiences, the precise pattern of which will be influenced by their circumstances and stage of development. Psychosis and schizophrenia are commonly preceded by a so‑called prodromal period, lasting up to 12 months, in which the child or young person's behaviour and experience are altered. Relatives may become aware of these changes first. Changes include the emergence of transient and/or attenuated psychotic symptoms, such as hallucinations and/or delusions with associated impaired functioning. More subtly, the child or young person may become socially withdrawn or suspicious, with alterations in expressed feeling. It is important to note that most children and young people with transient or attenuated psychotic symptoms do not go on to develop psychosis or schizophrenia, although those with such symptoms do appear to be at higher risk than other children and young people of developing psychosis and schizophrenia up to 10 years after onset of symptoms. The prevalence of psychotic disorders in children aged between 5 and 18 years has been estimated to be 0.4% (the figure across all ages and populations in the UK is 0.7%). Schizophrenia accounts for 24.5% of all psychiatric admissions in young people aged 10 to 18 years (the overall admission rate is 0.46 per 1000 for this age range), with an exponential rise across the adolescent years. The rise in incidence increases most from age 15 onwards. There is a worse prognosis for psychosis and schizophrenia when onset is in childhood or adolescence. The symptoms and experience of psychosis and schizophrenia are often distressing and the effects of the illness are pervasive. Although about one‑fifth of children and young people with schizophrenia have a good outcome with only mild impairment, one‑third have severe impairment that needs intensive social and psychiatric support. Psychosis and schizophrenia can have a major detrimental effect on children and young people's personal, social, educational and occupational functioning, placing a heavy burden on them and their parents and carers. Although the mainstay of treatment for psychosis and schizophrenia has been antipsychotic medication, there is limited evidence of its efficacy in children and young people. There are also concerns that children and young people are more sensitive than adults to the potential adverse effects of antipsychotics, including weight gain, metabolic effects and movement disorders. A number of psychological interventions, including family intervention, cognitive behavioural therapy (CBT) and arts therapies, have been used but evidence of efficacy is currently unavailable in children and young people and provision of these therapies for children and young people and for adults is variable. This guideline covers the care provided by primary, community, secondary, tertiary and other health and social care professionals who have direct contact with, and make decisions concerning, the care of children and young people with psychosis or schizophrenia, including child and adolescent mental health services (CAMHS) and early intervention in psychosis services. Early intervention in psychosis services provide people aged 14 to 35 years with a more intensive therapeutic service than traditional community services. They are designed to intervene early, and deliver support and evidence‑based interventions in a 'normalising' environment for the first 3 years after onset of psychosis. There is geographical variation in the configuration and integration of CAMHS and early intervention in psychosis services, and in the provision and integration of other services for children and young people with psychosis and schizophrenia, including education, employment and rehabilitation, and social services. In particular, provision for the needs of 16- and 17‑year‑olds with psychosis and schizophrenia can be fragmented and inadequate and they can experience difficulties in gaining access to appropriate accommodation and vocational or occupational support and rehabilitation. A number of recommendations in this guideline have been adapted from recommendations in other NICE clinical guidelines. Where this occurred, the guideline committee was careful to preserve the meaning and intent of the original recommendation. Changes to wording or structure were made in order to fit the recommendations into this guideline. In all cases, the original source of any adapted recommendation is indicated in a footnote. The guideline incorporates NICE's technology appraisal guidance on aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years.# Recommendations for research In 2013 the guideline committee made the following recommendations for research. # What are the long-term outcomes, both psychotic and non‑psychotic, for children and young people with attenuated or transient psychotic symptoms suggestive of a developing psychosis, and can the criteria for 'at risk states' be refined to better predict those who will and those who will not go on to develop psychosis? The suggested programme of research would be in two phases. First, a systematic review and meta‑analysis of prospective observational studies or cohorts of children and young people identified at high or ultra‑high risk of developing psychosis would be undertaken. The review would identify risk and protective factors most strongly associated with the later development of psychotic and non‑psychotic outcomes. Second, the factors identified in the first phase would be used to identify a large cohort of children and young people with these factors and to evaluate the effectiveness of these refined criteria for predicting the later development of psychotic and non‑psychotic outcomes. ## Why this is important A major problem with trials of treatments for populations of children and young people deemed to be 'at risk' or 'at ultra‑high risk' of developing psychosis is identifying the precise symptoms and/or behaviours or (risk) factors that are most strongly associated with the development of psychosis; and conversely, which (protective) factors are likely to be associated with a lowered risk of later psychosis. At present, identified factors have a low predictive value, with only about 10 to 20% of children and young people who have been identified as at high risk going on to develop psychosis. If these risk and protective factors could be refined, it would be possible to better target children and young people who are most at risk, and reduce the numbers of those thought to be 'at risk' who do not go on to later develop psychosis. # What is the clinical and cost effectiveness for family intervention combined with individual CBT in the treatment of children and young people considered to be at high risk of developing psychosis and their parents or carers? The suggested programme of research would need to test out, using an adequately powered, multicentre, randomised controlled design, the likely benefits and costs of providing family intervention, combined with individual CBT, for children and young people at high risk of developing psychosis and their parents or carers. The outcomes considered should include transition to psychosis, quality of life, symptomatic and functional improvements, treatment acceptability and self‑harm. There should be follow‑up at 3 years. The trial should also estimate the cost effectiveness of intervening. ## Why this is important A number of interventions have been trialled in an attempt to avert the development of psychosis, including drugs, psychological interventions and other interventions. After the first episode of psychosis, family intervention as an adjunct to antipsychotic medication substantially and significantly reduces relapse rates. A single small trial combining CBT family treatment with individual CBT without antipsychotic treatment suggested an important reduction in transition rates to the first psychosis. # What is the clinical and cost effectiveness of psychological intervention alone, compared with antipsychotic medication and compared with psychological intervention and antipsychotic medication combined, in young people with first episode psychosis? The programme of research would compare the clinical and cost effectiveness of psychological intervention alone, compared with antipsychotic medication, and compared with psychological intervention and antipsychotic medication combined, for young people in the early stages of psychosis using an adequately powered study with a randomised controlled design. The combination of psychological interventions most likely to have an impact is family intervention and individual CBT. The key outcomes should include symptoms, relapse rates, quality of life, treatment acceptability, experience of care, level of psychosocial functioning and the cost effectiveness of the interventions. ## Why this is important The personal and financial cost of psychosis and schizophrenia to the person, their family and friends, and to society is considerable. The personal cost is reflected in a suicide rate of nearly 15% among people with schizophrenia, a lifelong unemployment rate that varies between 50 and 75%, depending on geographical location, and reduced life expectancy. The additional cost to the healthcare system for one person with schizophrenia is estimated to reach over £50,000 per year, on average, throughout their life. Currently, the mainstay of treatment is antipsychotic medication, but the potential adverse effects are such that there is considerable impetus to develop alternative treatment strategies to allow either lower doses or to remove the need for medication entirely. It has been recognised that psychological interventions as an adjunct to antipsychotic medication have an important part to play in the treatment of schizophrenia. NICE guideline CG82 identified family intervention and CBT as adjunct treatments and current evidence suggests that these interventions are cost saving. However, evidence for adjunctive family intervention and CBT is lacking in children and young people with psychosis. Furthermore, there has been one recent positive trial of CBT as a first‑line treatment, without antipsychotics, for young people in the early stages of psychosis. # What is the clinical effectiveness of clozapine for children and young people with schizophrenia with symptoms unresponsive to antipsychotic medication and psychological treatment combined? The suggested programme of research would need to test out, using an adequately powered, randomised controlled design, the likely benefits of using clozapine, compared with another antipsychotic, for children and young people with symptoms of schizophrenia unresponsive to antipsychotic medication and psychological treatment combined. The outcomes considered should include quality of life, symptomatic and functional improvements, treatment acceptability, side effects and length of hospitalisation. ## Why this is important Currently, about 30% of people with schizophrenia have symptoms that do not respond adequately to treatment with an antipsychotic. Although precise figures are unavailable, especially for children and young people, smaller percentages of people do not respond when a second, alternative, antipsychotic and an adequate course of psychological treatment have been tried. For these people, clozapine, which has a different dopamine receptor subtype blocking profile from other antipsychotics, has become an important treatment option in adults. However, evidence is lacking (only one study) about the effectiveness of clozapine for 'treatment‑resistant schizophrenia' in children and young people. # What is the most effective management strategy for preventing the development of excessive weight gain and metabolic syndrome associated with the use of antipsychotic medication in children and young people? The suggested programme of research would be in two parts: (1) a longitudinal cohort study (a national observational database of at least 12 months' duration) to determine the incidence and predictors of adverse physical effects of antipsychotic medication; (2) a randomised controlled trial of behavioural and/or medical approaches to reduce weight gain and the risk of metabolic syndrome associated with antipsychotic medication. ## Why this is important Rapid weight gain associated with antipsychotic medication and poor physical health (smoking, lack of exercise) leading to type 2 diabetes and metabolic syndrome are major sources of morbidity and premature mortality in young people with psychosis and schizophrenia. Most evidence of adverse effects comes from short‑term studies of antipsychotics (maximum 8 to 12 weeks). In contrast, very little is known about the longer term adverse effects of these drugs. Evidence is needed both on longer term adverse effects as well as on effective early intervention strategies that reduce these risk factors and improve physical health outcomes.# Supplementary information on baseline investigations and monitoring Baseline investigations before starting antipsychotic medication Monitor weekly for the first 6 weeks Monitor at 12 weeks Monitor every 6 months thereafter Monitor regularly throughout treatment, and especially during titration Weight (plotted on a growth chart) Calculate and document BMI (percentile). Yes Yes Yes Yes Height (plotted on a growth chart) Calculate and document BMI (percentile). Yes Yes Waist circumference (plotted on a percentile chart) Yes Yes Pulse Yes Yes Yes Blood pressure (plotted on a percentile chart) Yes Yes Yes Fasting blood glucose or HbA1c (glycosylated haemoglobin) Yes Yes Yes Blood lipid profile Yes Yes Yes Prolactin level Yes Yes Yes Movement disorders (extrapyramidal symptoms, akathisia, dystonia and tardive dyskinesia) Yes Yes Even if no baseline assessment (and at each clinic visit if more frequent) Nutritional status, diet and level of physical activity Yes Yes The side effects the child or young person is most or least willing to tolerate Yes ECG Yes If specified in the SPC for adults and/or children; a physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure); there is personal history of cardiovascular disease; there is a family history of cardiovascular disease such as sudden cardiac death or prolonged QT interval; or the child or young person is being admitted as an inpatient. Efficacy Yes Side effects Yes Adherence Yes	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nAll recommendations relate to children and young people (younger than 18\xa0years) unless otherwise specified.\n\n# General principles of care\n\n## Working safely and effectively with children and young people\n\nHealth and social care professionals working with children and young people with psychosis or schizophrenia should be trained and competent to work with children and young people with mental health problems of all levels of learning ability, cognitive capacity, emotional maturity and development. See also NICE's guideline on babies, children and young people's experience of healthcare. \n\nHealth and social care professionals should ensure that they:\n\ncan assess capacity and competence, including 'Gillick competence', in children and young people of all ages, and\n\nunderstand how to apply legislation, including the Children Act (1989; amended 2004), the Mental Health Act (1983; amended 1995 and 2007; including the Code of Practice: Mental Health Act 1983) and the Mental Capacity Act (2005), in the care and treatment of children and young people. \n\nConsider children and young people with psychosis or schizophrenia for assessment according to local safeguarding procedures if there are concerns regarding exploitation or self‑care, or if they have been in contact with the criminal justice system. \n\nHealth and social care providers should ensure that children and young people with psychosis or schizophrenia:\n\ncan routinely receive care and treatment from a single multidisciplinary community team\n\nare not passed from one team to another unnecessarily\n\ndo not undergo multiple assessments unnecessarily. \n\nHelp the child or young person to continue their education. Contact the school or college, subject to consent, to ask for additional educational support if their performance has been affected by their condition. \n\n## Establishing relationships with children and young people and their parents or carers\n\nWork in partnership with children and young people with psychosis or schizophrenia of an appropriate developmental level, emotional maturity and cognitive capacity and parents or carers. Offer help, treatment and care in an atmosphere of hope and optimism. Take time to build trusting, supportive, empathic and non‑judgemental relationships as an essential part of care. \n\nWhen working with children and young people with psychosis or schizophrenia:\n\naim to foster autonomy, promote active participation in treatment decisions, and support self‑management and access to peer support in children and young people of an appropriate developmental level, emotional maturity and cognitive capacity\n\nmaintain continuity of individual therapeutic relationships wherever possible\n\noffer access to a trained advocate. \n\nWhen working with children and young people with psychosis or schizophrenia and their parents or carers:\n\nmake sure that discussions take place in settings in which confidentiality, privacy and dignity are respected\n\nbe clear with the child or young person and their parents or carers about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others). \n\nDiscuss with young people with psychosis or schizophrenia of an appropriate developmental level, emotional maturity and cognitive capacity how they want their parents or carers to be involved in their care. Such discussions should take place at intervals to take account of any changes in circumstances, including developmental level, and should not happen only once. \n\nAdvise parents and carers about their right to a formal carer's assessment of their own physical and mental health needs, and explain how to access this. \n\n## Communication and information\n\nHealth and social care professionals working with children and young people with psychosis or schizophrenia should be trained and skilled in:\n\nnegotiating and working with parents and carers, and\n\nmanaging issues relating to information sharing and confidentiality as these apply to children and young people. \n\nIf a young person is 'Gillick competent' ask them what information can be shared before discussing their condition and treatment with their parents or carers. \n\nWhen communicating with children and young people with psychosis or schizophrenia and their parents or carers:\n\ntake into account the child or young person's developmental level, emotional maturity and cognitive capacity including any learning disabilities, sight or hearing problems or delays in language development\n\nuse plain language where possible and clearly explain any clinical language\n\ncheck that the child or young person and their parents or carers understand what is being said\n\nuse communication aids (such as pictures, symbols, large print, braille, different languages or sign language) if needed. \n\nProvide children and young people with psychosis or schizophrenia and their parents or carers, comprehensive written information about:\n\nthe nature of, and interventions for, psychosis and schizophrenia (including biomedical and psychosocial perspectives on causes and treatment) in an appropriate language or format, including any relevant 'Information for the public' booklets\n\nsupport groups, such as third sector, including voluntary, organisations. \n\nEnsure that you are:\n\nfamiliar with local and national sources (organisations and websites) of information and/or support for children and young people with psychosis or schizophrenia and their parents or carers\n\nable to discuss and advise how to access these resources\n\nable to discuss and actively support children and young people and their parents or carers to engage with these resources. \n\nWhen communicating with a child or young person with psychosis or schizophrenia, use diverse media, including letters, phone calls, emails or text messages, according to their preference. \n\nCopy all written communications with other health or social care professionals to the child or young person and/or their parents or carers at the address of their choice, unless this is declined. \n\n## Culture, ethnicity and social inclusion\n\nWhen working with children and young people with psychosis or schizophrenia and their parents or carers:\n\ntake into account that stigma and discrimination are often associated with using mental health services\n\nbe respectful of and sensitive to children and young people's gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability\n\nbe aware of possible variations in the presentation of mental health problems in children and young people of different genders, ages, cultural, ethnic, religious or other diverse backgrounds. \n\nWhen working with children and young people and their parents or carers who have difficulties speaking or reading English:\n\nprovide and work proficiently with interpreters if needed\n\noffer a list of local education providers who can provide English language teaching. \n\nHealth and social care professionals working with children and young people with psychosis or schizophrenia and their parents or carers should have competence in:\n\nassessment skills for people from diverse ethnic and cultural backgrounds\n\nusing explanatory models of illness for people from diverse ethnic and cultural backgrounds\n\nexplaining the possible causes of psychosis and schizophrenia and treatment options\n\naddressing cultural and ethnic differences in treatment expectations and adherence\n\naddressing cultural and ethnic differences in beliefs regarding biological, social and family influences on the possible causes of mental health problems\n\nconflict management and conflict resolution. \n\nHealth and social care professionals inexperienced in working with children and young people with psychosis or schizophrenia from diverse ethnic and cultural backgrounds, and their parents or carers, should seek advice and supervision from healthcare professionals who are experienced in working transculturally. \n\nLocal mental health services should work with primary care, other secondary care and local third sector, including voluntary, organisations to ensure that:\n\nall children and young people with psychosis or schizophrenia have equal access to services based on clinical need and irrespective of gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability\n\nservices are culturally appropriate. \n\nMental health services should work with local voluntary black and minority ethnic groups to jointly ensure that culturally appropriate psychological and psychosocial treatment, consistent with this guideline and delivered by competent practitioners, is provided to children and young people from diverse ethnic and cultural backgrounds. \n\n## Transfer and discharge\n\nAnticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in children and young people with psychosis or schizophrenia and their parents or carers. Ensure that:\n\nsuch changes, especially discharge and transfer from CAMHS to adult services, or to primary care, are discussed and planned carefully beforehand with the child or young person and their parents or carers, and are structured and phased\n\nthe care plan supports effective collaboration with social care and other care providers during endings and transitions, and includes details of how to access services in times of crisis\n\nwhen referring a child or young person for an assessment in other services (including for psychological interventions), they are supported during the referral period and arrangements for support are agreed beforehand with them. \n\n# Possible psychosis\n\n## Referral from primary care\n\nWhen a child or young person experiences transient or attenuated psychotic symptoms or other experiences suggestive of possible psychosis, refer for assessment without delay to a specialist mental health service such as CAMHS or an early intervention in psychosis service (14\xa0years or over). \n\n## Assessment in specialist mental health services\n\nCarry out an assessment of the child or young person with possible psychosis, ensuring that:\n\nassessments in CAMHS include a consultant psychiatrist\n\nassessments in early intervention in psychosis services are multidisciplinary\n\nwhere there is considerable uncertainty about the diagnosis, or concern about underlying neurological illness, there is an assessment by a consultant psychiatrist with training in child and adolescent mental health. \n\nIf a clear diagnosis of psychosis cannot be made, monitor regularly for further changes in symptoms and functioning for up to 3\xa0years. Determine the frequency and duration of monitoring by:\n\nthe severity and frequency of symptoms\n\nthe level of impairment and/or distress in the child or young person, and\n\nthe degree of family disruption or concern. \n\nIf discharge from the service is requested, offer follow‑up appointments and the option to self‑refer at a later date. Ask the GP to continue monitoring changes in mental state. \n\n## Treatment options for symptoms not sufficient for a diagnosis of psychosis or schizophrenia\n\nWhen transient or attenuated psychotic symptoms or other mental state changes associated with distress, impairment or help‑seeking behaviour are not sufficient for a diagnosis of psychosis or schizophrenia:\n\nconsider individual cognitive behavioural therapy (CBT) (delivered as set out in recommendation\xa01.3.29) with or without family intervention (delivered as set out in recommendation\xa01.3.28), and\n\noffer treatments recommended in NICE guidance for children and young people with any of the anxiety disorders, depression, emerging personality disorder or substance misuse. \n\nDo not offer antipsychotic medication:\n\nfor psychotic symptoms or mental state changes that are not sufficient for a diagnosis of psychosis or schizophrenia, or\n\nwith the aim of decreasing the risk of psychosis. \n\n# First episode psychosis\n\n## Referral from primary care\n\nUrgently refer all children and young people with a first presentation of sustained psychotic symptoms (lasting 4\xa0weeks or more) to a specialist mental health service, either CAMHS (up to 17\xa0years) or an early intervention in psychosis service (14\xa0years or over), which includes a consultant psychiatrist with training in child and adolescent mental health. \n\nAntipsychotic medication in children and young people with a first presentation of sustained psychotic symptoms should not be started in primary care unless it is done in consultation with a consultant psychiatrist with training in child and adolescent mental health. \n\n## Assessment and care planning in secondary care\n\nWhen carrying out an assessment:\n\nensure there is enough time for:\n\n\n\nthe child or young person and their parents or carers to describe and discuss their problems\n\nsummarising the conclusions of the assessment and for discussion, with questions and answers\n\n\n\nexplain and give written material in an accessible format about any diagnosis given\n\ngive information about different treatment options, including pharmacological and psychological interventions, and their benefits and side effects, to promote discussion and shared understanding\n\noffer support after the assessment, particularly if sensitive issues, such as childhood trauma, have been discussed. \n\nEnsure that children and young people with first episode psychosis receive a comprehensive multidisciplinary assessment. The assessment should address the following domains:\n\npsychiatric (mental health problems, risk of harm to self or others, alcohol consumption and prescribed and non‑prescribed drug history)\n\nmedical, including medical history and full physical examination to identify physical illness (including organic brain disorders) and prescribed drug treatments that may result in psychosis\n\npsychological and psychosocial, including social networks, relationships and history of trauma\n\ndevelopmental (social, cognitive and motor development and skills, including coexisting neurodevelopmental conditions)\n\nphysical health and wellbeing (including weight and height, and information about smoking, diet and exercise, and sexual health)\n\nsocial (accommodation, culture and ethnicity, leisure activities and recreation, carer responsibilities [for example, of parents or siblings])\n\neducational and occupational (attendance at school or college, educational attainment, employment and functional activity)\n\neconomic (family's economic status). \n\nRoutinely monitor for other coexisting mental health problems, including depression and anxiety, and substance misuse, particularly in the early phases of treatment. \n\nDevelop a care plan with the parents or carers of younger children, or jointly with the young person and their parents or carers, as soon as possible, and:\n\ninclude activities that promote physical health and social inclusion, especially education, but also employment, volunteering and other occupations such as leisure activities\n\nprovide support to help the child or young person and their parents or carers realise the plan\n\ngive an up-to-date written copy of the care plan to the young person and their parents or carers if the young person agrees to this; give a copy of the care plan to the parents or carers of younger children; agree a suitable time to review it\n\nsend a copy to the primary healthcare professional who made the referral. \n\nSupport children and young people to develop strategies, including risk- and self‑management plans, to promote and maintain independence and self‑efficacy, wherever possible. Incorporate these strategies into the care plan. \n\nIf the child or young person is at risk of crisis, develop a crisis plan with the parents or carers of younger children, or jointly with the young person and their parents or carers, and with their care coordinator. The plan should be respected and implemented, incorporated into the care plan and include:\n\npossible early warning signs of a crisis and coping strategies\n\nsupport available to help prevent hospitalisation\n\nwhere the child or young person would like to be admitted in the event of hospitalisation\n\ndefinitions of the roles of primary and secondary care professionals and the degree to which parents or carers are involved\n\ninformation about 24‑hour access to services\n\nthe names of key clinical contacts. \n\nFor children and young people with first episode psychosis who are unable to attend mainstream school or college, facilitate alternative educational input in line with their capacity to engage with educational activity and according to their individual needs, with an ultimate goal of returning to mainstream education, training or employment. \n\nIf the child or young person and/or their parent or carer is unhappy about the assessment, diagnosis or care plan, give them time to discuss this and offer them the opportunity for a second opinion. \n\n## Treatment options for first episode psychosis\n\nFor children and young people with first episode psychosis offer:\n\noral antipsychotic medication (see recommendations\xa01.3.14 to 1.3.26) in conjunction with\n\npsychological interventions (family intervention with individual CBT, delivered as set out in recommendations\xa01.3.27 to 1.3.33). In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\nIf the child or young person and their parents or carers wish to try psychological interventions (family intervention with individual CBT) alone without antipsychotic medication, advise that psychological interventions are more effective when delivered in conjunction with antipsychotic medication. If the child or young person and their parents or carers still wish to try psychological interventions alone, then offer family intervention with individual CBT. Agree a time limit (1\xa0month or less) for reviewing treatment options, including introducing antipsychotic medication. Continue to monitor symptoms, level of distress, impairment and level of functioning, including educational engagement and achievement, regularly. \n\nIf the child or young person shows symptoms and behaviour sufficient for a diagnosis of an affective psychosis or disorder, including bipolar disorder and unipolar psychotic depression, follow the recommendations in NICE's guidelines on bipolar disorder: assessment and management or depression in children and young people: identification and management. \n\n## Choice of antipsychotic medication\n\nThe choice of antipsychotic medication should be made by the parents or carers of younger children, or jointly with the young person and their parents or carers, and healthcare professionals. Provide age‑appropriate information and discuss the likely benefits and possible side effects of each drug including:\n\nmetabolic (including weight gain and diabetes)\n\nextrapyramidal (including akathisia, dyskinesia and dystonia)\n\ncardiovascular (including prolonging the QT interval)\n\nhormonal (including increasing plasma prolactin)\n\nother (including unpleasant subjective experiences).In May 2016, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\nWhen choosing between olanzapine and other 'second generation' antipsychotic medications, discuss with the young person and their parents or carers the increased likelihood of greater weight gain with olanzapine.Inform them that this effect is likely to happen soon after starting treatment. In May 2016, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. [new 2016]\n\n## How to use oral antipsychotic medication\n\nBefore starting antipsychotic medication, undertake and record the following baseline investigations (see supplementary information for a table of baseline investigations and monitoring for children and young people who are prescribed antipsychotic medication [read in conjunction with the BNF, BNFC and SPC]):\n\nweight and height (both plotted on a growth chart)\n\nwaist and hip circumference\n\npulse and blood pressure\n\nfasting blood glucose or glycosylated haemoglobin (HbA1c)\n\nblood lipid profile and prolactin levels\n\nassessment of any movement disorders\n\nassessment of nutritional status, diet and level of physical activity. In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\nBefore starting antipsychotic medication, offer the child or young person an electrocardiogram (ECG) if:\n\nspecified in the SPC for adults and/or children\n\na physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure)\n\nthere is a personal history of cardiovascular disease\n\nthere is a family history of cardiovascular disease such as premature sudden cardiac death or prolonged QT interval, or\n\nthe child or young person is being admitted as an inpatient. \n\nTreatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following:\n\nFrom a discussion with the child or young person and their parent or carer, record the side effects the child or young person is most and least willing to tolerate.\n\nRecord the indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects.\n\nAt the start of treatment give a dose below the lower end of the licensed range for adults if the drug is not licensed for children and young people and at the lower end of the licensed range if the drug is licensed for children and young people; slowly titrate upwards within the dose range given in the British national formulary (BNF), the British national formulary for children (BNFC) or the SPC.\n\nJustify and record reasons for dosages above the range given in the BNF, BNFC or SPC.\n\nRecord the rationale for continuing, changing or stopping medication, and the effects of such changes.\n\nCarry out a trial of the medication at optimum dosage for 4–6\xa0weeks. In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\nMonitor and record the following regularly and systematically throughout treatment, but especially during titration (see supplementary information for a table of baseline investigations and monitoring for children and young people who are prescribed antipsychotic medication [read in conjunction with the BNF, BNFC and SPC]):\n\nefficacy, including changes in symptoms and behaviour\n\nside effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia (for example, the overlap between akathisia and agitation or anxiety)\n\nthe emergence of movement disorders\n\nweight, weekly for the first 6\xa0weeks, then at 12\xa0weeks and then every 6\xa0months (plotted on a growth chart)\n\nheight every 6\xa0months (plotted on a growth chart)\n\nwaist circumference every 6\xa0months (plotted on a percentile chart)\n\npulse and blood pressure (plotted on a percentile chart) at 12\xa0weeks and then every 6\xa0months\n\nfasting blood glucose or HbA1c, and blood lipid and prolactin levels at 12\xa0weeks and then every 6\xa0months\n\nadherence\n\nphysical health.The secondary care team should maintain responsibility for monitoring physical health and the effects of antipsychotic medication in children and young people for at least the first 12\xa0months or until their condition has stabilised. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared care arrangements. \n\nDiscuss any non-prescribed therapies that children or young people, or their parents or carers, wish to use (including complementary therapies) with them. Discuss the safety and efficacy of the therapies, and possible interference with the therapeutic effects of prescribed medication and psychological interventions. \n\nDiscuss the use of alcohol, tobacco, prescription and non‑prescription medication and illicit drugs with the child or young person, and their parents or carers where this has been agreed. Discuss their possible interference with the therapeutic effects of prescribed medication and psychological interventions and the potential of illicit drugs to exacerbate psychotic symptoms. \n\n'As required' (p.r.n.) prescriptions of antipsychotic medication should be made as described in recommendation\xa01.3.18. Review clinical indications, frequency of administration, therapeutic benefits and side effects at least weekly. Check whether 'p.r.n.' prescriptions have led to a dosage above the maximum specified in the BNF, BNFC or SPC. \n\nDo not use a loading dose of antipsychotic medication (often referred to as 'rapid neuroleptisation'). \n\nDo not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication). \n\nIf prescribing chlorpromazine, warn of its potential to cause skin photosensitivity. Advise using sunscreen if necessary. \n\nReview antipsychotic medication annually, including observed benefits and any side effects. \n\n## How to deliver psychological interventions\n\nWhen delivering psychological interventions for children and young people with psychosis or schizophrenia, take into account their developmental level, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems or delays in language development. \n\nFamily intervention should:\n\ninclude the child or young person with psychosis or schizophrenia if practical\n\nbe carried out for between 3\xa0months and 1\xa0year\n\ninclude at least 10\xa0planned sessions\n\ntake account of the whole family's preference for either single‑family intervention or multi‑family group intervention\n\ntake account of the relationship between the parent or carer and the child or young person with psychosis or schizophrenia\n\nhave a specific supportive, educational or treatment function and include negotiated problem solving or crisis management work. \n\nCBT should be delivered on a one‑to‑one basis over at least 16\xa0planned sessions (although longer may be needed) and:\n\nfollow a treatment manual so that:\n\n\n\nchildren and young people can establish links between their thoughts, feelings or actions and their current or past symptoms, and/or functioning\n\nthe re-evaluation of the child or young person's perceptions, beliefs or reasoning relates to the target symptoms\n\n\n\nalso include at least one of the following components:\n\n\n\nnormalising, leading to understanding and acceptability of their experience\n\nchildren and young people monitoring their own thoughts, feelings or behaviours with respect to their symptoms or recurrence of symptoms\n\npromoting alternative ways of coping with the target symptom\n\nreducing distress\n\nimproving functioning. Treatment manuals that have evidence for their efficacy from clinical trials are preferred. If developed for adults, the approach should be adapted to suit the age and developmental level of the child or young person. \n\n\n\n## Monitoring and reviewing psychological interventions\n\nWhen providing psychological interventions, routinely and systematically monitor a range of outcomes across relevant areas, including the child or young person's satisfaction and, if appropriate, parents' or carers' satisfaction. \n\nHealthcare teams working with children and young people with psychosis or schizophrenia should identify a lead healthcare professional within the team whose responsibility is to monitor and review:\n\naccess to and engagement with psychological interventions\n\ndecisions to offer psychological interventions and equality of access across different ethnic groups. \n\n## Competencies for delivering psychological interventions\n\nHealthcare professionals delivering psychological interventions should:\n\nhave an appropriate level of competence in delivering the intervention to children and young people with psychosis or schizophrenia\n\nbe regularly supervised during psychological therapy by a competent therapist and supervisor. \n\nTrusts should provide access to training that equips healthcare professionals with the competencies required to deliver the psychological interventions for children and young people recommended in this guideline.\n\n# Subsequent acute episodes of psychosis or schizophrenia\n\nFor children and young people with an acute exacerbation or recurrence of psychosis or schizophrenia offer:\n\noral antipsychotic medication in conjunction with\n\npsychological interventions (family intervention with individual CBT). In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\n## Pharmacological interventions\n\nFor children or young people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer oral antipsychotic medication or review existing medication. The choice of drug should be influenced by the same criteria recommended for starting treatment (see recommendations\xa01.3.14 to 1.3.26). Take into account the clinical response to and side effects associated with current and previous medication, and monitor as described in recommendation\xa01.3.19.In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\nAripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17\xa0years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone. [This recommendation is from NICE's technology appraisal guidance on aripiprazole for the treatment of schizophrenia in people aged 15 to 17\xa0years.] \n\n## Psychological and psychosocial interventions\n\nOffer family intervention (delivered as set out in recommendation\xa01.3.28) to all families of children and young people with psychosis or schizophrenia, particularly for preventing and reducing relapse. This can be started either during the acute phase or later, including in inpatient settings. \n\nOffer CBT (delivered as set out in recommendation\xa01.3.29) to all children and young people with psychosis or schizophrenia, particularly for symptom reduction. This can be started either during the acute phase or later, including in inpatient settings. \n\nConsider arts therapies (for example, dance movement, music or art therapy or dramatherapy) for all children and young people with psychosis or schizophrenia, particularly for the alleviation of negative symptoms. This can be started either during the acute phase or later, including in inpatient settings. \n\nIf arts therapies are considered, they should be provided by Health Professions Council (HPC) registered arts therapists, with experience of working with children and young people with psychosis or schizophrenia. The intervention should be provided in groups unless difficulties with acceptability and access and engagement indicate otherwise. Arts therapies should combine psychotherapeutic techniques with activity aimed at promoting creative expression, which is often unstructured and led by the child or young person. Aims of arts therapies should include:\n\nenabling children and young people with psychosis or schizophrenia to experience themselves differently and to develop new ways of relating to others\n\nhelping children and young people to express themselves and to organise their experience into a satisfying aesthetic form\n\nhelping children and young people to accept and understand feelings that may have emerged during the creative process (including, in some cases, how they came to have these feelings) at a pace suited to them. \n\nDo not routinely offer counselling and supportive psychotherapy (as specific interventions) to children and young people with psychosis or schizophrenia. However, take the child or young person's and their parents' or carers' preferences into account, especially if other more efficacious psychological interventions, such as CBT, family intervention and arts therapies, are not available locally. \n\nDo not offer adherence therapy (as a specific intervention) to children and young people with psychosis or schizophrenia. \n\nDo not routinely offer social skills training (as a specific intervention) to children and young people with psychosis or schizophrenia. \n\nWhen psychological interventions, including arts therapies, are started in the acute phase (including in inpatient settings), the full course should be continued after discharge without unnecessary interruption. \n\n# Referral in crisis and challenging behaviour\n\nWhen a child or young person is referred in crisis they should be seen by specialist mental health secondary care services within 4\xa0hours of referral. \n\nTo avoid admission, aim to:\n\nexplore with the child or young person and their parents or carers what support systems they have, including other family members and friends\n\nsupport a child or young person in crisis and their parents or carers in their home environment\n\nmake early plans to help the child or young person maintain their day‑to‑day activities, including education, work, voluntary work, and other occupations and leisure activities, wherever possible. \n\nAt the end of a crisis assessment, ensure that the decision to start home treatment depends not on the diagnosis, but on:\n\nthe level of distress\n\nthe severity of the problems\n\nthe vulnerability of the child or young person and issues of safety and support at home\n\nthe child or young person's cooperation with treatment. \n\nConsider the support and care needs of parents or carers of children or young people in crisis. Where needs are identified, ensure they are met when it is safe and practicable to do so. \n\nFollow the recommendations in NICE's guideline on self-harm: assessment, management and preventing recurrence when managing acts of self‑harm in children and young people with psychosis or schizophrenia who are 8\xa0years or over. \n\n## Hospital care\n\nIf a child or young person needs hospital care, this should be in a setting appropriate to their age and developmental level. \n\nBefore referral for hospital care, think about the impact on the child or young person and their parents, carers and other family members, especially when the inpatient unit is a long way from where they live. Consider alternative care within the community wherever possible. If hospital admission is unavoidable, provide support for parents or carers when the child or young person is admitted. \n\nGive verbal and written information to children and young people with psychosis or schizophrenia admitted to hospital, and their parents or carers, about:\n\nthe hospital and the ward in which the child or young person will stay\n\ntreatments, activities and services available\n\nexpected contact from health and social care professionals\n\nrules of the ward (including substance misuse policy)\n\ntheir rights, responsibilities and freedom to move around the ward and outside\n\nmeal times\n\nvisiting arrangements.Make sure there is enough time for the child or young person and their parents or carers to ask questions. \n\nUndertake shared decision-making routinely with children or young people in hospital who are of an appropriate developmental level, emotional maturity and cognitive capacity, including, whenever possible, those who are subject to the Mental Health Act (1983; amended 1995 and 2007). Include their parents or carers if appropriate. \n\nEnsure that children and young people of compulsory school age have access to a full educational programme while in hospital. The programme should meet the National Curriculum, be matched to the child or young person's developmental level and educational attainment, and should take account of their illness and degree of impairment. \n\nEnsure that children and young people in hospital continue to have access to a wide range of meaningful and culturally appropriate occupations and activities 7\xa0days per week, and not restricted to 9am to 5pm. These should include creative and leisure activities, exercise, self‑care and community access activities (where appropriate). Activities should be facilitated by appropriately trained educational, health or social care professionals. \n\nChildren and young people receiving community care before hospital admission should be routinely visited while in hospital by the health and social care professionals responsible for their community care. \n\nPromote good physical health, including healthy eating, exercise and smoking cessation. \n\n## Rapid tranquillisation and restraint\n\nHealthcare professionals undertaking rapid tranquillisation and/or restraint in children and young people with psychosis or schizophrenia should be trained and competent in undertaking these procedures in children and young people. \n\nOccasionally children and young people with psychosis or schizophrenia pose an immediate risk to themselves or others during an acute episode and may need rapid tranquillisation. Be particularly cautious when considering high‑potency antipsychotic medication (such as haloperidol) in children and young people, especially those who have not taken antipsychotic medication before, because of the increased risk of acute dystonic reactions in that age group. \n\nAfter rapid tranquillisation, offer the child or young person the opportunity to discuss their experiences. Provide them with a clear explanation of the decision to use urgent sedation. Record this in their notes. \n\n# Early post-acute period\n\nIn the early period of recovery following an acute episode, reflect upon the episode and its impact with the child or young person and their parents or carers, and make plans for recovery and possible future care. \n\nInform the child or young person and their parents or carers that there is a high risk of relapse if medication is stopped in the 1 to 2\xa0years following an acute episode. \n\nIf withdrawing antipsychotic medication, undertake gradually and monitor regularly for signs and symptoms of relapse. \n\nAfter withdrawal from antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2\xa0years. \n\n# Promoting recovery and providing possible future care in primary care\n\nDevelop and use practice case registers to monitor the physical and mental health of children and young people with psychosis or schizophrenia in primary care. \n\nGPs and other primary healthcare professionals should monitor the physical health of children and young people with psychosis or schizophrenia at least once a year. They should bear in mind that people with schizophrenia are at higher risk of cardiovascular disease than the general population. \n\nIdentify children and young people with psychosis or schizophrenia who smoke or who have high blood pressure, raised lipid levels or increased waist measurement at the earliest opportunity and monitor for the emergence of cardiovascular disease and diabetes. \n\nTreat children and young people with psychosis or schizophrenia who have diabetes and/or cardiovascular disease in primary care. Use the appropriate NICE guidance for children and young people where available. (See NICE's guideline on diabetes (type 1 and type 2) in children and young people: diagnosis and management.) \n\nHealthcare professionals in secondary care should ensure, as part of the care programme approach (CPA) in England and care and treatment plans in Wales, that children and young people with psychosis or schizophrenia receive physical healthcare from primary care as described in recommendations\xa01.7.2 to 1.7.4. Healthcare professionals in secondary care should continue to maintain responsibility for monitoring and managing any side effects of antipsychotic medication. \n\nWhen a child or young person with a diagnosis of psychosis or schizophrenia presents with a suspected relapse (for example, with increased psychotic symptoms or a significant increase in the use of alcohol or other substances) and is still receiving treatment, primary healthcare professionals should refer to the crisis section of the care plan. Consider referral to the key clinician or care coordinator identified in the crisis plan. \n\nFor a child or young person with psychosis or schizophrenia being cared for in primary care, consider referral to secondary care again if there is:\n\npoor response to treatment\n\nnon-adherence to medication\n\nintolerable side effects from medication or the child or young person or their parents or carers request a review of side effects\n\nthe child or young person or their parents or carers request psychological interventions not available in primary care\n\ncomorbid substance misuse\n\nrisk to self or others. \n\n# Promoting recovery and providing possible future care in secondary care\n\nChildren and young people with psychosis or schizophrenia who are being treated in an early intervention in psychosis service should have access to that service for up to 3\xa0years (or until their 18th\xa0birthday, whichever is longer) whatever the age of onset of psychosis or schizophrenia. \n\n## Psychological interventions\n\nOffer family intervention to families of children and young people with psychosis or schizophrenia to promote recovery. Deliver family intervention as described in recommendation\xa01.3.28. \n\nConsider family intervention particularly for families of children and young people with psychosis or schizophrenia who have:\n\nrecently relapsed or are at risk of relapse\n\npersisting symptoms. \n\nOffer CBT to assist in promoting recovery in children and young people with persisting positive and negative symptoms and for those in remission. Deliver CBT as described in recommendation\xa01.3.29. \n\nConsider arts therapies (see recommendation\xa01.4.7) to assist in promoting recovery, particularly in children and young people with negative symptoms. \n\n## Pharmacological interventions\n\nThe choice of drug should be influenced by the same criteria recommended for starting treatment (see recommendations\xa01.3.14 to 1.3.26). In January 2013, this was an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines. \n\nDo not use targeted, intermittent dosage maintenance strategies routinely. However, consider them for children and young people with psychosis or schizophrenia who are unwilling to accept a continuous maintenance regimen or if there is another contraindication to maintenance therapy, such as side‑effect sensitivity. Dosage maintenance strategies are defined as the use of antipsychotic medication only during periods of incipient relapse or symptom exacerbation rather than continuously. \n\n## Interventions for children and young people whose illness has not responded adequately to treatment\n\nIn January 2013, recommendations 1.8.8 to 1.8.10 were an off-label use of most antipsychotic medication for children and young people. See NICE's information on prescribing medicines.\n\nFor children and young people with psychosis or schizophrenia whose illness has not responded adequately to pharmacological or psychological interventions:\n\nreview the diagnosis\n\nestablish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct duration\n\nreview engagement with and use of psychological interventions and ensure that these have been offered according to this guideline; if family intervention has been undertaken suggest CBT; if CBT has been undertaken suggest family intervention for children and young people in close contact with their families\n\nconsider other causes of non‑response, such as comorbid substance misuse (including alcohol), the concurrent use of other prescribed medication or physical illness. \n\nOffer clozapine to children and young people with schizophrenia whose illness has not responded adequately to pharmacological treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs each used for 6 to 8\xa0weeks. \n\nFor children and young people whose illness has not responded adequately to clozapine at an optimised dose, consider a multidisciplinary review, and recommendation\xa01.8.8 (including measuring therapeutic drug levels) before adding a second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8 to 10\xa0weeks. Choose a drug that does not compound the common side effects of clozapine. \n\n## Education, employment and occupational activities for children and young people with psychosis and schizophrenia\n\nFor children and young people of compulsory school age, liaise with the child or young person's school and educational authority, subject to consent, to ensure that ongoing education is provided. \n\nLiaise with the child or young person's school and with their parents or carers, subject to consent, to determine whether a special educational needs assessment is necessary. If it is agreed that this is needed, explain to parents or carers how to apply for an assessment and offer support throughout the process. \n\nProvide supported employment programmes for those young people with psychosis or schizophrenia above compulsory school age who wish to return to work or find employment. Consider other work‑related activities and programmes when individuals are unable to work or are unsuccessful in their attempts to find employment. \n\nMental health services should work in partnership with local stakeholders, including those representing black and minority ethnic groups, to enable young people with psychosis or schizophrenia to access local employment and educational opportunities. This should be sensitive to the young person's needs and skill level and is likely to involve working with agencies such as Jobcentre Plus, disability employment advisers and non‑statutory providers. \n\nRoutinely record the daytime activities of children and young people with psychosis or schizophrenia in their care plans, including educational and occupational outcomes. ", 'Context': "This guideline is concerned with the recognition and management of psychosis and schizophrenia in children and young people up to the age of 18. The term 'psychosis' is used in this guideline to refer to the group of psychotic disorders that includes schizophrenia, schizoaffective disorder, schizophreniform disorder and delusional disorder. This guideline also addresses those children and young people considered clinically to be at high risk or prodromal for psychosis and schizophrenia. The recognition, treatment and management of affective psychoses (such as bipolar disorder or unipolar psychotic depression) are covered by other NICE guidelines.\n\nPsychosis and the specific diagnosis of schizophrenia in children and young people represent a major psychiatric disorder, or cluster of disorders that alters a person's perception, thoughts, mood and behaviour. The symptoms of psychosis are usually divided into 'positive symptoms', including hallucinations (perception in the absence of any stimulus) and delusions (fixed or falsely held beliefs), and 'negative symptoms' (such as emotional apathy, lack of drive, poverty of speech, social withdrawal and self‑neglect). Children and young people who develop psychosis will have their own unique combination of symptoms and experiences, the precise pattern of which will be influenced by their circumstances and stage of development.\n\nPsychosis and schizophrenia are commonly preceded by a so‑called prodromal period, lasting up to 12\xa0months, in which the child or young person's behaviour and experience are altered. Relatives may become aware of these changes first. Changes include the emergence of transient and/or attenuated psychotic symptoms, such as hallucinations and/or delusions with associated impaired functioning. More subtly, the child or young person may become socially withdrawn or suspicious, with alterations in expressed feeling. It is important to note that most children and young people with transient or attenuated psychotic symptoms do not go on to develop psychosis or schizophrenia, although those with such symptoms do appear to be at higher risk than other children and young people of developing psychosis and schizophrenia up to 10\xa0years after onset of symptoms.\n\nThe prevalence of psychotic disorders in children aged between 5 and 18\xa0years has been estimated to be 0.4% (the figure across all ages and populations in the UK is 0.7%). Schizophrenia accounts for 24.5% of all psychiatric admissions in young people aged 10 to 18\xa0years (the overall admission rate is 0.46 per 1000 for this age range), with an exponential rise across the adolescent years. The rise in incidence increases most from age\xa015 onwards.\n\nThere is a worse prognosis for psychosis and schizophrenia when onset is in childhood or adolescence. The symptoms and experience of psychosis and schizophrenia are often distressing and the effects of the illness are pervasive. Although about one‑fifth of children and young people with schizophrenia have a good outcome with only mild impairment, one‑third have severe impairment that needs intensive social and psychiatric support. Psychosis and schizophrenia can have a major detrimental effect on children and young people's personal, social, educational and occupational functioning, placing a heavy burden on them and their parents and carers.\n\nAlthough the mainstay of treatment for psychosis and schizophrenia has been antipsychotic medication, there is limited evidence of its efficacy in children and young people. There are also concerns that children and young people are more sensitive than adults to the potential adverse effects of antipsychotics, including weight gain, metabolic effects and movement disorders. A number of psychological interventions, including family intervention, cognitive behavioural therapy (CBT) and arts therapies, have been used but evidence of efficacy is currently unavailable in children and young people and provision of these therapies for children and young people and for adults is variable.\n\nThis guideline covers the care provided by primary, community, secondary, tertiary and other health and social care professionals who have direct contact with, and make decisions concerning, the care of children and young people with psychosis or schizophrenia, including child and adolescent mental health services (CAMHS) and early intervention in psychosis services.\n\nEarly intervention in psychosis services provide people aged 14 to 35\xa0years with a more intensive therapeutic service than traditional community services. They are designed to intervene early, and deliver support and evidence‑based interventions in a 'normalising' environment for the first 3\xa0years after onset of psychosis.\n\nThere is geographical variation in the configuration and integration of CAMHS and early intervention in psychosis services, and in the provision and integration of other services for children and young people with psychosis and schizophrenia, including education, employment and rehabilitation, and social services. In particular, provision for the needs of 16- and 17‑year‑olds with psychosis and schizophrenia can be fragmented and inadequate and they can experience difficulties in gaining access to appropriate accommodation and vocational or occupational support and rehabilitation.\n\nA number of recommendations in this guideline have been adapted from recommendations in other NICE clinical guidelines. Where this occurred, the guideline committee was careful to preserve the meaning and intent of the original recommendation. Changes to wording or structure were made in order to fit the recommendations into this guideline. In all cases, the original source of any adapted recommendation is indicated in a footnote.\n\nThe guideline incorporates NICE's technology appraisal guidance on aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years.", 'Recommendations for research': "In 2013 the guideline committee made the following recommendations for research.\n\n# What are the long-term outcomes, both psychotic and non‑psychotic, for children and young people with attenuated or transient psychotic symptoms suggestive of a developing psychosis, and can the criteria for 'at risk states' be refined to better predict those who will and those who will not go on to develop psychosis?\n\nThe suggested programme of research would be in two phases. First, a systematic review and meta‑analysis of prospective observational studies or cohorts of children and young people identified at high or ultra‑high risk of developing psychosis would be undertaken. The review would identify risk and protective factors most strongly associated with the later development of psychotic and non‑psychotic outcomes. Second, the factors identified in the first phase would be used to identify a large cohort of children and young people with these factors and to evaluate the effectiveness of these refined criteria for predicting the later development of psychotic and non‑psychotic outcomes.\n\n## Why this is important\n\nA major problem with trials of treatments for populations of children and young people deemed to be 'at risk' or 'at ultra‑high risk' of developing psychosis is identifying the precise symptoms and/or behaviours or (risk) factors that are most strongly associated with the development of psychosis; and conversely, which (protective) factors are likely to be associated with a lowered risk of later psychosis. At present, identified factors have a low predictive value, with only about 10 to 20% of children and young people who have been identified as at high risk going on to develop psychosis. If these risk and protective factors could be refined, it would be possible to better target children and young people who are most at risk, and reduce the numbers of those thought to be 'at risk' who do not go on to later develop psychosis.\n\n# What is the clinical and cost effectiveness for family intervention combined with individual CBT in the treatment of children and young people considered to be at high risk of developing psychosis and their parents or carers?\n\nThe suggested programme of research would need to test out, using an adequately powered, multicentre, randomised controlled design, the likely benefits and costs of providing family intervention, combined with individual CBT, for children and young people at high risk of developing psychosis and their parents or carers. The outcomes considered should include transition to psychosis, quality of life, symptomatic and functional improvements, treatment acceptability and self‑harm. There should be follow‑up at 3\xa0years. The trial should also estimate the cost effectiveness of intervening.\n\n## Why this is important\n\nA number of interventions have been trialled in an attempt to avert the development of psychosis, including drugs, psychological interventions and other interventions. After the first episode of psychosis, family intervention as an adjunct to antipsychotic medication substantially and significantly reduces relapse rates. A single small trial combining CBT family treatment with individual CBT without antipsychotic treatment suggested an important reduction in transition rates to the first psychosis.\n\n# What is the clinical and cost effectiveness of psychological intervention alone, compared with antipsychotic medication and compared with psychological intervention and antipsychotic medication combined, in young people with first episode psychosis?\n\nThe programme of research would compare the clinical and cost effectiveness of psychological intervention alone, compared with antipsychotic medication, and compared with psychological intervention and antipsychotic medication combined, for young people in the early stages of psychosis using an adequately powered study with a randomised controlled design. The combination of psychological interventions most likely to have an impact is family intervention and individual CBT. The key outcomes should include symptoms, relapse rates, quality of life, treatment acceptability, experience of care, level of psychosocial functioning and the cost effectiveness of the interventions.\n\n## Why this is important\n\nThe personal and financial cost of psychosis and schizophrenia to the person, their family and friends, and to society is considerable. The personal cost is reflected in a suicide rate of nearly 15% among people with schizophrenia, a lifelong unemployment rate that varies between 50 and 75%, depending on geographical location, and reduced life expectancy. The additional cost to the healthcare system for one person with schizophrenia is estimated to reach over £50,000 per year, on average, throughout their life.\n\nCurrently, the mainstay of treatment is antipsychotic medication, but the potential adverse effects are such that there is considerable impetus to develop alternative treatment strategies to allow either lower doses or to remove the need for medication entirely. It has been recognised that psychological interventions as an adjunct to antipsychotic medication have an important part to play in the treatment of schizophrenia. NICE guideline CG82 identified family intervention and CBT as adjunct treatments and current evidence suggests that these interventions are cost saving. However, evidence for adjunctive family intervention and CBT is lacking in children and young people with psychosis. Furthermore, there has been one recent positive trial of CBT as a first‑line treatment, without antipsychotics, for young people in the early stages of psychosis.\n\n# What is the clinical effectiveness of clozapine for children and young people with schizophrenia with symptoms unresponsive to antipsychotic medication and psychological treatment combined?\n\nThe suggested programme of research would need to test out, using an adequately powered, randomised controlled design, the likely benefits of using clozapine, compared with another antipsychotic, for children and young people with symptoms of schizophrenia unresponsive to antipsychotic medication and psychological treatment combined. The outcomes considered should include quality of life, symptomatic and functional improvements, treatment acceptability, side effects and length of hospitalisation.\n\n## Why this is important\n\nCurrently, about 30% of people with schizophrenia have symptoms that do not respond adequately to treatment with an antipsychotic. Although precise figures are unavailable, especially for children and young people, smaller percentages of people do not respond when a second, alternative, antipsychotic and an adequate course of psychological treatment have been tried. For these people, clozapine, which has a different dopamine receptor subtype blocking profile from other antipsychotics, has become an important treatment option in adults. However, evidence is lacking (only one study) about the effectiveness of clozapine for 'treatment‑resistant schizophrenia' in children and young people.\n\n# What is the most effective management strategy for preventing the development of excessive weight gain and metabolic syndrome associated with the use of antipsychotic medication in children and young people?\n\nThe suggested programme of research would be in two parts: (1) a longitudinal cohort study (a national observational database of at least 12\xa0months' duration) to determine the incidence and predictors of adverse physical effects of antipsychotic medication; (2) a randomised controlled trial of behavioural and/or medical approaches to reduce weight gain and the risk of metabolic syndrome associated with antipsychotic medication.\n\n## Why this is important\n\nRapid weight gain associated with antipsychotic medication and poor physical health (smoking, lack of exercise) leading to type\xa02 diabetes and metabolic syndrome are major sources of morbidity and premature mortality in young people with psychosis and schizophrenia. Most evidence of adverse effects comes from short‑term studies of antipsychotics (maximum 8 to 12\xa0weeks). In contrast, very little is known about the longer term adverse effects of these drugs. Evidence is needed both on longer term adverse effects as well as on effective early intervention strategies that reduce these risk factors and improve physical health outcomes.", 'Supplementary information on baseline investigations and monitoring': '-\n\nBaseline investigations before starting antipsychotic medication\n\nMonitor weekly for the first 6\xa0weeks\n\nMonitor at 12\xa0weeks\n\nMonitor every 6\xa0months thereafter\n\nMonitor regularly throughout treatment, and especially during titration\n\nWeight (plotted on a growth chart) Calculate and document BMI (percentile).\n\nYes\n\nYes\n\nYes\n\nYes\n\n-\n\nHeight (plotted on a growth chart) Calculate and document BMI (percentile).\n\nYes\n\n-\n\n-\n\nYes\n\n-\n\nWaist circumference (plotted on a percentile chart)\n\nYes\n\n-\n\n-\n\nYes\n\n-\n\nPulse\n\nYes\n\n-\n\nYes\n\nYes\n\n-\n\nBlood pressure (plotted on a percentile chart)\n\nYes\n\n-\n\nYes\n\nYes\n\n-\n\nFasting blood glucose or HbA1c (glycosylated haemoglobin)\n\nYes\n\n-\n\nYes\n\nYes\n\n-\n\nBlood lipid profile\n\nYes\n\n-\n\nYes\n\nYes\n\n-\n\nProlactin level\n\nYes\n\n-\n\nYes\n\nYes\n\n-\n\nMovement disorders (extrapyramidal symptoms, akathisia, dystonia and tardive dyskinesia)\n\nYes\n\n-\n\n-\n\n-\n\nYes\n\nEven if no baseline assessment (and at each clinic visit if more frequent)\n\nNutritional status, diet and level of physical activity\n\nYes\n\n-\n\n-\n\n-\n\nYes\n\nThe side effects the child or young person is most or least willing to tolerate\n\nYes\n\n-\n\n-\n\n-\n\n-\n\nECG\n\nYes\n\nIf specified in the SPC for adults and/or children; a physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure); there is personal history of cardiovascular disease; there is a family history of cardiovascular disease such as sudden cardiac death or prolonged QT interval; or the child or young person is being admitted as an inpatient.\n\n-\n\n-\n\n-\n\n-\n\nEfficacy\n\n-\n\n-\n\n-\n\n-\n\nYes\n\nSide effects\n\n-\n\n-\n\n-\n\n-\n\nYes\n\nAdherence\n\n-\n\n-\n\n-\n\n-\n\nYes'}	https://www.nice.org.uk/guidance/cg155	This guideline covers recognising and managing psychosis and schizophrenia in children and young people. It aims to improve early recognition of psychosis and schizophrenia so that children and young people can be offered the treatment and care they need to live with the condition.
24f503ca76a3580303af523c10510e8f02c621ba	nice	Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor	Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor Evidence-based recommendations on certolizumab pegol (Cimzia) for treating severe active rheumatoid arthritis in adults who have had a tumour necrosis factor-alpha inhibitor. # Recommendations Certolizumab pegol, in combination with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other disease-modifying antirheumatic drugs (DMARDs) including at least 1 tumour necrosis factor‑alpha (TNF‑alpha) inhibitor, only if: disease activity is severe and rituximab is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme. Certolizumab pegol, as monotherapy, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1 TNF‑alpha inhibitor, only if: disease activity is severe and rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme. Continue treatment only if there is at least a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months. After an initial response within 6 months, withdraw treatment if at least a moderate EULAR response is not maintained. Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the disease activity score and make any appropriate adjustments. This guidance is not intended to affect the position of patients whose treatment with certolizumab pegol was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Certolizumab pegol (Cimzia, UCB Pharma) is a recombinant humanised antibody Fab' fragment against tumour necrosis factor-alpha (TNF‑alpha) and is conjugated to polyethylene glycol (PEG). TNF‑alpha is a pro-inflammatory mediator that is partly responsible for damage to the joints in rheumatoid arthritis. Marketing authorisation Certolizumab pegol in combination with methotrexate (MTX) has a marketing authorisation in the UK for 'the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including MTX, has been inadequate'. Certolizumab pegol can be given as 'monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate'. Certolizumab pegol also has a marketing authorisation in combination with MTX for 'the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX or other DMARDs', but this is not within the remit of this technology appraisal. Adverse reactions Certolizumab pegol is contraindicated in people with active tuberculosis or other severe infections, and in people with moderate or severe heart failure. The summary of product characteristics lists no adverse reactions as very common but notes that in clinical trials the most common adverse reactions were bacterial and viral infections. For full details of adverse reactions and contraindications see the summary of product characteristics. Recommended dose and schedule The recommended starting dose of certolizumab pegol for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. After the starting dose, the recommended maintenance dose of certolizumab pegol is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenance dosing of 400 mg every 4 weeks can be considered. MTX should be continued during treatment with certolizumab pegol when appropriate. Price The net price of certolizumab pegol is £357.50 per 200‑mg prefilled syringe (excluding VAT; 'British national formulary' edition 71). The company has agreed a patient access scheme with the Department of Health. In the scheme, the first 12 weeks of therapy (currently 10 pre-loaded syringes of 200 mg each) with certolizumab pegol are free of charge. The acquisition cost is £6,793 in the first year of treatment and then £9,295 per year. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of certolizumab pegol, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of certolizumab pegol by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical need and practice The committee understood that the remit is to appraise certolizumab pegol when the response to other disease-modifying antirheumatic drugs (DMARDS), including a tumour necrosis factor‑alpha (TNF‑alpha) inhibitor, has been inadequate. It noted existing NICE guidance at this point in the treatment pathway (NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis, golimumab for rheumatoid arthritis and tocilizumab for rheumatoid arthritis). These recommend rituximab plus methotrexate after an inadequate response or intolerance to other DMARDs, including at least 1 TNF‑alpha inhibitor. The committee was also aware that the guidance recommends adalimumab, etanercept, infliximab, abatacept, tocilizumab and golimumab (each with methotrexate) as options, when rituximab (plus methotrexate) is contraindicated or not tolerated and adalimumab and etanercept monotherapy as alternative options if rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated. The committee heard from the patient experts that response to treatment is difficult to predict, because responses to biological DMARDs (bDMARDs) differ between people. The clinical expert emphasised the importance of a range of options for bDMARD treatments, particularly when rituximab plus methotrexate cannot be offered because of well-documented risks of adverse events occurring (for example, after infusion). The committee concluded that an additional treatment option for rheumatoid arthritis that has not responded to a TNF‑alpha inhibitor would be valued by both patients and clinicians. The committee was aware that the marketing authorisation covers the use of certolizumab pegol in moderate to severe disease. It was reminded that NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs have failed recommends that treatment with a bDMARD should only be started when disease is severe, that is a disease activity (DAS28) score of more than 5.1. The committee understood that, at the point in the treatment pathway when treatment with the first bDMARD has not given an adequate response, severity of disease would have already been established. The committee was aware that there is a group of patients whose DAS28 score may be more than 5.1 when starting treatment with a first bDMARD, but whose DAS28 score may subsequently be less than 5.1 even though the disease has not adequately responded to the first bDMARD. The committee understood that this group would be small. It also understood from the consultation comments that this group would be considered to have severe disease, because the disease has already been confirmed as severe at an earlier point in the treatment pathway. The committee further noted that NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis and golimumab for rheumatoid arthritis do not define disease severity in the recommendations. Therefore, the committee did not consider it necessary to define disease severity using the DAS28 score measure when starting a second bDMARD. # Decision problem The committee considered the comparators for certolizumab pegol set out in the scope. It noted that the comparator was rituximab plus methotrexate. It was aware that, in line with existing NICE technology appraisal guidance (see section 4.1), alternative bDMARD treatment options were listed as comparators for those people for whom rituximab or methotrexate are contraindicated or withdrawn. The committee noted that the company had presented the evidence for 3 distinct populations, all of whom have been treated with a TNF‑alpha inhibitor: people for whom rituximab is contraindicated or not tolerated people for whom methotrexate is contraindicated or not tolerated people for whom rituximab plus methotrexate is a treatment option. The committee concluded that it was appropriate to consider the 3 groups as distinct from each other, and went on to consider the company's choice of comparators for each group. The committee noted that the company compared treatment sequences for the defined populations. The 3 tables below, show the sequences presented by the company. For the populations for whom methotrexate or rituximab is contraindicated, the sequences were of equal length and the comparator bDMARDs were: Abatacept, adalimumab, etanercept, golimumab, infliximab and tocilizumab (each plus methotrexate) when rituximab is contraindicated or not tolerated (table 1). Adalimumab monotherapy, etanercept monotherapy or tocilizumab monotherapy when rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated (table 2). Line of therapy Sequence with certolizumab pegol (plus methotrexate) Comparator sequence bDMARD (plus methotrexate) st Certolizumab pegol Comparator biological nd Methotrexate plus hydroxychloroquine plus sulfasalazine Methotrexate plus hydroxychloroquine plus sulfasalazine rd Leflunomide Leflunomide th Gold injection Gold injection th Ciclosporin Ciclosporin th Azathioprine Azathioprine th Palliative care Palliative care Line of therapy Sequence with certolizumab pegol (monotherapy) Comparator sequence bDMARD (monotherapy) st Certolizumab pegol Comparator biological nd Leflunomide Leflunomide rd Gold injection Gold injection th Ciclosporin Ciclosporin th Azathioprine Azathioprine th Palliative care Palliative care Line of therapy Sequence with certolizumab pegol and bDMARDs (plus methotrexate) Comparator sequence bDMARD (plus methotrexate) st Certolizumab pegol Rituximab nd Rituximab Tocilizumab rd Tocilizumab Abatacept th Abatacept Methotrexate plus hydroxychloroquine plus sulfasalazine th Methotrexate plus hydroxychloroquine plus sulfasalazine Non-biological (weighted mix of leflunomide, gold, azathioprine and ciclosporin) th Non-biologic (weighted mix of leflunomide, gold, azathioprine and ciclosporin) Palliative care th Palliative care The committee accepted the sequences for people for whom rituximab or methotrexate were contraindicated or not tolerated. It noted that for people for whom rituximab is a treatment option, the company compared treatment sequences of different lengths. The sequence containing certolizumab pegol placed certolizumab pegol before rituximab and therefore was not a strict comparison with rituximab because certolizumab pegol did not replace it, as with the other populations defined in the scope (see section 4.3). The committee considered that the sequences included treatments that would be offered to people whose disease has been classified as severe at the start of a first biological treatment. It recognised that the data provided by the company included people with moderate to severe disease, however the company did not separately compare treatment sequences for a population with moderate disease activity only. The committee therefore agreed it should focus on people with severe disease activity. The committee heard evidence from the clinical expert on the use of biosimilar bDMARDs in clinical practice. It heard that infliximab biosimilars are not used in rheumatology and that the etanercept biosimilar has only been launched recently. It also heard that the etanercept biosimilar should be used in preference to its originator because it has lower acquisition costs. The committee concluded that, because the etanercept biosimilar is being used in clinical practice, it was appropriate to consider it in its decision-making. # Clinical effectiveness The committee considered the company's clinical evidence and accepted that the results showed that certolizumab pegol was more clinically effective than placebo. It understood that the only evidence available on the comparative effectiveness of certolizumab pegol and the bDMARDs was from the company's mixed treatment comparisons. The committee heard from the evidence review group (ERG) that there were problems with the methods used for these comparisons. In its response to consultation, the company acknowledged that there was heterogeneity between the studies and it provided a random-effects network meta-analysis to compare with its original fixed-effect network meta-analysis. The results from these analyses are academic in confidence and cannot be included here. The guide to the processes of technology appraisal states that in the interests of public transparency, data marked as confidential should be kept to an absolute minimum. Although it disagrees with the company assertion that including the analysis results would inhibit publication elsewhere, NICE considers it unreasonable to delay the appraisal and access for patients to negotiate further confidentiality lifting with the company, especially as the results were not fundamental to the committee's decision. In addition, while the point estimates from the network meta-analyses were marked as academic-in-confidence, the conclusions were presented publically and showed that the mean effect sizes from the random-effects model were equal to those of the fixed-effects model. The committee concluded that there are uncertainties in the estimates from the methods used and it could not reliably conclude whether certolizumab pegol was more clinically effective than the comparator bDMARDs on the basis of the mixed treatment comparisons presented by the company. The committee reasoned that certolizumab pegol has a similar mechanism of action to other TNF‑alpha inhibitors, therefore it was plausible to assume that it would have comparative efficacy to other bDMARDs. This reasoning was strengthened when the committee heard from the clinical expert that certolizumab pegol is already in use in clinical practice and is not considered to be better or worse than other TNF‑alpha inhibitors. The committee concluded that certolizumab pegol has a similar efficacy to other available bDMARDs # Cost effectiveness The committee considered the cost-effectiveness evidence for the 3 populations defined in the company's submission (see section 4.1). ## People for whom rituximab or methotrexate are contraindicated or not tolerated The committee was aware of its conclusion on the efficacy of certolizumab pegol and other bDMARDs (see section 4.6), It queried the base-case incremental cost-effective ratios (ICERs) in the company's submission for the populations of people for whom either rituximab or methotrexate are contraindicated or not tolerated. It would have expected to see similar quality-adjusted life year (QALY) gains to other bDMARDs, but the incremental QALY gain for certolizumab pegol plus methotrexate and certolizumab pegol as monotherapy, were 0.260 for both populations. The committee noted that the company stated there was a lack of comparative evidence in the population who have had TNF‑alpha inhibitors before and therefore had to place assumptions on comparative effectiveness for the comparator bDMARDs. Therefore, the model assumed that the efficacy of adalimumab, etanercept and infliximab were equivalent to golimumab. The efficacies of adalimumab monotherapy and etanercept monotherapy were modelled using the effect size estimates for golimumab compared with certolizumab pegol (both in combination with methotrexate) from the network meta-analysis. The committee noted that these assumptions were not applied to certolizumab pegol. The committee then considered the ERG's scenario analysis in which it assumed that certolizumab pegol had equal efficacy to etanercept, adalimumab and infliximab (all plus methotrexate) for people for whom rituximab is contraindicated or not tolerated. The ERG also assumed that certolizumab pegol monotherapy had equal efficacy to etanercept and adalimumab monotherapies for people for whom methotrexate was contraindicated or not tolerated. The committee was aware that the etanercept biosimilar had been included in this sequence and agreed that this was appropriate. The committee noted for these equal length sequence analyses, that the ICERs for certolizumab pegol with methotrexate and as monotherapy were dominated; that is, certolizumab pegol plus methotrexate was more expensive but just as effective as the comparator bDMARDs. When the committee looked at the incremental increase in total costs between certolizumab pegol and the etanercept biosimilar it noted that there was very little difference so equivalence among the bDMARDs could be accepted. The committee considered the ICERs that incorporated confidential patient access schemes for abatacept and tocilizumab, the results of which cannot be shown here. Even when these schemes were taken into account, the committee noted that there were similarities in effects and costs and so concluded that certolizumab pegol plus methotrexate, or as monotherapy, can be considered a cost-effective use of NHS resources for people for whom rituximab or methotrexate are contraindicated or not tolerated. ## People for whom rituximab plus methotrexate is a treatment option The committee had concerns about the company's approach to evaluating the cost effectiveness of certolizumab pegol plus methotrexate for this population. In particular, it was not persuaded that an intervention treatment sequence containing certolizumab pegol and 6 other treatments should be compared with the same sequence without certolizumab pegol (see section 4.4). The committee was aware from past technology appraisals that using different sequence lengths can increase modelling uncertainties. It heard from the ERG that the company's model may not be appropriate for comparing sequences of different lengths and this point was highlighted in the ERG's exploratory analysis in which the use of the same model type resulted in some counterintuitive results; the clinical benefit (shown by the QALY gain) appeared to be greater if a person had received rituximab plus methotrexate than if a person had received both certolizumab pegol plus methotrexate and rituximab plus methotrexate. In addition the committee also understood that not all possible treatment sequences for this population had been included in the company's analysis. It noted that, to address this, the ERG had included 2 additional sequences in its exploratory analyses, in which certolizumab pegol plus methotrexate was placed after, and instead of, rituximab plus methotrexate. The committee noted that, after consultation, the company had accepted the relevance of the replacement sequence (that is, instead of rituximab plus methotrexate), but did not consider the sequence of certolizumab pegol after rituximab to be within the scope of the appraisal. The committee agreed with this but commented that placing certolizumab pegol plus methotrexate before rituximab plus methotrexate was also unsatisfactory (see section 4.4). It concluded that treatment sequences of the same length are preferable because they are subject to less uncertainty and that its focus should be on the sequence in which certolizumab pegol plus methotrexate replaces rituximab plus methotrexate. In the revised base-case analysis submitted by the company after consultation, the committee understood that the company had accepted most of the ERG's preferred assumptions, except treatment duration for biological therapies, and the retreatment interval for rituximab. The committee noted that these were key drivers of cost effectiveness. It concluded that each of these should be examined before considering the ICERs for its preferred treatment sequence. The company provided evidence from 2 studies to support an assumption of equal treatment duration for all biological therapies. A study by Ramiro et al. (2015) provided the evidence for a longer treatment duration with TNF‑alpha inhibitors compared with non‑TNF‑alpha inhibitors, whereas a study by Du Pan et al. (2012) provided evidence for a shorter treatment duration with TNF‑alpha inhibitors compared with non‑TNF‑alpha inhibitors. The committee was not persuaded that this opposing evidence should be interpreted as a basis for equal treatment duration. Also, it was not persuaded that these sources of evidence were methodologically stronger than the source preferred by the ERG (the REFLEX extension trial). In the Ramiro et al. (2015) trial, more people received a TNF‑alpha inhibitor than a non‑TNF‑alpha inhibitor. Also, this study was done in the USA where prescription patterns, reimbursement decisions and patients' comorbidities differ from England. The committee had fewer concerns with the Du Pan et al. (2012) study because it had enrolled more comparable numbers of people on TNF‑alpha and non‑TNF‑alpha inhibitors. Although the committee acknowledged the company's concerns that trial conditions may not represent clinical practice, it regarded the evidence for rituximab, the comparator of interest, to be superior to that for a collection of non‑TNF‑alpha inhibitor technologies. The committee concluded that the data from the extension phase of the REFLEX trial provided the most appropriate source of evidence for treatment duration. The committee considered the most plausible assumption for the retreatment interval of rituximab in the model. It noted that the summary of product characteristics for rituximab states that the 'need for further courses should be evaluated 24 weeks after the previous course', but did not consider that this was the same as specifying a 6‑month retreatment interval. It also noted that the committee had previously discussed this assumption in NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis, and concluded that treatment was unlikely to be as frequent as every 6 months for every person receiving rituximab. It therefore preferred the ERG's value of 10.09 months, which was sourced from the REFLEX trial. The committee considered that it was appropriate to use available trial evidence for rituximab to inform this assumption, and concluded that it was appropriate to use a retreatment interval for rituximab of 10.09 months. In line with its conclusion about treatment sequences (see section 4.4), the committee considered the ICERs when certolizumab pegol plus methotrexate was placed in a sequence instead of rituximab plus methotrexate. The company's base-case estimate for this comparison was in excess of £130,000 per QALY gained. However, the committee recognised that its preferred assumptions for the treatment duration for bDMARDs and the rituximab retreatment interval were not incorporated in this estimate. When these preferred assumptions were included, certolizumab pegol plus methotrexate was dominated by rituximab plus methotrexate. This analysis did not take into account the confidential patient access scheme discount for tocilizumab, a treatment included in the treatment sequence after rituximab. When the confidential discount for tocilizumab was included, certolizumab pegol plus methotrexate was still dominated. In summary, the committee concluded that certolizumab pegol plus methotrexate could not be considered a cost-effective use of NHS resources when rituximab plus methotrexate is a treatment option. For completeness, the committee looked at the elongated sequence, in which certolizumab pegol plus methotrexate was placed before rituximab plus methotrexate, which the committee had rejected earlier (see section 4.4 and section 4.10). The committee concluded that, with its preferred assumptions this sequence was still dominated and therefore was not a cost-effective use of NHS resources. # Equality issues The committee heard from the British Society of Rheumatology that certolizumab pegol may be used in pregnancy and that this was a potential equality issue. The committee was aware that the use of certolizumab pegol in pregnancy was outside the marketing authorisation. Because the committee makes recommendations within a technology's marketing authorisation, it could not consider including certolizumab pegol for use in pregnancy in its final recommendations. The committee concluded that it did not need to change its recommendations. # Innovation The company stated that not all the benefits of certolizumab pegol are captured by the QALY calculation, such as the effect the drug has on workplace and household productivity. However the committee considered that it had not been presented with any evidence to show an additional benefit over and above that already captured in the QALY. It concluded that all relevant benefits and costs were adequately captured by the QALY calculation. # Pharmaceutical price regulations scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. TA415 Appraisal title: Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF Inhibitor Section Key conclusion The committee considered that the incremental cost-effectiveness ratios (ICERs) showed that certolizumab pegol, in combination with methotrexate, is a cost-effective option for treating active rheumatoid arthritis in adults who have had an inadequate response to, or who cannot tolerate, other disease-modifying antirheumatic drugs (DMARDs), including at least 1 tumour necrosis factor‑alpha (TNF‑alpha) inhibitor, only if: disease activity is severe and the person cannot have rituximab therapy because rituximab is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme. The committee considered the ICERs showed that certolizumab pegol, as monotherapy, is a cost-effective option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1 TNF‑alpha inhibitor, only if: disease activity is severe and rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme. The committee concluded that the ICERs showed that certolizumab, in combination with methotrexate, was not a cost-effective option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1 TNF‑alpha inhibitor when disease activity is severe and when rituximab therapy can be considered a treatment option. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard from the clinical and patient expert that response to treatment is difficult to predict because patients' responses differ to biological DMARDs. The clinical expert expressed that a range of additional options of bDMARDs is valued at the positions in the pathway within existing NICE guidance. It is especially useful to have a range of bDMARDs when rituximab plus methotrexate cannot be considered due to adverse events related with rituximab. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee did not consider any claims about innovation that suggested there are additional innovative benefits that have not already been captured in the estimate of the quality-adjusted life year (QALY). What is the position of the treatment in the pathway of care for the condition? People whose disease has responded inadequately to treatment with a TNF‑alpha inhibitor. This is at the same point as the existing NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF-alpha inhibitor, golimumab for rheumatoid arthritis, and tocilizumab for rheumatoid arthritis. Adverse reactions No specific committee considerations. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee understood that the trials only showed a comparison of certolizumab pegol with placebo and accepted it was clinically effective over placebo. The committee understood that there were no trials comparing certolizumab pegol with comparator bDMARDs and that only mixed treatment comparisons were available. Relevance to general clinical practice in the NHS There were no direct head-to-head trials with treatments currently used in the NHS. Uncertainties generated by the evidence The committee was aware of uncertainties in the estimates from the meta-analyses methods used and it could not reliably conclude whether certolizumab pegol was more clinically effective than the comparator bDMARDs on the basis of the mixed treatment comparisons presented by the company. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No specific committee considerations. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee noted that the effect size estimates from the company's mixed treatment comparison, comparing certolizumab pegol with comparator bDMARDs, were uncertain and concluded from the clinical expert's view that there was similar efficacy among the bDMARDs. Evidence for cost effectiveness Availability and nature of evidence The company presented analyses of 3 distinct populations and a series of treatment sequences for people who have received a prior TNF‑alpha inhibitor. For people for whom rituximab is a treatment option, the committee agreed with the company that placing certolizumab pegol plus methotrexate after rituximab plus methotrexate was not a relevant comparator but noted that this was also true when placing certolizumab pegol plus methotrexate before rituximab plus methotrexate. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee noted that the evidence review group's (ERG's) scenario analysis applied an assumption of equal efficacy among some of the bDMARDs. This resulted in the ICERs being dominated (that is, certolizumab pegol was more expensive but just as effective as the comparator bDMARDs), for the population for whom rituximab plus methotrexate is contraindicated or not tolerated and for whom methotrexate is contraindicated or not tolerated. The committee noted the similarities in costs and its conclusions on comparative efficacy, so that equivalence among bDMARDs could be accepted. The committee heard that the company compared a longer intervention sequence that included another 6 treatments, with a comparator sequence without the intervention. It was aware that differential sequence lengths can exacerbate modelling uncertainties and, as such, skews the results in favour of the intervention. After consultation, the committee expressed uncertainties about the assumptions used in the company's model and preferred the ERG's values for the retreatment interval for rituximab and treatment durations (for TNF‑alpha inhibitors and non‑TNF‑alpha inhibitors) from the REFLEX study and the extension to this study. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? No other health-related benefits have been identified that have not been captured in the QALY calculation. Are there specific groups of people for whom the technology is particularly cost effective? No specific committee consideration. What are the key drivers of cost effectiveness? For people for whom rituximab is a treatment option, the committee looked at the elongated sequences used by the company in the analysis when certolizumab pegol plus methotrexate was placed before rituximab plus methotrexate. After consultation, the committee acknowledged that key drivers when certolizumab pegol plus methotrexate was used instead of rituximab plus methotrexate, were the retreatment interval for rituximab and the treatment durations for non‑TNF‑alpha inhibitors and TNF‑alpha inhibitors. It concluded that a retreatment interval of 10.09 months, from the REFLEX study, was more plausible than that of 6.00 months used by the company. It also concluded that the original retreatment durations from NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor were more plausible than an equal duration used by the company. The committee noted the comparative efficacy assumptions placed on bDMARDs in the analysis for people for whom methotrexate is contraindicated or not tolerated. In the ERG's scenario analysis, this resulted in ICERs that were dominated for certolizumab pegol. Most likely cost-effectiveness estimate (given as an ICER) The committee concluded from the ERG scenario analyses that there was little difference in costs between comparator bDMARDs and certolizumab pegol so that equivalence among bDMARDs can be accepted for people for whom rituximab is contraindicated or not tolerated, and for people for whom methotrexate is contraindicated or not tolerated. The committee concluded that the most likely ICER for people for whom rituximab plus methotrexate is a treatment option was above the normal range that would be considered a cost-effective use of NHS resources. The intervention was still dominated when the confidential patient access scheme for tocilizumab was taken into account. Additional factors taken into account Patient access schemes (PPRS) Patient access schemes were taken into account for certolizumab pegol, golimumab, tocilizumab and abatacept. End-of-life considerations Not applicable. Equalities considerations and social value judgements The committee heard that certolizumab pegol may be beneficial in treating rheumatoid arthritis in pregnant women but acknowledged this use was outside the marketing authorisation. Because the committee makes recommendations within the marketing authorisation, it could not consider certolizumab pegol for use in pregnancy in its final recommendations. The committee concluded that it did not need to change its recommendations.	{'Recommendations': 'Certolizumab pegol, in combination with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other disease-modifying antirheumatic drugs (DMARDs) including at least 1\xa0tumour necrosis factor‑alpha (TNF‑alpha) inhibitor, only if:\n\ndisease activity is severe and\n\nrituximab is contraindicated or not tolerated and\n\nthe company provides certolizumab pegol with the agreed patient access scheme.\n\nCertolizumab pegol, as monotherapy, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1\xa0TNF‑alpha inhibitor, only if:\n\ndisease activity is severe and\n\nrituximab therapy cannot be given because methotrexate is contraindicated or not tolerated and\n\nthe company provides certolizumab pegol with the agreed patient access scheme.\n\nContinue treatment only if there is at least a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months. After an initial response within 6\xa0months, withdraw treatment if at least a moderate EULAR response is not maintained.\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the disease activity score and make any appropriate adjustments.\n\nThis guidance is not intended to affect the position of patients whose treatment with certolizumab pegol was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nCertolizumab pegol (Cimzia, UCB Pharma) is a recombinant humanised antibody Fab' fragment against tumour necrosis factor-alpha (TNF‑alpha) and is conjugated to polyethylene glycol (PEG). TNF‑alpha is a pro-inflammatory mediator that is partly responsible for damage to the joints in rheumatoid arthritis.\n\nMarketing authorisation\n\nCertolizumab pegol in combination with methotrexate (MTX) has a marketing authorisation in the UK for 'the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including MTX, has been inadequate'. Certolizumab pegol can be given as 'monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate'.\n\nCertolizumab pegol also has a marketing authorisation in combination with MTX for 'the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX or other DMARDs', but this is not within the remit of this technology appraisal.\n\nAdverse reactions\n\nCertolizumab pegol is contraindicated in people with active tuberculosis or other severe infections, and in people with moderate or severe heart failure. The summary of product characteristics lists no adverse reactions as very common but notes that in clinical trials the most common adverse reactions were bacterial and viral infections. For full details of adverse reactions and contraindications see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended starting dose of certolizumab pegol for adult patients is 400\xa0mg (given as 2\xa0subcutaneous injections of 200\xa0mg each) at weeks 0, 2 and 4. After the starting dose, the recommended maintenance dose of certolizumab pegol is 200\xa0mg every 2\xa0weeks. Once clinical response is confirmed, an alternative maintenance dosing of 400\xa0mg every 4\xa0weeks can be considered. MTX should be continued during treatment with certolizumab pegol when appropriate.\n\nPrice\n\nThe net price of certolizumab pegol is £357.50 per 200‑mg prefilled syringe (excluding VAT; 'British national formulary' [BNF] edition\xa071). The company has agreed a patient access scheme with the Department of Health. In the scheme, the first 12\xa0weeks of therapy (currently 10\xa0pre-loaded syringes of 200\xa0mg each) with certolizumab pegol are free of charge. The acquisition cost is £6,793 in the first year of treatment and then £9,295 per year. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of certolizumab pegol, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of certolizumab pegol by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and practice\n\nThe committee understood that the remit is to appraise certolizumab pegol when the response to other disease-modifying antirheumatic drugs (DMARDS), including a tumour necrosis factor‑alpha (TNF‑alpha) inhibitor, has been inadequate. It noted existing NICE guidance at this point in the treatment pathway (NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis, golimumab for rheumatoid arthritis and tocilizumab for rheumatoid arthritis). These recommend rituximab plus methotrexate after an inadequate response or intolerance to other DMARDs, including at least 1\xa0TNF‑alpha inhibitor. The committee was also aware that the guidance recommends adalimumab, etanercept, infliximab, abatacept, tocilizumab and golimumab (each with methotrexate) as options, when rituximab (plus methotrexate) is contraindicated or not tolerated and adalimumab and etanercept monotherapy as alternative options if rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated. The committee heard from the patient experts that response to treatment is difficult to predict, because responses to biological DMARDs (bDMARDs) differ between people. The clinical expert emphasised the importance of a range of options for bDMARD treatments, particularly when rituximab plus methotrexate cannot be offered because of well-documented risks of adverse events occurring (for example, after infusion). The committee concluded that an additional treatment option for rheumatoid arthritis that has not responded to a TNF‑alpha inhibitor would be valued by both patients and clinicians.\n\nThe committee was aware that the marketing authorisation covers the use of certolizumab pegol in moderate to severe disease. It was reminded that NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs have failed recommends that treatment with a bDMARD should only be started when disease is severe, that is a disease activity (DAS28) score of more than\xa05.1. The committee understood that, at the point in the treatment pathway when treatment with the first bDMARD has not given an adequate response, severity of disease would have already been established. The committee was aware that there is a group of patients whose DAS28 score may be more than\xa05.1 when starting treatment with a first bDMARD, but whose DAS28 score may subsequently be less than\xa05.1 even though the disease has not adequately responded to the first bDMARD. The committee understood that this group would be small. It also understood from the consultation comments that this group would be considered to have severe disease, because the disease has already been confirmed as severe at an earlier point in the treatment pathway. The committee further noted that NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis and golimumab for rheumatoid arthritis do not define disease severity in the recommendations. Therefore, the committee did not consider it necessary to define disease severity using the DAS28 score measure when starting a second bDMARD.\n\n# Decision problem\n\nThe committee considered the comparators for certolizumab pegol set out in the scope. It noted that the comparator was rituximab plus methotrexate. It was aware that, in line with existing NICE technology appraisal guidance (see section\xa04.1), alternative bDMARD treatment options were listed as comparators for those people for whom rituximab or methotrexate are contraindicated or withdrawn. The committee noted that the company had presented the evidence for 3\xa0distinct populations, all of whom have been treated with a TNF‑alpha inhibitor:\n\npeople for whom rituximab is contraindicated or not tolerated\n\npeople for whom methotrexate is contraindicated or not tolerated\n\npeople for whom rituximab plus methotrexate is a treatment option.\n\nThe committee concluded that it was appropriate to consider the 3\xa0groups as distinct from each other, and went on to consider the company's choice of comparators for each group. The committee noted that the company compared treatment sequences for the defined populations. The 3 tables below, show the sequences presented by the company. For the populations for whom methotrexate or rituximab is contraindicated, the sequences were of equal length and the comparator bDMARDs were:\n\nAbatacept, adalimumab, etanercept, golimumab, infliximab and tocilizumab (each plus methotrexate) when rituximab is contraindicated or not tolerated (table 1).\n\nAdalimumab monotherapy, etanercept monotherapy or tocilizumab monotherapy when rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated (table 2).\n\nLine of therapy\n\nSequence with certolizumab pegol (plus methotrexate)\n\nComparator sequence bDMARD (plus methotrexate)\n\nst\n\nCertolizumab pegol\n\nComparator biological\n\nnd\n\nMethotrexate plus hydroxychloroquine plus sulfasalazine\n\nMethotrexate plus hydroxychloroquine plus sulfasalazine\n\nrd\n\nLeflunomide\n\nLeflunomide\n\nth\n\nGold injection\n\nGold injection\n\nth\n\nCiclosporin\n\nCiclosporin\n\nth\n\nAzathioprine\n\nAzathioprine\n\nth\n\nPalliative care\n\nPalliative care\n\nLine of therapy\n\nSequence with certolizumab pegol (monotherapy)\n\nComparator sequence bDMARD (monotherapy)\n\nst\n\nCertolizumab pegol\n\nComparator biological\n\nnd\n\nLeflunomide\n\nLeflunomide\n\nrd\n\nGold injection\n\nGold injection\n\nth\n\nCiclosporin\n\nCiclosporin\n\nth\n\nAzathioprine\n\nAzathioprine\n\nth\n\nPalliative care\n\nPalliative care\n\nLine of therapy\n\nSequence with certolizumab pegol and bDMARDs (plus methotrexate)\n\nComparator sequence bDMARD (plus methotrexate)\n\nst\n\nCertolizumab pegol\n\nRituximab\n\nnd\n\nRituximab\n\nTocilizumab\n\nrd\n\nTocilizumab\n\nAbatacept\n\nth\n\nAbatacept\n\nMethotrexate plus hydroxychloroquine plus sulfasalazine\n\nth\n\nMethotrexate plus hydroxychloroquine plus sulfasalazine\n\nNon-biological (weighted mix of leflunomide, gold, azathioprine and ciclosporin)\n\nth\n\nNon-biologic (weighted mix of leflunomide, gold, azathioprine and ciclosporin)\n\nPalliative care\n\nth\n\nPalliative care\n\n–\n\nThe committee accepted the sequences for people for whom rituximab or methotrexate were contraindicated or not tolerated. It noted that for people for whom rituximab is a treatment option, the company compared treatment sequences of different lengths. The sequence containing certolizumab pegol placed certolizumab pegol before rituximab and therefore was not a strict comparison with rituximab because certolizumab pegol did not replace it, as with the other populations defined in the scope (see section\xa04.3). The committee considered that the sequences included treatments that would be offered to people whose disease has been classified as severe at the start of a first biological treatment. It recognised that the data provided by the company included people with moderate to severe disease, however the company did not separately compare treatment sequences for a population with moderate disease activity only. The committee therefore agreed it should focus on people with severe disease activity.\n\nThe committee heard evidence from the clinical expert on the use of biosimilar bDMARDs in clinical practice. It heard that infliximab biosimilars are not used in rheumatology and that the etanercept biosimilar has only been launched recently. It also heard that the etanercept biosimilar should be used in preference to its originator because it has lower acquisition costs. The committee concluded that, because the etanercept biosimilar is being used in clinical practice, it was appropriate to consider it in its decision-making.\n\n# Clinical effectiveness\n\nThe committee considered the company's clinical evidence and accepted that the results showed that certolizumab pegol was more clinically effective than placebo. It understood that the only evidence available on the comparative effectiveness of certolizumab pegol and the bDMARDs was from the company's mixed treatment comparisons. The committee heard from the evidence review group (ERG) that there were problems with the methods used for these comparisons. In its response to consultation, the company acknowledged that there was heterogeneity between the studies and it provided a random-effects network meta-analysis to compare with its original fixed-effect network meta-analysis. The results from these analyses are academic in confidence and cannot be included here. The guide to the processes of technology appraisal states that in the interests of public transparency, data marked as confidential should be kept to an absolute minimum. Although it disagrees with the company assertion that including the analysis results would inhibit publication elsewhere, NICE considers it unreasonable to delay the appraisal and access for patients to negotiate further confidentiality lifting with the company, especially as the results were not fundamental to the committee's decision. In addition, while the point estimates from the network meta-analyses were marked as academic-in-confidence, the conclusions were presented publically and showed that the mean effect sizes from the random-effects model were equal to those of the fixed-effects model. The committee concluded that there are uncertainties in the estimates from the methods used and it could not reliably conclude whether certolizumab pegol was more clinically effective than the comparator bDMARDs on the basis of the mixed treatment comparisons presented by the company. The committee reasoned that certolizumab pegol has a similar mechanism of action to other TNF‑alpha inhibitors, therefore it was plausible to assume that it would have comparative efficacy to other bDMARDs. This reasoning was strengthened when the committee heard from the clinical expert that certolizumab pegol is already in use in clinical practice and is not considered to be better or worse than other TNF‑alpha inhibitors. The committee concluded that certolizumab pegol has a similar efficacy to other available bDMARDs\n\n# Cost effectiveness\n\nThe committee considered the cost-effectiveness evidence for the 3\xa0populations defined in the company's submission (see section\xa04.1).\n\n## People for whom rituximab or methotrexate are contraindicated or not tolerated\n\nThe committee was aware of its conclusion on the efficacy of certolizumab pegol and other bDMARDs (see section\xa04.6), It queried the base-case incremental cost-effective ratios (ICERs) in the company's submission for the populations of people for whom either rituximab or methotrexate are contraindicated or not tolerated. It would have expected to see similar quality-adjusted life year (QALY) gains to other bDMARDs, but the incremental QALY gain for certolizumab pegol plus methotrexate and certolizumab pegol as monotherapy, were 0.260 for both populations. The committee noted that the company stated there was a lack of comparative evidence in the population who have had TNF‑alpha inhibitors before and therefore had to place assumptions on comparative effectiveness for the comparator bDMARDs. Therefore, the model assumed that the efficacy of adalimumab, etanercept and infliximab were equivalent to golimumab. The efficacies of adalimumab monotherapy and etanercept monotherapy were modelled using the effect size estimates for golimumab compared with certolizumab pegol (both in combination with methotrexate) from the network meta-analysis. The committee noted that these assumptions were not applied to certolizumab pegol.\n\nThe committee then considered the ERG's scenario analysis in which it assumed that certolizumab pegol had equal efficacy to etanercept, adalimumab and infliximab (all plus methotrexate) for people for whom rituximab is contraindicated or not tolerated. The ERG also assumed that certolizumab pegol monotherapy had equal efficacy to etanercept and adalimumab monotherapies for people for whom methotrexate was contraindicated or not tolerated. The committee was aware that the etanercept biosimilar had been included in this sequence and agreed that this was appropriate. The committee noted for these equal length sequence analyses, that the ICERs for certolizumab pegol with methotrexate and as monotherapy were dominated; that is, certolizumab pegol plus methotrexate was more expensive but just as effective as the comparator bDMARDs. When the committee looked at the incremental increase in total costs between certolizumab pegol and the etanercept biosimilar it noted that there was very little difference so equivalence among the bDMARDs could be accepted. The committee considered the ICERs that incorporated confidential patient access schemes for abatacept and tocilizumab, the results of which cannot be shown here. Even when these schemes were taken into account, the committee noted that there were similarities in effects and costs and so concluded that certolizumab pegol plus methotrexate, or as monotherapy, can be considered a cost-effective use of NHS resources for people for whom rituximab or methotrexate are contraindicated or not tolerated.\n\n## People for whom rituximab plus methotrexate is a treatment option\n\nThe committee had concerns about the company's approach to evaluating the cost effectiveness of certolizumab pegol plus methotrexate for this population. In particular, it was not persuaded that an intervention treatment sequence containing certolizumab pegol and 6 other treatments should be compared with the same sequence without certolizumab pegol (see section\xa04.4). The committee was aware from past technology appraisals that using different sequence lengths can increase modelling uncertainties. It heard from the ERG that the company's model may not be appropriate for comparing sequences of different lengths and this point was highlighted in the ERG's exploratory analysis in which the use of the same model type resulted in some counterintuitive results; the clinical benefit (shown by the QALY gain) appeared to be greater if a person had received rituximab plus methotrexate than if a person had received both certolizumab pegol plus methotrexate and rituximab plus methotrexate. In addition the committee also understood that not all possible treatment sequences for this population had been included in the company's analysis. It noted that, to address this, the ERG had included 2\xa0additional sequences in its exploratory analyses, in which certolizumab pegol plus methotrexate was placed after, and instead of, rituximab plus methotrexate. The committee noted that, after consultation, the company had accepted the relevance of the replacement sequence (that is, instead of rituximab plus methotrexate), but did not consider the sequence of certolizumab pegol after rituximab to be within the scope of the appraisal. The committee agreed with this but commented that placing certolizumab pegol plus methotrexate before rituximab plus methotrexate was also unsatisfactory (see section\xa04.4). It concluded that treatment sequences of the same length are preferable because they are subject to less uncertainty and that its focus should be on the sequence in which certolizumab pegol plus methotrexate replaces rituximab plus methotrexate.\n\nIn the revised base-case analysis submitted by the company after consultation, the committee understood that the company had accepted most of the ERG's preferred assumptions, except treatment duration for biological therapies, and the retreatment interval for rituximab. The committee noted that these were key drivers of cost effectiveness. It concluded that each of these should be examined before considering the ICERs for its preferred treatment sequence.\n\nThe company provided evidence from 2\xa0studies to support an assumption of equal treatment duration for all biological therapies. A study by Ramiro et al. (2015) provided the evidence for a longer treatment duration with TNF‑alpha inhibitors compared with non‑TNF‑alpha inhibitors, whereas a study by Du Pan et al. (2012) provided evidence for a shorter treatment duration with TNF‑alpha inhibitors compared with non‑TNF‑alpha inhibitors. The committee was not persuaded that this opposing evidence should be interpreted as a basis for equal treatment duration. Also, it was not persuaded that these sources of evidence were methodologically stronger than the source preferred by the ERG (the REFLEX extension trial). In the Ramiro et al. (2015) trial, more people received a TNF‑alpha inhibitor than a non‑TNF‑alpha inhibitor. Also, this study was done in the USA where prescription patterns, reimbursement decisions and patients' comorbidities differ from England. The committee had fewer concerns with the Du Pan et al. (2012) study because it had enrolled more comparable numbers of people on TNF‑alpha and non‑TNF‑alpha inhibitors. Although the committee acknowledged the company's concerns that trial conditions may not represent clinical practice, it regarded the evidence for rituximab, the comparator of interest, to be superior to that for a collection of non‑TNF‑alpha inhibitor technologies. The committee concluded that the data from the extension phase of the REFLEX trial provided the most appropriate source of evidence for treatment duration.\n\nThe committee considered the most plausible assumption for the retreatment interval of rituximab in the model. It noted that the summary of product characteristics for rituximab states that the 'need for further courses should be evaluated 24\xa0weeks after the previous course', but did not consider that this was the same as specifying a 6‑month retreatment interval. It also noted that the committee had previously discussed this assumption in NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis, and concluded that treatment was unlikely to be as frequent as every 6\xa0months for every person receiving rituximab. It therefore preferred the ERG's value of 10.09\xa0months, which was sourced from the REFLEX trial. The committee considered that it was appropriate to use available trial evidence for rituximab to inform this assumption, and concluded that it was appropriate to use a retreatment interval for rituximab of 10.09\xa0months.\n\nIn line with its conclusion about treatment sequences (see section\xa04.4), the committee considered the ICERs when certolizumab pegol plus methotrexate was placed in a sequence instead of rituximab plus methotrexate. The company's base-case estimate for this comparison was in excess of £130,000 per QALY gained. However, the committee recognised that its preferred assumptions for the treatment duration for bDMARDs and the rituximab retreatment interval were not incorporated in this estimate. When these preferred assumptions were included, certolizumab pegol plus methotrexate was dominated by rituximab plus methotrexate. This analysis did not take into account the confidential patient access scheme discount for tocilizumab, a treatment included in the treatment sequence after rituximab. When the confidential discount for tocilizumab was included, certolizumab pegol plus methotrexate was still dominated. In summary, the committee concluded that certolizumab pegol plus methotrexate could not be considered a cost-effective use of NHS resources when rituximab plus methotrexate is a treatment option. For completeness, the committee looked at the elongated sequence, in which certolizumab pegol plus methotrexate was placed before rituximab plus methotrexate, which the committee had rejected earlier (see section\xa04.4 and section\xa04.10). The committee concluded that, with its preferred assumptions this sequence was still dominated and therefore was not a cost-effective use of NHS resources.\n\n# Equality issues\n\nThe committee heard from the British Society of Rheumatology that certolizumab pegol may be used in pregnancy and that this was a potential equality issue. The committee was aware that the use of certolizumab pegol in pregnancy was outside the marketing authorisation. Because the committee makes recommendations within a technology's marketing authorisation, it could not consider including certolizumab pegol for use in pregnancy in its final recommendations. The committee concluded that it did not need to change its recommendations.\n\n# Innovation\n\nThe company stated that not all the benefits of certolizumab pegol are captured by the QALY calculation, such as the effect the drug has on workplace and household productivity. However the committee considered that it had not been presented with any evidence to show an additional benefit over and above that already captured in the QALY. It concluded that all relevant benefits and costs were adequately captured by the QALY calculation.\n\n# Pharmaceutical price regulations scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\nTA415\n\nAppraisal title: Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF Inhibitor\n\nSection\n\nKey conclusion\n\nThe committee considered that the incremental cost-effectiveness ratios (ICERs) showed that certolizumab pegol, in combination with methotrexate, is a cost-effective option for treating active rheumatoid arthritis in adults who have had an inadequate response to, or who cannot tolerate, other disease-modifying antirheumatic drugs (DMARDs), including at least 1\xa0tumour necrosis factor‑alpha (TNF‑alpha) inhibitor, only if: disease activity is severe and the person cannot have rituximab therapy because rituximab is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme.\n\nThe committee considered the ICERs showed that certolizumab pegol, as monotherapy, is a cost-effective option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1\xa0TNF‑alpha inhibitor, only if: disease activity is severe and rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme.\n\nThe committee concluded that the ICERs showed that certolizumab, in combination with methotrexate, was not a cost-effective option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1\xa0TNF‑alpha inhibitor when disease activity is severe and when rituximab therapy can be considered a treatment option.\n\n, 1.2\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the clinical and patient expert that response to treatment is difficult to predict because patients' responses differ to biological DMARDs. The clinical expert expressed that a range of additional options of bDMARDs is valued at the positions in the pathway within existing NICE guidance. It is especially useful to have a range of bDMARDs when rituximab plus methotrexate cannot be considered due to adverse events related with rituximab.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee did not consider any claims about innovation that suggested there are additional innovative benefits that have not already been captured in the estimate of the quality-adjusted life year (QALY).\n\n–\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nPeople whose disease has responded inadequately to treatment with a TNF‑alpha inhibitor. This is at the same point as the existing NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF-alpha inhibitor, golimumab for rheumatoid arthritis, and tocilizumab for rheumatoid arthritis.\n\n\n\nAdverse reactions\n\nNo specific committee considerations.\n\n–\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee understood that the trials only showed a comparison of certolizumab pegol with placebo and accepted it was clinically effective over placebo. The committee understood that there were no trials comparing certolizumab pegol with comparator bDMARDs and that only mixed treatment comparisons were available.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThere were no direct head-to-head trials with treatments currently used in the NHS.\n\n–\n\nUncertainties generated by the evidence\n\nThe committee was aware of uncertainties in the estimates from the meta-analyses methods used and it could not reliably conclude whether certolizumab pegol was more clinically effective than the comparator bDMARDs on the basis of the mixed treatment comparisons presented by the company.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo specific committee considerations.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee noted that the effect size estimates from the company's mixed treatment comparison, comparing certolizumab pegol with comparator bDMARDs, were uncertain and concluded from the clinical expert's view that there was similar efficacy among the bDMARDs.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented analyses of 3\xa0distinct populations and a series of treatment sequences for people who have received a prior TNF‑alpha inhibitor. For people for whom rituximab is a treatment option, the committee agreed with the company that placing certolizumab pegol plus methotrexate after rituximab plus methotrexate was not a relevant comparator but noted that this was also true when placing certolizumab pegol plus methotrexate before rituximab plus methotrexate.\n\n, 4.4, 4.10\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee noted that the evidence review group's (ERG's) scenario analysis applied an assumption of equal efficacy among some of the bDMARDs. This resulted in the ICERs being dominated (that is, certolizumab pegol was more expensive but just as effective as the comparator bDMARDs), for the population for whom rituximab plus methotrexate is contraindicated or not tolerated and for whom methotrexate is contraindicated or not tolerated. The committee noted the similarities in costs and its conclusions on comparative efficacy, so that equivalence among bDMARDs could be accepted.\n\nThe committee heard that the company compared a longer intervention sequence that included another 6\xa0treatments, with a comparator sequence without the intervention. It was aware that differential sequence lengths can exacerbate modelling uncertainties and, as such, skews the results in favour of the intervention. After consultation, the committee expressed uncertainties about the assumptions used in the company's model and preferred the ERG's values for the retreatment interval for rituximab and treatment durations (for TNF‑alpha inhibitors and non‑TNF‑alpha inhibitors) from the REFLEX study and the extension to this study.\n\n, 4.9, 4.10, 4.12, 4.13\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo other health-related benefits have been identified that have not been captured in the QALY calculation.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific committee consideration.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nFor people for whom rituximab is a treatment option, the committee looked at the elongated sequences used by the company in the analysis when certolizumab pegol plus methotrexate was placed before rituximab plus methotrexate. After consultation, the committee acknowledged that key drivers when certolizumab pegol plus methotrexate was used instead of rituximab plus methotrexate, were the retreatment interval for rituximab and the treatment durations for non‑TNF‑alpha inhibitors and TNF‑alpha inhibitors. It concluded that a retreatment interval of 10.09\xa0months, from the REFLEX study, was more plausible than that of 6.00\xa0months used by the company. It also concluded that the original retreatment durations from NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor were more plausible than an equal duration used by the company.\n\nThe committee noted the comparative efficacy assumptions placed on bDMARDs in the analysis for people for whom methotrexate is contraindicated or not tolerated. In the ERG's scenario analysis, this resulted in ICERs that were dominated for certolizumab pegol.\n\n, 4.12, 4.13, 4.8, 4.9\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded from the ERG scenario analyses that there was little difference in costs between comparator bDMARDs and certolizumab pegol so that equivalence among bDMARDs can be accepted for people for whom rituximab is contraindicated or not tolerated, and for people for whom methotrexate is contraindicated or not tolerated.\n\nThe committee concluded that the most likely ICER for people for whom rituximab plus methotrexate is a treatment option was above the normal range that would be considered a cost-effective use of NHS resources. The intervention was still dominated when the confidential patient access scheme for tocilizumab was taken into account.\n\n, 4.9, 4.14\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nPatient access schemes were taken into account for certolizumab pegol, golimumab, tocilizumab and abatacept.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee heard that certolizumab pegol may be beneficial in treating rheumatoid arthritis in pregnant women but acknowledged this use was outside the marketing authorisation. Because the committee makes recommendations within the marketing authorisation, it could not consider certolizumab pegol for use in pregnancy in its final recommendations. The committee concluded that it did not need to change its recommendations.\n\n"}	https://www.nice.org.uk/guidance/ta415	Evidence-based recommendations on certolizumab pegol (Cimzia) for treating severe active rheumatoid arthritis in adults who have had a tumour necrosis factor-alpha inhibitor.
70fb07c34842e2f2de11bec16975fb8dd84a9bf8	nice	Single-incision short sling mesh insertion for stress urinary incontinence in women	Single-incision short sling mesh insertion for stress urinary incontinence in women Evidence-based recommendations on single-incision short sling mesh insertion for stress urinary incontinence in women. This involves putting 2 short slings around the tube that carries urine from the bladder to support it. # Recommendations The evidence on the safety of single-incision short sling mesh insertion for stress urinary incontinence in women shows infrequent but serious complications. These include lasting pain, discomfort and failure of the procedure. The mesh implant is intended to be permanent but, if removal is needed because of complications, the anchoring system can make the device very difficult or impossible to remove. The evidence on efficacy in the long term is inadequate in quality and quantity. Therefore, this procedure should not be used unless there are special arrangements in place for clinical governance, consent, and audit or research. Clinicians wishing to do single-incision short sling mesh insertion for stress urinary incontinence in women should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy, including that there is the potential for the procedure to fail and for serious long-term complications from the device, and that the mesh implant is intended to be permanent so removal, if needed, may be difficult or impossible. Provide patients with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having single-incision short sling mesh insertion for stress urinary incontinence in women (see section 7.1). Patient selection should be done by a multidisciplinary team with experience in the assessment and management of women with stress urinary incontinence. This procedure should only be done by clinicians with specific training in transobturator surgical techniques. Removal of a short sling mesh should only be done by people with expertise in this specialised surgery. NICE encourages further research into single-incision short sling mesh insertion for stress urinary incontinence in women and may update the guidance on publication of further evidence. Studies should include details of patient selection, and should measure long-term outcomes including effects on quality of life and other patient-reported outcomes.# Indications and current treatments Stress urinary incontinence is the involuntary leakage of urine during exercise or certain movements such as coughing, sneezing and laughing. In women, it is most commonly associated with previous pregnancy, with or without recognised obstetric trauma. Previous urogynaecological surgery may also result in stress urinary incontinence. Conventional treatment is conservative, and includes lifestyle changes such as weight loss and pelvic floor muscle training. Surgery is considered if these conservative measures do not help. Different types of surgery may be used, including intramural bulking procedures, insertion of a synthetic tension-free vaginal tape, insertion of a transobturator tape or other sling procedures, colposuspension or insertion of an artificial urinary sphincter.# The procedure Single-incision short sling mesh insertion aims to reduce the risk of urinary leakage in women with stress urinary incontinence. It is considered when conservative options (see section 2.2) have been tried but incontinence persists. The procedure aims to minimise the risk of major adverse events such as bladder, vaginal, urethral and vascular perforations or erosions, and chronic pain that are associated with minimally-invasive sling procedures. The single-incision short slings have shorter tape lengths and different fixation systems to transobturator minimally-invasive slings. These fixation systems do not enter the retropubic space (minimising the risk of major vessel or visceral injury) or the lateral half of the obturator foramen (potentially reducing the risk of groin pain), but they are anchored in the obturator membrane or in the obturator muscles. With the patient under local (with or without sedation), regional or general anaesthesia, a small incision is made in the vaginal wall, under the urethra. The sling, which is typically 8–14 cm long, is inserted using a delivery needle through the obturator foramen and retracted to deploy the sling into the obturator internus muscle. This is repeated with a second sling on the contralateral side. A special tip anchors the sling in place behind the mid urethra. Sling tension is then controlled using the delivery device until the appropriate tension is achieved. The delivery device is then removed and the incision is closed. The slings are permanent implants. Cystoscopy is used to check that bladder perforation has not occurred during the procedure. Single-incision short sling systems may differ in the length of the sling, the fixation method, the fixation location and the method of tension adjustment or control.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a systematic review and meta-analysis of 3,308 women from 26 randomised controlled trials (RCTs) comparing single-incision mini sling (SIMS, n=1,735) procedures with standard midurethral sling (SMUS, n=1,573) procedures in women with stress urinary incontinence, there was no statistically significant difference in objective cure rates at a mean follow-up of 18.6 months between SIMS (tension-free vaginal tape 'Secur' trials excluded) and SMUS (risk ratio 0.98; 95% confidence interval 0.94 to 1.01, n=11, I2=7%). There were similar results when SIMS was compared with transobturator tension-free vaginal tape (TOT, RR 0.98; 95% CI 0.94 to 1.01, n=10, I2=11%) and with retropubic tension-free vaginal tape (r‑TVT, RR 0.81; 95% CI 0.48 to 1.40, n=1). In the systematic review and meta-analysis of 3,308 women, there was no statistically significant difference in patient-reported cure rates at a mean follow-up of 18.6 months between SIMS ('TVT Secur' trials excluded) and SMUS (RR 0.94; 95% CI 0.88 to 1.00, n=11, I2=57%). There were similar results when SIMS was compared with TOT (RR 0.96; 95% CI 0.92 to 1.00, n=9, I2=20%) and with r‑TVT (RR 0.71; 95% CI 0.42 to 1.20, n=2, I2=75%). In a Cochrane systematic review and meta-analysis of 3,290 women with stress urinary incontinence from 31 randomised or quasi-randomised trials, women were more likely to remain incontinent after surgery with SIMS (41% ) than with r‑TVT (26% ; RR 2.08, 95% CI 1.04 to 4.14). Four out of 5 studies in the comparison included 'TVT Secur', which has been withdrawn from use as a single-incision sling. In the same study, incontinence rates were also higher with SIMS than with inside-out TOT (30% versus 11%; RR 2.55, 95% CI 1.93 to 3.36). However, if the trials in which 'TVT Secur' was not used were excluded, it showed that a high risk of incontinence was mainly associated with use of this device (RR 2.65, 95% CI 1.98 to 3.54). The evidence was insufficient to show a difference in incontinence rates with other SIMS ('TVT Secur' trials excluded) compared with inside-out or outside-in TOT. In an RCT of 80 women (40 SIMS versus 40 TOT), there were no statistically significant differences between groups for the cough stress pad test (CSPT) values before and after the procedure. However, there were statistically significant differences within groups in CSPT values before and after the procedure (mean±standard deviation, grams: 71±18 versus 0.66±0.8 in the SIMS group, p=0.0001, and 73±27 versus 0.41±0.4 in the TOT group, p=0.0002). In a prospective case series of 120 women treated by SIMS, the mean daily pad use decreased statistically significantly from 2.4 before the procedure to 0.1 at 1 month and 0.2 at 12 months (p<0.01 versus baseline). In a prospective comparative study of 240 women treated by SIMS (n=120) or r‑TVT (n=120), detrusor instability scores did not change statistically significantly in the SIMS group from baseline (2.1±1.3 versus 2.2±1.3 at 24 months after the procedure). In the r‑TVT group, the scores statistically significantly worsened from baseline (2.4±1.5 versus 2.9±1.9 at 24 months, p<0.05). In the prospective case series of 120 women, the mean urogenital distress inventory scores (a 6‑item questionnaire) decreased statistically significantly from 65% before the procedure to 3% at 1 month and 13% at 12 months (p<0.01 versus baseline). In the prospective case series of 120 women, the mean Incontinence impact scores (a 7‑item short-form questionnaire) decreased statistically significantly from 87% before the procedure to 3% at 1 month and 13% at 12 months (p<0.01 versus baseline). In an RCT of 225 women treated by SIMS (n=112) or TOT (n=113), the proportion of women using antimuscarinics 12 months after the procedure was statistically significantly lower in the SIMS group than in the TOT group (6% versus 16% , p=0.034). In the systematic review and meta-analysis of 3,308 women, women with SIMS ('TVT Secur' trials excluded) returned to normal activities statistically significantly earlier (weighted means difference 5.08 days; 95% CI −9.59 to −0.56, n=2, I2=63%) and to work statistically significantly earlier (WMD −7.20 days; 95% CI −12.43 to −1.98, n=2, I2=38%). In the systematic review and meta-analysis of 3,308 women, there was no statistically significant difference in quality-of-life scores (measured with the Incontinence Impact Questionnaire–Short Form IIQ7 and King's Health Questionnaire 7) between SIMS ('TVT Secur' trials excluded) and SMUS (WMD 1.23; 95% CI −2.76 to 5.21, n=3, I2=56%). All 3 RCTs included in the analysis reported improvement in quality-of-life scores at follow-up compared with baseline, with no statistically significant differences between SIMS and SMUS. In the prospective comparative study of 240 women treated by SIMS (n=120) or r‑TVT (n=120), patient satisfaction (assessed using a visual analogue scale ) was 7.5±2.6 in the SIMS group compared with 7.4±1.7 in the r‑TVT group (level of significance not stated). In the systematic review and meta-analysis of 3,308 women, there was no statistically significant difference in Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ12) scores between SIMS ('TVT Secur' trials excluded) and SMUS at a mean 18‑month follow-up (WMD 0.39; 95% CI −0.89 to 1.67, n=2, I2=17%). The specialist advisers listed the following key efficacy outcomes: objective and subjective cure of stress urinary incontinence, reduction in stress urinary leakage and reduction in stress incontinence episodes for more than 1 year. Twenty two commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Pain after the procedure was statistically significantly lower in the single-incision mini sling (SIMS) group (tension-free vaginal tape 'Secur' trials excluded) than in the standard midurethral sling (SMUS) group (weighted means difference −3.13; 95% confidence interval −4.89 to −1.36, n=4, I2=93%, p<0.0005), and groin pain was also statistically significantly lower (risk ratio 0.30; 95% CI 0.18 to 0.49, n=10, I2=19%, p<0.00001) in a systematic review and meta-analysis of 3,308 women from 26 randomised controlled trials (RCTs) comparing SIMS procedures (n=1,735) with SMUS (n=1,573) procedures in women with stress urinary incontinence. Haemorrhage during the procedure was reported in 2% (2/120) of women in the SIMS group (including treatment with 'TVT Secur' slings) and in 1% (1/120) of women in the retropubic TVT (r‑TVT) group in a prospective comparative study of 240 women. In the same study, haemoglobin drop within 30 days of the procedure was reported in 1% (1/120) of women in the SIMS group and in none of the women in the r‑TVT group (p value not significant). Pelvic haematoma was reported in 1 woman in a prospective case series of 116 women treated by SIMS; it developed after revision surgery needed because of urinary outlet obstruction. Vaginal tape erosion rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR 1.43; 95% CI 0.61 to 3.35, n=11, I2=0%, p=0.41). Vaginal mesh exposure rate was statistically significantly greater in the SIMS group ('TVT Secur' trials included) than in the transobturator sling (TOT) group in a Cochrane systematic review and meta-analysis of 3,290 women with stress urinary incontinence from 31 randomised or quasi-randomised trials (RR 2.59, 95% CI 1.21 to 5.56, n=9, I2=4%, p=0.015). In the same systematic review, bladder or urethral erosion rate was statistically significantly greater in the SIMS group ('TVT Secur' trials included) than in the TOT group (RR 17.79, 95% CI 1.06 to 298.88, n=2, I2=0%, p=0.046). Mesh extrusion was reported in 4% (4/113) of women in the prospective case series of 116 women with stress urinary incontinence treated with SIMS, within 12 months of the procedure. Three of the 4 mesh extrusions were treated by revision surgery that included trimming and excision; 1 mesh extrusion was asymptomatic and successfully treated with oestrogen cream. Erosion-free rates 5 years after the procedures were not statistically significantly different between the single-incision sling group and the transobturator vaginal tape group in a comparative study of 381 women (99% versus 96%, p=0.15). Urethrovaginal fistula was reported in 1 women treated by SIMS in a single case report. The same patient had also bladder mesh erosion and vaginal mesh exposure. She was treated by excision of midurethral mesh, urethroplasty, Martius flap tissue transfer and cystourethroscopy but continued to have mild stress urinary incontinence. De novo urgency or worsening of pre-existing surgery rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR 1.09; 95% CI 0.78 to 1.54, n=12, I2=0%, p=0.61). Rates of de novo overactive bladder symptoms 5 years after the procedure were statistically significantly higher in the single-incision sling group compared with the transobturator vaginal tape group in the comparative study of 381 women (9% versus 3%, p=0.012). Repeat continence surgery rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR 2.00; 95% CI 0.93 to 4.31, n=10, I2=0%, p=0.08). Lower urinary tract injury rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR 0.99; 95% CI 0.38 to 2.56, n=13, I2=0%, p=0.99). Bladder perforation was reported in 3% (3/120) of women in a prospective case series of 120 women. The patients were treated with a Foley catheter overnight, which was removed 1 day after the procedure. Vaginal wall perforation was reported in 1% of women in the SIMS group, in 3% of women in the TVT group and in 4% of women in the TOT group in a retrospective comparative study of 531 women (relative number of women not reported). Voiding difficulties after the procedure rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR 0.58; 95% CI 0.26 to 1.31, n=11, I2=31%, p=0.19). Urinary tract infection within 30 days of the procedure was reported in 3% (3/120) of women in the SIMS group and in 4% (5/120) of women in the r‑TVT group in the prospective comparative study of 240 women (p value not statistically significant). A bladder stone was reported in 1 woman 3 years after the procedure in a second case report. It was treated by excision of mesh transvaginally, separation of the stone from the eroded mucosal mesh and subsequent transurethral stone removal. The patient continued to have persistent stress urinary incontinence that had worsened after SIMS removal. She was subsequently treated with periurethral bulking and her symptoms of stress urinary incontinence improved. Dyspareunia was reported in 1 woman in the prospective case series of 116 women, within 12 months of the procedure. Delayed wound healing was reported in 1 woman in the prospective case series of 116 women, within 12 months of the procedure. Anchor displacement was reported in 1 woman at the 1‑year follow-up visit in the RCT of 80 women (40 SIMS versus 40 TOT). The anchor was removed with the patient under local anaesthesia and the patient remained continent. In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any new anecdotal adverse event. They considered that the following were theoretical adverse events: reaction to tape and poor anchoring of tape leading to failure in the short or long term.# Further information This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2116-4	{'Recommendations': "The evidence on the safety of single-incision short sling mesh insertion for stress urinary incontinence in women shows infrequent but serious complications. These include lasting pain, discomfort and failure of the procedure. The mesh implant is intended to be permanent but, if removal is needed because of complications, the anchoring system can make the device very difficult or impossible to remove. The evidence on efficacy in the long term is inadequate in quality and quantity. Therefore, this procedure should not be used unless there are special arrangements in place for clinical governance, consent, and audit or research.\n\nClinicians wishing to do single-incision short sling mesh insertion for stress urinary incontinence in women should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy, including that there is the potential for the procedure to fail and for serious long-term complications from the device, and that the mesh implant is intended to be permanent so removal, if needed, may be difficult or impossible. Provide patients with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having single-incision short sling mesh insertion for stress urinary incontinence in women (see section\xa07.1).\n\nPatient selection should be done by a multidisciplinary team with experience in the assessment and management of women with stress urinary incontinence.\n\nThis procedure should only be done by clinicians with specific training in transobturator surgical techniques. Removal of a short sling mesh should only be done by people with expertise in this specialised surgery.\n\nNICE encourages further research into single-incision short sling mesh insertion for stress urinary incontinence in women and may update the guidance on publication of further evidence. Studies should include details of patient selection, and should measure long-term outcomes including effects on quality of life and other patient-reported outcomes.", 'Indications and current treatments': 'Stress urinary incontinence is the involuntary leakage of urine during exercise or certain movements such as coughing, sneezing and laughing. In women, it is most commonly associated with previous pregnancy, with or without recognised obstetric trauma. Previous urogynaecological surgery may also result in stress urinary incontinence.\n\nConventional treatment is conservative, and includes lifestyle changes such as weight loss and pelvic floor muscle training. Surgery is considered if these conservative measures do not help. Different types of surgery may be used, including intramural bulking procedures, insertion of a synthetic tension-free vaginal tape, insertion of a transobturator tape or other sling procedures, colposuspension or insertion of an artificial urinary sphincter.', 'The procedure': 'Single-incision short sling mesh insertion aims to reduce the risk of urinary leakage in women with stress urinary incontinence. It is considered when conservative options (see section\xa02.2) have been tried but incontinence persists. The procedure aims to minimise the risk of major adverse events such as bladder, vaginal, urethral and vascular perforations or erosions, and chronic pain that are associated with minimally-invasive sling procedures. The single-incision short slings have shorter tape lengths and different fixation systems to transobturator minimally-invasive slings. These fixation systems do not enter the retropubic space (minimising the risk of major vessel or visceral injury) or the lateral half of the obturator foramen (potentially reducing the risk of groin pain), but they are anchored in the obturator membrane or in the obturator muscles.\n\nWith the patient under local (with or without sedation), regional or general anaesthesia, a small incision is made in the vaginal wall, under the urethra. The sling, which is typically 8–14\xa0cm long, is inserted using a delivery needle through the obturator foramen and retracted to deploy the sling into the obturator internus muscle. This is repeated with a second sling on the contralateral side. A special tip anchors the sling in place behind the mid urethra. Sling tension is then controlled using the delivery device until the appropriate tension is achieved. The delivery device is then removed and the incision is closed. The slings are permanent implants. Cystoscopy is used to check that bladder perforation has not occurred during the procedure.\n\nSingle-incision short sling systems may differ in the length of the sling, the fixation method, the fixation location and the method of tension adjustment or control.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review and meta-analysis of 3,308\xa0women from 26\xa0randomised controlled trials (RCTs) comparing single-incision mini sling (SIMS, n=1,735) procedures with standard midurethral sling (SMUS, n=1,573) procedures in women with stress urinary incontinence, there was no statistically significant difference in objective cure rates at a mean follow-up of 18.6\xa0months between SIMS (tension-free vaginal tape [TVT] 'Secur' trials excluded) and SMUS (risk ratio [RR]\xa00.98; 95% confidence interval\xa0[CI] 0.94 to 1.01, n=11, I2=7%). There were similar results when SIMS was compared with transobturator tension-free vaginal tape (TOT, RR\xa00.98; 95%\xa0CI 0.94 to 1.01, n=10, I2=11%) and with retropubic tension-free vaginal tape (r‑TVT, RR\xa00.81; 95%\xa0CI 0.48 to 1.40, n=1).\n\nIn the systematic review and meta-analysis of 3,308\xa0women, there was no statistically significant difference in patient-reported cure rates at a mean follow-up of 18.6\xa0months between SIMS ('TVT\xa0Secur' trials excluded) and SMUS (RR\xa00.94; 95%\xa0CI 0.88 to 1.00, n=11, I2=57%). There were similar results when SIMS was compared with TOT (RR\xa00.96; 95%\xa0CI 0.92 to 1.00, n=9, I2=20%) and with r‑TVT (RR\xa00.71; 95%\xa0CI 0.42 to 1.20, n=2, I2=75%).\n\nIn a Cochrane systematic review and meta-analysis of 3,290\xa0women with stress urinary incontinence from 31\xa0randomised or quasi-randomised trials, women were more likely to remain incontinent after surgery with SIMS (41% [121/292]) than with r‑TVT (26% [72/281]; RR\xa02.08, 95%\xa0CI 1.04 to 4.14). Four out of 5\xa0studies in the comparison included 'TVT Secur', which has been withdrawn from use as a single-incision sling. In the same study, incontinence rates were also higher with SIMS than with inside-out TOT (30% versus 11%; RR\xa02.55, 95%\xa0CI 1.93 to 3.36). However, if the trials in which 'TVT Secur' was not used were excluded, it showed that a high risk of incontinence was mainly associated with use of this device (RR\xa02.65, 95%\xa0CI 1.98 to 3.54). The evidence was insufficient to show a difference in incontinence rates with other SIMS ('TVT Secur' trials excluded) compared with inside-out or outside-in TOT.\n\nIn an RCT of 80\xa0women (40\xa0SIMS versus 40\xa0TOT), there were no statistically significant differences between groups for the cough stress pad test (CSPT) values before and after the procedure. However, there were statistically significant differences within groups in CSPT values before and after the procedure (mean±standard deviation, grams: 71±18 versus 0.66±0.8 in the SIMS group, p=0.0001, and 73±27 versus 0.41±0.4 in the TOT group, p=0.0002).\n\nIn a prospective case series of 120\xa0women treated by SIMS, the mean daily pad use decreased statistically significantly from 2.4 before the procedure to 0.1 at 1\xa0month and 0.2 at 12\xa0months (p<0.01 versus baseline).\n\nIn a prospective comparative study of 240\xa0women treated by SIMS (n=120) or r‑TVT (n=120), detrusor instability scores did not change statistically significantly in the SIMS group from baseline (2.1±1.3 versus 2.2±1.3 at 24\xa0months after the procedure). In the r‑TVT group, the scores statistically significantly worsened from baseline (2.4±1.5 versus 2.9±1.9 at 24\xa0months, p<0.05).\n\nIn the prospective case series of 120\xa0women, the mean urogenital distress inventory scores (a 6‑item questionnaire) decreased statistically significantly from 65% before the procedure to 3% at 1\xa0month and 13% at 12\xa0months (p<0.01 versus baseline).\n\nIn the prospective case series of 120\xa0women, the mean Incontinence impact scores (a 7‑item short-form questionnaire) decreased statistically significantly from 87% before the procedure to 3% at 1\xa0month and 13% at 12\xa0months (p<0.01 versus baseline).\n\nIn an RCT of 225\xa0women treated by SIMS (n=112) or TOT (n=113), the proportion of women using antimuscarinics 12\xa0months after the procedure was statistically significantly lower in the SIMS group than in the TOT group (6% [5/87] versus 16% [15/95], p=0.034).\n\nIn the systematic review and meta-analysis of 3,308\xa0women, women with SIMS ('TVT Secur' trials excluded) returned to normal activities statistically significantly earlier (weighted means difference [WMD]\xa05.08\xa0days; 95%\xa0CI −9.59 to −0.56, n=2, I2=63%) and to work statistically significantly earlier (WMD\xa0−7.20\xa0days; 95%\xa0CI −12.43 to −1.98, n=2, I2=38%).\n\nIn the systematic review and meta-analysis of 3,308\xa0women, there was no statistically significant difference in quality-of-life scores (measured with the Incontinence Impact Questionnaire–Short Form IIQ7 and King's Health Questionnaire\xa07) between SIMS ('TVT\xa0Secur' trials excluded) and SMUS (WMD\xa01.23; 95%\xa0CI −2.76 to 5.21, n=3, I2=56%). All 3\xa0RCTs included in the analysis reported improvement in quality-of-life scores at follow-up compared with baseline, with no statistically significant differences between SIMS and SMUS.\n\nIn the prospective comparative study of 240\xa0women treated by SIMS (n=120) or r‑TVT (n=120), patient satisfaction (assessed using a visual analogue scale [0\xa0to 10, from low to high satisfaction]) was 7.5±2.6 in the SIMS group compared with 7.4±1.7 in the r‑TVT group (level of significance not stated).\n\nIn the systematic review and meta-analysis of 3,308\xa0women, there was no statistically significant difference in Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ12) scores between SIMS ('TVT Secur' trials excluded) and SMUS at a mean 18‑month follow-up (WMD\xa00.39; 95%\xa0CI −0.89 to 1.67, n=2, I2=17%).\n\nThe specialist advisers listed the following key efficacy outcomes: objective and subjective cure of stress urinary incontinence, reduction in stress urinary leakage and reduction in stress incontinence episodes for more than 1\xa0year.\n\nTwenty two commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nPain after the procedure was statistically significantly lower in the single-incision mini sling (SIMS) group (tension-free vaginal tape [TVT] 'Secur' trials excluded) than in the standard midurethral sling (SMUS) group (weighted means difference [WMD] −3.13; 95% confidence interval [CI] −4.89 to −1.36, n=4, I2=93%, p<0.0005), and groin pain was also statistically significantly lower (risk ratio [RR] 0.30; 95%\xa0CI 0.18 to 0.49, n=10, I2=19%, p<0.00001) in a systematic review and meta-analysis of 3,308 women from 26\xa0randomised controlled trials (RCTs) comparing SIMS procedures (n=1,735) with SMUS (n=1,573) procedures in women with stress urinary incontinence.\n\nHaemorrhage during the procedure was reported in 2% (2/120) of women in the SIMS group (including treatment with 'TVT Secur' slings) and in 1% (1/120) of women in the retropubic TVT (r‑TVT) group in a prospective comparative study of 240\xa0women. In the same study, haemoglobin drop within 30\xa0days of the procedure was reported in 1% (1/120) of women in the SIMS group and in none of the women in the r‑TVT group (p value not significant). Pelvic haematoma was reported in 1\xa0woman in a prospective case series of 116\xa0women treated by SIMS; it developed after revision surgery needed because of urinary outlet obstruction.\n\nVaginal tape erosion rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR\xa01.43; 95%\xa0CI 0.61 to 3.35, n=11, I2=0%, p=0.41). Vaginal mesh exposure rate was statistically significantly greater in the SIMS group ('TVT Secur' trials included) than in the transobturator sling (TOT) group in a Cochrane systematic review and meta-analysis of 3,290 women with stress urinary incontinence from 31\xa0randomised or quasi-randomised trials (RR\xa02.59, 95%\xa0CI 1.21 to 5.56, n=9, I2=4%, p=0.015). In the same systematic review, bladder or urethral erosion rate was statistically significantly greater in the SIMS group ('TVT Secur' trials included) than in the TOT group (RR\xa017.79, 95%\xa0CI 1.06 to 298.88, n=2, I2=0%, p=0.046). Mesh extrusion was reported in 4% (4/113) of women in the prospective case series of 116\xa0women with stress urinary incontinence treated with SIMS, within 12\xa0months of the procedure. Three of the 4\xa0mesh extrusions were treated by revision surgery that included trimming and excision; 1\xa0mesh extrusion was asymptomatic and successfully treated with oestrogen cream. Erosion-free rates 5\xa0years after the procedures were not statistically significantly different between the single-incision sling group and the transobturator vaginal tape group in a comparative study of 381\xa0women (99% versus 96%, p=0.15).\n\nUrethrovaginal fistula was reported in 1\xa0women treated by SIMS in a single case report. The same patient had also bladder mesh erosion and vaginal mesh exposure. She was treated by excision of midurethral mesh, urethroplasty, Martius flap tissue transfer and cystourethroscopy but continued to have mild stress urinary incontinence.\n\nDe novo urgency or worsening of pre-existing surgery rates were not statistically significantly different between the SIMS group ('TVT\xa0Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR\xa01.09; 95%\xa0CI 0.78 to 1.54, n=12, I2=0%, p=0.61). Rates of de novo overactive bladder symptoms 5\xa0years after the procedure were statistically significantly higher in the single-incision sling group compared with the transobturator vaginal tape group in the comparative study of 381\xa0women (9% versus 3%, p=0.012).\n\nRepeat continence surgery rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR\xa02.00; 95%\xa0CI 0.93 to 4.31, n=10, I2=0%, p=0.08).\n\nLower urinary tract injury rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR\xa00.99; 95%\xa0CI 0.38 to 2.56, n=13, I2=0%, p=0.99). Bladder perforation was reported in 3% (3/120) of women in a prospective case series of 120\xa0women. The patients were treated with a Foley catheter overnight, which was removed 1\xa0day after the procedure.\n\nVaginal wall perforation was reported in 1% of women in the SIMS group, in 3% of women in the TVT group and in 4% of women in the TOT group in a retrospective comparative study of 531\xa0women (relative number of women not reported).\n\nVoiding difficulties after the procedure rates were not statistically significantly different between the SIMS group ('TVT Secur' trials excluded) and the SMUS group in the systematic review and meta-analysis of 3,308 women (RR\xa00.58; 95%\xa0CI 0.26 to 1.31, n=11, I2=31%, p=0.19).\n\nUrinary tract infection within 30\xa0days of the procedure was reported in 3% (3/120) of women in the SIMS group and in 4% (5/120) of women in the r‑TVT group in the prospective comparative study of 240\xa0women (p value not statistically significant).\n\nA bladder stone was reported in 1\xa0woman 3\xa0years after the procedure in a second case report. It was treated by excision of mesh transvaginally, separation of the stone from the eroded mucosal mesh and subsequent transurethral stone removal. The patient continued to have persistent stress urinary incontinence that had worsened after SIMS removal. She was subsequently treated with periurethral bulking and her symptoms of stress urinary incontinence improved.\n\nDyspareunia was reported in 1\xa0woman in the prospective case series of 116\xa0women, within 12\xa0months of the procedure.\n\nDelayed wound healing was reported in 1\xa0woman in the prospective case series of 116\xa0women, within 12\xa0months of the procedure.\n\nAnchor displacement was reported in 1\xa0woman at the 1‑year follow-up visit in the RCT of 80\xa0women (40\xa0SIMS versus 40\xa0TOT). The anchor was removed with the patient under local anaesthesia and the patient remained continent.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any new anecdotal adverse event. They considered that the following were theoretical adverse events: reaction to tape and poor anchoring of tape leading to failure in the short or long term.", 'Further information': 'This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2116-4'}	https://www.nice.org.uk/guidance/ipg566	Evidence-based recommendations on single-incision short sling mesh insertion for stress urinary incontinence in women. This involves putting 2 short slings around the tube that carries urine from the bladder to support it.
ca1379ed24c945d5e8a12ac6957f0fdd3b3f03f0	nice	Crizotinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer	Crizotinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer Evidence-based recommendations on crizotinib (Xalkori) for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. # Recommendations Crizotinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.# The technology Description of the technology Crizotinib (Xalkori, Pfizer) is an inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor and its variants. Marketing authorisation Crizotinib has a marketing authorisation in the UK which includes 'the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC)'. Adverse reactions The summary of product characteristics lists the following as the most common adverse reactions associated with crizotinib: visual disorder, diarrhoea, nausea, vomiting, constipation, oedema, fatigue, decreased appetite, neutropenia, elevated aminotransferases, anaemia, leukopenia, neuropathy, dysgeusia, dizziness, bradycardia, abdominal pain and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended dosage of crizotinib is 250 mg twice daily. Price The list price of crizotinib is £4,689 for 60 capsules (excluding VAT; 'British national formulary' online, accessed February 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of crizotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 7) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data on the clinical and cost effectiveness of crizotinib, having considered evidence on the nature of untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) and the value placed on the benefits of crizotinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee considered the nature of the condition noting that the prognosis for advanced NSCLC is poor, and that there is no cure. The committee heard from the clinical and patient experts that crizotinib could potentially extend life and improve quality of life. The committee concluded that additional treatment options would be valuable to people with ALK-positive NSCLC. The committee considered the population relevant to this appraisal and noted that the marketing authorisation includes adults with ALK-positive advanced NSCLC, whereas the company's base case focused on non-squamous ALK-positive advanced NSCLC. The committee heard from a clinical expert that the ALK-positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC. It heard that testing for the ALK mutation is routinely done in the non-squamous population. Because the ALK-positive mutation is relatively rare in people with squamous advanced NSCLC, the committee concluded that the population in the company's submission, that is, people with non-squamous advanced NSCLC, accurately reflects people with ALK-positive advanced NSCLC seen in UK clinical practice. The committee considered the treatment pathway for people with untreated ALK-positive NSCLC and the comparators relevant to this appraisal: The committee heard from the clinical experts that most people with ALK-positive NSCLC in England would first have a platinum-based chemotherapy (as described in NICE's guideline on diagnosing and managing lung cancer and NICE's technology appraisal on pemetrexed for first-line treatment of non-small-cell lung cancer). The committee was aware that pemetrexed can be given in combination with either cisplatin or carboplatin, which the experts considered to be equally effective. The committee concluded that platinum-based chemotherapy was the most relevant comparator for crizotinib. The committee noted that the company's submission only compared crizotinib with platinum-based chemotherapy, and therefore did not consider people who could not take platinum-based chemotherapy. It heard from clinical experts that there is no biological reason to expect a different response with crizotinib in this group. The committee discussed whether testing for the ALK mutation is established practice in the NHS. It heard from the clinical experts that ALK-mutation testing is needed before starting crizotinib, and that all people whose condition is considered for treatment, almost all with non-squamous disease, are tested. The committee concluded that the cost of ALK-mutation testing of non-squamous tumours should be taken into account, to reflect current clinical practice. # Clinical effectiveness The committee considered the clinical-effectiveness evidence for crizotinib. It acknowledged that the main trial presented by the company was PROFILE 1014, which investigated whether crizotinib prolongs progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with locally advanced, recurrent or metastatic non-squamous NSCLC. The committee was aware that crizotinib treatment continued until (and in some cases beyond) disease progression, whereas pemetrexed with either cisplatin or carboplatin was given for a maximum of 6 cycles. At disease progression, the trial allowed patients to switch treatment groups. The committee noted the evidence review group's (ERG) comments that the trial population was younger and had a higher proportion of patients who do not smoke compared with other studies of NSCLC. The committee heard from the company and the clinical experts that the patients' characteristics in PROFILE 1014 reflected people with ALK-positive NSCLC in England, and so the committee concluded that PROFILE 1014 was suitable for its decision-making. ## Progression-free survival The committee discussed the results of PROFILE 1014 and the primary outcome measure of progression-free survival: It noted that progression was determined using radiographic criteria, specifically the Response Evaluation Criteria in Solid Tumours (RECIST). The committee heard from the clinical experts that radiographic criteria are the gold standard for monitoring NSCLC. The committee noted that crizotinib increased progression-free survival compared with pemetrexed with either cisplatin or carboplatin (hazard ratio 0.45; 95% confidence interval 0.35 to 0.60). The committee was aware that the company used a Cox proportional hazards model to estimate the hazard ratio for progression-free survival. It noted the ERG's critique that in this case, the proportional hazards assumptions needed to analyse data using a Cox proportional hazards model may not hold because the 2 treatment regimens are given differently (in PROFILE 1014, crizotinib was given until progression whereas platinum-based chemotherapy was given for a finite number of cycles). The ERG stated that this did not have a large effect on cost effectiveness, but because patient-level data were available, the company could have modelled the data using separate independent parametric curves with fewer assumptions.On balance, the committee concluded that crizotinib increases progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC. ## Overall survival The committee discussed the results of PROFILE 1014 and the secondary outcome measure of overall survival. It noted the ERG's comments that the results for overall survival were based on relatively immature data, that is, that few patients had died at the time of data analysis. It also noted that a high proportion of patients crossed over from chemotherapy to crizotinib. The committee was aware that because crossover occurred at or after disease progression, it would not affect progression-free survival, but would affect overall survival. The committee concluded that it was appropriate for the company to adjust for crossover when estimating the size of the benefit on overall survival associated with crizotinib. The committee discussed the methods for adjusting for crossover in PROFILE 1014. The company presented evidence using different methods to adjust overall survival for crossover (rank-preserving structural failure time, iterative parameter estimation, and 2‑stage methods) and presented a range of analyses, which accounted for different confounders. The committee recognised that the company had used the 2‑stage method for its cost-effectiveness analyses. It was aware that there was some uncertainty about whether all confounders were measured at the time of crossover, but noted that the ERG agreed this was the most appropriate approach because it did not assume a common treatment effect (that is, that the treatment effect is the same regardless of when a person starts treatment). The committee concluded that the 2‑stage method was appropriate. The committee discussed the size of the benefits associated with crizotinib on overall survival. The committee noted that crizotinib increased overall survival compared with pemetrexed plus either cisplatin or carboplatin (HR 0.62; 95% CI 0.41 to 0.96), when using the 2‑stage method to account for crossover. It noted that applying different methods to account for crossover did not vary the hazard ratio substantially. It noted the ERG's comments that the results for overall survival were based on relatively immature data (that is, few patients had died at the time of data analysis). The committee recognised that the size of the benefit was uncertain because of relatively immature data and the high proportion of patients crossing over from chemotherapy to crizotinib. On balance, the committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain. # Cost effectiveness The committee considered the approach and structure of the company's economic model. The company used a semi-Markov model structure with 3 health states: the progression-free health state, progressed-disease health state and death. The model included either crizotinib or chemotherapy as the first treatment, followed by docetaxel and then best supportive care. The committee concluded that the model was consistent with the approaches used for other appraisals in NSCLC. ## Clinical parameters and treatment effect The committee discussed the company's approach to modelling overall and progression-free survival. It noted that, to generate more realistic survival estimates relevant to the UK population, the company had adjusted PROFILE 1014 data to reflect the characteristics of patients in a retrospective cohort study from the US and Canada (Davis et al. 2015). The committee discussed whether the characteristics of patients in the study reflected those of patients in England and noted from the company's sensitivity analyses that the assumptions were conservative. The committee concluded that it was satisfied with the company's approach. The committee considered whether assuming proportional hazards between treatments was appropriate for extrapolating progression-free and overall survival to estimate how long, on average, crizotinib extended the progression-free period and delayed death. The committee noted consultation comments from the company that the recommended statistical checks in NICE's Decision Support Unit technical support document 14, including log-cumulative hazard plots for overall survival, had shown that the proportional hazards assumptions held. The committee recalled the different methods of administration between treatments (see section 4.6) and noted that the log-cumulative hazard plots for each treatment were not parallel. The committee therefore disagreed with the company, noting that the hazard ratios were likely to change over time and that the assumption of proportional hazards was unlikely to hold. The committee was aware that NICE's Decision Support Unit technical support document 14 suggests using separate parametric curves for each treatment group. The committee concluded that using separate parametric curves for each group was appropriate. The committee considered whether the parameters used to adjust the parametric curves to the UK population should be the same or different for both treatments (that is, use independent covariate stratification). The committee noted comments received during consultation that there is no evidence suggesting a difference in prognosis between treatments or that covariates (such as age or sex) influence outcomes depending on treatment. The committee heard from the ERG that stratifying covariates independently uses fewer assumptions, and noted that it had a minor effect on the incremental cost-effectiveness ratios (ICERs). On balance, the committee agreed that it was appropriate to adjust each treatment for the population separately and concluded that using independent prognostic covariates was appropriate. The committee discussed which parametric curves for extrapolating progression-free and overall survival it considered most plausible: The committee was aware that the company's base case used a generalised gamma distribution for progression-free survival and a Weibull distribution for overall survival. It noted that the ERG presented exploratory analyses using separate parametric curves for each treatment (that is: progression-free survival – a log-normal distribution for crizotinib and a generalised gamma distribution for chemotherapy; overall survival – a generalised gamma distribution for crizotinib; and an exponential distribution for chemotherapy). The committee recognised that different parametric distributions predicted a range of differences in progression-free and overall survival. The committee noted comments received from the company during consultation that the overall survival increase using the ERG's selected distributions was implausible (0.8 months increased survival with crizotinib compared with chemotherapy). It heard from the clinical experts that they expected no less than a 6‑month increase in overall survival with crizotinib. The committee agreed that curves used in the ERG's exploratory analysis (that is: progression-free survival – a log-normal distribution for crizotinib and a generalised gamma distribution for chemotherapy; overall survival – a generalised gamma distribution for crizotinib; and an exponential distribution for chemotherapy) were not plausible. The committee considered statistical tests of model fit and noted that, based on either the Akaike information criterion (AIC) or the Bayesian information criterion (BIC), there were no large differences between the distributions. It noted comments received from the company during consultation that the exponential distribution (for both crizotinib and chemotherapy) had the lowest cumulative AIC and BIC. The committee agreed that it did not consider adding AIC and BIC scores together to be routine statistical practice, and that selecting parametric curves for extrapolation should not be based on statistical methods alone. To extrapolate overall survival, the committee noted that the company, in its response to the appraisal consultation document, preferred the exponential distribution for crizotinib, and the exponential or Weibull distributions for chemotherapy. The company provided its 4 criteria for selecting parametric curves: Overall survival with chemotherapy must be less than 24 months; the committee agreed that this was reasonable given the committee's discussion of end-of-life criteria (see section 4.21). The mean overall-survival gain with crizotinib must be more than 7.1 months based on an estimate from PROFILE 1007, a trial used in NICE's technology appraisal guidance for crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. The company suggested that crizotinib should be more effective as a first-line treatment for NSCLC than as a second-line treatment. However, the committee recognised that PROFILE 1007 was based on a different population, a different comparator (docetaxel), and a different duration of treatment. The committee was also aware that in NICE's technology appraisal guidance for crizotinib for previously treated NSCLC associated with an ALK-fusion gene, overall survival was uncertain because of crossover between treatments. The committee heard from the company that although several years of additional follow-up data were collected for PROFILE 1014, the next re-analysis will be done when median overall survival is reached (as per protocol). The committee agreed that the dataset for overall survival remained incomplete and that the gain in overall-survival data was uncertain. The mean gain must be more than the median gain in overall survival: the committee heard from the clinical experts that some people on crizotinib live longer than expected, and agreed that this criterion is plausible and appropriate. The mean gain in overall survival should be clinically plausible; the committee agreed that this criterion was appropriate.The committee acknowledged there was uncertainty about the size of the average gain in overall survival. It was aware that the company planned to do more analyses and emphasised the need for mature overall-survival data. The committee noted that using different parametric curves for overall survival had a major effect on the ICERs. Given the limited data available, the committee agreed to use the same distributions for both treatments to minimise the differences in assumptions between treatments. The committee noted that the exponential, log-normal and log-logistic distributions had a median overall-survival gain of more than 6 months and a mean overall-survival gain higher than the median overall-survival gain, and agreed that these distributions were all plausible and considered these for its decision-making. The committee discussed the time on treatment assumed in the company's model. The committee was concerned about the way in which the company estimated time on crizotinib treatment using PROFILE 1014. The company assumed that people taking crizotinib stopped treatment at the end of the trial (that is, they were censored), and applied this in the model. The ERG considered that this substantially underestimated the time on treatment after progression. The committee agreed that it was inappropriate to assume that patients in the trial who stopped treatment because the trial ended would also stop treatment in real life, and preferred the ERG's analyses using a parametric survival curve, that accounts for censoring, to estimate the mean duration of treatment. However, it noted that the ERG did not adjust the analyses to reflect the population in England because it did not have access to the relevant data. The committee noted that in response to the appraisal consultation document, the company presented a revised analysis reflecting the population in England. The committee agreed that this was appropriate. The committee discussed the approach to second-line treatment in the company's model: Docetaxel: the committee noted that the company assumed that everyone with progressed disease had docetaxel (as described in NICE's guideline on diagnosing and managing lung cancer), but it heard from the clinical experts that some people are not fit enough for second-line docetaxel. It also noted the ERG's comments that in PROFILE 1014, people went on to have a wide range of therapies (other than docetaxel) after disease progression. Second-line crizotinib: the committee noted that the company did not include second-line crizotinib in its model. It heard from the clinical experts that people who have first-line platinum-based chemotherapy may go on to have second-line crizotinib. The committee was aware that crizotinib is not recommended in NICE's technology appraisal for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene, and that second-line treatment with crizotinib was only available through the Cancer Drugs Fund. Second-line ceritinib: the committee was aware that ceritinib is recommended in NICE's technology appraisal guidance for previously treated anaplastic lymphoma kinase positive non-small-cell lung cancer. The committee noted that ceritinib is considered as an option after treatment with crizotinib.Therefore, the committee was unclear on whether the company's model accurately reflected second-line treatment for people with ALK-positive NSCLC in England. However, the committee was also aware that the ERG presented analyses without second-line treatment because of sparse data on time on second-line treatment, which suggested that the effect on the ICER would likely be small. On balance, the committee concluded that, in the absence of robust data and because of uncertainty about second-line treatments, excluding second-line treatment from the model was the most robust approach. ## Utilities The committee discussed the utility values used in the company's model: The company applied a lower utility for the progression-free health state in its model for platinum-based chemotherapy (0.72) than it did for crizotinib (0.81). The committee noted that this may underestimate the utility associated with platinum-based chemotherapy because health-related quality-of-life data were collected for patients only during chemotherapy, but not after chemotherapy had finished. The committee was aware that the ERG presented analyses with a higher utility value (0.81) for the progression-free health state with a platinum-based chemotherapy. In its response to the appraisal consultation document, the company accepted that it had underestimated the utility value for chemotherapy and suggested a higher utility value of 0.75. The committee heard from the ERG that the revised utility value also underestimated the utility decrement associated with chemotherapy because it included minor and not major adverse events, and that the data were based only on people on treatment. The committee heard from the clinical experts that people treated with cisplatin can have ongoing peripheral neuropathy and a lower quality of life compared with people taking oral treatments. On balance, the committee concluded that the utility value was closer to 0.75 than 0.81 and that the company's revised utility was appropriate. The committee noted that the company applied a utility value (0.74) for the period after a patient's disease has progressed but they continue to take crizotinib. It noted that this value averaged the utility for first-line treatment with crizotinib (before disease progression, 0.81) and the utility for second-line treatment with docetaxel (after disease progression, 0.66). It noted that this was not based on evidence. In its response to the appraisal consultation document, the company used a higher utility value (0.78) estimated from PROFILE 1014. The ERG stated that there was a risk of attrition bias for this estimate (that is, sicker patients were lost to follow-up earlier and not included in the analysis), which reduced the difference in the health-related quality of life of patients before and after progression. The committee heard from the clinical experts that despite progression, a patient on crizotinib may not have symptoms of lung cancer. The committee concluded that the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib was uncertain but likely to be between 0.74 and 0.78. ## Costs The committee discussed the costs used in the company's model: The committee considered the appropriate cost for ALK testing in the model and noted that the ERG considered that the company had underestimated the cost of testing. The committee heard from the ERG that a recent Cancer Research UK study reported the cost of ALK-mutation testing as £153 per patient. The ERG estimated that the cost of identifying a person with the ALK mutation was around £4,500, because over 29 people with NSCLC need to be tested to identify 1 person with the mutation. The committee heard from a clinical expert that the cost of immunohistochemistry was between £50 and £100 (excluding laboratory costs). In its response to the appraisal consultation document, the company assumed a cost of £75 for immunohistochemistry, increasing the cost of identifying a person with the ALK mutation to £2,380. The ERG suggested that the company underestimated the cost because it excluded laboratory costs. The committee heard from the company that the sequence of tests is a recent change, so the costs of ALK-mutation testing were still uncertain. Although the true cost for ALK-mutation testing is unknown, the committee considered that the cost of ALK-mutation testing was between £2,380 and £4,500. The committee discussed administration costs for crizotinib, and noted that the company did not include them in its model. It heard from the clinical experts that there would be administration costs, and also noted that these costs were included in NICE's technology appraisal on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. The committee recognised that the ERG took this into account in its exploratory analyses. However, the committee agreed with consultation comments from the company that the lower administration cost, based on that used in the NICE technology appraisal on ceritinib for previously treated anaplastic lymphoma kinase positive non-small-cell lung cancer was more appropriate than the cost used by the ERG in its exploratory analyses. The committee considered 4 results for the cost effectiveness of crizotinib compared with pemetrexed plus either cisplatin or carboplatin for people with advanced ALK-positive NSCLC: Company's revised base case: £49,186 per quality-adjusted life year (QALY) gained that: assumes proportional hazards without independent covariate stratification reflects changes to the original company submission: higher patient access scheme discount alternative utility values (see section 4.17) adjusted time on treatment (see section 4.15) adjusted administration costs and ALK-mutation testing costs (see section 4.18). Company's independent parametric curve analysis: £47,921 per QALY gained that: no longer assumes proportional hazards between treatment groups, but uses independent exponential curves for both treatments adjusts each treatment for the population separately (independent covariate stratification). ERG's revised exploratory analysis: £58,029 per QALY gained that: assumes proportional hazards without independent covariate stratification reflects changes to the company's revised analysis: higher utility for platinum-based chemotherapy for the progression-free health state (0.81 rather than 0.75) lower utility when a patient's disease progresses and they continue crizotinib (0.74 rather than 0.78) higher ALK-mutation testing cost (£4,500 rather than £2,380) higher administration cost for crizotinib (£163.85 rather than £14.40). ERG's independent parametric curves analysis: £55,131 per QALY gained that: no longer assumes proportional hazards between treatment groups but uses independent exponential curves for both treatments adjusts each treatment for the population separately (independent covariate stratification).The committee recalled its preferred assumptions relating to time on treatment (see section 4.15), utilities (see section 4.17), costs (see section 4.18), proportional hazards (see section 4.12), independent covariate stratification (see section 4.13), and extrapolation (see section 4.14). It concluded that the company's independent parametric curve analysis (with an estimated ICER of £47,291 per QALY gained) most closely reflected the committee's preferred assumptions and noted that the ICERs for other alternative curves (such as the log-normal and log-logistic distributions for both treatments) were similar. However, the committee acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain (such as the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib, and the cost of testing for an ALK mutation), and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. The committee was aware that it needed to be increasingly certain of the cost effectiveness of a technology as the technology's effect on NHS resources increases, as described in NICE's guide to the methods of technology appraisal. It recalled that ALK-positive mutation is rare in people with advanced NSCLC and considered the effect of adopting the technology as relatively small. On balance, the committee concluded that even after accounting for the uncertainty in the cost effectiveness, the most plausible ICER was likely to be at a level at which crizotinib could be considered a cost-effective use of NHS resources when the end-of-life criteria to apply. # End-of–life considerations The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee discussed whether crizotinib for untreated ALK-positive advanced NSCLC met the end-of-life criteria. It considered the life expectancy criterion and noted that the company's revised model (using data from PROFILE 1014 and an exponential distribution for overall survival for both treatments) showed that the life expectancy of people with ALK-positive NSCLC is a median 14.8 months and a mean 20.8 months with platinum-based chemotherapy. The committee was aware that the data from PROFILE 1014 were adjusted so that the trial population reflected the patient population in a retrospective cohort study (Davis et al. 2015; see section 4.11), and considered this to be a conservative assumption. The committee agreed that the short life expectancy criterion was met. The committee discussed the life-extension criterion and noted the evidence that crizotinib is likely to extend life by an additional 3 months compared with a platinum-based chemotherapy. The company's revised model (using data from PROFILE 1014 and an exponential distribution for overall survival for both treatments) showed an extension to life of a median 9.9 months and a mean of 13.1 months with crizotinib compared with platinum-based chemotherapy. Crizotinib extended life by a median or mean of at least 3 months compared with platinum-based chemotherapy when using other parametric survival curves (such as a log-normal or log-logistic distribution for both treatments). The committee heard from the ERG that the estimates of overall survival were highly uncertain because the data were considered immature and because of extensive crossover from chemotherapy to crizotinib. The committee considered that although the size of the benefit was unclear, it could be sufficiently confident that crizotinib would offer at least an additional mean survival benefit of 3 months.The committee concluded that both the life expectancy and the extension-to-life criteria were met. # Innovation The committee considered whether crizotinib is an innovative treatment. It noted that the company considered crizotinib as innovative because the current standard of care for advanced NSCLC is intravenous chemotherapy every 3 weeks. It also noted that crizotinib is the only available oral therapy and that people value oral therapies. The committee further noted that the company did not incorporate the expected benefits of crizotinib to patients' carers in its model. However, the committee noted that it had not been presented with evidence about the extent to which these benefits were realised in practice. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of crizotinib in this appraisal. # Summary of appraisal committee's key conclusions TA406 Appraisal title: Crizotinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer Section Key conclusion Crizotinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The committee concluded that the company's independent parametric curve analysis (with an estimated incremental cost-effectiveness ratio of £47,291 per quality-adjusted life year gained) most closely reflected the committee's preferred assumptions and noted that the ICERs for other alternative curves (such as the log-normal and log-logistic distributions for both treatments) were similar. However, the committee acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. On balance, the committee concluded that even after accounting for the uncertainty in the cost effectiveness, the most plausible ICER was likely to be at a level at which crizotinib could be considered a cost-effective use of NHS resources when the end-of-life criteria to apply. Current practice Clinical need of patients, including the availability of alternative treatments The committee noted that the prognosis for advanced non-small-cell lung cancer (NSCLC) is poor and that there is no cure, and concluded that additional treatment options would be valuable for people with anaplastic lymphoma kinase (ALK)-positive NSCLC. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee concluded that crizotinib increases progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC. The committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs. What is the position of the treatment in the pathway of care for the condition? The committee was aware that crizotinib has a marketing authorisation in the UK for 'the first-line treatment of adults with ALK-positive advanced NSCLC'. Evidence for clinical effectiveness Availability, nature and quality of evidence Relevance to general clinical practice in the NHS The committee heard from the company and the clinical experts that the patients' characteristics in PROFILE 1014 reflected people with ALK-positive NSCLC in England, and so the committee concluded that PROFILE 1014 was suitable for its decision-making. Uncertainties generated by the evidence The committee recognised that the company had used the 2‑stage method for its cost-effectiveness analyses. It was aware that there was some uncertainty about whether all confounders were measured at the time of crossover. The committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee heard that there is no biological reason to expect a different response with crizotinib in people who cannot take platinum-based chemotherapy, but was aware that there was little evidence specific to this group of patients. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee noted that crizotinib increased progression-free survival compared with pemetrexed with either cisplatin or carboplatin (hazard ratio 0.45; 95% confidence interval 0.35 to 0.60). The committee noted that crizotinib increased overall survival compared with pemetrexed plus either cisplatin or carboplatin (HR 0.62; 95% CI 0.41 to 0.96), when using the 2‑stage method to account for crossover. It noted that applying different methods to account for crossover did not vary the hazard ratio substantially. Evidence for cost effectiveness Availability and nature of evidence The committee concluded that the model was consistent with the approaches used for other appraisals in NSCLC. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee recalled its preferred assumptions relating to time on treatment, utilities, costs, proportional hazards, independent covariate stratification, and extrapolation. It concluded that the company's independent parametric curve analysis most closely reflected the committee's preferred assumptions. It acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain (such as the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib, and the cost of testing for an ALK mutation), and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee concluded that the utility value for the progression-free health state for platinum-based chemotherapy was closer to 0.75 than 0.81 and that the company's revised utility was appropriate. The committee concluded that the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib was uncertain but likely to be between 0.74 and 0.78. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs. Are there specific groups of people for whom the technology is particularly cost effective? The committee heard from a clinical expert that the ALK-positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC. What are the key drivers of cost effectiveness? The committee noted that using different parametric curves for overall survival had a major effect on the ICERs. The committee was also aware that analyses without second-line treatment suggested that the effect on the ICER would likely be small. The committee noted that the ICERs for parametric survival curves (such as the log-normal and log-logistic distributions for both treatments) were similar. Most likely cost-effectiveness estimate (given as an ICER) The committee concluded that the company's independent parametric curve analysis (with an estimated ICER of £47,291 per QALY gained) most closely reflected the committee's preferred assumptions and noted that the ICERs for other alternative distributions (such as the log-normal and log-logistic distributions for both treatments) were similar. However, the committee acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. On balance, the committee concluded that even after accounting for the uncertainty in the cost effectiveness, the most plausible ICER was likely to be at a level at which crizotinib could be considered a cost-effective use of NHS resources when the end-of-life criteria to apply. Additional factors taken into account Patient access schemes (PPRS) The committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of crizotinib. End-of-life considerations The committee concluded that both the life expectancy and the extension-to-life criteria were met. Equalities considerations and social value judgements The following potential equality issues were identified during the scoping process: That testing could be restricted to people with a diagnosis of adenocarcinoma. That there could be inequitable access if regional variations in ALK-mutation testing exist. The potential equality issues identified during the scoping process were noted by the committee. None of these issues related to protected characteristics, as defined by the Equalities Act (2010), and so were not considered equality issues. -# Recommendations for research The committee was aware that follow-up for PROFILE 1014 was ongoing and that the next planned analysis of the trial would be done when median survival has been reached. The committee agreed that this additional analysis would give useful data on overall survival with crizotinib for people with untreated ALK-positive non-small-cell lung cancer.	{'Recommendations': 'Crizotinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults. The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nCrizotinib (Xalkori, Pfizer) is an inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor and its variants.\n\nMarketing authorisation\n\nCrizotinib has a marketing authorisation in the UK which includes 'the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC)'.\n\nAdverse reactions\n\nThe summary of product characteristics lists the following as the most common adverse reactions associated with crizotinib: visual disorder, diarrhoea, nausea, vomiting, constipation, oedema, fatigue, decreased appetite, neutropenia, elevated aminotransferases, anaemia, leukopenia, neuropathy, dysgeusia, dizziness, bradycardia, abdominal pain and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dosage of crizotinib is 250\xa0mg twice daily.\n\nPrice\n\nThe list price of crizotinib is £4,689 for 60\xa0capsules (excluding VAT; 'British national formulary' [BNF] online, accessed February 2016).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of crizotinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section 7) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data on the clinical and cost effectiveness of crizotinib, having considered evidence on the nature of untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) and the value placed on the benefits of crizotinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee considered the nature of the condition noting that the prognosis for advanced NSCLC is poor, and that there is no cure. The committee heard from the clinical and patient experts that crizotinib could potentially extend life and improve quality of life. The committee concluded that additional treatment options would be valuable to people with ALK-positive NSCLC.\n\nThe committee considered the population relevant to this appraisal and noted that the marketing authorisation includes adults with ALK-positive advanced NSCLC, whereas the company's base case focused on non-squamous ALK-positive advanced NSCLC. The committee heard from a clinical expert that the ALK-positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC. It heard that testing for the ALK mutation is routinely done in the non-squamous population. Because the ALK-positive mutation is relatively rare in people with squamous advanced NSCLC, the committee concluded that the population in the company's submission, that is, people with non-squamous advanced NSCLC, accurately reflects people with ALK-positive advanced NSCLC seen in UK clinical practice.\n\nThe committee considered the treatment pathway for people with untreated ALK-positive NSCLC and the comparators relevant to this appraisal:\n\nThe committee heard from the clinical experts that most people with ALK-positive NSCLC in England would first have a platinum-based chemotherapy (as described in NICE's guideline on diagnosing and managing lung cancer and NICE's technology appraisal on pemetrexed for first-line treatment of non-small-cell lung cancer). The committee was aware that pemetrexed can be given in combination with either cisplatin or carboplatin, which the experts considered to be equally effective. The committee concluded that platinum-based chemotherapy was the most relevant comparator for crizotinib.\n\nThe committee noted that the company's submission only compared crizotinib with platinum-based chemotherapy, and therefore did not consider people who could not take platinum-based chemotherapy. It heard from clinical experts that there is no biological reason to expect a different response with crizotinib in this group.\n\nThe committee discussed whether testing for the ALK mutation is established practice in the NHS. It heard from the clinical experts that ALK-mutation testing is needed before starting crizotinib, and that all people whose condition is considered for treatment, almost all with non-squamous disease, are tested. The committee concluded that the cost of ALK-mutation testing of non-squamous tumours should be taken into account, to reflect current clinical practice.\n\n# Clinical effectiveness\n\nThe committee considered the clinical-effectiveness evidence for crizotinib. It acknowledged that the main trial presented by the company was PROFILE\xa01014, which investigated whether crizotinib prolongs progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with locally advanced, recurrent or metastatic non-squamous NSCLC. The committee was aware that crizotinib treatment continued until (and in some cases beyond) disease progression, whereas pemetrexed with either cisplatin or carboplatin was given for a maximum of 6\xa0cycles. At disease progression, the trial allowed patients to switch treatment groups. The committee noted the evidence review group's (ERG) comments that the trial population was younger and had a higher proportion of patients who do not smoke compared with other studies of NSCLC. The committee heard from the company and the clinical experts that the patients' characteristics in PROFILE\xa01014 reflected people with ALK-positive NSCLC in England, and so the committee concluded that PROFILE\xa01014 was suitable for its decision-making.\n\n## Progression-free survival\n\nThe committee discussed the results of PROFILE\xa01014 and the primary outcome measure of progression-free survival:\n\nIt noted that progression was determined using radiographic criteria, specifically the Response Evaluation Criteria in Solid Tumours (RECIST). The committee heard from the clinical experts that radiographic criteria are the gold standard for monitoring NSCLC.\n\nThe committee noted that crizotinib increased progression-free survival compared with pemetrexed with either cisplatin or carboplatin (hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.35 to 0.60).\n\nThe committee was aware that the company used a Cox proportional hazards model to estimate the hazard ratio for progression-free survival. It noted the ERG's critique that in this case, the proportional hazards assumptions needed to analyse data using a Cox proportional hazards model may not hold because the 2\xa0treatment regimens are given differently (in PROFILE\xa01014, crizotinib was given until progression whereas platinum-based chemotherapy [the control group] was given for a finite number of cycles). The ERG stated that this did not have a large effect on cost effectiveness, but because patient-level data were available, the company could have modelled the data using separate independent parametric curves with fewer assumptions.On balance, the committee concluded that crizotinib increases progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC.\n\n## Overall survival\n\nThe committee discussed the results of PROFILE\xa01014 and the secondary outcome measure of overall survival. It noted the ERG's comments that the results for overall survival were based on relatively immature data, that is, that few patients had died at the time of data analysis. It also noted that a high proportion of patients crossed over from chemotherapy to crizotinib. The committee was aware that because crossover occurred at or after disease progression, it would not affect progression-free survival, but would affect overall survival. The committee concluded that it was appropriate for the company to adjust for crossover when estimating the size of the benefit on overall survival associated with crizotinib.\n\nThe committee discussed the methods for adjusting for crossover in PROFILE\xa01014. The company presented evidence using different methods to adjust overall survival for crossover (rank-preserving structural failure time, iterative parameter estimation, and 2‑stage methods) and presented a range of analyses, which accounted for different confounders. The committee recognised that the company had used the 2‑stage method for its cost-effectiveness analyses. It was aware that there was some uncertainty about whether all confounders were measured at the time of crossover, but noted that the ERG agreed this was the most appropriate approach because it did not assume a common treatment effect (that is, that the treatment effect is the same regardless of when a person starts treatment). The committee concluded that the 2‑stage method was appropriate.\n\nThe committee discussed the size of the benefits associated with crizotinib on overall survival. The committee noted that crizotinib increased overall survival compared with pemetrexed plus either cisplatin or carboplatin (HR\xa00.62; 95% CI\xa00.41 to\xa00.96), when using the 2‑stage method to account for crossover. It noted that applying different methods to account for crossover did not vary the hazard ratio substantially. It noted the ERG's comments that the results for overall survival were based on relatively immature data (that is, few patients had died at the time of data analysis). The committee recognised that the size of the benefit was uncertain because of relatively immature data and the high proportion of patients crossing over from chemotherapy to crizotinib. On balance, the committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain.\n\n# Cost effectiveness\n\nThe committee considered the approach and structure of the company's economic model. The company used a semi-Markov model structure with 3\xa0health states: the progression-free health state, progressed-disease health state and death. The model included either crizotinib or chemotherapy as the first treatment, followed by docetaxel and then best supportive care. The committee concluded that the model was consistent with the approaches used for other appraisals in NSCLC.\n\n## Clinical parameters and treatment effect\n\nThe committee discussed the company's approach to modelling overall and progression-free survival. It noted that, to generate more realistic survival estimates relevant to the UK population, the company had adjusted PROFILE\xa01014 data to reflect the characteristics of patients in a retrospective cohort study from the US and Canada (Davis et al. 2015). The committee discussed whether the characteristics of patients in the study reflected those of patients in England and noted from the company's sensitivity analyses that the assumptions were conservative. The committee concluded that it was satisfied with the company's approach.\n\nThe committee considered whether assuming proportional hazards between treatments was appropriate for extrapolating progression-free and overall survival to estimate how long, on average, crizotinib extended the progression-free period and delayed death. The committee noted consultation comments from the company that the recommended statistical checks in NICE's Decision Support Unit technical support document\xa014, including log-cumulative hazard plots for overall survival, had shown that the proportional hazards assumptions held. The committee recalled the different methods of administration between treatments (see section\xa04.6) and noted that the log-cumulative hazard plots for each treatment were not parallel. The committee therefore disagreed with the company, noting that the hazard ratios were likely to change over time and that the assumption of proportional hazards was unlikely to hold. The committee was aware that NICE's Decision Support Unit technical support document\xa014 suggests using separate parametric curves for each treatment group. The committee concluded that using separate parametric curves for each group was appropriate.\n\nThe committee considered whether the parameters used to adjust the parametric curves to the UK population should be the same or different for both treatments (that is, use independent covariate stratification). The committee noted comments received during consultation that there is no evidence suggesting a difference in prognosis between treatments or that covariates (such as age or sex) influence outcomes depending on treatment. The committee heard from the ERG that stratifying covariates independently uses fewer assumptions, and noted that it had a minor effect on the incremental cost-effectiveness ratios (ICERs). On balance, the committee agreed that it was appropriate to adjust each treatment for the population separately and concluded that using independent prognostic covariates was appropriate.\n\nThe committee discussed which parametric curves for extrapolating progression-free and overall survival it considered most plausible:\n\nThe committee was aware that the company's base case used a generalised gamma distribution for progression-free survival and a Weibull distribution for overall survival. It noted that the ERG presented exploratory analyses using separate parametric curves for each treatment (that is: progression-free survival – a log-normal distribution for crizotinib and a generalised gamma distribution for chemotherapy; overall survival – a generalised gamma distribution for crizotinib; and an exponential distribution for chemotherapy). The committee recognised that different parametric distributions predicted a range of differences in progression-free and overall survival. The committee noted comments received from the company during consultation that the overall survival increase using the ERG's selected distributions was implausible (0.8\xa0months increased survival with crizotinib compared with chemotherapy). It heard from the clinical experts that they expected no less than a 6‑month increase in overall survival with crizotinib. The committee agreed that curves used in the ERG's exploratory analysis (that is: progression-free survival – a log-normal distribution for crizotinib and a generalised gamma distribution for chemotherapy; overall survival – a generalised gamma distribution for crizotinib; and an exponential distribution for chemotherapy) were not plausible.\n\nThe committee considered statistical tests of model fit and noted that, based on either the Akaike information criterion (AIC) or the Bayesian information criterion (BIC), there were no large differences between the distributions. It noted comments received from the company during consultation that the exponential distribution (for both crizotinib and chemotherapy) had the lowest cumulative AIC and BIC. The committee agreed that it did not consider adding AIC and BIC scores together to be routine statistical practice, and that selecting parametric curves for extrapolation should not be based on statistical methods alone.\n\nTo extrapolate overall survival, the committee noted that the company, in its response to the appraisal consultation document, preferred the exponential distribution for crizotinib, and the exponential or Weibull distributions for chemotherapy. The company provided its 4\xa0criteria for selecting parametric curves:\n\n\n\nOverall survival with chemotherapy must be less than 24\xa0months; the committee agreed that this was reasonable given the committee's discussion of end-of-life criteria (see section\xa04.21).\n\nThe mean overall-survival gain with crizotinib must be more than 7.1\xa0months based on an estimate from PROFILE\xa01007, a trial used in NICE's technology appraisal guidance for crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. The company suggested that crizotinib should be more effective as a first-line treatment for NSCLC than as a second-line treatment. However, the committee recognised that PROFILE\xa01007 was based on a different population, a different comparator (docetaxel), and a different duration of treatment. The committee was also aware that in NICE's technology appraisal guidance for crizotinib for previously treated NSCLC associated with an ALK-fusion gene, overall survival was uncertain because of crossover between treatments. The committee heard from the company that although several years of additional follow-up data were collected for PROFILE\xa01014, the next re-analysis will be done when median overall survival is reached (as per protocol). The committee agreed that the dataset for overall survival remained incomplete and that the gain in overall-survival data was uncertain.\n\nThe mean gain must be more than the median gain in overall survival: the committee heard from the clinical experts that some people on crizotinib live longer than expected, and agreed that this criterion is plausible and appropriate.\n\nThe mean gain in overall survival should be clinically plausible; the committee agreed that this criterion was appropriate.The committee acknowledged there was uncertainty about the size of the average gain in overall survival. It was aware that the company planned to do more analyses and emphasised the need for mature overall-survival data. The committee noted that using different parametric curves for overall survival had a major effect on the ICERs. Given the limited data available, the committee agreed to use the same distributions for both treatments to minimise the differences in assumptions between treatments. The committee noted that the exponential, log-normal and log-logistic distributions had a median overall-survival gain of more than 6\xa0months and a mean overall-survival gain higher than the median overall-survival gain, and agreed that these distributions were all plausible and considered these for its decision-making.\n\n\n\nThe committee discussed the time on treatment assumed in the company's model. The committee was concerned about the way in which the company estimated time on crizotinib treatment using PROFILE\xa01014. The company assumed that people taking crizotinib stopped treatment at the end of the trial (that is, they were censored), and applied this in the model. The ERG considered that this substantially underestimated the time on treatment after progression. The committee agreed that it was inappropriate to assume that patients in the trial who stopped treatment because the trial ended would also stop treatment in real life, and preferred the ERG's analyses using a parametric survival curve, that accounts for censoring, to estimate the mean duration of treatment. However, it noted that the ERG did not adjust the analyses to reflect the population in England because it did not have access to the relevant data. The committee noted that in response to the appraisal consultation document, the company presented a revised analysis reflecting the population in England. The committee agreed that this was appropriate.\n\nThe committee discussed the approach to second-line treatment in the company's model:\n\nDocetaxel: the committee noted that the company assumed that everyone with progressed disease had docetaxel (as described in NICE's guideline on diagnosing and managing lung cancer), but it heard from the clinical experts that some people are not fit enough for second-line docetaxel. It also noted the ERG's comments that in PROFILE\xa01014, people went on to have a wide range of therapies (other than docetaxel) after disease progression.\n\nSecond-line crizotinib: the committee noted that the company did not include second-line crizotinib in its model. It heard from the clinical experts that people who have first-line platinum-based chemotherapy may go on to have second-line crizotinib. The committee was aware that crizotinib is not recommended in NICE's technology appraisal for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene, and that second-line treatment with crizotinib was only available through the Cancer Drugs Fund.\n\nSecond-line ceritinib: the committee was aware that ceritinib is recommended in NICE's technology appraisal guidance for previously treated anaplastic lymphoma kinase positive non-small-cell lung cancer. The committee noted that ceritinib is considered as an option after treatment with crizotinib.Therefore, the committee was unclear on whether the company's model accurately reflected second-line treatment for people with ALK-positive NSCLC in England. However, the committee was also aware that the ERG presented analyses without second-line treatment because of sparse data on time on second-line treatment, which suggested that the effect on the ICER would likely be small. On balance, the committee concluded that, in the absence of robust data and because of uncertainty about second-line treatments, excluding second-line treatment from the model was the most robust approach.\n\n## Utilities\n\nThe committee discussed the utility values used in the company's model:\n\nThe company applied a lower utility for the progression-free health state in its model for platinum-based chemotherapy (0.72) than it did for crizotinib (0.81). The committee noted that this may underestimate the utility associated with platinum-based chemotherapy because health-related quality-of-life data were collected for patients only during chemotherapy, but not after chemotherapy had finished. The committee was aware that the ERG presented analyses with a higher utility value (0.81) for the progression-free health state with a platinum-based chemotherapy. In its response to the appraisal consultation document, the company accepted that it had underestimated the utility value for chemotherapy and suggested a higher utility value of 0.75. The committee heard from the ERG that the revised utility value also underestimated the utility decrement associated with chemotherapy because it included minor and not major adverse events, and that the data were based only on people on treatment. The committee heard from the clinical experts that people treated with cisplatin can have ongoing peripheral neuropathy and a lower quality of life compared with people taking oral treatments. On balance, the committee concluded that the utility value was closer to 0.75 than 0.81 and that the company's revised utility was appropriate.\n\nThe committee noted that the company applied a utility value (0.74) for the period after a patient's disease has progressed but they continue to take crizotinib. It noted that this value averaged the utility for first-line treatment with crizotinib (before disease progression, 0.81) and the utility for second-line treatment with docetaxel (after disease progression, 0.66). It noted that this was not based on evidence. In its response to the appraisal consultation document, the company used a higher utility value (0.78) estimated from PROFILE\xa01014. The ERG stated that there was a risk of attrition bias for this estimate (that is, sicker patients were lost to follow-up earlier and not included in the analysis), which reduced the difference in the health-related quality of life of patients before and after progression. The committee heard from the clinical experts that despite progression, a patient on crizotinib may not have symptoms of lung cancer. The committee concluded that the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib was uncertain but likely to be between 0.74 and 0.78.\n\n## Costs\n\nThe committee discussed the costs used in the company's model:\n\nThe committee considered the appropriate cost for ALK testing in the model and noted that the ERG considered that the company had underestimated the cost of testing. The committee heard from the ERG that a recent Cancer Research UK study reported the cost of ALK-mutation testing as £153 per patient. The ERG estimated that the cost of identifying a person with the ALK mutation was around £4,500, because over 29\xa0people with NSCLC need to be tested to identify 1\xa0person with the mutation. The committee heard from a clinical expert that the cost of immunohistochemistry was between £50 and £100 (excluding laboratory costs). In its response to the appraisal consultation document, the company assumed a cost of £75 for immunohistochemistry, increasing the cost of identifying a person with the ALK mutation to £2,380. The ERG suggested that the company underestimated the cost because it excluded laboratory costs. The committee heard from the company that the sequence of tests is a recent change, so the costs of ALK-mutation testing were still uncertain. Although the true cost for ALK-mutation testing is unknown, the committee considered that the cost of ALK-mutation testing was between £2,380 and £4,500.\n\nThe committee discussed administration costs for crizotinib, and noted that the company did not include them in its model. It heard from the clinical experts that there would be administration costs, and also noted that these costs were included in NICE's technology appraisal on crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. The committee recognised that the ERG took this into account in its exploratory analyses. However, the committee agreed with consultation comments from the company that the lower administration cost, based on that used in the NICE technology appraisal on ceritinib for previously treated anaplastic lymphoma kinase positive non-small-cell lung cancer was more appropriate than the cost used by the ERG in its exploratory analyses.\n\nThe committee considered 4\xa0results for the cost effectiveness of crizotinib compared with pemetrexed plus either cisplatin or carboplatin for people with advanced ALK-positive NSCLC:\n\nCompany's revised base case: £49,186 per quality-adjusted life year (QALY) gained that:\n\n\n\nassumes proportional hazards without independent covariate stratification\n\nreflects changes to the original company submission:\n\n\n\nhigher patient access scheme discount\n\nalternative utility values (see section\xa04.17)\n\nadjusted time on treatment (see section\xa04.15)\n\nadjusted administration costs and ALK-mutation testing costs (see section\xa04.18).\n\n\n\n\n\nCompany's independent parametric curve analysis: £47,921 per QALY gained that:\n\n\n\nno longer assumes proportional hazards between treatment groups, but uses independent exponential curves for both treatments\n\nadjusts each treatment for the population separately (independent covariate stratification).\n\n\n\nERG's revised exploratory analysis: £58,029 per QALY gained that:\n\n\n\nassumes proportional hazards without independent covariate stratification\n\nreflects changes to the company's revised analysis:\n\n\n\nhigher utility for platinum-based chemotherapy for the progression-free health state (0.81 rather than 0.75)\n\nlower utility when a patient's disease progresses and they continue crizotinib (0.74 rather than 0.78)\n\nhigher ALK-mutation testing cost (£4,500 rather than £2,380)\n\nhigher administration cost for crizotinib (£163.85 rather than £14.40).\n\n\n\n\n\nERG's independent parametric curves analysis: £55,131 per QALY gained that:\n\n\n\nno longer assumes proportional hazards between treatment groups but uses independent exponential curves for both treatments\n\nadjusts each treatment for the population separately (independent covariate stratification).The committee recalled its preferred assumptions relating to time on treatment (see section\xa04.15), utilities (see section\xa04.17), costs (see section\xa04.18), proportional hazards (see section\xa04.12), independent covariate stratification (see section\xa04.13), and extrapolation (see section\xa04.14). It concluded that the company's independent parametric curve analysis (with an estimated ICER of £47,291 per QALY gained) most closely reflected the committee's preferred assumptions and noted that the ICERs for other alternative curves (such as the log-normal and log-logistic distributions for both treatments) were similar. However, the committee acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain (such as the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib, and the cost of testing for an ALK mutation), and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. The committee was aware that it needed to be increasingly certain of the cost effectiveness of a technology as the technology's effect on NHS resources increases, as described in NICE's guide to the methods of technology appraisal. It recalled that ALK-positive mutation is rare in people with advanced NSCLC and considered the effect of adopting the technology as relatively small. On balance, the committee concluded that even after accounting for the uncertainty in the cost effectiveness, the most plausible ICER was likely to be at a level at which crizotinib could be considered a cost-effective use of NHS resources when the end-of-life criteria to apply.\n\n\n\n# End-of–life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\nThe committee discussed whether crizotinib for untreated ALK-positive advanced NSCLC met the end-of-life criteria.\n\nIt considered the life expectancy criterion and noted that the company's revised model (using data from PROFILE\xa01014 and an exponential distribution for overall survival for both treatments) showed that the life expectancy of people with ALK-positive NSCLC is a median 14.8\xa0months and a mean 20.8\xa0months with platinum-based chemotherapy. The committee was aware that the data from PROFILE\xa01014 were adjusted so that the trial population reflected the patient population in a retrospective cohort study (Davis et al. 2015; see section\xa04.11), and considered this to be a conservative assumption. The committee agreed that the short life expectancy criterion was met.\n\nThe committee discussed the life-extension criterion and noted the evidence that crizotinib is likely to extend life by an additional 3\xa0months compared with a platinum-based chemotherapy. The company's revised model (using data from PROFILE\xa01014 and an exponential distribution for overall survival for both treatments) showed an extension to life of a median 9.9\xa0months and a mean of 13.1\xa0months with crizotinib compared with platinum-based chemotherapy. Crizotinib extended life by a median or mean of at least 3\xa0months compared with platinum-based chemotherapy when using other parametric survival curves (such as a log-normal or log-logistic distribution for both treatments). The committee heard from the ERG that the estimates of overall survival were highly uncertain because the data were considered immature and because of extensive crossover from chemotherapy to crizotinib. The committee considered that although the size of the benefit was unclear, it could be sufficiently confident that crizotinib would offer at least an additional mean survival benefit of 3\xa0months.The committee concluded that both the life expectancy and the extension-to-life criteria were met.\n\n# Innovation\n\nThe committee considered whether crizotinib is an innovative treatment. It noted that the company considered crizotinib as innovative because the current standard of care for advanced NSCLC is intravenous chemotherapy every 3\xa0weeks. It also noted that crizotinib is the only available oral therapy and that people value oral therapies. The committee further noted that the company did not incorporate the expected benefits of crizotinib to patients' carers in its model. However, the committee noted that it had not been presented with evidence about the extent to which these benefits were realised in practice. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of crizotinib in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA406\n\nAppraisal title: Crizotinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer\n\nSection\n\nKey conclusion\n\nCrizotinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults.\n\nThe committee concluded that the company's independent parametric curve analysis (with an estimated incremental cost-effectiveness ratio [ICER] of £47,291 per quality-adjusted life year [QALY] gained) most closely reflected the committee's preferred assumptions and noted that the ICERs for other alternative curves (such as the log-normal and log-logistic distributions for both treatments) were similar. However, the committee acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. On balance, the committee concluded that even after accounting for the uncertainty in the cost effectiveness, the most plausible ICER was likely to be at a level at which crizotinib could be considered a cost-effective use of NHS resources when the end-of-life criteria to apply.\n\n, 4.19\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee noted that the prognosis for advanced non-small-cell lung cancer (NSCLC) is poor and that there is no cure, and concluded that additional treatment options would be valuable for people with anaplastic lymphoma kinase (ALK)-positive NSCLC.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that crizotinib increases progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC. The committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain.\n\nThe committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs.\n\n, 4.9, 4.22\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee was aware that crizotinib has a marketing authorisation in the UK for 'the first-line treatment of adults with ALK-positive advanced NSCLC'.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nRelevance to general clinical practice in the NHS\n\nThe committee heard from the company and the clinical experts that the patients' characteristics in PROFILE\xa01014 reflected people with ALK-positive NSCLC in England, and so the committee concluded that PROFILE\xa01014 was suitable for its decision-making.\n\n\n\nUncertainties generated by the evidence\n\nThe committee recognised that the company had used the 2‑stage method for its cost-effectiveness analyses. It was aware that there was some uncertainty about whether all confounders were measured at the time of crossover.\n\nThe committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain.\n\n, 4.9\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee heard that there is no biological reason to expect a different response with crizotinib in people who cannot take platinum-based chemotherapy, but was aware that there was little evidence specific to this group of patients.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee noted that crizotinib increased progression-free survival compared with pemetrexed with either cisplatin or carboplatin (hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.35 to 0.60).\n\nThe committee noted that crizotinib increased overall survival compared with pemetrexed plus either cisplatin or carboplatin (HR\xa00.62; 95% CI\xa00.41 to\xa00.96), when using the 2‑stage method to account for crossover. It noted that applying different methods to account for crossover did not vary the hazard ratio substantially.\n\n, 4.9\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee concluded that the model was consistent with the approaches used for other appraisals in NSCLC.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee recalled its preferred assumptions relating to time on treatment, utilities, costs, proportional hazards, independent covariate stratification, and extrapolation. It concluded that the company's independent parametric curve analysis most closely reflected the committee's preferred assumptions. It acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain (such as the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib, and the cost of testing for an ALK mutation), and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large.\n\n–4.19\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee concluded that the utility value for the progression-free health state for platinum-based chemotherapy was closer to 0.75 than 0.81 and that the company's revised utility was appropriate.\n\nThe committee concluded that the utility value for the period after a patient's disease has progressed but the patient continues to take crizotinib was uncertain but likely to be between 0.74 and 0.78.\n\nThe committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs.\n\n, 4.22\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee heard from a clinical expert that the ALK-positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee noted that using different parametric curves for overall survival had a major effect on the ICERs.\n\nThe committee was also aware that analyses without second-line treatment suggested that the effect on the ICER would likely be small.\n\nThe committee noted that the ICERs for parametric survival curves (such as the log-normal and log-logistic distributions for both treatments) were similar.\n\n, 4.16, 4.19\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that the company's independent parametric curve analysis (with an estimated ICER of £47,291 per QALY gained) most closely reflected the committee's preferred assumptions and noted that the ICERs for other alternative distributions (such as the log-normal and log-logistic distributions for both treatments) were similar. However, the committee acknowledged that this used some assumptions that the committee did not prefer or that the committee considered to be uncertain and therefore acknowledged that uncertainty on the cost effectiveness of crizotinib remained fairly large. On balance, the committee concluded that even after accounting for the uncertainty in the cost effectiveness, the most plausible ICER was likely to be at a level at which crizotinib could be considered a cost-effective use of NHS resources when the end-of-life criteria to apply.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of crizotinib.\n\n\n\nEnd-of-life considerations\n\nThe committee concluded that both the life expectancy and the extension-to-life criteria were met.\n\n, 4.21\n\nEqualities considerations and social value judgements\n\nThe following potential equality issues were identified during the scoping process:\n\nThat testing could be restricted to people with a diagnosis of adenocarcinoma.\n\nThat there could be inequitable access if regional variations in ALK-mutation testing exist.\n\nThe potential equality issues identified during the scoping process were noted by the committee. None of these issues related to protected characteristics, as defined by the Equalities Act (2010), and so were not considered equality issues.\n\n-", 'Recommendations for research': 'The committee was aware that follow-up for PROFILE\xa01014 was ongoing and that the next planned analysis of the trial would be done when median survival has been reached. The committee agreed that this additional analysis would give useful data on overall survival with crizotinib for people with untreated ALK-positive non-small-cell lung cancer.'}	https://www.nice.org.uk/guidance/ta406	Evidence-based recommendations on crizotinib (Xalkori) for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults.
6eedaf4745a823f40ff668e95fae335d4f46b4d7	nice	Secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF-alpha inhibitors	Secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF-alpha inhibitors Evidence-based recommendations on secukinumab (Cosentyx) for treating active ankylosing spondylitis that has not responded well enough to conventional therapy. # Recommendations Secukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis in adults whose disease has responded inadequately to conventional therapy (non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme. Assess the response to secukinumab after 16 weeks of treatment and only continue if there is clear evidence of response, defined as: a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more. When using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.# The technology Description of the technology Secukinumab (Cosentyx, Novartis). It is a monoclonal antihuman antibody of the IgG1/kappa isotype that targets interleukin‑17A. Marketing authorisation Secukinumab has a marketing authorisation in the UK for the treatment of active ankylosing spondylitis 'in adults who have responded inadequately to conventional therapy'. Adverse reactions The overall incidence of treatment-emergent adverse events up to week 16 in the MEASURE 2 trial was comparable between the secukinumab 150‑mg group (65.3%) and the placebo group (63.5%). In MEASURE 1 there was a higher rate in the secukinumab 150‑mg group than with placebo (69.6% compared with 55.7%). There were no treatment-related deaths. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended dose is 150 mg once weekly given by subcutaneous injection at weeks 0, 1, 2 and 3; followed by a maintenance dose once a month starting at week 4. Price Secukinumab is available at the list price of £609.39 for a 150‑mg pre-filled pen or syringe (excluding VAT, 'British national formulary' July 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of secukinumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). It also considered evidence received from patient and professional groups. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of secukinumab, having considered evidence on the nature of ankylosing spondylitis (AS) and the value placed on the benefits of secukinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness The committee discussed the clinical-effectiveness evidence presented by the company, its critique by the evidence review group (ERG) and evidence submitted by patient and professional groups. The clinical-effectiveness evidence for secukinumab is in the company's submission (pages 42–155) and in the ERG report (pages 33–87). ## Current clinical management of active ankylosing spondylitis The clinical experts stated that the response criteria used in NICE's technology appraisal on TNF‑alpha inhibitors for AS – that is, a reduction in the BASDAI score to 50% of the pre-treatment value or by 2 or more units, and a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more – are used in clinical practice and are relevant to the appraisal of secukinumab in active AS. People with AS may have additional non-spinal manifestations of disease such as uveitis, colitis, psoriasis, and peripheral arthritis. TNF‑alpha inhibitors have different effects on extra‑articular manifestations and so the choice of TNF‑alpha inhibitor in clinical practice is based on individual patient characteristics and guided by any additional indications included in the marketing authorisation. Secukinumab has a licence for, and is recommended in NICE's technology appraisal guidance on, secukinumab for the treatment of moderate to severe plaque psoriasis. It also has a licence for psoriatic arthritis and is the subject of an ongoing NICE technology appraisal. The committee understood that the choice of agent for treating AS is made on an individual patient basis, based on disease characteristics and extra-articular symptoms. The committee noted that a patient organisation submission included a survey of several hundred patients with AS, which summarised the major effect that the disease has on people's health and quality of life. The committee heard that having a greater choice of treatments would be particularly valuable to people with this condition, allowing them and their clinicians to choose treatments that take into account their individual needs and preferences and giving them a feeling of more control over their condition. The clinical experts stated that the novel mechanism of action of secukinumab, and its other marketing authorisations for psoriasis and psoriatic arthritis, would give patients and clinicians a greater choice of targeted treatment options. A patient expert stated that it is particularly important to have the option of a treatment with a different mechanism of action for patients whose disease did not respond to one or more TNF‑alpha inhibitors. The committee concluded that the availability of an effective new treatment option would be valuable for people with active AS. ## The evidence from the MEASURE trials The MEASURE 1 and MEASURE 2 trials, which compared secukinumab with placebo in active AS, were conducted across international sites. The committee expressed concern that concomitant treatments, which were not used in trials for TNF‑alpha inhibitors (such as methotrexate and sulfasalazine), might have affected the results of the trials and their generalisability to UK clinical practice. The clinical experts stated that non-biological agents such as methotrexate and sulfasalazine have no proven activity in spinal disease but may be prescribed for extra-articular manifestations. The committee noted that MEASURE 1 and MEASURE 2 did not assess the effect of treatments on extra-articular manifestations, only the effects on AS. It also considered whether the results of MEASURE 1 were relevant to the use of subcutaneously administered secukinumab in UK clinical practice, as an intravenously administered dose was used up to week 4 (at week 8 and every subsequent 4 weeks secukinumab was administered subcutaneously), not reflecting the regimen which was subsequently licensed. The clinical experts stated that the magnitude of response in both studies was similar despite the differences between them in administration and loading dose. The committee concluded that the results from MEASURE 1 and MEASURE 2 were comparable and generalisable to the UK population. The primary outcome measure in the MEASURE trials was the proportion of patients who had an Assessment in Spondyloarthritis International Society (ASAS) 20 response at week 16. The proportion of patients whose Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improved by 50% from baseline, and also the change in Bath Ankylosing Spondylitis Functional Index (BASFI) score from baseline, were collected as secondary endpoints. The committee noted that the MEASURE 1 and 2 trials assessed patients at 16 weeks (in accordance with the marketing authorisation) rather than 12 weeks, which is the standard assessment point used for TNF‑alpha inhibitors (see NICE's technology appraisal guidance on TNF-alpha inhibitors for AS). The clinical experts stated that patients on TNF‑alpha inhibitors are routinely assessed at 12 weeks as recommended in the guidance. However, if a patient had a partial response to treatment at 12 weeks clinicians might continue TNF‑alpha inhibitor treatment and reassess at 6 months. The MEASURE trials demonstrated statistically significant improvements in ASAS 20 for secukinumab; 60.8% (odds ratio 3.89, 95% confidence interval 2.28 to 6.65, p<0.05) in MEASURE 1, and 61.1% (OR 4.38, 95% CI 2.14 to 8.96, p<0.05) in MEASURE 2, compared with 28.7% and 28.4% for placebo respectively. There were also statistically significant improvements in the BASDAI 50 (the proportion of patients achieving a 50% improvement in BASDAI score) and in the change from baseline BASFI scores in the secukinumab arms of the trials compared with placebo. The committee noted, and the clinical experts confirmed, that the magnitude of response in the MEASURE trials was broadly stable between 12 and 16 weeks. The committee concluded that the outcome measures used in the trials were appropriate, and that the 16‑week assessment of response was in line with the marketing authorisation, and acceptable for decision making. The committee concluded that secukinumab was associated with a statistically significant improvement, compared with placebo, for the disease outcomes included in MEASURE 1 and 2. ## Adverse effects In MEASURE 1 there was a higher rate of treatment‑emergent adverse events in the secukinumab 150‑mg group than in the placebo group (69.6% compared with 55.7%). But in MEASURE 2 the overall incidence of adverse events in the secukinumab 150‑mg group (65.3%) was comparable to placebo (63.5%). Nasopharyngitis was the most frequently reported adverse event in both trials and was observed more often in the secukinumab groups than in the placebo groups of the trials. The committee concluded that the adverse effect profile of secukinumab is acceptable. ## The company's network meta-analysis The company did a network meta-analysis to estimate the relative effectiveness of secukinumab 150 mg and the relevant comparator therapies in a mixed population of patients with AS that had been treated with a biologic agent before (biologic‑experienced) or had not (biologic‑naive), with a subgroup analysis in the biologic‑naive population only. The committee noted that the marketing authorisations for the TNF‑alpha inhibitors are for 'active severe AS' and the marketing authorisation for secukinumab is for 'active AS'. However the clinical experts explained that the inclusion criteria for severity in all the clinical trials was a BASDAI score equal to or greater than 4, and so all the treatments had been compared in a similar population. The company's base-case analysis was based on the time of primary endpoint assessment for each treatment, which was week 12 for the TNF‑alpha inhibitors and week 16 for secukinumab. The data from both the MEASURE trials was pooled for secukinumab. The clinical experts advised that because the magnitude of response was similar in MEASURE 1 and 2, it was reasonable for the company to include them both in its meta-analysis. The company's mixed‑treatment comparison showed higher efficacy for secukinumab 150 mg compared with placebo across all outcomes for the whole population and also for the biologic-naive subgroup, with similar efficacy in both populations. The committee concluded that secukinumab has a similar efficacy to the TNF‑alpha inhibitors. # Cost effectiveness The committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. The cost-effectiveness evidence is in the company's submission (pages 156–239), in the company's response to clarification and in the ERG report (pages 88–186). ## The company's model The company based its model's structure on the York model developed for NICE's technology appraisal guidance on TNF-alpha inhibitors for AS. The committee noted that the York model had been criticised by the committee for that appraisal for the manner in which the response rates and absolute change from baseline at the end of the induction period were derived independently from evidence synthesis. The committee acknowledged the ERG's comment that an alternative model, such as patient-level simulation, could have been used. This would have reflected patient heterogeneity, the dependence between baseline BASDAI and BASFI values, the change from baseline values and response rates at the end of the induction period. However, the committee concluded that for the purposes of this appraisal, the broad principles of the York model were appropriate. The company's base‑case cost-effectiveness analysis, for the biologic‑naive population, took into account the patient access schemes for secukinumab, golimumab and certolizumab pegol. The committee noted that: secukinumab had the lowest acquisition and administration costs and was associated with more quality-adjusted life years (QALYs) than most of the TNF‑alpha inhibitors. in all of the scenarios explored by the company, secukinumab was the least expensive treatment compared with all the TNF‑alpha inhibitors (see table 107 of the company's submission for more details). The company's base-case cost‑effectiveness analysis for the biologic-experienced population also took into account the patient access scheme for secukinumab. The incremental cost-effectiveness ratio (ICER) for secukinumab compared to conventional care was £2,245 per QALY gained for the biologic‑experienced population. ## The ERG's analyses The ERG's exploratory analyses used a network meta-analysis, including secukinumab data from both MEASURE 1 and MEASURE 2, assessing response at week 12 instead of week 16, and using a standard withdrawal rate for all treatments as in the York model. The results of the ERG's exploratory base case were similar to the company's in that secukinumab remained the least expensive treatment, although the QALYs gained (9.185) were lower than in the company's base-case analysis (9.805) and were also lower than most TNF‑alpha inhibitors except etanercept and its biosimilars. The committee noted that the ICERs for the TNF‑alpha inhibitors compared with secukinumab ranged from approximately £38,800 to £71,600 per QALY gained, which is outside the range that is normally considered to be a cost‑effective use of NHS resources. The ERG's additional scenario analyses tested structural uncertainties in the assumptions in the base case. The committee noted that in the biologic‑naive population, secukinumab dominates etanercept (both original and biosimilar version); that is, it results in more QALYs and lower costs in all scenarios. Infliximab (both original and biosimilar version at list price) is associated with higher QALYs and higher costs than secukinumab. Adalimumab, golimumab and certolizumab pegol are mostly associated with higher QALYs and higher costs than secukinumab. For the scenarios in which different treatment effectiveness inputs were used (for example, from different network meta-analyses), secukinumab dominates these treatments; that is, secukinumab provides higher QALYs with lower costs. In the biologic-experienced population, in almost all of the ERG's scenario analyses, secukinumab was associated with higher QALYs and higher costs, with ICER values below £20,000 per QALY. ## The committee's conclusions Based on the analyses presented by the company and ERG, the committee concluded that secukinumab was less expensive and resulted in a similar number of QALYs to the TNF‑alpha inhibitors in people with AS that had not been treated with a biologic agent before. The committee concluded that secukinumab could be considered a cost-effective use of NHS resources for people with AS that has not been previously treated with TNF‑alpha inhibitors. In the biologic‑experienced population, the committee noted that the ICER for secukinumab compared to conventional care was £2,245 per QALY gained in the company base case and was similar in the ERG's exploratory base case (£2,223 per QALY gained). The committee concluded that secukinumab could be considered a cost-effective use of NHS resources for people with AS that has been previously treated with TNF‑alpha inhibitors. ## Innovation The company stated that secukinumab is innovative and a step change in the management of active AS, because it is the first in its class and differs in its mechanism of action from existing treatments. The committee accepted that secukinumab is a promising new advance in treating people with active AS. The committee concluded that secukinumab could be considered an innovative new treatment for the treatment of active AS but did not identify any quantifiable additional effects which had not been taken into account in the calculation of cost effectiveness. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA407 Appraisal title: Secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors Section Key conclusion Secukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis (AS) in adults whose disease has responded inadequately to conventional therapy (non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme. The committee concluded that secukinumab could be considered a cost-effective use of NHS resources for people with AS that has, or has not, been previously treated with TNF-alpha inhibitors. Current practice Clinical need of patients, including the availability of alternative treatments The committee understood the important role of TNF‑alpha inhibitors in the management of AS and that the choice of agent is made on an individual patient basis, based on disease characteristics and extra-articular symptoms (non-spinal manifestations of disease). The committee concluded that the availability of an effective new treatment option would be valuable for people with active AS. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Secukinumab is the first in its class of interleukin‑17A inhibitors and has a different mechanism of action than the TNF‑alpha inhibitors. The committee accepted that secukinumab is a promising new advance and could be considered an innovative new treatment for the treatment of active AS. What is the position of the treatment in the pathway of care for the condition? The committee concluded that secukinumab could be considered an effective new treatment option for people with AS that has, or has not, been previously treated with TNF‑alpha inhibitors. Adverse reactions In the MEASURE 1 trial there was a higher rate of treatment‑emergent adverse events in the secukinumab 150‑mg group than in the placebo group. But in MEASURE 2, the overall incidence of adverse events in the secukinumab group was comparable to placebo. The committee concluded that the adverse effect profile of secukinumab is acceptable. Evidence for clinical effectiveness Availability, nature and quality of evidence The MEASURE 1 and MEASURE 2 trials compared secukinumab with placebo in active AS, and were conducted across international sites. Relevance to general clinical practice in the NHS The committee concluded that the results from MEASURE 1 and MEASURE 2 were comparable and generalisable to the UK population. Uncertainties generated by the evidence The committee expressed concern that concomitant treatments, which were not used in trials for TNF‑alpha inhibitors, might have affected the results of the trials. It also considered whether the results of MEASURE 1 were relevant to the use of subcutaneously administered secukinumab in UK clinical practice as an intravenously administered dose was used up to week 8, not reflecting the regimen which was subsequently licensed. The committee concluded that the results from MEASURE 1 and MEASURE 2 were comparable and generalisable to the UK population. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that secukinumab was associated with a statistically significant improvement, compared with placebo, for the disease outcomes included in MEASURE 1 and MEASURE 2. The company's mixed‑treatment comparison showed higher efficacy for secukinumab 150 mg compared with placebo across all outcomes for the whole population and also for the biologic-naive subgroup, with similar efficacy in both populations. The committee concluded that secukinumab has a similar efficacy to the TNF‑alpha inhibitors. Evidence for cost effectiveness Availability and nature of evidence The company based its model's structure on the York model developed for NICE's technology appraisal guidance on TNF-alpha inhibitors for AS. The committee concluded that for the purposes of this appraisal, the broad principles of the York model were appropriate. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee noted that the York model had been criticised for the manner in which the response rates and absolute change from baseline at the end of the induction period were derived independently from evidence synthesis. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The company based its model's structure on the York model developed for NICE's technology appraisal on TNF-alpha inhibitors for AS in which the response rates and absolute change from baseline at the end of the induction period were derived independently from evidence synthesis. Are there specific groups of people for whom the technology is particularly cost effective? There are no specific groups of people with active AS for whom secukinumab is particularly cost effective. What are the key drivers of cost effectiveness? The cost of secukinumab and the choice of network meta-analysis. Most likely cost-effectiveness estimate (given as an ICER) Based on the analyses presented by the company and ERG, the committee concluded that secukinumab was less expensive and resulted in a similar number of QALYs to the TNF‑alpha inhibitors in people with AS that had not been treated with a biologic agent before. In the biologic‑experienced population, the committee noted that the ICER for secukinumab compared to conventional care was £2,245 per QALY gained in the company base case and was similar in the ERG's exploratory base case (£2,223 per QALY gained). Additional factors taken into account Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of secukinumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End-of-life considerations Equalities considerations and social value judgements None.	{'Recommendations': 'Secukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis in adults whose disease has responded inadequately to conventional therapy (non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\nAssess the response to secukinumab after 16\xa0weeks of treatment and only continue if there is clear evidence of response, defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.\n\nWhen using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.', 'The technology': "Description of the technology\n\nSecukinumab (Cosentyx, Novartis). It is a monoclonal antihuman antibody of the IgG1/kappa isotype that targets interleukin‑17A.\n\nMarketing authorisation\n\nSecukinumab has a marketing authorisation in the UK for the treatment of active ankylosing spondylitis 'in adults who have responded inadequately to conventional therapy'.\n\nAdverse reactions\n\nThe overall incidence of treatment-emergent adverse events up to week\xa016 in the MEASURE\xa02 trial was comparable between the secukinumab 150‑mg group (65.3%) and the placebo group (63.5%). In MEASURE\xa01 there was a higher rate in the secukinumab 150‑mg group than with placebo (69.6% compared with 55.7%). There were no treatment-related deaths. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dose is 150\xa0mg once weekly given by subcutaneous injection at weeks\xa00, 1, 2 and\xa03; followed by a maintenance dose once a month starting at week\xa04.\n\nPrice\n\nSecukinumab is available at the list price of £609.39 for a 150‑mg pre-filled pen or syringe (excluding VAT, 'British national formulary' [BNF] July 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of secukinumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). It also considered evidence received from patient and professional groups. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of secukinumab, having considered evidence on the nature of ankylosing spondylitis (AS) and the value placed on the benefits of secukinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe committee discussed the clinical-effectiveness evidence presented by the company, its critique by the evidence review group (ERG) and evidence submitted by patient and professional groups. The clinical-effectiveness evidence for secukinumab is in the company's submission (pages\xa042–155) and in the ERG report (pages\xa033–87).\n\n## Current clinical management of active ankylosing spondylitis\n\nThe clinical experts stated that the response criteria used in NICE's technology appraisal on TNF‑alpha inhibitors for AS – that is, a reduction in the BASDAI score to 50% of the pre-treatment value or by 2\xa0or more units, and a reduction in the spinal pain visual analogue scale (VAS) by 2\xa0cm or more – are used in clinical practice and are relevant to the appraisal of secukinumab in active AS.\n\nPeople with AS may have additional non-spinal manifestations of disease such as uveitis, colitis, psoriasis, and peripheral arthritis. TNF‑alpha inhibitors have different effects on extra‑articular manifestations and so the choice of TNF‑alpha inhibitor in clinical practice is based on individual patient characteristics and guided by any additional indications included in the marketing authorisation. Secukinumab has a licence for, and is recommended in NICE's technology appraisal guidance on, secukinumab for the treatment of moderate to severe plaque psoriasis. It also has a licence for psoriatic arthritis and is the subject of an ongoing NICE technology appraisal. The committee understood that the choice of agent for treating AS is made on an individual patient basis, based on disease characteristics and extra-articular symptoms.\n\nThe committee noted that a patient organisation submission included a survey of several hundred patients with AS, which summarised the major effect that the disease has on people's health and quality of life. The committee heard that having a greater choice of treatments would be particularly valuable to people with this condition, allowing them and their clinicians to choose treatments that take into account their individual needs and preferences and giving them a feeling of more control over their condition. The clinical experts stated that the novel mechanism of action of secukinumab, and its other marketing authorisations for psoriasis and psoriatic arthritis, would give patients and clinicians a greater choice of targeted treatment options. A patient expert stated that it is particularly important to have the option of a treatment with a different mechanism of action for patients whose disease did not respond to one or more TNF‑alpha inhibitors. The committee concluded that the availability of an effective new treatment option would be valuable for people with active AS.\n\n## The evidence from the MEASURE trials\n\nThe MEASURE\xa01 and MEASURE\xa02 trials, which compared secukinumab with placebo in active AS, were conducted across international sites. The committee expressed concern that concomitant treatments, which were not used in trials for TNF‑alpha inhibitors (such as methotrexate and sulfasalazine), might have affected the results of the trials and their generalisability to UK clinical practice. The clinical experts stated that non-biological agents such as methotrexate and sulfasalazine have no proven activity in spinal disease but may be prescribed for extra-articular manifestations. The committee noted that MEASURE\xa01 and MEASURE\xa02 did not assess the effect of treatments on extra-articular manifestations, only the effects on AS. It also considered whether the results of MEASURE\xa01 were relevant to the use of subcutaneously administered secukinumab in UK clinical practice, as an intravenously administered dose was used up to week\xa04 (at week\xa08 and every subsequent 4\xa0weeks secukinumab was administered subcutaneously), not reflecting the regimen which was subsequently licensed. The clinical experts stated that the magnitude of response in both studies was similar despite the differences between them in administration and loading dose. The committee concluded that the results from MEASURE\xa01 and MEASURE\xa02 were comparable and generalisable to the UK population.\n\nThe primary outcome measure in the MEASURE trials was the proportion of patients who had an Assessment in Spondyloarthritis International Society (ASAS)\xa020 response at week\xa016. The proportion of patients whose Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improved by 50% from baseline, and also the change in Bath Ankylosing Spondylitis Functional Index (BASFI) score from baseline, were collected as secondary endpoints. The committee noted that the MEASURE\xa01 and\xa02 trials assessed patients at 16\xa0weeks (in accordance with the marketing authorisation) rather than 12\xa0weeks, which is the standard assessment point used for TNF‑alpha inhibitors (see NICE's technology appraisal guidance on TNF-alpha inhibitors for AS). The clinical experts stated that patients on TNF‑alpha inhibitors are routinely assessed at 12\xa0weeks as recommended in the guidance. However, if a patient had a partial response to treatment at 12\xa0weeks clinicians might continue TNF‑alpha inhibitor treatment and reassess at 6\xa0months.\n\nThe MEASURE trials demonstrated statistically significant improvements in ASAS\xa020 for secukinumab; 60.8% (odds ratio [OR] 3.89, 95%\xa0confidence interval [CI] 2.28 to 6.65, p<0.05) in MEASURE\xa01, and 61.1% (OR 4.38, 95%\xa0CI 2.14 to 8.96, p<0.05) in MEASURE\xa02, compared with 28.7% and 28.4% for placebo respectively. There were also statistically significant improvements in the BASDAI 50 (the proportion of patients achieving a 50% improvement in BASDAI score) and in the change from baseline BASFI scores in the secukinumab arms of the trials compared with placebo. The committee noted, and the clinical experts confirmed, that the magnitude of response in the MEASURE trials was broadly stable between 12\xa0and 16\xa0weeks. The committee concluded that the outcome measures used in the trials were appropriate, and that the 16‑week assessment of response was in line with the marketing authorisation, and acceptable for decision making. The committee concluded that secukinumab was associated with a statistically significant improvement, compared with placebo, for the disease outcomes included in MEASURE\xa01 and\xa02.\n\n## Adverse effects\n\nIn MEASURE\xa01 there was a higher rate of treatment‑emergent adverse events in the secukinumab 150‑mg group than in the placebo group (69.6% compared with 55.7%). But in MEASURE\xa02 the overall incidence of adverse events in the secukinumab 150‑mg group (65.3%) was comparable to placebo (63.5%). Nasopharyngitis was the most frequently reported adverse event in both trials and was observed more often in the secukinumab groups than in the placebo groups of the trials. The committee concluded that the adverse effect profile of secukinumab is acceptable.\n\n## The company's network meta-analysis\n\nThe company did a network meta-analysis to estimate the relative effectiveness of secukinumab 150\xa0mg and the relevant comparator therapies in a mixed population of patients with AS that had been treated with a biologic agent before (biologic‑experienced) or had not (biologic‑naive), with a subgroup analysis in the biologic‑naive population only. The committee noted that the marketing authorisations for the TNF‑alpha inhibitors are for 'active severe AS' and the marketing authorisation for secukinumab is for 'active AS'. However the clinical experts explained that the inclusion criteria for severity in all the clinical trials was a BASDAI score equal to or greater than\xa04, and so all the treatments had been compared in a similar population.\n\nThe company's base-case analysis was based on the time of primary endpoint assessment for each treatment, which was week\xa012 for the TNF‑alpha inhibitors and week\xa016 for secukinumab. The data from both the MEASURE trials was pooled for secukinumab. The clinical experts advised that because the magnitude of response was similar in MEASURE\xa01 and\xa02, it was reasonable for the company to include them both in its meta-analysis. The company's mixed‑treatment comparison showed higher efficacy for secukinumab 150\xa0mg compared with placebo across all outcomes for the whole population and also for the biologic-naive subgroup, with similar efficacy in both populations. The committee concluded that secukinumab has a similar efficacy to the TNF‑alpha inhibitors.\n\n# Cost effectiveness\n\nThe committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. The cost-effectiveness evidence is in the company's submission (pages 156–239), in the company's response to clarification and in the ERG report (pages 88–186).\n\n## The company's model\n\nThe company based its model's structure on the York model developed for NICE's technology appraisal guidance on TNF-alpha inhibitors for AS. The committee noted that the York model had been criticised by the committee for that appraisal for the manner in which the response rates and absolute change from baseline at the end of the induction period were derived independently from evidence synthesis. The committee acknowledged the ERG's comment that an alternative model, such as patient-level simulation, could have been used. This would have reflected patient heterogeneity, the dependence between baseline BASDAI and BASFI values, the change from baseline values and response rates at the end of the induction period. However, the committee concluded that for the purposes of this appraisal, the broad principles of the York model were appropriate.\n\nThe company's base‑case cost-effectiveness analysis, for the biologic‑naive population, took into account the patient access schemes for secukinumab, golimumab and certolizumab pegol. The committee noted that:\n\nsecukinumab had the lowest acquisition and administration costs and was associated with more quality-adjusted life years (QALYs) than most of the TNF‑alpha inhibitors.\n\nin all of the scenarios explored by the company, secukinumab was the least expensive treatment compared with all the TNF‑alpha inhibitors (see table\xa0107 of the company's submission for more details).\n\nThe company's base-case cost‑effectiveness analysis for the biologic-experienced population also took into account the patient access scheme for secukinumab. The incremental cost-effectiveness ratio (ICER) for secukinumab compared to conventional care was £2,245 per QALY gained for the biologic‑experienced population.\n\n## The ERG's analyses\n\nThe ERG's exploratory analyses used a network meta-analysis, including secukinumab data from both MEASURE\xa01 and MEASURE\xa02, assessing response at week\xa012 instead of week\xa016, and using a standard withdrawal rate for all treatments as in the York model. The results of the ERG's exploratory base case were similar to the company's in that secukinumab remained the least expensive treatment, although the QALYs gained (9.185) were lower than in the company's base-case analysis (9.805) and were also lower than most TNF‑alpha inhibitors except etanercept and its biosimilars. The committee noted that the ICERs for the TNF‑alpha inhibitors compared with secukinumab ranged from approximately £38,800 to £71,600 per QALY gained, which is outside the range that is normally considered to be a cost‑effective use of NHS resources.\n\nThe ERG's additional scenario analyses tested structural uncertainties in the assumptions in the base case. The committee noted that in the biologic‑naive population, secukinumab dominates etanercept (both original and biosimilar version); that is, it results in more QALYs and lower costs in all scenarios. Infliximab (both original and biosimilar version at list price) is associated with higher QALYs and higher costs than secukinumab. Adalimumab, golimumab and certolizumab pegol are mostly associated with higher QALYs and higher costs than secukinumab. For the scenarios in which different treatment effectiveness inputs were used (for example, from different network meta-analyses), secukinumab dominates these treatments; that is, secukinumab provides higher QALYs with lower costs. In the biologic-experienced population, in almost all of the ERG's scenario analyses, secukinumab was associated with higher QALYs and higher costs, with ICER values below £20,000 per QALY.\n\n## The committee's conclusions\n\nBased on the analyses presented by the company and ERG, the committee concluded that secukinumab was less expensive and resulted in a similar number of QALYs to the TNF‑alpha inhibitors in people with AS that had not been treated with a biologic agent before. The committee concluded that secukinumab could be considered a cost-effective use of NHS resources for people with AS that has not been previously treated with TNF‑alpha inhibitors.\n\nIn the biologic‑experienced population, the committee noted that the ICER for secukinumab compared to conventional care was £2,245 per QALY gained in the company base case and was similar in the ERG's exploratory base case (£2,223 per QALY gained). The committee concluded that secukinumab could be considered a cost-effective use of NHS resources for people with AS that has been previously treated with TNF‑alpha inhibitors.\n\n## Innovation\n\nThe company stated that secukinumab is innovative and a step change in the management of active AS, because it is the first in its class and differs in its mechanism of action from existing treatments. The committee accepted that secukinumab is a promising new advance in treating people with active AS. The committee concluded that secukinumab could be considered an innovative new treatment for the treatment of active AS but did not identify any quantifiable additional effects which had not been taken into account in the calculation of cost effectiveness.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA407\n\nAppraisal title: Secukinumab for active ankylosing spondylitis after treatment with non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors\n\nSection\n\nKey conclusion\n\nSecukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis (AS) in adults whose disease has responded inadequately to conventional therapy (non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors). The drug is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\nThe committee concluded that secukinumab could be considered a cost-effective use of NHS resources for people with AS that has, or has not, been previously treated with TNF-alpha inhibitors.\n\n, 4.17, 4.18\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee understood the important role of TNF‑alpha inhibitors in the management of AS and that the choice of agent is made on an individual patient basis, based on disease characteristics and extra-articular symptoms (non-spinal manifestations of disease). The committee concluded that the availability of an effective new treatment option would be valuable for people with active AS.\n\n, 4.4\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nSecukinumab is the first in its class of interleukin‑17A inhibitors and has a different mechanism of action than the TNF‑alpha inhibitors. The committee accepted that secukinumab is a promising new advance and could be considered an innovative new treatment for the treatment of active AS.\n\n, 4.19\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that secukinumab could be considered an effective new treatment option for people with AS that has, or has not, been previously treated with TNF‑alpha inhibitors.\n\n, 4.18, 4.19\n\nAdverse reactions\n\nIn the MEASURE\xa01 trial there was a higher rate of treatment‑emergent adverse events in the secukinumab 150‑mg group than in the placebo group. But in MEASURE\xa02, the overall incidence of adverse events in the secukinumab group was comparable to placebo. The committee concluded that the adverse effect profile of secukinumab is acceptable.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe MEASURE\xa01 and MEASURE\xa02 trials compared secukinumab with placebo in active AS, and were conducted across international sites.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that the results from MEASURE\xa01 and MEASURE\xa02 were comparable and generalisable to the UK population.\n\n\n\nUncertainties generated by the evidence\n\nThe committee expressed concern that concomitant treatments, which were not used in trials for TNF‑alpha inhibitors, might have affected the results of the trials. It also considered whether the results of MEASURE\xa01 were relevant to the use of subcutaneously administered secukinumab in UK clinical practice as an intravenously administered dose was used up to week\xa08, not reflecting the regimen which was subsequently licensed. The committee concluded that the results from MEASURE\xa01 and MEASURE\xa02 were comparable and generalisable to the UK population.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\n–\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that secukinumab was associated with a statistically significant improvement, compared with placebo, for the disease outcomes included in MEASURE\xa01 and MEASURE\xa02.\n\nThe company's mixed‑treatment comparison showed higher efficacy for secukinumab 150\xa0mg compared with placebo across all outcomes for the whole population and also for the biologic-naive subgroup, with similar efficacy in both populations. The committee concluded that secukinumab has a similar efficacy to the TNF‑alpha inhibitors.\n\n, 4.10\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company based its model's structure on the York model developed for NICE's technology appraisal guidance on TNF-alpha inhibitors for AS. The committee concluded that for the purposes of this appraisal, the broad principles of the York model were appropriate.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee noted that the York model had been criticised for the manner in which the response rates and absolute change from baseline at the end of the induction period were derived independently from evidence synthesis.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe company based its model's structure on the York model developed for NICE's technology appraisal on TNF-alpha inhibitors for AS in which the response rates and absolute change from baseline at the end of the induction period were derived independently from evidence synthesis.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThere are no specific groups of people with active AS for whom secukinumab is particularly cost effective.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe cost of secukinumab and the choice of network meta-analysis.\n\n, 4.15\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nBased on the analyses presented by the company and ERG, the committee concluded that secukinumab was less expensive and resulted in a similar number of QALYs to the TNF‑alpha inhibitors in people with AS that had not been treated with a biologic agent before.\n\nIn the biologic‑experienced population, the committee noted that the ICER for secukinumab compared to conventional care was £2,245 per QALY gained in the company base case and was similar in the ERG's exploratory base case (£2,223 per QALY gained).\n\n, 4.18\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of secukinumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\n–\n\n–\n\nEqualities considerations and social value judgements\n\nNone.\n\n–"}	https://www.nice.org.uk/guidance/ta407	Evidence-based recommendations on secukinumab (Cosentyx) for treating active ankylosing spondylitis that has not responded well enough to conventional therapy.
26c7efd38ca6ddbfd8542bfa439ee61dc4d8d57b	nice	Pegaspargase for treating acute lymphoblastic leukaemia	Pegaspargase for treating acute lymphoblastic leukaemia Evidence-based recommendations on pegaspargase (Oncaspar) for treating acute lymphoblastic leukaemia. # Recommendations Pegaspargase, as part of antineoplastic combination therapy, is recommended as an option for treating acute lymphoblastic leukaemia in children, young people and adults only when they have untreated newly diagnosed disease. This guidance is not intended to affect the position of patients whose treatment with pegaspargase was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or the child or young person's parents or carers.# The technology Description of the technology Pegaspargase (Oncaspar, Baxalta ) is a polyethylene glycol conjugate of Escherichia coli (E. coli)‑derived L‑asparaginase. L‑asparaginase is a bacterial enzyme that depletes circulating asparagine, an essential amino acid on which leukaemic cells, incapable of synthesising asparagine, depend. This leads to cell death. Marketing authorisation Pegaspargase received its marketing authorisation in January 2016. It is indicated as 'a component of antineoplastic combination therapy in acute lymphoblastic leukaemia in paediatric patients from birth to 18 years, and adult patients'. Adverse reactions The most common side effects with pegaspargase (which may affect more than 1 in 10 people) are allergic reactions (including serious allergic reactions), hives, rash, high blood sugar levels, pancreatitis, diarrhoea, and abdominal pain. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Pegaspargase is administered as either an intramuscular or intravenous infusion. Summary of product characteristics Pegaspargase is usually used as part of combination chemotherapy protocols with other antineoplastic agents. Paediatric patients and adults ≤21 years The recommended dose of pegaspargase in patients with a body surface area ≥0.6 m2 and who are ≤21 years of age is 2500 IU (equivalent to 3.3 ml pegaspargase)/m2 body surface area every 14 days. Children with a body surface area <0.6 m2 should have 82.5 IU (equivalent to 0.1 ml pegaspargase)/kg body weight every 14 days. Adults >21 years Unless otherwise prescribed, the recommended posology in adults aged >21 years is 2000 IU/m2 every 14 days. Clinical practice The protocols for the ongoing UKALL trials, on which current clinical practice is based, recommend a dosage of 1,000 IU/m2. The UKALL trials have demonstrated that in clinical practice, dosing frequency depends on the patient's age, the phase of treatment in which pegaspargase is given (induction, consolidation, intensification, and so on), and the length of each phase. The average length of a course of treatment depends on the individual UKALL treatment protocols for patients in different age groups. Price The acquisition cost of pegaspargase is £1,296.19 per vial (excluding VAT; price confirmed by company). For paediatric and young adult patients, a course of pegaspargase costs between £5,144 (intermediate/standard-risk patients) and £15,246 (high-risk patients), assuming that patients complete the treatment (with no hypersensitivity) as per the UKALL 2003 protocol. For adult patients, a course of pegaspargase costs between £6,034 (for those aged 41 years or over) and £7,544 (for those aged 40 years and under), assuming that patients complete the treatment (with no hypersensitivity) as per the UKALL14 protocol, and don't have a transplant. Costs are based on a dose of 1,000 IU/m2 as used in clinical practice, which equates to 1 vial of pegaspargase per dose. Although the summary of product characteristics dose is higher (2,000 to 2,500 IU/m2), only 1 vial would be used per treatment administration. Costs may vary in different settings because of negotiated procurement discounts.# Evidence The appraisal committee (section 6) considered evidence submitted by Baxalta (now part of Shire Pharmaceuticals) and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of pegaspargase, having considered evidence on the nature of acute lymphoblastic leukaemia and the value placed on the benefits of pegaspargase by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical management of acute lymphoblastic leukaemia The committee understood that a diagnosis of acute lymphoblastic leukaemia can have a profound effect on a person's physical and psychological wellbeing. It also acknowledged that acute lymphoblastic leukaemia does not affect the patient in isolation, but also places emotional strain on their families and friends. The committee was aware that, because of this, access to effective treatments and improving quality of life are significant benefits to patients and their families. The committee heard from the clinical expert that most people with newly diagnosed acute lymphoblastic leukaemia have pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, and that pegaspargase has been included in NHS England baseline commissioning since April 2013, even though pegaspargase did not have a marketing authorisation in the UK. The committee also heard that most patients in the UK are enrolled into the UKALL trials: UKALL 2011 for children and young adults up to the age of 25 years (previously UKALL 2003, October 2003 to June 2009), UKALL14 for adults aged 25 to 65 years, and UKALL60+ for people over the age of 60 years. Even if a patient is not enrolled in these trials directly, they will still have treatment based on the UKALL protocols because the protocols inform clinical practice in England. Both the UKALL 2011 (and previously UKALL 2003) and UKALL14 trials include pegaspargase as the preferred choice of asparaginase therapy, as a component of the multi-agent chemotherapy regimen. This is because pegaspargase has a longer half-life than the non-pegylated forms of asparaginase (Escherichia coli ‑derived L‑asparaginase and Erwinia chrysanthemi‑derived L‑asparaginase) and so can be given less frequently. This is important to patients because native E. coli‑derived asparaginase is only available in injectable (intramuscular) forms. Intramuscular injections are painful, so less frequent injections are preferable. In addition, pegaspargase is considered preferable to native E. coli‑derived asparaginase because pegaspargase appears to be less immunogenic. This leads to the production of anti-asparaginase antibodies in 45% to 75% of patients, which frequently cause hypersensitivity reactions that limit treatment effectiveness. The UKALL protocols also mandate switching to Erwinia‑derived asparaginase rather than to another E. coli‑derived asparaginase following hypersensitivity to pegaspargase, because of the risk of cross reactivity and subsequent hypersensitivity. The committee heard that adult patients with Philadelphia-positive acute lymphoblastic leukaemia may not necessarily benefit from pegaspargase. This is because evidence suggests that these patients can achieve high remission rates with tyrosine kinase inhibitor-based induction therapies without the added risks of asparaginase therapy. To this end, the UKALL14 protocol specifies that patients with Philadelphia-positive acute lymphoblastic leukaemia do not have asparaginase therapy. The committee concluded that the current treatment pathway in England for most people with newly diagnosed acute lymphoblastic leukaemia is pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity. ## Company's decision problem The committee discussed the company's decision problem in relation to the marketing authorisation for pegaspargase and the final scope issued by NICE. The committee was aware that the population specified in pegaspargase's marketing authorisation was 'for acute lymphoblastic leukaemia in paediatric patients from birth to 18 years, and adult patients'. The committee was aware that the company's decision problem was narrower than both the marketing authorisation for pegaspargase and the final NICE scope, in that it focused on pegaspargase as the preferred choice of asparaginase therapy for people with untreated, newly diagnosed acute lymphoblastic leukaemia. The committee noted that the marketing authorisation does not preclude pegaspargase's use following other asparaginase therapies or as a treatment for relapsed disease. The company considered that the current use of pegaspargase in the UK for people with untreated, newly diagnosed acute lymphoblastic leukaemia was driven by the UKALL protocols. It was also aware that the UKALL protocols do not include people with relapsed disease and that the committee was not presented with evidence on the use of pegaspargase for treating relapsed acute lymphoblastic leukaemia. The committee concluded that the company's decision problem for people with untreated, newly diagnosed acute lymphoblastic leukaemia was appropriate for its decision-making because this best reflected the use of pegaspargase in established clinical practice in England. # Clinical effectiveness ## Untreated and newly diagnosed acute lymphoblastic leukaemia For children and young people, the committee noted that the company had identified 2 studies as the focus of its submission (CCG‑1962 and UKALL 2003) and 3 further studies (CCG‑1961, DFCI‑91‑01 and DFCI ALL 05‑00) as supporting evidence in children and young people. The committee was aware that all of these studies compared pegaspargase 2,500 IU/m2 with native E. coli‑derived asparaginase. The committee also noted that the evidence review group (ERG) had identified 3 further studies from the company's systematic review: DFCI ALL 05‑01, which compared pegaspargase 2,500 IU/m2 with native E. coli‑derived asparaginase; and the DFCI‑95‑01 and EORTC‑CLG 58881 studies, which compared Erwinia‑derived asparaginase with native E. coli‑derived asparaginase. The committee accepted the ERG's concerns about CCG‑1962 being a small study and UKALL 2003 being a non-comparative study. Nevertheless, it agreed that despite the limitations of these studies, it was appropriate to consider all the available studies in its decision-making. For adults, the committee noted that both the company and ERG had identified 3 non-comparative studies (Douer 2007, Douer 2014 and Wetzler 2007), all of which examined the efficacy of pegaspargase 2,000 IU/m2 or 2,500 IU/m2. The committee accepted the ERG's concerns that each study was non-comparative, and so provided no evidence for the relative effectiveness of pegaspargase compared with other asparaginases as listed in the final scope issued by NICE. The committee agreed that despite the limitations of these studies, it was appropriate to consider all the available studies in its decision-making. The committee discussed the generalisability of the results from all the trials comparing a 2,000 IU/m2 to 2,500 IU/m2 dose of pegaspargase with E. coli‑derived asparaginase or Erwinia‑derived asparaginase to clinical practice in England (see section 4.2). The committee noted that the summary of product characteristics also recommends a pegaspargase dose of 2,000 to 2,500 IU/m2. In contrast, all the UKALL protocols used 1,000 IU/m2. The committee was aware from the company, the clinical expert and a statement received from a professional group that UKALL 2003 provided favourable long-term outcomes and safety evidence for pegaspargase 1,000 IU/m2 in more than 3,200 children and young adults with acute lymphoblastic leukaemia between 2003 and 2011, accounting for more than 97% of the eligible patient population over that time. The committee was also aware that these data had reassured the clinical community in its continued use of 1,000 IU/m2 as the standard of care in the UKALL 2011 paediatric protocol and to adopt it in the UKALL14 adult protocol. The committee heard from the clinical expert that there is currently no intent among clinicians to increase the dose of pegaspargase to the levels recommended in the summary of product characteristics because of the increased risk of treatment-related toxicity, which is of particular concern in children over 10 years who have higher rates of toxicity-related mortality. The committee heard that in children, clinical practice is moving towards giving lower doses more frequently, and that children will have a maximum of 8 doses of pegaspargase during their treatment for acute lymphoblastic leukaemia. The committee also heard that most clinicians choose not to increase the dosage above 1,000 IU/m2 in adults and that most are offered bone or stem cell transplant if disease clearance is not achieved with 1,000 IU/m2 doses of pegaspargase. The committee concluded that although there was no comparative evidence available for pegaspargase 1,000 IU/m2 compared with other asparaginases or with pegaspargase 2,500 IU/m2, it was appropriate for it to use the lower dose of pegaspargase in its decision-making, because this is reflective of the dose used in clinical practice in England. The committee was aware that 4 studies provided survival data in children for the comparison of pegaspargase 2,500 IU/m2 with native E. coli‑derived asparaginase. Of these studies, it noted that 2 showed results in favour of pegaspargase in terms of event-free survival (CCG‑1961 and CCG‑1962), 1 showed non-statistically significant results in favour of E. coli‑derived asparaginase in terms of event-free survival (DFCI ALL 91‑01), and 1 showed little difference between the 2 interventions in terms of overall survival and event-free survival (DFCI ALL 05‑001). The committee also noted that the company's meta-analysis of 39 studies in children showed results in favour of pegaspargase in terms of 5‑year event-free survival and overall survival. The committee accepted that the studies in children did not show a difference in the clinical effectiveness of pegaspargase and E. coli‑derived asparaginase, and agreed that it was unclear as to whether this was a result of the lack of evidence or simply a lack of a difference in effect. None of the included studies was powered to assess equivalence and it was not appropriate to pool the results from the different studies because of their heterogeneity. The committee noted the lack of comparative evidence for the relative effectiveness of pegaspargase with other asparaginase therapies in adults (see section 4.6), and was aware that most of the trials in acute lymphoblastic leukaemia have been done in children and young people. The committee was also aware that as part of its regulatory submission to the European Medicines Agency, the company had included data from the UKALL 2003 and Douer 2007 trials to support its application for pegaspargase's marketing authorisation to apply to all ages. The committee heard from the clinical expert, and was aware from the statements received from professional organisations representing clinicians, that although it was difficult to establish clinical equivalence of pegaspargase and the other asparaginase therapies based on the studies alone, clinicians consider pegaspargase and E. coli‑derived asparaginase to be equivalent in terms of clinical effectiveness in both children and adults based on their experience in the UKALL trials. Furthermore, clinicians prefer to use pegaspargase because of the reduced risk of hypersensitivity reactions and its longer half-life (see section 4.2). The committee acknowledged that uncertainty around the clinical effectiveness of pegaspargase in people of different ages might be addressed in the ongoing UKALL 2011 and UKALL14 trials and in the post-authorisation studies required by the European Medicines Agency as a condition of its granting of the marketing authorisation. The committee accepted that although there was some uncertainty in terms of the clinical effectiveness of pegaspargase compared with E. coli‑derived asparaginase, it was reasonable to assume on current available evidence that they were equivalent in terms of event-free survival and overall survival in people of all ages with untreated newly diagnosed acute lymphoblastic leukaemia. ## Previously treated acute lymphoblastic leukaemia The committee noted that that it had not been presented with any evidence for the efficacy of pegaspargase in people with relapsed acute lymphoblastic leukaemia, because the company's decision problem was based on how pegaspargase is used in clinical practice for people with untreated, newly diagnosed acute lymphoblastic leukaemia (see section 4.6). The committee concluded that it was inappropriate to make a recommendation for pegaspargase in people with previously treated relapsed acute lymphoblastic leukaemia. # Cost effectiveness ## Economic model The company presented a combined decision tree and health state transition Markov model. The committee agreed that the structures of both parts of the model were appropriate and the combination of the 2 was well suited for the purpose of the appraisal, because it accurately reflected the treatment pathway for acute lymphoblastic leukaemia. The committee also noted that the model only included patients with untreated, newly diagnosed acute lymphoblastic leukaemia, and it heard from the clinical expert that the model structure reflected clinical practice in England. The committee concluded that the model was in line with accepted NICE methods and therefore appropriate for its decision-making. ## Treatment sequences modelled The company modelled 3 treatment sequences: Pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, compared with E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase in cases of hypersensitivity (comparison 1). Pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, compared with Erwinia‑derived asparaginase followed by pegaspargase in cases of hypersensitivity (comparison 2). Pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, compared with Erwinia‑derived asparaginase followed by E. coli‑derived asparaginase in cases of hypersensitivity (comparison 3).The committee agreed that comparisons 2 and 3 were not relevant for its decision-making, because there was no clinical scenario in which Erwinia‑derived asparaginase would be used as the preferred choice of asparaginase, or in which pegaspargase would be used in cases of hypersensitivity (see section 4.2). For this reason it also agreed not to consider either the company's or the ERG's cost-effectiveness analyses for comparisons 2 and 3 any further. The committee considered whether comparison 1 was relevant for its decision-making. It acknowledged that although E. coli‑derived asparaginase is no longer used as the first choice of asparaginase therapy, it was the standard of care before pegaspargase became available. The committee therefore concluded that comparison 1 was the appropriate comparison for its decision-making. ## Model inputs The committee discussed the assumption that pegaspargase, E. coli‑derived and Erwinia‑derived asparaginase were equivalent in terms of overall survival and event-free survival. The committee noted that both the company and the ERG had used this assumption in their respective base-case analyses, and that both had included a 'worst-case scenario' in which it was assumed that event-free survival was worse for pegaspargase than for E. coli‑derived asparaginase. The committee also noted that the ERG had included a 'best-case scenario' in which it assumed that overall survival and event-free survival were better for pegaspargase than for E. coli‑derived asparaginase. The committee recalled that it had heard from the clinical expert that clinicians consider the 3 asparaginase treatments to be equivalent in terms of clinical effectiveness in both children and adults (see section 4.6). It therefore agreed that it was appropriate to assume that pegaspargase, E. coli‑derived and Erwinia‑derived asparaginase were equivalent in terms of overall survival and event-free survival. The committee discussed the dosage of pegaspargase used in the model. The committee noted that both the company and the ERG had presented their base-case analysis results using the 1,000 IU/m2 dose of pegaspargase, and scenario analyses using the 2,500 IU/m2 dose of pegaspargase. The committee agreed that it preferred to use the 1,000 IU/m2 dose of pegaspargase because it reflected the dose used in clinical practice (see section 4.6). The committee discussed the dosing ratio for E. coli- or Erwinia‑derived asparaginase compared with pegaspargase. The committee noted that, based on expert opinion, the company had assumed a rate of 6 doses of E. coli‑derived asparaginase or Erwinia‑derived asparaginase for each dose of pegaspargase. The committee also noted the ERG's comments that there was no scientific evidence to prove that this was the best ratio of the different formulations and that in other countries; it is considered that 4 doses of E. coli- or Erwinia‑derived asparaginase correspond with 1 dose of pegaspargase. The committee was aware of an ERG scenario analyses in which this ratio of 4:1 had been used. The committee heard from the clinical expert that the dosing ratio for E. coli- or Erwinia‑derived asparaginase compared with pegaspargase would be closer to 6:1 in clinical practice, and therefore agreed that it was appropriate to use this ratio in the economic model. The committee discussed the risk of hypersensitivity used in the economic model. In its base-case analysis, the company had assumed that the risk of hypersensitivity leading to treatment switch was 2% for both first- and second-line asparaginase therapy, based on the first-line hypersensitivity observed in UKALL 2003 with the lower dose (1,000 IU/m2) of pegaspargase. The committee noted that the ERG had used a higher risk of hypersensitivity to pegaspargase in its base-case analysis, based on Nordic data for the 1,000 IU/m2 dose. The committee heard from the clinical expert that the company's assumption of a 2% risk of hypersensitivity was closer to the risk seen in clinical practice for children with acute lymphoblastic leukaemia. The committee therefore concluded that for all ages it preferred to use the company's assumption of 2% risk of hypersensitivity leading to treatment switch in its decision-making. ## Cost-effectiveness estimates The committee noted that in the company's base-case analysis, pegaspargase followed by Erwinia‑derived asparaginase dominated (that is, was both less costly and more effective than) E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase in adults, children, and the whole (combined) population. The committee also noted that pegaspargase followed by Erwinia‑derived asparaginase continued to dominate E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase in all but 1 of the company's scenario analyses for the whole population: the 'worst-case scenario', which produced an incremental cost-effectiveness ratio (ICER) of £20,326 saved per quality-adjusted life year (QALY) lost The committee agreed that the company's worst-case scenario was not relevant to its decision-making (see section 4.11). The committee was aware that the ERG had provided a revised base case and scenario analyses for the whole population. The committee noted that the ERG's base-case analysis for the whole population was consistent with that presented by the company: that is, pegaspargase followed by Erwinia‑derived asparaginase dominated E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase. The committee also noted that pegaspargase followed by Erwinia‑derived asparaginase continued to dominate E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase in all but 2 of the ERG's scenario analyses: the worst-case scenario and the scenario in which 4 doses of E. coli- or Erwinia‑derived asparaginase were applied for each dose of pegaspargase (respective ICERs of £4,810 saved per QALY lost and £36,499 per QALY gained ). The committee agreed that neither of these scenarios were relevant to its decision-making (see sections 4.11 and 4.13). The committee agreed that both the company's and the ERG's scenario analyses demonstrated the robustness of the cost-effectiveness results for pegaspargase followed by Erwinia‑derived asparaginase compared with E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase; that is, pegaspargase followed by Erwinia‑derived asparaginase dominated (that is, was both less costly and more effective). It therefore concluded that it could recommend pegaspargase as a cost-effective use of NHS resources for treating acute lymphoblastic leukaemia in children, young people and adults with untreated, newly diagnosed disease. # Innovation The company stated that it considered pegaspargase to be innovative, because it has become the standard of care for first-line asparaginase treatment for acute lymphoblastic leukaemia in people of all ages. The committee heard from the clinical expert that in clinical practice, pegaspargase is now considered to be an incremental change in the treatment of acute lymphoblastic leukaemia rather than a step change because it has been used in clinical practice for a number of years. The committee concluded that pegaspargase should not be considered a step change in the treatment of acute lymphoblastic leukaemia. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA408 Appraisal title: Pegaspargase for treating acute lymphoblastic leukaemia Section Key conclusion Pegaspargase, as part of antineoplastic combination therapy, is recommended as an option for treating acute lymphoblastic leukaemia in children, young people and adults only when they have untreated newly diagnosed disease. This guidance is not intended to affect the position of patients whose treatment with pegaspargase was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person or the child or young person's parents or carers. The committee accepted that although there was some uncertainty in terms of the clinical effectiveness of pegaspargase compared with that of Escherichia coli (E. coli)‑derived asparaginase, it was reasonable to assume on the current available evidence that they were equivalent in terms of event-free survival and overall survival in people of all ages with untreated, newly diagnosed acute lymphoblastic leukaemia. The committee agreed that both the company's and the evidence review group's (ERG's) scenario analyses demonstrated the robustness of the cost-effectiveness results for pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity compared with E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase in cases of hypersensitivity; that is, pegaspargase followed by Erwinia‑derived asparaginase dominated (was both less costly and more effective) than E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase. The committee therefore concluded that it could recommend pegaspargase as a cost-effective use of NHS resources for treating acute lymphoblastic leukaemia in children, young people and adults with untreated, newly diagnosed disease. Current practice Clinical need of patients, including the availability of alternative treatments The committee understood that a diagnosis of acute lymphoblastic leukaemia can have a profound effect on a person's physical and psychological wellbeing. It also acknowledged that acute lymphoblastic leukaemia does not affect the patient in isolation, but also places emotional strain on their families and friends. The committee was aware that, because of this, access to effective treatments and improving quality of life are significant benefits to patients and their families. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee heard that pegaspargase has a longer half-life than the non-pegylated forms of asparaginase (E. coli‑derived asparaginase and Erwinia‑derived asparaginase), so can be given less frequently to patients. This is important to patients because native E. coli‑derived asparaginase is only available in an injectable form; intramuscular injections are painful, so less frequent injections are preferable. In addition, pegaspargase is considered preferable to native E. coli‑derived asparaginase because pegaspargase appears to be less immunogenic. This leads to the production of anti-asparaginase antibodies in 45% to 75% of patients, which frequently cause hypersensitivity reactions that limit treatment effectiveness. The committee heard from the clinical expert that in clinical practice, pegaspargase is now considered to be an incremental change in the treatment of acute lymphoblastic leukaemia rather than a step change because it has been used in clinical practice for a number of years. The committee concluded that pegaspargase should not be considered a step change in the treatment of acute lymphoblastic leukaemia. What is the position of the treatment in the pathway of care for the condition? The committee heard from the clinical expert that most people with newly diagnosed acute lymphoblastic leukaemia have pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity and that pegaspargase has been included in NHS England baseline commissioning since April 2003. The committee also heard that most patients in the UK are enrolled into the UKALL trials. Even if a patient is not enrolled in these trials directly, they will still have treatment based on the UKALL protocols, which form the basis of clinical practice in England. Both the UKALL 2011 (and previously UKALL 2003) and UKALL14 trials include pegaspargase as the preferred choice of asparaginase therapy, as a component of the multi-agent chemotherapy regimen. Adverse reactions The most common side effects with pegaspargase (which may affect more than 1 in 10 people) are allergic reactions (including serious allergic reactions), hives, rash, high blood sugar levels, pancreatitis, diarrhoea, and abdominal pain. Evidence for clinical effectiveness Availability, nature and quality of evidence For children and young people, the company identified 2 studies as the focus of its submission (CCG‑1962 and UKALL 2003) and 3 further studies (CCG‑1961, DFCI‑91‑01 and DFCI ALL 05‑00) as supporting evidence. These studies compared pegaspargase 2,500 IU/m2 with native E. coli‑derived asparaginase. The ERG identified 3 further studies from the company's systematic review: DFCI ALL 05‑01, which compared pegaspargase 2,500 IU/m2 with native E. coli‑derived asparaginase; and the DFCI‑95‑01 and EORTC‑CLG 58881 studies, which compared Erwinia‑derived asparaginase with native E. coli‑derived asparaginase. In adults, both the company and ERG identified 3 non-comparative studies (Douer 2007, Douer 2014 and Wetzler 2007), all of which examined the efficacy of pegaspargase 2,000 IU/m2 or 2,500 IU/m2. The committee accepted the ERG's concerns about the quality of the studies in both the children and young people and adult populations. Nevertheless, it agreed that despite the limitations of these studies, it was appropriate to consider all the available studies in its decision-making. Relevance to general clinical practice in the NHS The committee concluded that although there was no comparative evidence available for pegaspargase 1,000 IU/m2 compared with other asparaginases or with pegaspargase 2,000–2,500 IU/m2, it was appropriate for it to take the lower dose of pegaspargase into consideration in its decision-making, because this was reflective of the dose used in clinical practice in England. Uncertainties generated by the evidence The committee accepted that the studies in children did not show a difference in the clinical effectiveness of pegaspargase and E. coli‑derived asparaginase, but agreed that it was unclear as to whether this was a result of the lack of evidence or simply a lack of a difference in effect. None of the included studies were powered to assess equivalence and it was not appropriate to pool the results from the different studies because of their heterogeneity. The committee noted the lack of comparative evidence for the relative effectiveness of pegaspargase with other asparaginase therapies in adults, but was aware that most of the trials in acute lymphoblastic leukaemia have been done in children and young people. The committee also agreed that there was no comparative evidence available for pegaspargase at a dose of 1,000 IU/m2 compared with other asparaginases or with pegaspargase at a dose of 2,000–2,500 IU/m2. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No subgroups were considered by the committee. Evidence for cost effectiveness Availability and nature of evidence The company provided an economic model that combined a decision tree and a health state transition Markov model. The committee agreed the structures of the decision tree and Markov models to be appropriate and the combination of the 2 models was well suited for the purpose of the appraisal because it reflected the treatment pathway for acute lymphoblastic leukaemia. The committee concluded that the model was in line with accepted NICE methods and therefore appropriate for its decision-making. Uncertainties around and plausibility of assumptions and inputs in the economic model Assumption that pegaspargase, E. coli‑derived and Erwinia‑derived asparaginase were equivalent in terms of overall survival and event-free survival. Dosage of pegaspargase used in the model (1,000 IU/m2 or 2,000–2,500 IU/m2). Dosing ratio for E. coli- or Erwinia‑derived asparaginase compared with pegaspargase. Risk of hypersensitivity leading to treatment switch. Incorporation of health-related quality-of-life benefits and utility values Not considered by committee. Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? None identified. Are there specific groups of people for whom the technology is particularly cost effective? Not considered by committee. What are the key drivers of cost effectiveness? The key drivers of the cost-effectiveness analysis were the event-free survival estimate for pegaspargase and the dosing ratio for E. coli- or Erwinia‑derived asparaginase compared with pegaspargase. Most likely cost-effectiveness estimate (given as an ICER) Pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity dominated (that is, was both less costly and more effective than) E. coli‑derived asparaginase followed by Erwinia‑derived asparaginase in cases of hypersensitivity. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End-of-life considerations Not applicable. Equalities considerations and social value judgements Consultees and commentators highlighted the following potential equality issues: Acute lymphoblastic leukaemia is an orphan disease. It is unusual in that it is more common in children aged less than 14 years. As such, any decision not to recommend pegaspargase would disproportionately affect children. If NICE does not approve pegaspargase, children in the UK with acute lymphoblastic leukaemia will be the only children among developed countries not to have access to the drug. The committee agreed that the increased prevalence in children and young people and the low number of people diagnosed with acute lymphoblastic leukaemia is a feature of the disease. Any recommendation resulting from this appraisal will apply to all people so age, as defined by the Equalities Act, is not a relevant equalities issue. The committee also agreed that variation in access to treatments between countries does not normally constitute an equality issue under equality legislation, because recommendations made by the technology appraisal committee do not address equality of access between countries.	{'Recommendations': "Pegaspargase, as part of antineoplastic combination therapy, is recommended as an option for treating acute lymphoblastic leukaemia in children, young people and adults only when they have untreated newly diagnosed disease.\n\nThis guidance is not intended to affect the position of patients whose treatment with pegaspargase was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person, or the child or young person's parents or carers.", 'The technology': "Description of the technology\n\nPegaspargase (Oncaspar, Baxalta [now part of Shire Pharmaceuticals]) is a polyethylene glycol conjugate of Escherichia\xa0coli (E. coli)‑derived L‑asparaginase.\n\nL‑asparaginase is a bacterial enzyme that depletes circulating asparagine, an essential amino acid on which leukaemic cells, incapable of synthesising asparagine, depend. This leads to cell death.\n\nMarketing authorisation\n\nPegaspargase received its marketing authorisation in January 2016. It is indicated as 'a component of antineoplastic combination therapy in acute lymphoblastic leukaemia in paediatric patients from birth to 18\xa0years, and adult patients'.\n\nAdverse reactions\n\nThe most common side effects with pegaspargase (which may affect more than 1\xa0in 10\xa0people) are allergic reactions (including serious allergic reactions), hives, rash, high blood sugar levels, pancreatitis, diarrhoea, and abdominal pain. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nPegaspargase is administered as either an intramuscular or intravenous infusion.\n\n\n\nSummary of product characteristics\n\nPegaspargase is usually used as part of combination chemotherapy protocols with other antineoplastic agents.\n\n\n\nPaediatric patients and adults ≤21\xa0years\n\nThe recommended dose of pegaspargase in patients with a body surface area ≥0.6\xa0m2 and who are ≤21\xa0years of age is 2500\xa0IU (equivalent to 3.3\xa0ml pegaspargase)/m2 body surface area every 14\xa0days.\n\n\n\nChildren with a body surface area <0.6\xa0m2 should have 82.5\xa0IU (equivalent to 0.1\xa0ml pegaspargase)/kg body weight every 14\xa0days.\n\n\n\nAdults >21\xa0years\n\nUnless otherwise prescribed, the recommended posology in adults aged >21\xa0years is 2000\xa0IU/m2 every 14\xa0days.\n\n\n\nClinical practice\n\nThe protocols for the ongoing UKALL trials, on which current clinical practice is based, recommend a dosage of 1,000\xa0IU/m2.\n\n\n\nThe UKALL trials have demonstrated that in clinical practice, dosing frequency depends on the patient's age, the phase of treatment in which pegaspargase is given (induction, consolidation, intensification, and so on), and the length of each phase.\n\n\n\nThe average length of a course of treatment depends on the individual UKALL treatment protocols for patients in different age groups.\n\nPrice\n\nThe acquisition cost of pegaspargase is £1,296.19 per vial (excluding VAT; price confirmed by company).\n\n\n\nFor paediatric and young adult patients, a course of pegaspargase costs between £5,144 (intermediate/standard-risk patients) and £15,246 (high-risk patients), assuming that patients complete the treatment (with no hypersensitivity) as per the UKALL 2003 protocol.\n\n\n\nFor adult patients, a course of pegaspargase costs between £6,034 (for those aged 41\xa0years or over) and £7,544 (for those aged 40\xa0years and under), assuming that patients complete the treatment (with no hypersensitivity) as per the UKALL14 protocol, and don't have a transplant.\n\n\n\nCosts are based on a dose of 1,000\xa0IU/m2 as used in clinical practice, which equates to 1\xa0vial of pegaspargase per dose. Although the summary of product characteristics dose is higher (2,000\xa0to 2,500\xa0IU/m2), only 1\xa0vial would be used per treatment administration. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Baxalta (now part of Shire Pharmaceuticals) and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of pegaspargase, having considered evidence on the nature of acute lymphoblastic leukaemia and the value placed on the benefits of pegaspargase by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management of acute lymphoblastic leukaemia\n\nThe committee understood that a diagnosis of acute lymphoblastic leukaemia can have a profound effect on a person's physical and psychological wellbeing. It also acknowledged that acute lymphoblastic leukaemia does not affect the patient in isolation, but also places emotional strain on their families and friends. The committee was aware that, because of this, access to effective treatments and improving quality of life are significant benefits to patients and their families.\n\nThe committee heard from the clinical expert that most people with newly diagnosed acute lymphoblastic leukaemia have pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, and that pegaspargase has been included in NHS England baseline commissioning since April 2013, even though pegaspargase did not have a marketing authorisation in the UK. The committee also heard that most patients in the UK are enrolled into the UKALL trials: UKALL 2011 for children and young adults up to the age of 25\xa0years (previously UKALL 2003, October 2003 to June 2009), UKALL14 for adults aged 25\xa0to 65\xa0years, and UKALL60+ for people over the age of 60\xa0years. Even if a patient is not enrolled in these trials directly, they will still have treatment based on the UKALL protocols because the protocols inform clinical practice in England. Both the UKALL 2011 (and previously UKALL 2003) and UKALL14 trials include pegaspargase as the preferred choice of asparaginase therapy, as a component of the multi-agent chemotherapy regimen. This is because pegaspargase has a longer half-life than the non-pegylated forms of asparaginase (Escherichia coli [E.\xa0coli]‑derived L‑asparaginase and Erwinia chrysanthemi‑derived L‑asparaginase) and so can be given less frequently. This is important to patients because native E.\xa0coli‑derived asparaginase is only available in injectable (intramuscular) forms. Intramuscular injections are painful, so less frequent injections are preferable. In addition, pegaspargase is considered preferable to native E.\xa0coli‑derived asparaginase because pegaspargase appears to be less immunogenic. This leads to the production of anti-asparaginase antibodies in 45% to 75% of patients, which frequently cause hypersensitivity reactions that limit treatment effectiveness. The UKALL protocols also mandate switching to Erwinia‑derived asparaginase rather than to another E.\xa0coli‑derived asparaginase following hypersensitivity to pegaspargase, because of the risk of cross reactivity and subsequent hypersensitivity. The committee heard that adult patients with Philadelphia-positive acute lymphoblastic leukaemia may not necessarily benefit from pegaspargase. This is because evidence suggests that these patients can achieve high remission rates with tyrosine kinase inhibitor-based induction therapies without the added risks of asparaginase therapy. To this end, the UKALL14 protocol specifies that patients with Philadelphia-positive acute lymphoblastic leukaemia do not have asparaginase therapy. The committee concluded that the current treatment pathway in England for most people with newly diagnosed acute lymphoblastic leukaemia is pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity.\n\n## Company's decision problem\n\nThe committee discussed the company's decision problem in relation to the marketing authorisation for pegaspargase and the final scope issued by NICE. The committee was aware that the population specified in pegaspargase's marketing authorisation was 'for acute lymphoblastic leukaemia in paediatric patients from birth to 18\xa0years, and adult patients'. The committee was aware that the company's decision problem was narrower than both the marketing authorisation for pegaspargase and the final NICE scope, in that it focused on pegaspargase as the preferred choice of asparaginase therapy for people with untreated, newly diagnosed acute lymphoblastic leukaemia. The committee noted that the marketing authorisation does not preclude pegaspargase's use following other asparaginase therapies or as a treatment for relapsed disease. The company considered that the current use of pegaspargase in the UK for people with untreated, newly diagnosed acute lymphoblastic leukaemia was driven by the UKALL protocols. It was also aware that the UKALL protocols do not include people with relapsed disease and that the committee was not presented with evidence on the use of pegaspargase for treating relapsed acute lymphoblastic leukaemia. The committee concluded that the company's decision problem for people with untreated, newly diagnosed acute lymphoblastic leukaemia was appropriate for its decision-making because this best reflected the use of pegaspargase in established clinical practice in England.\n\n# Clinical effectiveness\n\n## Untreated and newly diagnosed acute lymphoblastic leukaemia\n\nFor children and young people, the committee noted that the company had identified 2\xa0studies as the focus of its submission (CCG‑1962 and UKALL 2003) and 3\xa0further studies (CCG‑1961, DFCI‑91‑01 and DFCI\xa0ALL 05‑00) as supporting evidence in children and young people. The committee was aware that all of these studies compared pegaspargase 2,500\xa0IU/m2 with native E.\xa0coli‑derived asparaginase. The committee also noted that the evidence review group (ERG) had identified 3\xa0further studies from the company's systematic review: DFCI\xa0ALL 05‑01, which compared pegaspargase 2,500\xa0IU/m2 with native E.\xa0coli‑derived asparaginase; and the DFCI‑95‑01 and EORTC‑CLG\xa058881 studies, which compared Erwinia‑derived asparaginase with native E.\xa0coli‑derived asparaginase. The committee accepted the ERG's concerns about CCG‑1962 being a small study and UKALL 2003 being a non-comparative study. Nevertheless, it agreed that despite the limitations of these studies, it was appropriate to consider all the available studies in its decision-making.\n\nFor adults, the committee noted that both the company and ERG had identified 3\xa0non-comparative studies (Douer 2007, Douer 2014 and Wetzler 2007), all of which examined the efficacy of pegaspargase 2,000\xa0IU/m2 or 2,500\xa0IU/m2. The committee accepted the ERG's concerns that each study was non-comparative, and so provided no evidence for the relative effectiveness of pegaspargase compared with other asparaginases as listed in the final scope issued by NICE. The committee agreed that despite the limitations of these studies, it was appropriate to consider all the available studies in its decision-making.\n\nThe committee discussed the generalisability of the results from all the trials comparing a 2,000\xa0IU/m2 to 2,500\xa0IU/m2 dose of pegaspargase with E.\xa0coli‑derived asparaginase or Erwinia‑derived asparaginase to clinical practice in England (see section\xa04.2). The committee noted that the summary of product characteristics also recommends a pegaspargase dose of 2,000\xa0to 2,500\xa0IU/m2. In contrast, all the UKALL protocols used 1,000\xa0IU/m2. The committee was aware from the company, the clinical expert and a statement received from a professional group that UKALL 2003 provided favourable long-term outcomes and safety evidence for pegaspargase 1,000\xa0IU/m2 in more than 3,200\xa0children and young adults with acute lymphoblastic leukaemia between 2003 and 2011, accounting for more than 97% of the eligible patient population over that time. The committee was also aware that these data had reassured the clinical community in its continued use of 1,000\xa0IU/m2 as the standard of care in the UKALL 2011 paediatric protocol and to adopt it in the UKALL14 adult protocol. The committee heard from the clinical expert that there is currently no intent among clinicians to increase the dose of pegaspargase to the levels recommended in the summary of product characteristics because of the increased risk of treatment-related toxicity, which is of particular concern in children over 10\xa0years who have higher rates of toxicity-related mortality. The committee heard that in children, clinical practice is moving towards giving lower doses more frequently, and that children will have a maximum of 8\xa0doses of pegaspargase during their treatment for acute lymphoblastic leukaemia. The committee also heard that most clinicians choose not to increase the dosage above 1,000\xa0IU/m2 in adults and that most are offered bone or stem cell transplant if disease clearance is not achieved with 1,000\xa0IU/m2 doses of pegaspargase. The committee concluded that although there was no comparative evidence available for pegaspargase 1,000\xa0IU/m2 compared with other asparaginases or with pegaspargase 2,500\xa0IU/m2, it was appropriate for it to use the lower dose of pegaspargase in its decision-making, because this is reflective of the dose used in clinical practice in England.\n\nThe committee was aware that 4\xa0studies provided survival data in children for the comparison of pegaspargase 2,500\xa0IU/m2 with native E.\xa0coli‑derived asparaginase. Of these studies, it noted that 2\xa0showed results in favour of pegaspargase in terms of event-free survival (CCG‑1961 and CCG‑1962), 1\xa0showed non-statistically significant results in favour of E.\xa0coli‑derived asparaginase in terms of event-free survival (DFCI\xa0ALL 91‑01), and 1\xa0showed little difference between the 2\xa0interventions in terms of overall survival and event-free survival (DFCI\xa0ALL 05‑001). The committee also noted that the company's meta-analysis of 39\xa0studies in children showed results in favour of pegaspargase in terms of 5‑year event-free survival and overall survival. The committee accepted that the studies in children did not show a difference in the clinical effectiveness of pegaspargase and E.\xa0coli‑derived asparaginase, and agreed that it was unclear as to whether this was a result of the lack of evidence or simply a lack of a difference in effect. None of the included studies was powered to assess equivalence and it was not appropriate to pool the results from the different studies because of their heterogeneity. The committee noted the lack of comparative evidence for the relative effectiveness of pegaspargase with other asparaginase therapies in adults (see section\xa04.6), and was aware that most of the trials in acute lymphoblastic leukaemia have been done in children and young people. The committee was also aware that as part of its regulatory submission to the European Medicines Agency, the company had included data from the UKALL 2003 and Douer 2007 trials to support its application for pegaspargase's marketing authorisation to apply to all ages. The committee heard from the clinical expert, and was aware from the statements received from professional organisations representing clinicians, that although it was difficult to establish clinical equivalence of pegaspargase and the other asparaginase therapies based on the studies alone, clinicians consider pegaspargase and E.\xa0coli‑derived asparaginase to be equivalent in terms of clinical effectiveness in both children and adults based on their experience in the UKALL trials. Furthermore, clinicians prefer to use pegaspargase because of the reduced risk of hypersensitivity reactions and its longer half-life (see section\xa04.2). The committee acknowledged that uncertainty around the clinical effectiveness of pegaspargase in people of different ages might be addressed in the ongoing UKALL 2011 and UKALL14 trials and in the post-authorisation studies required by the European Medicines Agency as a condition of its granting of the marketing authorisation. The committee accepted that although there was some uncertainty in terms of the clinical effectiveness of pegaspargase compared with E.\xa0coli‑derived asparaginase, it was reasonable to assume on current available evidence that they were equivalent in terms of event-free survival and overall survival in people of all ages with untreated newly diagnosed acute lymphoblastic leukaemia.\n\n## Previously treated acute lymphoblastic leukaemia\n\nThe committee noted that that it had not been presented with any evidence for the efficacy of pegaspargase in people with relapsed acute lymphoblastic leukaemia, because the company's decision problem was based on how pegaspargase is used in clinical practice for people with untreated, newly diagnosed acute lymphoblastic leukaemia (see section\xa04.6). The committee concluded that it was inappropriate to make a recommendation for pegaspargase in people with previously treated relapsed acute lymphoblastic leukaemia.\n\n# Cost effectiveness\n\n## Economic model\n\nThe company presented a combined decision tree and health state transition Markov model. The committee agreed that the structures of both parts of the model were appropriate and the combination of the\xa02 was well suited for the purpose of the appraisal, because it accurately reflected the treatment pathway for acute lymphoblastic leukaemia. The committee also noted that the model only included patients with untreated, newly diagnosed acute lymphoblastic leukaemia, and it heard from the clinical expert that the model structure reflected clinical practice in England. The committee concluded that the model was in line with accepted NICE methods and therefore appropriate for its decision-making.\n\n## Treatment sequences modelled\n\nThe company modelled 3\xa0treatment sequences:\n\nPegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, compared with E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase in cases of hypersensitivity (comparison\xa01).\n\nPegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, compared with Erwinia‑derived asparaginase followed by pegaspargase in cases of hypersensitivity (comparison\xa02).\n\nPegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity, compared with Erwinia‑derived asparaginase followed by E.\xa0coli‑derived asparaginase in cases of hypersensitivity (comparison\xa03).The committee agreed that comparisons 2\xa0and\xa03 were not relevant for its decision-making, because there was no clinical scenario in which Erwinia‑derived asparaginase would be used as the preferred choice of asparaginase, or in which pegaspargase would be used in cases of hypersensitivity (see section\xa04.2). For this reason it also agreed not to consider either the company's or the ERG's cost-effectiveness analyses for comparisons 2\xa0and\xa03 any further. The committee considered whether comparison 1\xa0was relevant for its decision-making. It acknowledged that although E.\xa0coli‑derived asparaginase is no longer used as the first choice of asparaginase therapy, it was the standard of care before pegaspargase became available. The committee therefore concluded that comparison\xa01 was the appropriate comparison for its decision-making.\n\n## Model inputs\n\nThe committee discussed the assumption that pegaspargase, E.\xa0coli‑derived and Erwinia‑derived asparaginase were equivalent in terms of overall survival and event-free survival. The committee noted that both the company and the ERG had used this assumption in their respective base-case analyses, and that both had included a 'worst-case scenario' in which it was assumed that event-free survival was worse for pegaspargase than for E.\xa0coli‑derived asparaginase. The committee also noted that the ERG had included a 'best-case scenario' in which it assumed that overall survival and event-free survival were better for pegaspargase than for E.\xa0coli‑derived asparaginase. The committee recalled that it had heard from the clinical expert that clinicians consider the 3\xa0asparaginase treatments to be equivalent in terms of clinical effectiveness in both children and adults (see section\xa04.6). It therefore agreed that it was appropriate to assume that pegaspargase, E.\xa0coli‑derived and Erwinia‑derived asparaginase were equivalent in terms of overall survival and event-free survival.\n\nThe committee discussed the dosage of pegaspargase used in the model. The committee noted that both the company and the ERG had presented their base-case analysis results using the 1,000\xa0IU/m2 dose of pegaspargase, and scenario analyses using the 2,500\xa0IU/m2 dose of pegaspargase. The committee agreed that it preferred to use the 1,000\xa0IU/m2 dose of pegaspargase because it reflected the dose used in clinical practice (see section\xa04.6).\n\nThe committee discussed the dosing ratio for E.\xa0coli- or Erwinia‑derived asparaginase compared with pegaspargase. The committee noted that, based on expert opinion, the company had assumed a rate of 6\xa0doses of E.\xa0coli‑derived asparaginase or Erwinia‑derived asparaginase for each dose of pegaspargase. The committee also noted the ERG's comments that there was no scientific evidence to prove that this was the best ratio of the different formulations and that in other countries; it is considered that 4\xa0doses of E.\xa0coli- or Erwinia‑derived asparaginase correspond with 1\xa0dose of pegaspargase. The committee was aware of an ERG scenario analyses in which this ratio of\xa04:1 had been used. The committee heard from the clinical expert that the dosing ratio for E.\xa0coli- or Erwinia‑derived asparaginase compared with pegaspargase would be closer to 6:1\xa0in clinical practice, and therefore agreed that it was appropriate to use this ratio in the economic model.\n\nThe committee discussed the risk of hypersensitivity used in the economic model. In its base-case analysis, the company had assumed that the risk of hypersensitivity leading to treatment switch was 2% for both first- and second-line asparaginase therapy, based on the first-line hypersensitivity observed in UKALL 2003 with the lower dose (1,000\xa0IU/m2) of pegaspargase. The committee noted that the ERG had used a higher risk of hypersensitivity to pegaspargase in its base-case analysis, based on Nordic data for the 1,000\xa0IU/m2 dose. The committee heard from the clinical expert that the company's assumption of a 2% risk of hypersensitivity was closer to the risk seen in clinical practice for children with acute lymphoblastic leukaemia. The committee therefore concluded that for all ages it preferred to use the company's assumption of 2% risk of hypersensitivity leading to treatment switch in its decision-making.\n\n## Cost-effectiveness estimates\n\nThe committee noted that in the company's base-case analysis, pegaspargase followed by Erwinia‑derived asparaginase dominated (that is, was both less costly and more effective than) E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase in adults, children, and the whole (combined) population. The committee also noted that pegaspargase followed by Erwinia‑derived asparaginase continued to dominate E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase in all but 1\xa0of the company's scenario analyses for the whole population: the 'worst-case scenario', which produced an incremental cost-effectiveness ratio (ICER) of £20,326 saved per quality-adjusted life year (QALY) lost The committee agreed that the company's worst-case scenario was not relevant to its decision-making (see section\xa04.11). The committee was aware that the ERG had provided a revised base case and scenario analyses for the whole population. The committee noted that the ERG's base-case analysis for the whole population was consistent with that presented by the company: that is, pegaspargase followed by Erwinia‑derived asparaginase dominated E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase. The committee also noted that pegaspargase followed by Erwinia‑derived asparaginase continued to dominate E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase in all but 2\xa0of the ERG's scenario analyses: the worst-case scenario and the scenario in which 4\xa0doses of E.\xa0coli- or Erwinia‑derived asparaginase were applied for each dose of pegaspargase (respective ICERs of £4,810 saved per QALY lost and £36,499 per QALY gained [incremental costs £739, incremental QALYs 0.02]). The committee agreed that neither of these scenarios were relevant to its decision-making (see sections\xa04.11 and\xa04.13). The committee agreed that both the company's and the ERG's scenario analyses demonstrated the robustness of the cost-effectiveness results for pegaspargase followed by Erwinia‑derived asparaginase compared with E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase; that is, pegaspargase followed by Erwinia‑derived asparaginase dominated (that is, was both less costly and more effective). It therefore concluded that it could recommend pegaspargase as a cost-effective use of NHS resources for treating acute lymphoblastic leukaemia in children, young people and adults with untreated, newly diagnosed disease.\n\n# Innovation\n\nThe company stated that it considered pegaspargase to be innovative, because it has become the standard of care for first-line asparaginase treatment for acute lymphoblastic leukaemia in people of all ages. The committee heard from the clinical expert that in clinical practice, pegaspargase is now considered to be an incremental change in the treatment of acute lymphoblastic leukaemia rather than a step change because it has been used in clinical practice for a number of years. The committee concluded that pegaspargase should not be considered a step change in the treatment of acute lymphoblastic leukaemia.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA408\n\nAppraisal title: Pegaspargase for treating acute lymphoblastic leukaemia\n\nSection\n\nKey conclusion\n\nPegaspargase, as part of antineoplastic combination therapy, is recommended as an option for treating acute lymphoblastic leukaemia in children, young people and adults only when they have untreated newly diagnosed disease.\n\nThis guidance is not intended to affect the position of patients whose treatment with pegaspargase was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. For children and young people, this decision should be made jointly by the clinician and the child or young person or the child or young person's parents or carers.\n\nThe committee accepted that although there was some uncertainty in terms of the clinical effectiveness of pegaspargase compared with that of Escherichia coli (E.\xa0coli)‑derived asparaginase, it was reasonable to assume on the current available evidence that they were equivalent in terms of event-free survival and overall survival in people of all ages with untreated, newly diagnosed acute lymphoblastic leukaemia.\n\nThe committee agreed that both the company's and the evidence review group's (ERG's) scenario analyses demonstrated the robustness of the cost-effectiveness results for pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity compared with E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase in cases of hypersensitivity; that is, pegaspargase followed by Erwinia‑derived asparaginase dominated (was both less costly and more effective) than E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase. The committee therefore concluded that it could recommend pegaspargase as a cost-effective use of NHS resources for treating acute lymphoblastic leukaemia in children, young people and adults with untreated, newly diagnosed disease.\n\n, 1.2, 4.7, 4.15\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee understood that a diagnosis of acute lymphoblastic leukaemia can have a profound effect on a person's physical and psychological wellbeing. It also acknowledged that acute lymphoblastic leukaemia does not affect the patient in isolation, but also places emotional strain on their families and friends. The committee was aware that, because of this, access to effective treatments and improving quality of life are significant benefits to patients and their families.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard that pegaspargase has a longer half-life than the non-pegylated forms of asparaginase (E.\xa0coli‑derived asparaginase and Erwinia‑derived asparaginase), so can be given less frequently to patients. This is important to patients because native E.\xa0coli‑derived asparaginase is only available in an injectable form; intramuscular injections are painful, so less frequent injections are preferable. In addition, pegaspargase is considered preferable to native E.\xa0coli‑derived asparaginase because pegaspargase appears to be less immunogenic. This leads to the production of anti-asparaginase antibodies in 45% to 75% of patients, which frequently cause hypersensitivity reactions that limit treatment effectiveness.\n\nThe committee heard from the clinical expert that in clinical practice, pegaspargase is now considered to be an incremental change in the treatment of acute lymphoblastic leukaemia rather than a step change because it has been used in clinical practice for a number of years. The committee concluded that pegaspargase should not be considered a step change in the treatment of acute lymphoblastic leukaemia.\n\n, 4.16\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard from the clinical expert that most people with newly diagnosed acute lymphoblastic leukaemia have pegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity and that pegaspargase has been included in NHS England baseline commissioning since April 2003. The committee also heard that most patients in the UK are enrolled into the UKALL trials. Even if a patient is not enrolled in these trials directly, they will still have treatment based on the UKALL protocols, which form the basis of clinical practice in England. Both the UKALL 2011 (and previously UKALL 2003) and UKALL14 trials include pegaspargase as the preferred choice of asparaginase therapy, as a component of the multi-agent chemotherapy regimen.\n\n\n\nAdverse reactions\n\nThe most common side effects with pegaspargase (which may affect more than 1\xa0in 10\xa0people) are allergic reactions (including serious allergic reactions), hives, rash, high blood sugar levels, pancreatitis, diarrhoea, and abdominal pain.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nFor children and young people, the company identified 2\xa0studies as the focus of its submission (CCG‑1962 and UKALL 2003) and 3\xa0further studies (CCG‑1961, DFCI‑91‑01 and DFCI\xa0ALL 05‑00) as supporting evidence. These studies compared pegaspargase 2,500\xa0IU/m2 with native E.\xa0coli‑derived asparaginase. The ERG identified 3\xa0further studies from the company's systematic review: DFCI\xa0ALL 05‑01, which compared pegaspargase 2,500\xa0IU/m2 with native E.\xa0coli‑derived asparaginase; and the DFCI‑95‑01 and EORTC‑CLG\xa058881 studies, which compared Erwinia‑derived asparaginase with native E.\xa0coli‑derived asparaginase. In adults, both the company and ERG identified 3\xa0non-comparative studies (Douer 2007, Douer 2014 and Wetzler 2007), all of which examined the efficacy of pegaspargase 2,000\xa0IU/m2 or 2,500\xa0IU/m2.\n\nThe committee accepted the ERG's concerns about the quality of the studies in both the children and young people and adult populations. Nevertheless, it agreed that despite the limitations of these studies, it was appropriate to consider all the available studies in its decision-making.\n\n, 4.5,\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that although there was no comparative evidence available for pegaspargase 1,000\xa0IU/m2 compared with other asparaginases or with pegaspargase 2,000–2,500\xa0IU/m2, it was appropriate for it to take the lower dose of pegaspargase into consideration in its decision-making, because this was reflective of the dose used in clinical practice in England.\n\n\n\nUncertainties generated by the evidence\n\nThe committee accepted that the studies in children did not show a difference in the clinical effectiveness of pegaspargase and E.\xa0coli‑derived asparaginase, but agreed that it was unclear as to whether this was a result of the lack of evidence or simply a lack of a difference in effect. None of the included studies were powered to assess equivalence and it was not appropriate to pool the results from the different studies because of their heterogeneity.\n\nThe committee noted the lack of comparative evidence for the relative effectiveness of pegaspargase with other asparaginase therapies in adults, but was aware that most of the trials in acute lymphoblastic leukaemia have been done in children and young people.\n\nThe committee also agreed that there was no comparative evidence available for pegaspargase at a dose of 1,000\xa0IU/m2 compared with other asparaginases or with pegaspargase at a dose of 2,000–2,500\xa0IU/m2.\n\n, 4.7\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups were considered by the committee.\n\n\n\n\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company provided an economic model that combined a decision tree and a health state transition Markov model. The committee agreed the structures of the decision tree and Markov models to be appropriate and the combination of the 2\xa0models was well suited for the purpose of the appraisal because it reflected the treatment pathway for acute lymphoblastic leukaemia. The committee concluded that the model was in line with accepted NICE methods and therefore appropriate for its decision-making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nAssumption that pegaspargase, E.\xa0coli‑derived and Erwinia‑derived asparaginase were equivalent in terms of overall survival and event-free survival.\n\nDosage of pegaspargase used in the model (1,000\xa0IU/m2 or 2,000–2,500\xa0IU/m2).\n\nDosing ratio for E.\xa0coli- or Erwinia‑derived asparaginase compared with pegaspargase.\n\nRisk of hypersensitivity leading to treatment switch.\n\n, 4.12, 4.13, 4.14\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nNot considered by committee.\n\n\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNone identified.\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot considered by committee.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of the cost-effectiveness analysis were the event-free survival estimate for pegaspargase and the dosing ratio for E.\xa0coli- or Erwinia‑derived asparaginase compared with pegaspargase.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nPegaspargase followed by Erwinia‑derived asparaginase in cases of hypersensitivity dominated (that is, was both less costly and more effective than) E.\xa0coli‑derived asparaginase followed by Erwinia‑derived asparaginase in cases of hypersensitivity.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nConsultees and commentators highlighted the following potential equality issues:\n\nAcute lymphoblastic leukaemia is an orphan disease.\n\nIt is unusual in that it is more common in children aged less than 14\xa0years. As such, any decision not to recommend pegaspargase would disproportionately affect children.\n\nIf NICE does not approve pegaspargase, children in the UK with acute lymphoblastic leukaemia will be the only children among developed countries not to have access to the drug.\n\nThe committee agreed that the increased prevalence in children and young people and the low number of people diagnosed with acute lymphoblastic leukaemia is a feature of the disease. Any recommendation resulting from this appraisal will apply to all people so age, as defined by the Equalities Act, is not a relevant equalities issue. The committee also agreed that variation in access to treatments between countries does not normally constitute an equality issue under equality legislation, because recommendations made by the technology appraisal committee do not address equality of access between countries.\n\n"}	https://www.nice.org.uk/guidance/ta408	Evidence-based recommendations on pegaspargase (Oncaspar) for treating acute lymphoblastic leukaemia.
77292e1b7cc9648ed8f83385b124f4ad9ce7832e	nice	Aflibercept for treating visual impairment caused by macular oedema after branch retinal vein occlusion	Aflibercept for treating visual impairment caused by macular oedema after branch retinal vein occlusion Evidence-based recommendations on aflibercept (Eylea) for treating visual impairment caused by macular oedema after branch retinal vein occlusion. # Recommendations Aflibercept is recommended as an option within its marketing authorisation for treating visual impairment in adults caused by macular oedema after branch retinal vein occlusion, only if the company provides aflibercept with the discount agreed in the patient access scheme.# The technology Description of the technology Aflibercept solution for injection (Eylea, Bayer) administered by intravitreal injection. It is a soluble vascular endothelial growth factor (VEGF) receptor fusion protein. Marketing authorisation Aflibercept has a marketing authorisation in the UK for treating 'visual impairment due to macular oedema secondary to retinal vein occlusion (branch or central)'. NICE has already issued guidance for aflibercept when treating visual impairment due to macular oedema secondary to central retinal vein occlusion. Adverse reactions Conjunctival haemorrhaging, reduction in visual acuity, eye pain, cataract, intraocular pressure increasing, vitreous detachment and vitreous floaters. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule The recommended dose of aflibercept is 2 mg, equivalent to 50 microlitres. Price The list price of aflibercept is £816 for 1 vial (excluding VAT; British National Formulary, accessed May 2016). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of aflibercept, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 6) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of aflibercept, having considered evidence on the nature of visual impairment caused by macular oedema after branch retinal vein occlusion and the value placed on the benefits of aflibercept by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Nature of the condition The committee considered the nature of visual impairment and how it affects the everyday life of patients. The committee understood from clinical experts that people with macular oedema after branch retinal vein occlusion experience different severities of visual impairment. It noted that in some people the condition can resolve without intervention, but for others, particularly where diagnosis is delayed, visual outcomes can be much worse. The committee heard from patient experts that loss of visual acuity can have a significant effect on a person's independence and severely affects their ability to undertake daily activities. The committee heard that laser photocoagulation (an alternative treatment, see section 4.3) can be painful and may take longer to provide a gain in visual acuity. It understood that having an injection in the eye can cause apprehension and pain, but that patients consider the improvement in visual acuity to be worth it. The committee concluded that the loss of visual acuity can have a severe effect on quality of life and that patients would welcome additional options to treat visual impairment caused by macular oedema after branch retinal vein occlusion. # Current clinical management The committee considered the treatments for visual impairment caused by macular oedema after branch retinal vein occlusion currently used in NHS clinical practice. It heard that in people with mild macular oedema, the condition would be observed to allow for spontaneous improvement. If some visual loss has already occurred, laser photocoagulation may be used if macular haemorrhaging isn't extensive. The committee understood that the NICE technology appraisal guidance on ranibizumab in this indication only recommends ranibizumab after laser photocoagulation has failed, or when it isn't an option. Similarly, NICE technology appraisal guidance on dexamethasone in this indication recommends dexamethasone intravitreal implant only if laser photocoagulation has failed or is unsuitable because of extensive macular haemorrhaging. However, the committee understood that clinicians and patients prefer to use anti‑ vascular endothelial growth factor (VEGF) treatments such as ranibizumab instead of laser photocoagulation because it is not necessary to wait for the haemorrhaging to resolve before starting treatment. The committee concluded that monitoring the condition would be the most appropriate approach for some people, whereas for others laser photocoagulation may be a suitable initial treatment for branch retinal vein occlusion. The committee further concluded that since NICE published guidance its technology appraisal on ranibizumab and dexamethasone, clinical practice has changed and anti‑VEGF and corticosteroid treatments are used in the initial treatment of visual impairment caused by macular oedema after branch retinal vein occlusion. The committee considered the comparators for aflibercept in the final scope of this appraisal. It noted that bevacizumab, ranibizumab and dexamethasone are relevant comparators because they represent current treatment options for macular oedema after branch retinal vein occlusion (see section 4.2). The committee questioned the clinical experts on bevacizumab's relevance as a comparator and noted that it is also available as a treatment option in current clinical practice. The committee recognised the consideration of bevacizumab as a comparator in the NICE technology appraisal of ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. It also noted the statement from the NICE board discussing bevacizumab. The committee concluded that the previous decision made in the appraisal of ranibizumab, the evidence available to the committee during this appraisal, and bevacizumab's licensing all meant that although bevacizumab could potentially be a comparator, it could not confidently assess the clinical or cost effectiveness of aflibercept compared with bevacizumab. # Clinical effectiveness The committee considered the evidence presented by the company on the clinical effectiveness of aflibercept. It was aware that the company's evidence comprised 3 separate comparisons: Aflibercept after laser photocoagulation compared with ranibizumab after laser photocoagulation (when appropriate). That is, comparing aflibercept with ranibizumab when branch retinal vein occlusion has been treated with laser photocoagulation. Aflibercept after laser photocoagulation compared with dexamethasone after laser photocoagulation (when appropriate). That is, comparing aflibercept with dexamethasone when branch retinal vein occlusion has been treated with laser photocoagulation. Aflibercept in patients with untreated visual impairment compared with aflibercept after laser photocoagulation (when appropriate). That is, 2 treatment sequences both containing laser and aflibercept: 1 with aflibercept first and 1 with laser first. ## Clinical trial The committee examined the clinical-effectiveness evidence for aflibercept in patients with untreated visual impairment compared with laser photocoagulation, using evidence provided by the company from the randomised control trial VIBRANT. The committee acknowledged that at 52 weeks, a significantly higher proportion of patients gained 15 or more letters in the initial aflibercept group compared with the laser photocoagulation group (57.1% and 41.1% respectively, p<0.05). However, because this was not as great as the benefit observed at week 24 (52.7 and 26.7 respectively, p<0.05), the committee was concerned that the long-term benefit of laser photocoagulation may not have been adequately captured at the 52‑week time point if this trend had been observed further. The company responded to this point, explaining that because 74% of patients in the laser arm went on to have aflibercept as a rescue treatment, the benefit in this arm at week 52 was not only because of laser photocoagulation, but also rescue aflibercept. The committee considered this to be a plausible explanation, given the high percentage of people who had rescue aflibercept. The committee concluded that on the basis of the trial evidence, aflibercept is more clinically effective than laser photocoagulation for untreated visual impairment caused by macular oedema after branch retinal vein occlusion. The committee went on to discuss whether there is a clinical benefit of using aflibercept before laser photocoagulation rather than after laser photocoagulation. It acknowledged that the trial was not designed to provide evidence of this. However, it recalled statements from clinical experts that anti‑VEGF treatments are more beneficial than laser because treatment can be started without a period of delay, during which visual acuity could further deteriorate. Therefore, the committee considered that starting treatment with aflibercept without delay could lead to a better clinical outcome in the long term than waiting for any haemorrhaging to resolve before starting treatment with laser photocoagulation. The committee concluded that clinical experience suggests that aflibercept is more clinically effective in patients with untreated visual impairment (caused by macular oedema after branch retinal vein occlusion) when given before, rather than after, laser photocoagulation. ## Network meta-analysis The committee considered the clinical effectiveness of aflibercept after laser photocoagulation compared with dexamethasone after laser photocoagulation and with ranibizumab after laser photocoagulation. The committee was aware that no direct trial evidence was available for these comparisons, and it discussed the results of the network meta-analysis presented by the company. It noted that both the mean and median odds ratios of gaining 15 or more letters favoured aflibercept when compared with dexamethasone (mean 0.39, median 0.34, 95% credible interval of distribution 0.12, 0.96). However, when compared with ranibizumab, the median odds ratio favoured aflibercept, whereas the mean odds ratio favoured ranibizumab (median 0.93, mean 1.04, 95% credible interval of distribution 0.38, 2.31). The committee considered that in all cases, the credible intervals around the distribution of treatment effects were wide, and that the point estimates should therefore be interpreted with caution. The committee understood that in the comparison with ranibizumab, the results were not statistically significant and that either ranibizumab or aflibercept could be considered marginally more clinically effective. The clinical experts informed the committee that ranibizumab and aflibercept are considered equivalent in terms of clinical efficacy and tolerability. Considering both the results of the network meta-analysis and the clinical experts' evidence, the committee concluded that aflibercept is clinically more effective than dexamethasone and likely to be equivalent to ranibizumab in terms of treating visual impairment after branch retinal vein occlusion. # Cost effectiveness The committee considered the cost-effectiveness evidence submitted by the company. The committee noted that the incremental cost-effectiveness ratio (ICER) of aflibercept in patients with untreated visual impairment compared with aflibercept after laser photocoagulation was estimated to be £15,365 per quality-adjusted life year (QALY) gained (including the patient access scheme). Costs and QALYs are confidential so cannot be presented here. The committee acknowledged the evidence review group's (ERG's) concerns with some of the assumptions used in the company's base case: Patients may need anti-vascular endothelial growth factor (VEGF) treatment for more than 5 years, whereas the company's base case stopped anti‑VEGF treatment after 5 years. The number of aflibercept injections in each year is likely to be higher in practice than assumed in the company's model. The probabilities used to estimate the likelihood of a person gaining or losing visual acuity were not derived directly from patient data. Quality-of-life data were taken from Czoski–Murray (2009) although more appropriate data were available. Quality-of-life estimation for the worst-seeing eye relative to best-seeing eye may not be as high as 30% as used in the model. The model assumed equal risk of developing cataracts with both aflibercept and dexamethasone.The committee considered each issue in turn, as detailed below. ## Anti‑VEGF dosing after 5 years The committee noted that in the company's base case, anti‑VEGF treatment was stopped after 5 years. The committee heard evidence from the ERG that studies have shown a need for continued anti‑VEGF beyond 5 years. It also heard from the clinical experts that around 30% of patients need ongoing anti‑VEGF treatment beyond 5 years. The committee concluded that it is clinically plausible to assume that anti‑VEGF treatment will continue beyond 5 years for some patients with visual impairment caused by macular oedema following branch retinal vein occlusion. ## Number of aflibercept injections in each year The committee was aware that the company used evidence from the VIBRANT trial to inform the assumptions of aflibercept dosing in year 1, and the results of a physician survey to inform the assumptions beyond year 1. The committee noted the ERG's concern that beyond 2 years of treatment, the physicians' survey seemed to underestimate the number of aflibercept injections that would be needed each year, especially compared with the RETAIN trial (physicians' survey: year 3, 2.61 injections; year 4, 1.12 injections; year 5, 0.58 injections). The committee was aware that the ERG's revised number of injections for year 3 and beyond, 3.2 aflibercept injections per year, was a 'worst-case' scenario'. It agreed that the number of aflibercept injections was likely to be higher than estimated in the physicians' survey but was uncertain of the true dosing frequency. The committee concluded that the ERG's assumed number of aflibercept injections for year 3 and beyond was a cautious assumption; fewer injections would lower the ERG's ICER, but it would remain higher than the company's own estimate. ## Transition probabilities The committee considered the source of transition probabilities used in the model. It noted that the company's model assumed that the probabilities of improving or worsening visual acuity were derived by fitting a model to long-term data. The committee understood that the probabilities could instead have been derived directly from patient data, and considered that there was no evidence to suggest that these data should not be used in the model. The committee noted that the ERG had used patient count data in its base case and concluded that using patient count data to estimate the probabilities of improving or worsening visual acuity was a preferable approach. ## Quality-of-life data The committee considered the source of quality-of-life data and the company's approach to modelling the utility gain in the worst-seeing eye as a proportion of that in the best-seeing eye. It heard that EQ‑5D data were collected in the VIBRANT trial, but that the company's economic model used health-state utility values from Czoski–Murray et al. (2009). It also heard that the company had presented a bilateral model that assumed that any change in visual acuity for the worst-seeing eye would equate to 30% of a similar change in utility for the best-seeing eye. The committee noted that in NICE technology appraisal on ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion, Czoski–Murray utility values were used for the best-seeing eye (10% of the population) and a maximum utility benefit of 0.1 QALY was applied for the worst-seeing eye (90% of the population) based on Brown (2009). The committee agreed to apply a similar utility assumption from this appraisal, specifically the maximum possible utility benefit. The committee was presented with 4 utility ranges from the ERG using different sources for the utilities (Brown and Czoski–Murray) and differing proportional impact on the worst-seeing eye (30% or 15%). The committee noted the utilities presented provided a range of maximum utility benefit from 0.062 to 0.137. The committee noted that while no 1 scenario provided a maximum quality of life gain of 0.1, using Czoski–Murray 15% and Brown 30% provided estimates closest to 0.1, so it agreed that these could be used as a basis for its decision-making. The committee concluded that the source of the utilities was subject to some uncertainty, but the maximum utility gain in the worst-seeing eye should not exceed 0.1 QALY. ## Assumed risk of cataracts The committee noted that in the company's model dexamethasone had been assumed to carry the same risk of causing cataracts as aflibercept. The committee was aware that treatment with a corticosteroid such as dexamethasone has a greater risk of developing cataracts compared with an anti‑VEGF treatment, such as aflibercept. The committee concluded that the modelled assumption of equal cataracts risk between dexamethasone and aflibercept is unfavourable to aflibercept. It further concluded that if a more realistic assumption had been used in the cost-effectiveness analyses, the ICER for aflibercept compared with dexamethasone would likely reduce, although it was not possible to estimate the size of the reduction. ## Aflibercept in patients with untreated branch retinal vein occlusion The committee considered the most plausible ICER for aflibercept in patients with untreated visual impairment, given some of its preferred assumptions as detailed in sections 4.8 and 4.10. It was aware that in this comparison aflibercept was compared with itself in 2 places in the pathway: before laser photocoagulation (that is, in patients with untreated branch retinal vein occlusion) and after laser photocoagulation (see section 4.4). It noted the ERG's exploratory base-case ICER of £21,500, in which these preferred assumptions had been incorporated. The committee further considered the preferred utility assumption as detailed in section 4.11, noting that utilities of Czoski–Murray 15% or Brown 30% produce ICERs of £24,900 per QALY gained and £27,300 per QALY gained respectively. The committee accepted these ICERs as the basis for its decision-marking with regard to aflibercept in patients with untreated visual impairment compared with aflibercept after laser photocoagulation. It concluded that the most plausible ICER was within the range that could be considered a cost-effective use of NHS resources, and recommended aflibercept in patients with untreated visual impairment (that is, before laser photocoagulation). ## Aflibercept after laser photocoagulation The committee considered the most plausible ICER for aflibercept after laser photocoagulation in which aflibercept, ranibizumab and dexamethasone were compared in an incremental cost-effectiveness analysis. The committee considered the ERG's estimated ICER which incorporated its preferred assumptions (see sections 4.8, 4.10 and 4.11). In this analysis, aflibercept dominated ranibizumab (that is, aflibercept was both less costly and more effective). The committee noted that this was based on the list price of ranibizumab (the ICER incorporating the patient access scheme for ranibizumab is commercial in confidence and cannot be reported here). The committee was mindful of its conclusions regarding the clinical effectiveness of aflibercept compared with ranibizumab (see section 4.6). It also considered the cost effectiveness of ranibizumab as assessed during its last NICE technology appraisal, and considered that aflibercept and ranibizumab could be similar in terms of cost effectiveness. The committee turned its attention to the comparison with dexamethasone. It noted that the ERG's estimated ICER for aflibercept compared with dexamethasone that incorporated its preferred assumptions (see sections 4.8, 4.10 and 4.11) was between £33,800 per QALY gained and £37,000 per QALY gained. It was aware that these ICERs may be overestimated because of certain modelling assumptions. In particular, the committee recalled its conclusion that the risk of cataracts had been overestimated for aflibercept compared with dexamethasone. It considered that if this was corrected in the economic model, the ICER would be lower. It also recalled that the number of aflibercept injections beyond 3 years in the ERG's base case was a cautious assumption (see section 4.9), and that a less pessimistic assumption may lower the ICERs. Given these uncertainties, the committee was confident that the most plausible ICER for the comparison of aflibercept with dexamethasone would be lower. In addition, the committee reasoned that it was appropriate to make a positive recommendation for aflibercept in line with that for ranibizumab, since the evidence had been presented to support the cost effectiveness of aflibercept in this comparison. It therefore concluded that aflibercept should be recommended as an option for treating visual impairment caused by macular oedema after branch retinal vein occlusion when treatment with laser photocoagulation has not been beneficial. # Innovation The committee considered the innovative aspects of aflibercept. It noted that the company considered it to be innovative because it has higher binding affinity for VEGF‑A compared with ranibizumab, and that it inhibits a wider range of growth factors. In those respects the committee agreed with the company that it could be considered innovative. However, the committee could not identify any health-related benefits that had not already been captured in the QALY calculation. The committee concluded that there was nothing additional regarding the innovative nature of aflibercept that needed to be taken into account for the purposes of this appraisal. # Pharmaceutical Price Regulation Scheme 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA409 Appraisal title: Aflibercept for treating visual impairment caused by macular oedema after branch retinal vein occlusion Section Key conclusion Aflibercept is recommended as an option within its marketing authorisation for treating visual impairment in adults caused by macular oedema after branch retinal vein occlusion, only if the company provides aflibercept with the discount agreed in the patient access scheme. The committee concluded that aflibercept is more clinically effective than laser photocoagulation for untreated visual impairment (caused by macular oedema after branch retinal vein occlusion) and clinical experience suggests that aflibercept is more clinically effective when given before, rather than after, laser photocoagulation. The committee also concluded that aflibercept is more effective than dexamethasone and equivalent to ranibizumab in terms of clinical effectiveness. Current practice Clinical need of patients, including the availability of alternative treatments The committee concluded that loss of visual acuity can have a severe effect on a person's quality of life and that patients would welcome additional options to treat visual impairment caused by macular oedema after branch retinal vein occlusion. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee concluded that there was nothing additional regarding the innovative nature of aflibercept that needed to be taken into account for the purposes of this appraisal. What is the position of the treatment in the pathway of care for the condition? The committee concluded that monitoring the condition, laser photocoagulation, anti‑ vascular endothelial growth factor (VEGF) and corticosteroid treatment are all used for treating visual impairment caused by macular oedema after branch retinal vein occlusion. The committee further concluded that since NICE published guidance its technology appraisal on ranibizumab and dexamethasone, clinical practice has changed and anti‑VEGF and corticosteroid treatments are used in the initial treatment of visual impairment caused by macular oedema after branch retinal vein occlusion. Adverse reactions The committee was aware that treatment with a corticosteroid such as dexamethasone has a greater risk of developing cataracts compared with an anti‑VEGF treatment, such as aflibercept. Evidence for clinical effectiveness Availability, nature and quality of evidence The committee examined the clinical-effectiveness evidence for aflibercept in patients with untreated visual impairment compared with laser photocoagulation, using evidence provided by the company from the randomised control trial VIBRANT. The committee was aware that no direct trial evidence was available for the comparisons of aflibercept with ranibizumab or dexamethasone, and instead considered the results of the company's network meta-analysis. Relevance to general clinical practice in the NHS Not an issue in this appraisal. Uncertainties generated by the evidence The committee noted that the long-term benefit of laser might not have been adequately captured at 52 weeks. The committee concluded that the source of the utilities was subject to some uncertainty, but the maximum utility gain in the worst-seeing eye should not exceed 0.1 quality-adjusted life year (QALY). Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No subgroups were identified. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee concluded that aflibercept is more clinically effective than laser photocoagulation for untreated visual impairment (caused by macular oedema after branch retinal vein occlusion) and that clinical experience suggests that aflibercept is more clinically effective when given before, rather than after, laser photocoagulation. Both the mean and median odds ratios favoured aflibercept when compared with dexamethasone (mean 0.39; median 0.34). When compared with ranibizumab, the median and mean odds ratios were close to 1. Clinical experts explained that ranibizumab and aflibercept are considered clinically equivalent. Evidence for cost effectiveness Availability and nature of evidence The company presented a bilateral economic model. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee acknowledged the following uncertainties in the company's model: Whether patients may need to have anti‑VEGF treatment for more than 5 years. The probabilities used to estimate the likelihood of changing visual acuity were not derived directly from patient data. Quality-of-life data were taken from Czoski–Murray (2009) and the worst-seeing eye relative to best-seeing eye may not be as high as 30%. Uncertain ongoing aflibercept dosing. The model assumed an equal risk of developing cataracts with both aflibercept and dexamethasone. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee agreed that the most plausible source of utilities and proportional impact to the worst-seeing eye would lie between Czoski–Murray 15% and Brown 30%. Are there specific groups of people for whom the technology is particularly cost effective? No subgroups were identified. What are the key drivers of cost effectiveness? The committee noted that when its preferred utilities of Czoski–Murray 15% or Brown 30% were implemented it increased the ICER. Most likely cost-effectiveness estimate (given as an ICER) The committee noted that when its preferred assumptions and utilities were implemented: Compared with aflibercept followed by laser: ICER between £24,900 and £27,300 per QALY gained. Compared with ranibizumab following laser: confidential ICER but within the range that could be considered a cost-effective use of NHS resources. Compared with dexamethasone following laser: ICER between £33,800 and £37,000 per QALY gained. Committee was concerned that these may be overestimated because of certain modelling assumptions, that corrected the ICER would be lower. Additional factors taken into account Patient access schemes (PPRS) Recommended only if the company provides aflibercept with the discount agree in the patient access scheme. The committee concluded that the Pharmaceutical Price Regulation Scheme payment mechanism was not relevant in considering the cost effectiveness of aflibercept. End-of-life considerations Not applicable. Equalities considerations and social value judgements No equality issues were identified.	{'Recommendations': 'Aflibercept is recommended as an option within its marketing authorisation for treating visual impairment in adults caused by macular oedema after branch retinal vein occlusion, only if the company provides aflibercept with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nAflibercept solution for injection (Eylea, Bayer) administered by intravitreal injection. It is a soluble vascular endothelial growth factor (VEGF) receptor fusion protein.\n\nMarketing authorisation\n\nAflibercept has a marketing authorisation in the UK for treating 'visual impairment due to macular oedema secondary to retinal vein occlusion (branch or central)'.\n\nNICE has already issued guidance for aflibercept when treating visual impairment due to macular oedema secondary to central retinal vein occlusion.\n\nAdverse reactions\n\nConjunctival haemorrhaging, reduction in visual acuity, eye pain, cataract, intraocular pressure increasing, vitreous detachment and vitreous floaters. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dose of aflibercept is 2\xa0mg, equivalent to 50\xa0microlitres.\n\nPrice\n\nThe list price of aflibercept is £816 for 1\xa0vial (excluding VAT; British National Formulary, accessed May 2016).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of aflibercept, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of aflibercept, having considered evidence on the nature of visual impairment caused by macular oedema after branch retinal vein occlusion and the value placed on the benefits of aflibercept by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Nature of the condition\n\nThe committee considered the nature of visual impairment and how it affects the everyday life of patients. The committee understood from clinical experts that people with macular oedema after branch retinal vein occlusion experience different severities of visual impairment. It noted that in some people the condition can resolve without intervention, but for others, particularly where diagnosis is delayed, visual outcomes can be much worse. The committee heard from patient experts that loss of visual acuity can have a significant effect on a person's independence and severely affects their ability to undertake daily activities. The committee heard that laser photocoagulation (an alternative treatment, see section\xa04.3) can be painful and may take longer to provide a gain in visual acuity. It understood that having an injection in the eye can cause apprehension and pain, but that patients consider the improvement in visual acuity to be worth it. The committee concluded that the loss of visual acuity can have a severe effect on quality of life and that patients would welcome additional options to treat visual impairment caused by macular oedema after branch retinal vein occlusion.\n\n# Current clinical management\n\nThe committee considered the treatments for visual impairment caused by macular oedema after branch retinal vein occlusion currently used in NHS clinical practice. It heard that in people with mild macular oedema, the condition would be observed to allow for spontaneous improvement. If some visual loss has already occurred, laser photocoagulation may be used if macular haemorrhaging isn't extensive. The committee understood that the NICE technology appraisal guidance on ranibizumab in this indication only recommends ranibizumab after laser photocoagulation has failed, or when it isn't an option. Similarly, NICE technology appraisal guidance on dexamethasone in this indication recommends dexamethasone intravitreal implant only if laser photocoagulation has failed or is unsuitable because of extensive macular haemorrhaging. However, the committee understood that clinicians and patients prefer to use anti‑ vascular endothelial growth factor (VEGF) treatments such as ranibizumab instead of laser photocoagulation because it is not necessary to wait for the haemorrhaging to resolve before starting treatment. The committee concluded that monitoring the condition would be the most appropriate approach for some people, whereas for others laser photocoagulation may be a suitable initial treatment for branch retinal vein occlusion. The committee further concluded that since NICE published guidance its technology appraisal on ranibizumab and dexamethasone, clinical practice has changed and anti‑VEGF and corticosteroid treatments are used in the initial treatment of visual impairment caused by macular oedema after branch retinal vein occlusion.\n\nThe committee considered the comparators for aflibercept in the final scope of this appraisal. It noted that bevacizumab, ranibizumab and dexamethasone are relevant comparators because they represent current treatment options for macular oedema after branch retinal vein occlusion (see section\xa04.2). The committee questioned the clinical experts on bevacizumab's relevance as a comparator and noted that it is also available as a treatment option in current clinical practice. The committee recognised the consideration of bevacizumab as a comparator in the NICE technology appraisal of ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. It also noted the statement from the NICE board discussing bevacizumab. The committee concluded that the previous decision made in the appraisal of ranibizumab, the evidence available to the committee during this appraisal, and bevacizumab's licensing all meant that although bevacizumab could potentially be a comparator, it could not confidently assess the clinical or cost effectiveness of aflibercept compared with bevacizumab.\n\n# Clinical effectiveness\n\nThe committee considered the evidence presented by the company on the clinical effectiveness of aflibercept. It was aware that the company's evidence comprised 3\xa0separate comparisons:\n\nAflibercept after laser photocoagulation compared with ranibizumab after laser photocoagulation (when appropriate). That is, comparing aflibercept with ranibizumab when branch retinal vein occlusion has been treated with laser photocoagulation.\n\nAflibercept after laser photocoagulation compared with dexamethasone after laser photocoagulation (when appropriate). That is, comparing aflibercept with dexamethasone when branch retinal vein occlusion has been treated with laser photocoagulation.\n\nAflibercept in patients with untreated visual impairment compared with aflibercept after laser photocoagulation (when appropriate). That is, 2\xa0treatment sequences both containing laser and aflibercept: 1\xa0with aflibercept first and 1\xa0with laser first.\n\n## Clinical trial\n\nThe committee examined the clinical-effectiveness evidence for aflibercept in patients with untreated visual impairment compared with laser photocoagulation, using evidence provided by the company from the randomised control trial VIBRANT. The committee acknowledged that at 52\xa0weeks, a significantly higher proportion of patients gained 15\xa0or more letters in the initial aflibercept group compared with the laser photocoagulation group (57.1% and 41.1% respectively, p<0.05). However, because this was not as great as the benefit observed at week\xa024 (52.7 and 26.7 respectively, p<0.05), the committee was concerned that the long-term benefit of laser photocoagulation may not have been adequately captured at the 52‑week time point if this trend had been observed further. The company responded to this point, explaining that because 74% of patients in the laser arm went on to have aflibercept as a rescue treatment, the benefit in this arm at week\xa052 was not only because of laser photocoagulation, but also rescue aflibercept. The committee considered this to be a plausible explanation, given the high percentage of people who had rescue aflibercept. The committee concluded that on the basis of the trial evidence, aflibercept is more clinically effective than laser photocoagulation for untreated visual impairment caused by macular oedema after branch retinal vein occlusion.\n\nThe committee went on to discuss whether there is a clinical benefit of using aflibercept before laser photocoagulation rather than after laser photocoagulation. It acknowledged that the trial was not designed to provide evidence of this. However, it recalled statements from clinical experts that anti‑VEGF treatments are more beneficial than laser because treatment can be started without a period of delay, during which visual acuity could further deteriorate. Therefore, the committee considered that starting treatment with aflibercept without delay could lead to a better clinical outcome in the long term than waiting for any haemorrhaging to resolve before starting treatment with laser photocoagulation. The committee concluded that clinical experience suggests that aflibercept is more clinically effective in patients with untreated visual impairment (caused by macular oedema after branch retinal vein occlusion) when given before, rather than after, laser photocoagulation.\n\n## Network meta-analysis\n\nThe committee considered the clinical effectiveness of aflibercept after laser photocoagulation compared with dexamethasone after laser photocoagulation and with ranibizumab after laser photocoagulation. The committee was aware that no direct trial evidence was available for these comparisons, and it discussed the results of the network meta-analysis presented by the company. It noted that both the mean and median odds ratios of gaining 15\xa0or more letters favoured aflibercept when compared with dexamethasone (mean 0.39, median 0.34, 95% credible interval of distribution 0.12, 0.96). However, when compared with ranibizumab, the median odds ratio favoured aflibercept, whereas the mean odds ratio favoured ranibizumab (median 0.93, mean 1.04, 95% credible interval of distribution 0.38, 2.31). The committee considered that in all cases, the credible intervals around the distribution of treatment effects were wide, and that the point estimates should therefore be interpreted with caution. The committee understood that in the comparison with ranibizumab, the results were not statistically significant and that either ranibizumab or aflibercept could be considered marginally more clinically effective. The clinical experts informed the committee that ranibizumab and aflibercept are considered equivalent in terms of clinical efficacy and tolerability. Considering both the results of the network meta-analysis and the clinical experts' evidence, the committee concluded that aflibercept is clinically more effective than dexamethasone and likely to be equivalent to ranibizumab in terms of treating visual impairment after branch retinal vein occlusion.\n\n# Cost effectiveness\n\nThe committee considered the cost-effectiveness evidence submitted by the company. The committee noted that the incremental cost-effectiveness ratio (ICER) of aflibercept in patients with untreated visual impairment compared with aflibercept after laser photocoagulation was estimated to be £15,365 per quality-adjusted life year (QALY) gained (including the patient access scheme). Costs and QALYs are confidential so cannot be presented here. The committee acknowledged the evidence review group's (ERG's) concerns with some of the assumptions used in the company's base case:\n\nPatients may need anti-vascular endothelial growth factor (VEGF) treatment for more than 5\xa0years, whereas the company's base case stopped anti‑VEGF treatment after 5\xa0years.\n\nThe number of aflibercept injections in each year is likely to be higher in practice than assumed in the company's model.\n\nThe probabilities used to estimate the likelihood of a person gaining or losing visual acuity were not derived directly from patient data.\n\nQuality-of-life data were taken from Czoski–Murray (2009) although more appropriate data were available.\n\nQuality-of-life estimation for the worst-seeing eye relative to best-seeing eye may not be as high as 30% as used in the model.\n\nThe model assumed equal risk of developing cataracts with both aflibercept and dexamethasone.The committee considered each issue in turn, as detailed below.\n\n## Anti‑VEGF dosing after 5\xa0years\n\nThe committee noted that in the company's base case, anti‑VEGF treatment was stopped after 5\xa0years. The committee heard evidence from the ERG that studies have shown a need for continued anti‑VEGF beyond 5\xa0years. It also heard from the clinical experts that around 30% of patients need ongoing anti‑VEGF treatment beyond 5\xa0years. The committee concluded that it is clinically plausible to assume that anti‑VEGF treatment will continue beyond 5\xa0years for some patients with visual impairment caused by macular oedema following branch retinal vein occlusion.\n\n## Number of aflibercept injections in each year\n\nThe committee was aware that the company used evidence from the VIBRANT trial to inform the assumptions of aflibercept dosing in year\xa01, and the results of a physician survey to inform the assumptions beyond year\xa01. The committee noted the ERG's concern that beyond 2\xa0years of treatment, the physicians' survey seemed to underestimate the number of aflibercept injections that would be needed each year, especially compared with the RETAIN trial (physicians' survey: year\xa03, 2.61\xa0injections; year\xa04, 1.12\xa0injections; year\xa05, 0.58\xa0injections). The committee was aware that the ERG's revised number of injections for year\xa03 and beyond, 3.2\xa0aflibercept injections per year, was a 'worst-case' scenario'. It agreed that the number of aflibercept injections was likely to be higher than estimated in the physicians' survey but was uncertain of the true dosing frequency. The committee concluded that the ERG's assumed number of aflibercept injections for year\xa03 and beyond was a cautious assumption; fewer injections would lower the ERG's ICER, but it would remain higher than the company's own estimate.\n\n## Transition probabilities\n\nThe committee considered the source of transition probabilities used in the model. It noted that the company's model assumed that the probabilities of improving or worsening visual acuity were derived by fitting a model to long-term data. The committee understood that the probabilities could instead have been derived directly from patient data, and considered that there was no evidence to suggest that these data should not be used in the model. The committee noted that the ERG had used patient count data in its base case and concluded that using patient count data to estimate the probabilities of improving or worsening visual acuity was a preferable approach.\n\n## Quality-of-life data\n\nThe committee considered the source of quality-of-life data and the company's approach to modelling the utility gain in the worst-seeing eye as a proportion of that in the best-seeing eye. It heard that EQ‑5D data were collected in the VIBRANT trial, but that the company's economic model used health-state utility values from Czoski–Murray et al. (2009). It also heard that the company had presented a bilateral model that assumed that any change in visual acuity for the worst-seeing eye would equate to 30% of a similar change in utility for the best-seeing eye. The committee noted that in NICE technology appraisal on ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion, Czoski–Murray utility values were used for the best-seeing eye (10% of the population) and a maximum utility benefit of 0.1\xa0QALY was applied for the worst-seeing eye (90% of the population) based on Brown (2009). The committee agreed to apply a similar utility assumption from this appraisal, specifically the maximum possible utility benefit. The committee was presented with 4\xa0utility ranges from the ERG using different sources for the utilities (Brown and Czoski–Murray) and differing proportional impact on the worst-seeing eye (30% or 15%). The committee noted the utilities presented provided a range of maximum utility benefit from 0.062 to 0.137. The committee noted that while no 1\xa0scenario provided a maximum quality of life gain of\xa00.1, using Czoski–Murray 15% and Brown 30% provided estimates closest to\xa00.1, so it agreed that these could be used as a basis for its decision-making. The committee concluded that the source of the utilities was subject to some uncertainty, but the maximum utility gain in the worst-seeing eye should not exceed 0.1\xa0QALY.\n\n## Assumed risk of cataracts\n\nThe committee noted that in the company's model dexamethasone had been assumed to carry the same risk of causing cataracts as aflibercept. The committee was aware that treatment with a corticosteroid such as dexamethasone has a greater risk of developing cataracts compared with an anti‑VEGF treatment, such as aflibercept. The committee concluded that the modelled assumption of equal cataracts risk between dexamethasone and aflibercept is unfavourable to aflibercept. It further concluded that if a more realistic assumption had been used in the cost-effectiveness analyses, the ICER for aflibercept compared with dexamethasone would likely reduce, although it was not possible to estimate the size of the reduction.\n\n## Aflibercept in patients with untreated branch retinal vein occlusion\n\nThe committee considered the most plausible ICER for aflibercept in patients with untreated visual impairment, given some of its preferred assumptions as detailed in sections\xa04.8 and 4.10. It was aware that in this comparison aflibercept was compared with itself in 2\xa0places in the pathway: before laser photocoagulation (that is, in patients with untreated branch retinal vein occlusion) and after laser photocoagulation (see section\xa04.4). It noted the ERG's exploratory base-case ICER of £21,500, in which these preferred assumptions had been incorporated. The committee further considered the preferred utility assumption as detailed in section\xa04.11, noting that utilities of Czoski–Murray 15% or Brown 30% produce ICERs of £24,900 per QALY gained and £27,300 per QALY gained respectively. The committee accepted these ICERs as the basis for its decision-marking with regard to aflibercept in patients with untreated visual impairment compared with aflibercept after laser photocoagulation. It concluded that the most plausible ICER was within the range that could be considered a cost-effective use of NHS resources, and recommended aflibercept in patients with untreated visual impairment (that is, before laser photocoagulation).\n\n## Aflibercept after laser photocoagulation\n\nThe committee considered the most plausible ICER for aflibercept after laser photocoagulation in which aflibercept, ranibizumab and dexamethasone were compared in an incremental cost-effectiveness analysis. The committee considered the ERG's estimated ICER which incorporated its preferred assumptions (see sections\xa04.8, 4.10 and 4.11). In this analysis, aflibercept dominated ranibizumab (that is, aflibercept was both less costly and more effective). The committee noted that this was based on the list price of ranibizumab (the ICER incorporating the patient access scheme for ranibizumab is commercial in confidence and cannot be reported here). The committee was mindful of its conclusions regarding the clinical effectiveness of aflibercept compared with ranibizumab (see section\xa04.6). It also considered the cost effectiveness of ranibizumab as assessed during its last NICE technology appraisal, and considered that aflibercept and ranibizumab could be similar in terms of cost effectiveness. The committee turned its attention to the comparison with dexamethasone. It noted that the ERG's estimated ICER for aflibercept compared with dexamethasone that incorporated its preferred assumptions (see sections\xa04.8, 4.10 and 4.11) was between £33,800 per QALY gained and £37,000 per QALY gained. It was aware that these ICERs may be overestimated because of certain modelling assumptions. In particular, the committee recalled its conclusion that the risk of cataracts had been overestimated for aflibercept compared with dexamethasone. It considered that if this was corrected in the economic model, the ICER would be lower. It also recalled that the number of aflibercept injections beyond 3\xa0years in the ERG's base case was a cautious assumption (see section\xa04.9), and that a less pessimistic assumption may lower the ICERs. Given these uncertainties, the committee was confident that the most plausible ICER for the comparison of aflibercept with dexamethasone would be lower. In addition, the committee reasoned that it was appropriate to make a positive recommendation for aflibercept in line with that for ranibizumab, since the evidence had been presented to support the cost effectiveness of aflibercept in this comparison. It therefore concluded that aflibercept should be recommended as an option for treating visual impairment caused by macular oedema after branch retinal vein occlusion when treatment with laser photocoagulation has not been beneficial.\n\n# Innovation\n\nThe committee considered the innovative aspects of aflibercept. It noted that the company considered it to be innovative because it has higher binding affinity for VEGF‑A compared with ranibizumab, and that it inhibits a wider range of growth factors. In those respects the committee agreed with the company that it could be considered innovative. However, the committee could not identify any health-related benefits that had not already been captured in the QALY calculation. The committee concluded that there was nothing additional regarding the innovative nature of aflibercept that needed to be taken into account for the purposes of this appraisal.\n\n# Pharmaceutical Price Regulation Scheme 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA409\n\nAppraisal title: Aflibercept for treating visual impairment caused by macular oedema after branch retinal vein occlusion\n\nSection\n\nKey conclusion\n\nAflibercept is recommended as an option within its marketing authorisation for treating visual impairment in adults caused by macular oedema after branch retinal vein occlusion, only if the company provides aflibercept with the discount agreed in the patient access scheme.\n\nThe committee concluded that aflibercept is more clinically effective than laser photocoagulation for untreated visual impairment (caused by macular oedema after branch retinal vein occlusion) and clinical experience suggests that aflibercept is more clinically effective when given before, rather than after, laser photocoagulation. The committee also concluded that aflibercept is more effective than dexamethasone and equivalent to ranibizumab in terms of clinical effectiveness.\n\n, 4.5, 4.6, 4.7\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee concluded that loss of visual acuity can have a severe effect on a person's quality of life and that patients would welcome additional options to treat visual impairment caused by macular oedema after branch retinal vein occlusion.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that there was nothing additional regarding the innovative nature of aflibercept that needed to be taken into account for the purposes of this appraisal.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that monitoring the condition, laser photocoagulation, anti‑ vascular endothelial growth factor (VEGF) and corticosteroid treatment are all used for treating visual impairment caused by macular oedema after branch retinal vein occlusion. The committee further concluded that since NICE published guidance its technology appraisal on ranibizumab and dexamethasone, clinical practice has changed and anti‑VEGF and corticosteroid treatments are used in the initial treatment of visual impairment caused by macular oedema after branch retinal vein occlusion.\n\n\n\nAdverse reactions\n\nThe committee was aware that treatment with a corticosteroid such as dexamethasone has a greater risk of developing cataracts compared with an anti‑VEGF treatment, such as aflibercept.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee examined the clinical-effectiveness evidence for aflibercept in patients with untreated visual impairment compared with laser photocoagulation, using evidence provided by the company from the randomised control trial VIBRANT.\n\nThe committee was aware that no direct trial evidence was available for the comparisons of aflibercept with ranibizumab or dexamethasone, and instead considered the results of the company's network meta-analysis.\n\n, 4.7\n\nRelevance to general clinical practice in the NHS\n\nNot an issue in this appraisal.\n\n–\n\nUncertainties generated by the evidence\n\nThe committee noted that the long-term benefit of laser might not have been adequately captured at 52\xa0weeks.\n\nThe committee concluded that the source of the utilities was subject to some uncertainty, but the maximum utility gain in the worst-seeing eye should not exceed 0.1\xa0quality-adjusted life year (QALY).\n\n, 4.12\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups were identified.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that aflibercept is more clinically effective than laser photocoagulation for untreated visual impairment (caused by macular oedema after branch retinal vein occlusion) and that clinical experience suggests that aflibercept is more clinically effective when given before, rather than after, laser photocoagulation.\n\nBoth the mean and median odds ratios favoured aflibercept when compared with dexamethasone (mean 0.39; median 0.34). When compared with ranibizumab, the median and mean odds ratios were close to\xa01. Clinical experts explained that ranibizumab and aflibercept are considered clinically equivalent.\n\n, 4.6, 4.7\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented a bilateral economic model.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee acknowledged the following uncertainties in the company's model:\n\nWhether patients may need to have anti‑VEGF treatment for more than 5\xa0years.\n\nThe probabilities used to estimate the likelihood of changing visual acuity were not derived directly from patient data.\n\nQuality-of-life data were taken from Czoski–Murray (2009) and the worst-seeing eye relative to best-seeing eye may not be as high as 30%.\n\nUncertain ongoing aflibercept dosing.\n\nThe model assumed an equal risk of developing cataracts with both aflibercept and dexamethasone.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee agreed that the most plausible source of utilities and proportional impact to the worst-seeing eye would lie between Czoski–Murray 15% and Brown 30%.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were identified.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee noted that when its preferred utilities of Czoski–Murray 15% or Brown 30% were implemented it increased the ICER.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee noted that when its preferred assumptions and utilities were implemented:\n\nCompared with aflibercept followed by laser: ICER between £24,900 and £27,300 per QALY gained.\n\nCompared with ranibizumab following laser: confidential ICER but within the range that could be considered a cost-effective use of NHS resources.\n\nCompared with dexamethasone following laser: ICER between £33,800 and £37,000 per QALY gained. Committee was concerned that these may be overestimated because of certain modelling assumptions, that corrected the ICER would be lower.\n\n, 4.15\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nRecommended only if the company provides aflibercept with the discount agree in the patient access scheme.\n\nThe committee concluded that the Pharmaceutical Price Regulation Scheme payment mechanism was not relevant in considering the cost effectiveness of aflibercept.\n\n, 4.17\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified.\n\n–"}	https://www.nice.org.uk/guidance/ta409	Evidence-based recommendations on aflibercept (Eylea) for treating visual impairment caused by macular oedema after branch retinal vein occlusion.
e8bacbc5845bb4c9419876f87f5447077749c967	nice	Talimogene laherparepvec for treating unresectable metastatic melanoma	Talimogene laherparepvec for treating unresectable metastatic melanoma Evidence-based recommendations on talimogene laherparepvec (Imlygic) for treating unresectable metastatic melanoma in adults when systemically administered immunotherapies are not suitable. # Recommendations Talimogene laherparepvec is recommended, in adults, as an option for treating unresectable, regionally or distantly metastatic (stage 3B, 3C or 4M1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if: treatment with systemically administered immunotherapies is not considered the best option by a multidisciplinary team and the company provides talimogene laherparepvec with the discount agreed in the patient access scheme. This guidance is not intended to affect the position of patients whose treatment with talimogene laherparepvec was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology # Description of the technology Talimogene laherparepvec (Imlygic, Amgen) is derived from the herpes simplex virus type-1. It is a modified form of the virus that kills cancer cells. It is injected directly into cutaneous, subcutaneous and nodal lesions that are visible on the skin, palpable, or detectable with ultrasound guidance. The company states that talimogene laherparepvec has 2 complementary mechanisms of action: replication that causes cell rupture/lysis and death (intracellular or direct effect) and post-lysis release of tumour-derived antigens and granulocyte macrophage colony-stimulating factor (GM-CSF), stimulating a systemic immune response from antigen-presenting cells upon distant tumour sites (extracellular or indirect effect). # Marketing authorisation Talimogene laherparepvec has a marketing authorisation in the UK for the treatment of adults with 'unresectable melanoma that is regionally or distantly metastatic (stage 3B, 3C and 4M1a) with no bone, brain, lung or other visceral disease'. # Adverse reactions The most common adverse reactions in clinical trials of metastatic melanoma were flu-like symptoms (very common), injection-site reactions (very common) and cellulitis (common and potentially serious). For full details of adverse reactions and contraindications, see the summary of product characteristics. # Recommended dose and schedule Administered by intralesional injection at an initial dose of 1,000,000 plaque forming units (PFU) per ml, followed by doses of 100,000,000 PFU per ml at 3 weeks and then every 2 weeks. # Price The acquisition cost of talimogene laherparepvec is £1,670 per 1 ml vial of either 1,000,000 plaque forming units (PFU) per ml or 100,000,000 PFU per ml (excluding VAT; company's submission). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of talimogene laherparepvec, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). It also considered evidence received from patient and professional groups. See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of talimogene laherparepvec, having considered evidence on the nature of metastatic melanoma and the value placed on the benefits of talimogene laherparepvec by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. # Clinical effectiveness The committee considered the clinical-effectiveness evidence presented by the company and its critique by the evidence review group (ERG). The clinical‑effectiveness evidence for talimogene laherparepvec is in the company's submission (pages 42 to 114) and in the ERG's report (pages 33 to 62). The committee also considered additional evidence submitted in response to consultation and a critique by the ERG. ## Current clinical management of unresectable, metastatic melanoma The marketing authorisation for talimogene laherparepvec is for unresectable melanoma that is regionally or distantly metastatic (stage 3B, 3C and 4M1a) with no bone, brain, lung or other visceral disease. The committee noted that this is based on evidence from a post-hoc subgroup within the OPTiM trial (57% of the overall trial population with no visceral metastatic disease). The clinical experts stated that in clinical practice, treatment with talimogene laherparepvec would be suitable for approximately 10 to 15% of people with unresectable metastatic melanoma. The patient expert stated that talimogene laherparepvec might be a particularly valuable option for people with visible skin tumours, which can be a source of great anxiety. The clinical experts considered the main benefits of talimogene laherparepvec to be that the method of administration is acceptable to patients, and that it has an improved toxicity profile compared to currently available systemic treatments (particularly ipilimumab). They stated that patients with melanoma that is suitable for treatment with talimogene laherparepvec may have multiple small lesions, which make surgical resection impractical, and that other localised therapies such as isolated limb perfusion are not widely available. Having a choice of effective treatments would be particularly valuable to people with this condition. The committee concluded that the availability of a new treatment option with a novel mechanism of action and improved tolerability would be valuable for people with metastatic melanoma, if it was shown to be as clinically effective as other available treatments. ## Comparators The comparators in the final scope were the immunotherapy agent ipilimumab, and the BRAF inhibitors vemurafenib and dabrafenib. The newer systemic immunotherapy agents, pembrolizumab and nivolumab, were not included as comparators in the scope of this appraisal. However, the committee noted the recent NICE technology appraisal guidance on pembrolizumab for treating advanced melanoma after disease progression with ipilimumab and on pembrolizumab for advanced melanoma not previously treated with ipilimumab and also on nivolumab for treating advanced (unresectable or metastatic) melanoma, which had been published by the time of the final meeting of the committee. The clinical experts noted that these treatments would be considered for the same group of patients as talimogene laherparepvec. For patients with BRAF negative or wild type disease the only alternative therapy in routine clinical practice would be systemically administered immunotherapy agents. However, for people with the BRAF‑V600 mutation, the disease can be treated either with immunotherapy or BRAF‑specific agents. This choice would be influenced by the overall burden of disease, and whether it is slowly or rapidly progressing. A BRAF inhibitor, such as vemurafenib or dabrafenib, is likely to be the preferred treatment for people with BRAF‑V600 mutations whose disease is progressing rapidly, while immunotherapies such as ipilimumab, pembrolizumab and nivolumab will be used for people with BRAF‑V600 mutations with more slowly progressive disease or a lower tumour burden. The committee heard that in the light of emerging evidence of long‑term benefit experienced by some people having immunotherapy, this would generally be used in preference to the BRAF inhibitors whenever clinically possible. For practical purposes, the group of patients considered for immunotherapy, and in particular talimogene laherparepvec (who have earlier stage disease and no visceral metastases) would not correspond with those for whom a BRAF inhibitor would be the first choice of treatment. The committee concluded that the most clinically relevant comparator within the scope for this appraisal was ipilimumab. The committee noted that the newer immunotherapies, pembrolizumab and nivolumab, were not included in the scope and therefore could not be considered as direct comparators as part of the appraisal process. However it was reasonable for the committee to acknowledge their increasing use in clinical practice, particularly since they had shown superior short‑term outcomes to ipilimumab in clinical trials and had lower toxicity than ipilimumab. ## Results of the OPTiM trial The evidence underpinning the marketing authorisation for talimogene laherparepvec came solely from an exploratory post-hoc subgroup analysis of people in the OPTiM trial who had melanoma with no visceral metastases. The committee was aware that the comparator arm in the trial was granulocyte macrophage colony-stimulating factor (GM-CSF), which in the view of the clinical experts is clinically ineffective, effectively equivalent to placebo, and is not used in clinical practice. The committee noted that, in common with ipilimumab, pembrolizumab and nivolumab, talimogene laherparepvec is a disease-modifying immunotherapy and some patients who have a complete or sustained response may require no further treatment for melanoma. The clinical experts stated that although durable response rate is a new, non-validated endpoint in clinical trials of advanced melanoma, it is considered to be more clinically meaningful than overall response rate because of its association with a reduced risk of recurrence. In the OPTiM trial, talimogene laherparepvec showed a statistically significant improvement of 25.3 months in overall survival (p value 0.0008), a durable response rate of 25.2% (compared with 1.2% for GM-CSF) and a complete response rate of 16.6% (compared with 0% for GM-CSF). The ERG raised concerns about the potential for bias in the trial because of limited blinding, differences in the withdrawal rates in the 2 arms, and the use of a non-validated primary endpoint, all of which made it difficult to interpret the efficacy results. The committee accepted that talimogene laherparepvec was clinically effective when compared with GM-CSF, although it also acknowledged that this was based on a post-hoc analysis of a subgroup in the trial, using a comparator that was considered ineffective and is not in clinical use in the NHS. ## Comparison with ipilimumab The committee acknowledged that it was not feasible for the company to carry out a network meta-analysis because of the lack of a common comparator in the trial network. It also understood that the population in the subgroup in OPTiM for which the licence was granted (stage 3B to 4M1a disease) was not directly comparable with the population in the ipilimumab trials, because there were substantial differences in the patient characteristics. In particular, only 11% to 17% of patients in the ipilimumab trials had stage 3B to 4M1a disease; the others had more advanced melanoma. Also, it was not clear what proportion of the small number of patients with stage 3B to 4M1a disease in the ipilimumab trials had injectable lesions that could have been treated with talimogene laherparepvec. The clinical experts stated that there is a lack of evidence on the effectiveness of any melanoma treatments for stage 3B to 4M1a advanced melanoma, and that the OPTiM trial represents the best evidence for this stage of disease. The committee also heard that the disease trajectory of stage III melanoma is likely to differ from that of stage 4M1a, with a different life expectancy, and also noted the clinical expert's comment that as a general rule, earlier-stage disease with a smaller tumour burden is likely to respond better to treatment than later-stage disease. The committee noted that the company had explored ways in which talimogene laherparepvec could be compared with ipilimumab for stage 3B to 4M1a disease using the modified and 2‑step Korn methods to correct for differences in patient characteristics between the ipilimumab trials and OPTiM. These adjusted the progression-free and overall survival data from the pooled ipilimumab trials by stage of disease and lactate dehydrogenase (LDH) level in the modified Korn method, and also adjusted for a better disease response in earlier-stage disease in the 2‑step Korn method. The 2 different estimates of ipilimumab efficacy were then used to calculate the relative effectiveness of talimogene laherparepvec compared with ipilimumab. When the modified Korn method was used (the best case), the adjusted survival estimates for ipilimumab were lower than for talimogene laherparepvec. However, the committee noted that the confidence intervals around the adjusted ipilimumab data overlapped with the talimogene laherparepvec trial results. The committee noted that when the 2‑step Korn method was used, which the company considered to be the 'worst case', the overall survival estimates for ipilimumab were very similar to those for talimogene laherparepvec in the OPTiM trial. The committee acknowledged that the company had made efforts to make a comparison with ipilimumab but noted the uncertainty of that comparison, largely because of the lack of efficacy data for ipilimumab in the relevant population. Of the 2 methods used by the company, the committee considered that the modified Korn (best case) was the less reliable because it had heard from the clinical expert that treatment response was likely to be better in early‑stage than in later‑stage disease, and the method did not take this into account. In the 2‑ step Korn method talimogene laherparepvec had not been shown to be superior to ipilimumab. The committee noted the ERG's comment that the company should be complimented on their thorough approach to the problem of defining an appropriate comparison with ipilimumab from the available trial data. However, it accepted the underlying concern of the ERG that the Korn method was flawed for modelling progression in stage 3B to 4M1a disease because the algorithm was developed using data from people with predominantly stage 4M1b and stage 4M1c disease, which have different disease trajectories. It also questioned the inclusion of an adjustment for LDH level in the modified Korn method, because this is of limited relevance for people with stage 3B, stage 3C or stage 4M1a disease. Also, the LDH adjustment had the effect of reducing the influence of other prognostic adjustment factors, leading to a potential overestimate of the efficacy of talimogene laherparepvec compared with ipilimumab. The committee agreed that the modifications to the Korn method (the modified and 2-step Korn) further compounded the underlying issues with the Korn method. The committee concluded that the evidence presented was not sufficient to draw any firm conclusions about the relative clinical effectiveness of talimogene laherparepvec compared with ipilimumab in this patient population. # Cost effectiveness The committee considered the cost-effectiveness evidence presented by the company and its critique by the ERG. The cost-effectiveness evidence is in the company's submission (pages 115 to 208), in the appendices to the company's submission and in the ERG report (pages 63 to 105). The committee also considered additional evidence submitted by the company in response to consultation and a critique by the ERG. ## The company's model The company's model compared talimogene laherparepvec with ipilimumab in people with stage 3B to stage 4M1a melanoma. The committee considered that the 3‑state model structure was similar to models used in other melanoma appraisals and therefore accepted that it was appropriate for decision‑making. The company had used a multi‑stage approach to modelling overall survival based on different data sources. The committee noted the ERG's comments that, in principle, the multi-stage approach (using Kaplan–Meier data directly followed by modelled projections of overall survival) was generally appropriate. However, the ERG questioned the sudden change in the shape of the curve at 62.1 months, and also the removal of any melanoma-related mortality after 10 years. The committee accepted the basic structure of the company's model, but gave further consideration to the assumptions used in the modelling of survival. The committee discussed the extrapolation of overall survival data in the talimogene laherparepvec arm of the company's model (based on the entire Kaplan–Meier curve to 60 months) and the ERG's exploratory analysis (which used a 2-part exponential model from 9 to 47 months, when the last death was recorded). These different approaches led to 2 divergent survival trends resulting in very different estimates of long-term survival for patients who had talimogene laherparepvec. The committee heard from the company's representative that it considered the entire Kaplan–Meier curve to be most relevant for the purposes of extrapolation because it uses the full extent of the trial follow‑up data. The committee noted that 24% of patients in the talimogene laherparepvec arm were alive at 47 months (when the estimated overall survival was 49%) and remained so at 60 months. The ERG stated that the Kaplan–Meier method estimates survival only for those time points when a death occurred, and therefore only the survival estimates at the time of these events can be legitimately used for fitting projective trends to trial data. Extending the data used for survival estimation beyond the last recorded death, as the company had done, involves assuming that, across an extended time period in which no deaths occur and beyond, any patient still alive can be expected to remain indefinitely free of the risk of death from any cause (not just melanoma). The ERG did not consider this method of extrapolating survival beyond 47 months to be plausible. The ERG also referred to the results of the Kaplan–Meier analysis from OPTiM, which indicated that, following the last recorded death at 47 months, 39 patients remained alive and at risk. These were all censored due to the termination of the trial on a particular date, even though the patients were recruited at different times. This means that the true time of death of these patients cannot be determined. The ERG's approach resulted in a reduction in mean overall survival from 108.5 months, as calculated by the company, to 73 months. This was lower than the overall survival in the ipilimumab trials, indicating that overall survival with talimogene laherparepvec could be less favourable than with ipilimumab. The committee noted the ERG's comment that the company had overestimated overall survival with talimogene laherparepvec by between 49% and 59%. The committee expressed concern that it had not seen enough evidence to be confident that talimogene laherparepvec was as clinically effective as ipilimumab or other currently available therapies in people with stage 3B to stage 4M1a melanoma. The committee concluded that, because of the lack of suitable effectiveness inputs in the economic model, it had not been presented with a plausible incremental cost‑effectiveness ratio (ICER) for talimogene laherparepvec compared with ipilimumab. The company submitted additional analyses in response to the appraisal consultation document, intended to address uncertainty in the relative clinical effectiveness of talimogene laherparepvec compared with ipilimumab. This included the use of the Korn method for adjusting the effectiveness of ipilimumab data in the intention to treat population from the OPTiM trial (stage 3B to 4M1c). The committee reconsidered the use of Korn methodology for adjusting the baseline characteristics of the ipilimumab trial, including the results of the Korn adjustment in the intention to treat population (stage 3B to 4M1c), which was a broader population than the marketing authorisation of talimogene laherparepvec. These results suggested that talimogene laherparepvec was at least as effective as ipilimumab. The committee noted that these analyses did not address the underlying methodological concern that the Korn algorithm (which was based predominantly on patients with later‑stage disease) was not valid because it had not been calibrated against patient‑level data from ipilimumab trials in a similar population to the OPTIM trial (see section 4.9). In response to consultation the company also submitted a 'naive' indirect comparison of talimogene laherparepvec with ipilimumab in which GM‑CSF, dacarbazine and gp100 were assumed to be equally ineffective in the treatment of metastatic melanoma. But the committee did not consider it to be a reliable method of establishing the relative effectiveness of these agents. The committee appreciated that the company had made every reasonable effort to adjust the ipilimumab data, but there is no methodologically valid way of comparing talimogene laherparepvec with ipilimumab in stage 3B to 4M1a melanoma. The committee noted the proven long‑term survival benefit in a proportion of patients who had ipilimumab (based on 5‑year overall survival data) and concluded that it is not possible to resolve the uncertainty about the relative effectiveness of talimogene laherparepvec compared with ipilimumab (and other newer systemically administered therapies). The committee considered that it needed to be very confident that talimogene laherparepvec is at least as effective as ipilimumab before recommending it as an option for all patients in the licensed population, given that ipilimumab monotherapy has been increasingly replaced by newer therapies that have shown better short‑term effectiveness in clinical trials, with lower toxicity. The committee considered additional analyses on the cost effectiveness of talimogene laherparepvec compared with dacarbazine (which has not been shown to prolong overall survival), and best supportive care that were submitted as part of the company's response to consultation. The committee noted that the ICERs for talimogene laherparepvec compared with dacarbazine and best supportive care were approximately £23,900 and £24,100 per QALY gained, and were substantially lower than the corresponding ICERs for ipilimumab compared with dacarbazine and best supportive care (approximately £47,900 and £42,200 per QALY gained, respectively, in NICE technology appraisal guidance on ipilimumab for previously untreated advanced melanoma and on ipilimumab for previously treated advanced melanoma). The committee noted that these figures applied to patients at different stages of disease and were not directly comparable, and so could not be used to draw conclusions about the relative cost effectiveness of these agents. The committee considered whether there may be a subgroup of patients for whom talimogene laherparepvec would be particularly beneficial, in particular whether there was a group of patients for whom talimogene laherparepvec might be the only effective option, such as those for whom systemic immunotherapy was contraindicated. The clinical expert, in response to consultation, had highlighted that there were people with BRAF‑negative disease for whom systemically administered immunotherapy is not suitable and who currently had no other effective treatment options. The committee noted the cost-effectiveness analyses presented comparing talimogene laherparepvec with dacarbazine and best supportive care. While these analyses did not specifically relate to a population with melanoma for whom systemically administered immunotherapies were not suitable, the committee was satisfied that they gave an indication of the cost effectiveness of talimogene laherparepvec in this situation. It concluded that talimogene laherparepvec is a clinically and cost-effective option for people with unresectable non-visceral metastatic melanoma for whom systemically administered immunotherapies are not suitable. The company stated that talimogene laherparepvec is innovative and a step change in the management of advanced melanoma because it has a novel mechanism of action, in that it produces local tumour control and leads to a systemic anti-tumour immune response. Also, it is the only treatment approved specifically for people with regionally or distantly metastatic melanoma with no visceral disease (stage 3B to stage 4M1a) and is associated with fewer treatment-related grade 3 and 4 adverse events compared with existing treatments. The committee agreed that intra-lesion injections are an innovative approach to the treatment of melanoma, although the marketing authorisation did not support the systemic action of talimogene laherparepvec. The committee also noted that talimogene laherparepvec is being investigated as a combination therapy with other agents, which it considered may be important in the future. However, the committee could not identify any specific health‑related benefit that had not already been captured in the QALY calculation. # Pharmaceutical Price Regulation Scheme (PPRS) 2014 The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of Appraisal Committee's key conclusions ## Key conclusion Talimogene laherparepvec is recommended, in adults, as an option for treating unresectable, regionally or distantly metastatic (stage 3B, 3C and 4M1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if: treatment with systemically administered immunotherapies is not suitable and the company provides talimogene laherparepvec with the discount agreed in the patient access scheme. The committee concluded that although it could not be confident in establishing a reliable estimate of the effectiveness of talimogene laherparepvec compared with immunotherapies currently used in clinical practice, it is clinically and cost effective in people for whom treatment with systemically administered immunotherapies is not suitable. The cost effectiveness of talimogene laherparepvec compared with best supportive care in people for whom systemically administered immunotherapy not suitable is approximately £24,000 per QALY gained. See sections 1.1, 4.9 and 4.16. ## Current practice The committee concluded that the availability of a new treatment option with a novel mechanism of action and improved tolerability would be valuable for people with metastatic melanoma. See section 4.3. ## The technology The committee agreed that talimogene laherparepvec is an innovative approach to the treatment of melanoma. It also noted that talimogene laherparepvec is being investigated as combination therapy with other agents, which it considered may be important in the future. However, the committee could not identify any specific health‑related benefit that had not already been captured in the QALY calculation. See section 4.17. Talimogene laherparepvec has a marketing authorisation for unresectable melanoma that is regionally or distantly metastatic (stage 3B, 3C and 4M1a) with no bone, brain, lung or other visceral disease. This is based on evidence from a post-hoc subgroup within the OPTiM trial (57% of the overall trial population, who had non-visceral metastatic disease). The committee heard from clinical experts that in clinical practice, treatment with talimogene laherparepvec would be suitable for approximately 10% to 15% of people with unresectable metastatic melanoma. See section 4.2. The committee heard from the patient and clinical experts that ipilimumab can be associated with severe side effects and that an alternative treatment with an improved toxicity profile would be desirable. Clinical experts considered the main benefits of talimogene laherparepvec to be that the method of administration is acceptable to patients, and that it has an improved toxicity profile compared to currently available treatments (particularly ipilimumab). See section 4.3. ## Evidence for clinical effectiveness The evidence underpinning the marketing authorisation came solely from an exploratory post-hoc subgroup analysis of people in the OPTiM trial who had non-visceral metastatic melanoma. The committee concluded that talimogene laherparepvec was clinically effective compared with an ineffective treatment (GM-CSF) but it was difficult to draw conclusions from these trial data alone on the effectiveness of talimogene laherparepvec compared with systemically administered immunotherapies used in current clinical practice. See sections 4.3 and 4.5. The committee heard from the clinical experts that patients suitable for treatment with talimogene laherparepvec may have multiple small lesions which make surgical resection impractical, and that other localised therapies such as isolated limb perfusion are not widely available. See section 4.4. The committee concluded that the evidence presented was not sufficient to draw any firm conclusions about the relative clinical effectiveness of talimogene laherparepvec compared with ipilimumab in this patient population. See section 4.9. The committee agreed that talimogene laherparepvec is a reasonable option for people with unresectable non-visceral metastatic melanoma for whom systemically administered immunotherapies are not suitable, and that it is clinically effective compared with best supportive care. See section 4.16. The evidence for effectiveness was based on a post-hoc analysis against a comparator (GM-CSF) which was not relevant for decision-making, and it was therefore difficult to draw conclusions from these trial data alone on the effectiveness of talimogene laherparepvec compared with immunotherapies in current clinical practice. The committee noted that in the OPTiM trial, talimogene laherparepvec showed a statistically significant improvement of 25.3 months in overall survival (p value 0.0008), durable response rate of 25.2% (compared with 1.2% with GM-CSF) and complete response rate of 16.6% (compared with 0% for GM-CSF). The committee concluded that talimogene laherparepvec is clinically effective in people for whom treatment with systemically administered immunotherapies is not suitable. See section 4.5. ## Evidence for cost effectiveness The committee noted that the company had used a multi‑stage approach to modelling overall survival based on different data sources to compare talimogene laherparepvec with ipilimumab in people with stage 3B to stage 4M1a melanoma. The committee accepted the basic structure of the company's model but questioned some of the model inputs. See section 4.11. The committee acknowledged the ERG's concerns that the Korn method was not suitable for modelling progression in stage 3B to stage 4M1a melanoma. It agreed that the modifications to the Korn method (the modified and 2‑step Korn) further compounded the underlying issues with the Korn method. The Committee concluded that the clinical effectiveness of talimogene laherparepvec compared with ipilimumab was uncertain, largely because of the lack of efficacy data for ipilimumab in the relevant population. See section 4.13. Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee could not identify any specific health‑related benefit that had not already been captured in the QALY calculation. See section 4.17. The committee concluded that talimogene laherparepvec is cost effective in people for whom treatment with systemically administered immunotherapies is not suitable. See section 4.16. The Committee concluded that the clinical effectiveness of talimogene laherparepvec compared with ipilimumab was uncertain, largely because of the lack of efficacy data for ipilimumab in the relevant population. See sections 4.13 and 4.15. The committee was not able to determine the ICER for talimogene laherparepvec compared with ipilimumab because of uncertainties in the relative clinical effectiveness of these agents. The committee considered talimogene laherparepvec to be cost effective compared with dacarbazine (£23,900 per QALY gained) and best supportive care (£24,100 per QALY gained) in people whose disease was not suitable for treatment with systemically administered immunotherapies. See sections 4.13, 4.15 and 4.16. ## Additional factors taken into account The committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. See section 4.20. The case for end-of-life considerations was not made during this appraisal. No equalities issues were raised in the evidence submissions or at the Committee meeting.	{'Recommendations': 'Talimogene laherparepvec is recommended, in adults, as an option for treating unresectable, regionally or distantly metastatic (stage 3B, 3C or 4M1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if:\n\n\n\ntreatment with systemically administered immunotherapies is not considered the best option by a multidisciplinary team and\n\nthe company provides talimogene laherparepvec with the discount agreed in the patient access scheme.\n\n\n\nThis guidance is not intended to affect the position of patients whose treatment with talimogene laherparepvec was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "# Description of the technology\n\nTalimogene laherparepvec (Imlygic, Amgen) is derived from the herpes simplex virus type-1. It is a modified form of the virus that kills cancer cells. It is injected directly into cutaneous, subcutaneous and nodal lesions that are visible on the skin, palpable, or detectable with ultrasound guidance. The company states that talimogene laherparepvec has 2 complementary mechanisms of action: replication that causes cell rupture/lysis and death (intracellular or direct effect) and post-lysis release of tumour-derived antigens and granulocyte macrophage colony-stimulating factor (GM-CSF), stimulating a systemic immune response from antigen-presenting cells upon distant tumour sites (extracellular or indirect effect).\n\n# Marketing authorisation\n\nTalimogene laherparepvec has a marketing authorisation in the UK for the treatment of adults with 'unresectable melanoma that is regionally or distantly metastatic (stage 3B, 3C and 4M1a) with no bone, brain, lung or other visceral disease'.\n\n# Adverse reactions\n\nThe most common adverse reactions in clinical trials of metastatic melanoma were flu-like symptoms (very common), injection-site reactions (very common) and cellulitis (common and potentially serious). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\n# Recommended dose and schedule\n\nAdministered by intralesional injection at an initial dose of 1,000,000 plaque forming units (PFU) per ml, followed by doses of 100,000,000\xa0PFU per ml at 3\xa0weeks and then every 2\xa0weeks.\n\n# Price\n\nThe acquisition cost of talimogene laherparepvec is £1,670 per 1 ml vial of either 1,000,000 plaque forming units (PFU) per ml or 100,000,000 PFU per ml (excluding VAT; company's submission).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of talimogene laherparepvec, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee considered evidence submitted by Amgen and a review of this submission by the evidence review group (ERG). It also considered evidence received from patient and professional groups. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of talimogene laherparepvec, having considered evidence on the nature of metastatic melanoma and the value placed on the benefits of talimogene laherparepvec by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe committee considered the clinical-effectiveness evidence presented by the company and its critique by the evidence review group (ERG). The clinical‑effectiveness evidence for talimogene laherparepvec is in the company's submission (pages 42 to 114) and in the ERG's report (pages 33 to 62). The committee also considered additional evidence submitted in response to consultation and a critique by the ERG.\n\n## Current clinical management of unresectable, metastatic melanoma\n\nThe marketing authorisation for talimogene laherparepvec is for unresectable melanoma that is regionally or distantly metastatic (stage\xa03B, 3C and 4M1a) with no bone, brain, lung or other visceral disease. The committee noted that this is based on evidence from a post-hoc subgroup within the OPTiM trial (57% of the overall trial population with no visceral metastatic disease). The clinical experts stated that in clinical practice, treatment with talimogene laherparepvec would be suitable for approximately 10 to 15% of people with unresectable metastatic melanoma.\n\nThe patient expert stated that talimogene laherparepvec might be a particularly valuable option for people with visible skin tumours, which can be a source of great anxiety. The clinical experts considered the main benefits of talimogene laherparepvec to be that the method of administration is acceptable to patients, and that it has an improved toxicity profile compared to currently available systemic treatments (particularly ipilimumab). They stated that patients with melanoma that is suitable for treatment with talimogene laherparepvec may have multiple small lesions, which make surgical resection impractical, and that other localised therapies such as isolated limb perfusion are not widely available. Having a choice of effective treatments would be particularly valuable to people with this condition. The committee concluded that the availability of a new treatment option with a novel mechanism of action and improved tolerability would be valuable for people with metastatic melanoma, if it was shown to be as clinically effective as other available treatments.\n\n## Comparators\n\nThe comparators in the final scope were the immunotherapy agent ipilimumab, and the BRAF inhibitors vemurafenib and dabrafenib. The newer systemic immunotherapy agents, pembrolizumab and nivolumab, were not included as comparators in the scope of this appraisal. However, the committee noted the recent NICE technology appraisal guidance on pembrolizumab for treating advanced melanoma after disease progression with ipilimumab and on pembrolizumab for advanced melanoma not previously treated with ipilimumab and also on nivolumab for treating advanced (unresectable or metastatic) melanoma, which had been published by the time of the final meeting of the committee. The clinical experts noted that these treatments would be considered for the same group of patients as talimogene laherparepvec. For patients with BRAF negative or wild type disease the only alternative therapy in routine clinical practice would be systemically administered immunotherapy agents. However, for people with the BRAF‑V600 mutation, the disease can be treated either with immunotherapy or BRAF‑specific agents. This choice would be influenced by the overall burden of disease, and whether it is slowly or rapidly progressing. A BRAF inhibitor, such as vemurafenib or dabrafenib, is likely to be the preferred treatment for people with BRAF‑V600 mutations whose disease is progressing rapidly, while immunotherapies such as ipilimumab, pembrolizumab and nivolumab will be used for people with BRAF‑V600 mutations with more slowly progressive disease or a lower tumour burden. The committee heard that in the light of emerging evidence of long‑term benefit experienced by some people having immunotherapy, this would generally be used in preference to the BRAF inhibitors whenever clinically possible. For practical purposes, the group of patients considered for immunotherapy, and in particular talimogene laherparepvec (who have earlier stage disease and no visceral metastases) would not correspond with those for whom a BRAF inhibitor would be the first choice of treatment. The committee concluded that the most clinically relevant comparator within the scope for this appraisal was ipilimumab. The committee noted that the newer immunotherapies, pembrolizumab and nivolumab, were not included in the scope and therefore could not be considered as direct comparators as part of the appraisal process. However it was reasonable for the committee to acknowledge their increasing use in clinical practice, particularly since they had shown superior short‑term outcomes to ipilimumab in clinical trials and had lower toxicity than ipilimumab.\n\n## Results of the OPTiM trial\n\nThe evidence underpinning the marketing authorisation for talimogene laherparepvec came solely from an exploratory post-hoc subgroup analysis of people in the OPTiM trial who had melanoma with no visceral metastases. The committee was aware that the comparator arm in the trial was granulocyte macrophage colony-stimulating factor (GM-CSF), which in the view of the clinical experts is clinically ineffective, effectively equivalent to placebo, and is not used in clinical practice. The committee noted that, in common with ipilimumab, pembrolizumab and nivolumab, talimogene laherparepvec is a disease-modifying immunotherapy and some patients who have a complete or sustained response may require no further treatment for melanoma. The clinical experts stated that although durable response rate is a new, non-validated endpoint in clinical trials of advanced melanoma, it is considered to be more clinically meaningful than overall response rate because of its association with a reduced risk of recurrence. In the OPTiM trial, talimogene laherparepvec showed a statistically significant improvement of 25.3\xa0months in overall survival (p value 0.0008), a durable response rate of 25.2% (compared with 1.2% for GM-CSF) and a complete response rate of 16.6% (compared with 0% for GM-CSF). The ERG raised concerns about the potential for bias in the trial because of limited blinding, differences in the withdrawal rates in the 2\xa0arms, and the use of a non-validated primary endpoint, all of which made it difficult to interpret the efficacy results. The committee accepted that talimogene laherparepvec was clinically effective when compared with GM-CSF, although it also acknowledged that this was based on a post-hoc analysis of a subgroup in the trial, using a comparator that was considered ineffective and is not in clinical use in the NHS.\n\n## Comparison with ipilimumab\n\nThe committee acknowledged that it was not feasible for the company to carry out a network meta-analysis because of the lack of a common comparator in the trial network. It also understood that the population in the subgroup in OPTiM for which the licence was granted (stage\xa03B to 4M1a disease) was not directly comparable with the population in the ipilimumab trials, because there were substantial differences in the patient characteristics. In particular, only 11% to 17% of patients in the ipilimumab trials had stage 3B to 4M1a disease; the others had more advanced melanoma. Also, it was not clear what proportion of the small number of patients with stage\xa03B to 4M1a disease in the ipilimumab trials had injectable lesions that could have been treated with talimogene laherparepvec.\n\nThe clinical experts stated that there is a lack of evidence on the effectiveness of any melanoma treatments for stage\xa03B to 4M1a advanced melanoma, and that the OPTiM trial represents the best evidence for this stage of disease. The committee also heard that the disease trajectory of stage\xa0III melanoma is likely to differ from that of stage\xa04M1a, with a different life expectancy, and also noted the clinical expert's comment that as a general rule, earlier-stage disease with a smaller tumour burden is likely to respond better to treatment than later-stage disease.\n\nThe committee noted that the company had explored ways in which talimogene laherparepvec could be compared with ipilimumab for stage\xa03B to 4M1a disease using the modified and 2‑step Korn methods to correct for differences in patient characteristics between the ipilimumab trials and OPTiM. These adjusted the progression-free and overall survival data from the pooled ipilimumab trials by stage of disease and lactate dehydrogenase (LDH) level in the modified Korn method, and also adjusted for a better disease response in earlier-stage disease in the 2‑step Korn method. The 2 different estimates of ipilimumab efficacy were then used to calculate the relative effectiveness of talimogene laherparepvec compared with ipilimumab. When the modified Korn method was used (the best case), the adjusted survival estimates for ipilimumab were lower than for talimogene laherparepvec. However, the committee noted that the confidence intervals around the adjusted ipilimumab data overlapped with the talimogene laherparepvec trial results. The committee noted that when the 2‑step Korn method was used, which the company considered to be the 'worst case', the overall survival estimates for ipilimumab were very similar to those for talimogene laherparepvec in the OPTiM trial. The committee acknowledged that the company had made efforts to make a comparison with ipilimumab but noted the uncertainty of that comparison, largely because of the lack of efficacy data for ipilimumab in the relevant population.\n\nOf the 2 methods used by the company, the committee considered that the modified Korn (best case) was the less reliable because it had heard from the clinical expert that treatment response was likely to be better in early‑stage than in later‑stage disease, and the method did not take this into account. In the 2‑ step Korn method talimogene laherparepvec had not been shown to be superior to ipilimumab. The committee noted the ERG's comment that the company should be complimented on their thorough approach to the problem of defining an appropriate comparison with ipilimumab from the available trial data. However, it accepted the underlying concern of the ERG that the Korn method was flawed for modelling progression in stage\xa03B to 4M1a disease because the algorithm was developed using data from people with predominantly stage\xa04M1b and stage\xa04M1c disease, which have different disease trajectories. It also questioned the inclusion of an adjustment for LDH level in the modified Korn method, because this is of limited relevance for people with stage\xa03B, stage\xa03C or stage\xa04M1a disease. Also, the LDH adjustment had the effect of reducing the influence of other prognostic adjustment factors, leading to a potential overestimate of the efficacy of talimogene laherparepvec compared with ipilimumab. The committee agreed that the modifications to the Korn method (the modified and 2-step Korn) further compounded the underlying issues with the Korn method. The committee concluded that the evidence presented was not sufficient to draw any firm conclusions about the relative clinical effectiveness of talimogene laherparepvec compared with ipilimumab in this patient population.\n\n# Cost effectiveness\n\nThe committee considered the cost-effectiveness evidence presented by the company and its critique by the ERG. The cost-effectiveness evidence is in the company's submission (pages 115 to 208), in the appendices to the company's submission and in the ERG report (pages 63 to 105). The committee also considered additional evidence submitted by the company in response to consultation and a critique by the ERG.\n\n## The company's model\n\nThe company's model compared talimogene laherparepvec with ipilimumab in people with stage\xa03B to stage\xa04M1a melanoma. The committee considered that the 3‑state model structure was similar to models used in other melanoma appraisals and therefore accepted that it was appropriate for decision‑making. The company had used a multi‑stage approach to modelling overall survival based on different data sources. The committee noted the ERG's comments that, in principle, the multi-stage approach (using Kaplan–Meier data directly followed by modelled projections of overall survival) was generally appropriate. However, the ERG questioned the sudden change in the shape of the curve at 62.1\xa0months, and also the removal of any melanoma-related mortality after 10\xa0years. The committee accepted the basic structure of the company's model, but gave further consideration to the assumptions used in the modelling of survival.\n\nThe committee discussed the extrapolation of overall survival data in the talimogene laherparepvec arm of the company's model (based on the entire Kaplan–Meier curve to 60\xa0months) and the ERG's exploratory analysis (which used a 2-part exponential model from 9\xa0to\xa047\xa0months, when the last death was recorded). These different approaches led to 2\xa0divergent survival trends resulting in very different estimates of long-term survival for patients who had talimogene laherparepvec. The committee heard from the company's representative that it considered the entire Kaplan–Meier curve to be most relevant for the purposes of extrapolation because it uses the full extent of the trial follow‑up data. The committee noted that 24% of patients in the talimogene laherparepvec arm were alive at 47\xa0months (when the estimated overall survival was 49%) and remained so at 60\xa0months. The ERG stated that the Kaplan–Meier method estimates survival only for those time points when a death occurred, and therefore only the survival estimates at the time of these events can be legitimately used for fitting projective trends to trial data. Extending the data used for survival estimation beyond the last recorded death, as the company had done, involves assuming that, across an extended time period in which no deaths occur and beyond, any patient still alive can be expected to remain indefinitely free of the risk of death from any cause (not just melanoma). The ERG did not consider this method of extrapolating survival beyond 47\xa0months to be plausible. The ERG also referred to the results of the Kaplan–Meier analysis from OPTiM, which indicated that, following the last recorded death at 47\xa0months, 39\xa0patients remained alive and at risk. These were all censored due to the termination of the trial on a particular date, even though the patients were recruited at different times. This means that the true time of death of these patients cannot be determined. The ERG's approach resulted in a reduction in mean overall survival from 108.5\xa0months, as calculated by the company, to 73\xa0months. This was lower than the overall survival in the ipilimumab trials, indicating that overall survival with talimogene laherparepvec could be less favourable than with ipilimumab. The committee noted the ERG's comment that the company had overestimated overall survival with talimogene laherparepvec by between 49% and 59%. The committee expressed concern that it had not seen enough evidence to be confident that talimogene laherparepvec was as clinically effective as ipilimumab or other currently available therapies in people with stage\xa03B to stage\xa04M1a melanoma. The committee concluded that, because of the lack of suitable effectiveness inputs in the economic model, it had not been presented with a plausible incremental cost‑effectiveness ratio (ICER) for talimogene laherparepvec compared with ipilimumab.\n\nThe company submitted additional analyses in response to the appraisal consultation document, intended to address uncertainty in the relative clinical effectiveness of talimogene laherparepvec compared with ipilimumab. This included the use of the Korn method for adjusting the effectiveness of ipilimumab data in the intention to treat population from the OPTiM trial (stage\xa03B\xa0to\xa04M1c). The committee reconsidered the use of Korn methodology for adjusting the baseline characteristics of the ipilimumab trial, including the results of the Korn adjustment in the intention to treat population (stage\xa03B to\xa04M1c), which was a broader population than the marketing authorisation of talimogene laherparepvec. These results suggested that talimogene laherparepvec was at least as effective as ipilimumab. The committee noted that these analyses did not address the underlying methodological concern that the Korn algorithm (which was based predominantly on patients with later‑stage disease) was not valid because it had not been calibrated against patient‑level data from ipilimumab trials in a similar population to the OPTIM trial (see section\xa04.9).\n\nIn response to consultation the company also submitted a 'naive' indirect comparison of talimogene laherparepvec with ipilimumab in which GM‑CSF, dacarbazine and gp100 were assumed to be equally ineffective in the treatment of metastatic melanoma. But the committee did not consider it to be a reliable method of establishing the relative effectiveness of these agents. The committee appreciated that the company had made every reasonable effort to adjust the ipilimumab data, but there is no methodologically valid way of comparing talimogene laherparepvec with ipilimumab in stage\xa03B to 4M1a melanoma. The committee noted the proven long‑term survival benefit in a proportion of patients who had ipilimumab (based on 5‑year overall survival data) and concluded that it is not possible to resolve the uncertainty about the relative effectiveness of talimogene laherparepvec compared with ipilimumab (and other newer systemically administered therapies). The committee considered that it needed to be very confident that talimogene laherparepvec is at least as effective as ipilimumab before recommending it as an option for all patients in the licensed population, given that ipilimumab monotherapy has been increasingly replaced by newer therapies that have shown better short‑term effectiveness in clinical trials, with lower toxicity.\n\nThe committee considered additional analyses on the cost effectiveness of talimogene laherparepvec compared with dacarbazine (which has not been shown to prolong overall survival), and best supportive care that were submitted as part of the company's response to consultation. The committee noted that the ICERs for talimogene laherparepvec compared with dacarbazine and best supportive care were approximately £23,900 and £24,100 per QALY gained, and were substantially lower than the corresponding ICERs for ipilimumab compared with dacarbazine and best supportive care (approximately £47,900 and £42,200 per QALY gained, respectively, in NICE technology appraisal guidance on ipilimumab for previously untreated advanced melanoma and on ipilimumab for previously treated advanced melanoma). The committee noted that these figures applied to patients at different stages of disease and were not directly comparable, and so could not be used to draw conclusions about the relative cost effectiveness of these agents.\n\nThe committee considered whether there may be a subgroup of patients for whom talimogene laherparepvec would be particularly beneficial, in particular whether there was a group of patients for whom talimogene laherparepvec might be the only effective option, such as those for whom systemic immunotherapy was contraindicated. The clinical expert, in response to consultation, had highlighted that there were people with BRAF‑negative disease for whom systemically administered immunotherapy is not suitable and who currently had no other effective treatment options. The committee noted the cost-effectiveness analyses presented comparing talimogene laherparepvec with dacarbazine and best supportive care. While these analyses did not specifically relate to a population with melanoma for whom systemically administered immunotherapies were not suitable, the committee was satisfied that they gave an indication of the cost effectiveness of talimogene laherparepvec in this situation. It concluded that talimogene laherparepvec is a clinically and cost-effective option for people with unresectable non-visceral metastatic melanoma for whom systemically administered immunotherapies are not suitable.\n\nThe company stated that talimogene laherparepvec is innovative and a step change in the management of advanced melanoma because it has a novel mechanism of action, in that it produces local tumour control and leads to a systemic anti-tumour immune response. Also, it is the only treatment approved specifically for people with regionally or distantly metastatic melanoma with no visceral disease (stage\xa03B to stage\xa04M1a) and is associated with fewer treatment-related grade\xa03 and\xa04 adverse events compared with existing treatments. The committee agreed that intra-lesion injections are an innovative approach to the treatment of melanoma, although the marketing authorisation did not support the systemic action of talimogene laherparepvec. The committee also noted that talimogene laherparepvec is being investigated as a combination therapy with other agents, which it considered may be important in the future. However, the committee could not identify any specific health‑related benefit that had not already been captured in the QALY calculation.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of Appraisal Committee's key conclusions\n\n## Key conclusion\n\nTalimogene laherparepvec is recommended, in adults, as an option for treating unresectable, regionally or distantly metastatic (stage 3B, 3C and 4M1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if:\n\ntreatment with systemically administered immunotherapies is not suitable and\n\nthe company provides talimogene laherparepvec with the discount agreed in the patient access scheme.\n\nThe committee concluded that although it could not be confident in establishing a reliable estimate of the effectiveness of talimogene laherparepvec compared with immunotherapies currently used in clinical practice, it is clinically and cost effective in people for whom treatment with systemically administered immunotherapies is not suitable.\n\nThe cost effectiveness of talimogene laherparepvec compared with best supportive care in people for whom systemically administered immunotherapy not suitable is approximately £24,000 per QALY gained.\n\nSee sections 1.1, 4.9 and 4.16.\n\n## Current practice\n\nThe committee concluded that the availability of a new treatment option with a novel mechanism of action and improved tolerability would be valuable for people with metastatic melanoma.\n\nSee section 4.3.\n\n## The technology\n\nThe committee agreed that talimogene laherparepvec is an innovative approach to the treatment of melanoma. It also noted that talimogene laherparepvec is being investigated as combination therapy with other agents, which it considered may be important in the future. However, the committee could not identify any specific health‑related benefit that had not already been captured in the QALY calculation.\n\nSee section 4.17.\n\nTalimogene laherparepvec has a marketing authorisation for unresectable melanoma that is regionally or distantly metastatic (stage\xa03B, 3C and 4M1a) with no bone, brain, lung or other visceral disease. This is based on evidence from a post-hoc subgroup within the OPTiM trial (57% of the overall trial population, who had non-visceral metastatic disease). The committee heard from clinical experts that in clinical practice, treatment with talimogene laherparepvec would be suitable for approximately 10% to 15% of people with unresectable metastatic melanoma.\n\nSee section 4.2.\n\nThe committee heard from the patient and clinical experts that ipilimumab can be associated with severe side effects and that an alternative treatment with an improved toxicity profile would be desirable. Clinical experts considered the main benefits of talimogene laherparepvec to be that the method of administration is acceptable to patients, and that it has an improved toxicity profile compared to currently available treatments (particularly ipilimumab).\n\nSee section 4.3.\n\n## Evidence for clinical effectiveness\n\nThe evidence underpinning the marketing authorisation came solely from an exploratory post-hoc subgroup analysis of people in the OPTiM trial who had non-visceral metastatic melanoma.\n\nThe committee concluded that talimogene laherparepvec was clinically effective compared with an ineffective treatment (GM-CSF) but it was difficult to draw conclusions from these trial data alone on the effectiveness of talimogene laherparepvec compared with systemically administered immunotherapies used in current clinical practice.\n\nSee sections 4.3 and 4.5.\n\nThe committee heard from the clinical experts that patients suitable for treatment with talimogene laherparepvec may have multiple small lesions which make surgical resection impractical, and that other localised therapies such as isolated limb perfusion are not widely available.\n\nSee section 4.4.\n\nThe committee concluded that the evidence presented was not sufficient to draw any firm conclusions about the relative clinical effectiveness of talimogene laherparepvec compared with ipilimumab in this patient population.\n\nSee section 4.9.\n\nThe committee agreed that talimogene laherparepvec is a reasonable option for people with unresectable non-visceral metastatic melanoma for whom systemically administered immunotherapies are not suitable, and that it is clinically effective compared with best supportive care.\n\nSee section 4.16.\n\nThe evidence for effectiveness was based on a post-hoc analysis against a comparator (GM-CSF) which was not relevant for decision-making, and it was therefore difficult to draw conclusions from these trial data alone on the effectiveness of talimogene laherparepvec compared with immunotherapies in current clinical practice.\n\nThe committee noted that in the OPTiM trial, talimogene laherparepvec showed a statistically significant improvement of 25.3\xa0months in overall survival (p value 0.0008), durable response rate of 25.2% (compared with 1.2% with GM-CSF) and complete response rate of 16.6% (compared with 0% for GM-CSF). The committee concluded that talimogene laherparepvec is clinically effective in people for whom treatment with systemically administered immunotherapies is not suitable.\n\nSee section 4.5.\n\n## Evidence for cost effectiveness\n\nThe committee noted that the company had used a multi‑stage approach to modelling overall survival based on different data sources to compare talimogene laherparepvec with ipilimumab in people with stage\xa03B to stage\xa04M1a melanoma. The committee accepted the basic structure of the company's model but questioned some of the model inputs.\n\nSee section 4.11.\n\nThe committee acknowledged the ERG's concerns that the Korn method was not suitable for modelling progression in stage\xa03B to stage\xa04M1a melanoma. It agreed that the modifications to the Korn method (the modified and 2‑step Korn) further compounded the underlying issues with the Korn method. The Committee concluded that the clinical effectiveness of talimogene laherparepvec compared with ipilimumab was uncertain, largely because of the lack of efficacy data for ipilimumab in the relevant population.\n\nSee section 4.13.\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee could not identify any specific health‑related benefit that had not already been captured in the QALY calculation.\n\nSee section 4.17.\n\nThe committee concluded that talimogene laherparepvec is cost effective in people for whom treatment with systemically administered immunotherapies is not suitable.\n\nSee section 4.16.\n\nThe Committee concluded that the clinical effectiveness of talimogene laherparepvec compared with ipilimumab was uncertain, largely because of the lack of efficacy data for ipilimumab in the relevant population.\n\nSee sections 4.13 and 4.15.\n\nThe committee was not able to determine the ICER for talimogene laherparepvec compared with ipilimumab because of uncertainties in the relative clinical effectiveness of these agents. The committee considered talimogene laherparepvec to be cost effective compared with dacarbazine (£23,900 per QALY gained) and best supportive care (£24,100 per QALY gained) in people whose disease was not suitable for treatment with systemically administered immunotherapies.\n\nSee sections 4.13, 4.15 and 4.16.\n\n## Additional factors taken into account\n\nThe committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\nSee section 4.20.\n\nThe case for end-of-life considerations was not made during this appraisal.\n\nNo equalities issues were raised in the evidence submissions or at the Committee meeting."}	https://www.nice.org.uk/guidance/ta410	Evidence-based recommendations on talimogene laherparepvec (Imlygic) for treating unresectable metastatic melanoma in adults when systemically administered immunotherapies are not suitable.
8873f7b3486de254b603257d461314e9c0c86e03	nice	Necitumumab for untreated advanced or metastatic squamous non-small-cell lung cancer	Necitumumab for untreated advanced or metastatic squamous non-small-cell lung cancer Evidence-based recommendations on necitumumab (Portrazza) for treating locally advanced or metastatic epidermal growth factor receptor (EGFR)-expressing squamous non-small-cell lung cancer in adults who have not had chemotherapy. # Recommendations Necitumumab, in combination with gemcitabine and cisplatin, is not recommended within its marketing authorisation for adults with locally advanced or metastatic epidermal growth factor receptor (EGFR)-expressing squamous non-small-cell lung cancer that has not been treated with chemotherapy. This guidance is not intended to affect the position of patients whose treatment with necitumumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Necitumumab (Portrazza, Eli Lilly) is a fully human monoclonal antibody, which inhibits the epidermal growth factor receptor (EGFR). Marketing authorisation Necitumumab has a marketing authorisation in the UK, in combination with gemcitabine and cisplatin chemotherapy, for treating locally advanced or metastatic EGFR-expressing squamous non-small-cell lung cancer (NSCLC), in adults who have not had chemotherapy for this condition. Adverse reactions The most common adverse reactions associated with necitumumab include skin reactions, venous thromboembolic events and laboratory abnormalities (hypomagnesaemia and albumin-corrected hypocalcaemia). For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Necitumumab is given by intravenous infusion, at a dose of 800 mg on days 1 and 8 of each 3‑week cycle. Price Necitumumab is available at a list price of £1,450 per 800‑mg vial (excluding VAT; company submission). This equates to £2,900 per cycle, and an average of £30,740 per course (excluding the cost of gemcitabine and cisplatin; based on an average of 4.6 cycles per course for induction therapy and 6 cycles per course for maintenance therapy). The company has agreed a patient access scheme with the Department of Health. If necitumumab had been recommended, this scheme would provide a simple discount to the list price of necitumumab with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence The appraisal committee (section 5) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of necitumumab, having considered evidence on the nature of squamous non-small-cell lung cancer (NSCLC) and the value placed on the benefits of necitumumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee heard from the clinical and patient experts that squamous NSCLC causes many distressing and debilitating symptoms, and typically has a poor prognosis. It heard that it is important for people with this condition to be able to function as fully as possible, for as long as possible, and that even a small extension to life would be very significant. The clinical and patient experts stated that there have been very few advances in first-line treatment of squamous NSCLC in the last 20 years. The committee concluded that there is an important unmet need for people with advanced or metastatic squamous NSCLC who have not had previous chemotherapy. The committee understood that previously untreated advanced or metastatic squamous NSCLC is usually treated with chemotherapy comprising a platinum drug in combination with gemcitabine, vinorelbine, docetaxel or paclitaxel (most commonly gemcitabine). The clinical experts stated that these platinum-based regimens were all similar in efficacy. Given that gemcitabine combinations are the most commonly used regimens and that necitumumab has a marketing authorisation in combination with gemcitabine plus cisplatin, the committee concluded that gemcitabine plus cisplatin was the most important comparator for necitumumab in this appraisal. The committee noted that necitumumab has a marketing authorisation for treating tumours that express the epidermal growth factor receptor (EGFR), and queried whether tests for EGFR expression are routinely carried out in clinical practice. The clinical experts stated that, although EGFR-mutation testing was common for lung cancer (particularly non‑squamous NSCLC), EGFR-expression testing was not widely used and would need to be introduced for people with squamous NSCLC if necitumumab were recommended. The experts stated that this test is already used for other cancers and so would be straightforward to implement for lung cancer. The committee heard from the clinical experts that differentiating between EGFR-expressing and non‑expressing tumours (that is, those with an H‑score above 0 or equal to 0 respectively) was appropriate, although the relevance of testing for different levels of EGFR expression (for example, high or low expression based on an H‑score above or below 200) was less certain. The committee concluded that it would be necessary to test tumours for EGFR expression in people with advanced or metastatic squamous NSCLC if necitumumab were to be introduced into clinical practice. # Clinical effectiveness The committee noted that the key clinical-effectiveness evidence for necitumumab was taken from the SQUIRE trial: a randomised, phase III study comparing necitumumab (in combination with gemcitabine plus cisplatin for induction therapy, followed by maintenance therapy with necitumumab alone; referred to in this document as the necitumumab group) with gemcitabine plus cisplatin. The committee noted that this trial included people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; 9% of people in the trial had a performance status of 2. It heard from the clinical experts that this was an advantage of the SQUIRE trial compared with previous trials in lung cancer, because people with a performance status of 2 are often excluded from trials, yet they comprise up to a quarter of people with advanced or metastatic squamous NSCLC in clinical practice. It also noted that 83% of the trial population was male, and heard from the clinical experts that this reflects the gender balance seen in clinical practice in England. The committee noted that patients were followed up for an average of more than 2 years, and that more than three-quarters of patients died during the study, and so considered that the data were relatively mature. The committee concluded that the SQUIRE trial was of good quality and that the results would be generalisable to clinical practice in England. The committee noted that the company presented evidence from 4 populations within the SQUIRE trial: the intention-to-treat population (ITT, n=1,093); patients having treatment in western Europe (n=348); patients with EGFR-expressing tumours in the whole-trial population (n=935; referred to in this document as 'EGFR-expressing '); and patients with EGFR-expressing tumours in the western European population (n=300; referred to in this document as 'EGFR-expressing western European'). The committee discussed in detail the most appropriate population to inform decision-making. It noted that necitumumab has a marketing authorisation for treating EGFR-expressing tumours. The European Medicines Agency granted this marketing authorisation because people with tumours that did not express EGFR did not appear to benefit from necitumumab. Most people in the SQUIRE trial had EGFR-expressing tumours (about 95% of people for whom tumour samples were available for analysis, and about 85% of the population overall), and the patient characteristics were well balanced between treatment groups in these populations. The committee noted that, in the SQUIRE trial, subgroups based on high or low EGFR expression (H‑score above or below 200) were prespecified; but, the EGFR-expressing populations were based on an H‑score above 0, and this was not prespecified in the trial. The committee concluded that, although the EGFR-expressing populations were not prespecified, it was appropriate to use the results from these groups to inform decision-making because they are consistent with the marketing authorisation for necitumumab. The committee heard from the clinical experts that it is helpful to identify populations that closely match clinical practice in England. However, the committee also noted that, on balance, the clinical experts considered that the whole-trial populations were likely to be more appropriate for decision-making than the western European groups. The committee agreed that there were important limitations in the analyses of the western European populations. It noted the concerns raised by the evidence review group (ERG), in particular that these populations were relatively small post-hoc subgroups with a high risk of bias and that there was no statistically significant interaction between subgroups based on region; it considered that these were important limitations. It also heard from the ERG that there was limited clinical justification for why the effectiveness of necitumumab may differ between regions, although it understood from 1 of the clinical experts that there may be some reasons why differences in effectiveness between regions could theoretically arise (for example, if people are diagnosed at different stages of disease or if there is varying effectiveness of a drug in people with different family origins). However, the committee understood that the ERG's clinical adviser considered that evidence from all geographical regions would be representative of people in England. The committee was aware that the overall survival in people with squamous NSCLC treated with necitumumab was similar in the ITT and western European populations, and that the apparent differences between the populations in overall-survival benefit were caused by lower survival in the gemcitabine plus cisplatin group of the western European populations. The committee was also aware that, in the western European populations, there were differences between the necitumumab and gemcitabine plus cisplatin treatment groups in the number of people with an ECOG performance status of 2. It heard from the clinical experts that performance status can strongly influence survival outcomes, and so considered that this imbalance may have influenced the outcomes in these populations. Because of the important limitations in these populations (including the high risk of bias and the potential influence of performance status on the outcomes), and taking into account the clinical experts' view that the whole-trial populations were more appropriate, the committee concluded that the western European populations were not appropriate for decision-making.The committee concluded that the most appropriate population on which to base its considerations was the EGFR-expressing (whole trial) population. The committee noted that in the EGFR-expressing (whole trial) population, necitumumab was associated with statistically significant improvements in overall survival and progression-free survival compared with gemcitabine plus cisplatin: the median overall-survival gain associated with necitumumab was 1.74 months (hazard ratio 0.79; 95% confidence interval 0.69 to 0.92; p=0.002). The clinical experts stated that the median overall-survival gain was small, but the hazard ratio showed that the results were highly clinically significant. The experts also highlighted that this hazard ratio is consistent with views, published in a recent article from the American Society of Clinical Oncology, on what constitutes a clinically meaningful treatment effect in lung cancer, and is similar to the hazard ratios seen in past clinical trials that have led to changes in practice. The patient expert emphasised that even small improvements in survival are very important for people with squamous NSCLC. The committee was reassured that the overall-survival benefit associated with necitumumab was consistent across prespecified subgroups, including in people with an ECOG performance status of 2. However, the committee was aware that necitumumab did not seem to be associated with improvements in quality of life, and understood the importance of improving quality of life for people with squamous NSCLC. The clinical experts emphasised that adding necitumumab to an established chemotherapy regimen did not worsen quality of life. The committee also heard from a clinical expert that a recently published subgroup analysis suggested that pain, breathlessness and quality of life improved in people with highly symptomatic disease. However, the committee was aware that this was a post-hoc analysis and so was subject to uncertainty. The committee concluded that it was uncertain whether necitumumab improves quality of life, but it is still an effective treatment option and offers small but clinically important improvements in overall survival compared with gemcitabine plus cisplatin. The committee considered the effectiveness of necitumumab compared with other platinum-based chemotherapies presented in the company's network meta-analysis. This analysis suggested that necitumumab was associated with improved overall survival and progression-free survival compared with all regimens included in the analysis, although the 95% credible intervals were wide and many of them crossed 1. The committee noted important limitations in the network meta-analysis raised by both the company and the ERG, including limitations in the quantity and quality of evidence informing the analysis, the large number of links in the network, differences between the trial populations, and concerns about the choice of an unadjusted fixed-effects model. The committee considered that the results of the network meta-analysis were uncertain and it was difficult to draw conclusions from this analysis. It recalled that the platinum-combination regimens commonly used for squamous NSCLC are similar in effectiveness (see section 4.2), and therefore concluded that it was sufficient to consider the clinical effectiveness of necitumumab compared with gemcitabine plus cisplatin using the direct evidence from the SQUIRE trial. The committee noted that in the SQUIRE trial, necitumumab was associated with a risk of hypomagnesaemia. The committee was also aware that the marketing authorisation for necitumumab in the US includes a warning about a risk of cardiopulmonary arrest. The committee acknowledged that the link between these 2 effects was unproven, and that the trial population included people with several comorbidities (including hypertension), but considered that both hypomagnesaemia and cardiopulmonary arrest may be important adverse effects of necitumumab. The committee was reassured by the clinical experts that hypomagnesaemia is a well-known effect of antibodies that target EGFR, and also chemotherapies such as cisplatin, and that magnesium levels are routinely monitored in people having chemotherapy for lung cancer. The committee concluded that the adverse effects associated with necitumumab were likely to be manageable in clinical practice. # Cost effectiveness The committee noted that the company's economic model used a state-transition structure with a lifetime time horizon, and costs and benefits were discounted at a rate of 3.5% per year. The committee noted that the ERG considered that the model was appropriately structured and well implemented, and the committee concluded that the company's economic model was suitable for decision-making. As in the clinical-effectiveness evidence, the committee noted that the company also presented results for 4 populations (ITT, western Europe, EGFR-expressing , and EGFR-expressing western European). In each population, necitumumab was compared with gemcitabine plus cisplatin and other platinum-based regimens using direct and indirect evidence respectively. The committee noted that the company considered the EGFR-expressing western European population to be the most generalisable to people in England and therefore the relevant population for its base case. The committee was aware that the population had a substantial effect on the economic model results: in the company's base case (EGFR-expressing western European population), necitumumab was associated with an incremental cost-effectiveness ratio (ICER) compared with gemcitabine plus cisplatin of £57,725 per quality-adjusted life year (QALY) gained, whereas in the EGFR-expressing (whole trial) population the ICER was £110,248 per QALY gained primarily due to the smaller QALY gain with necitumumab in the EGFR-expressing (whole trial) population. The committee recalled its considerations on the clinical-effectiveness evidence (see sections 4.5 and 4.7), and considered that it was appropriate to take the same approach for the cost-effectiveness evidence. That is, the committee concluded that the EGFR-expressing (whole trial) population was the most appropriate population on which to base its considerations, and that comparing necitumumab with gemcitabine plus cisplatin using direct evidence was appropriate for decision-making. The committee noted that the company extrapolated the overall-survival results from the SQUIRE trial to the lifetime time horizon of the model using a log-logistic function. The ERG commented that the clinical plausibility of the log-logistic extrapolation was uncertain, and proposed that a Weibull function may be more appropriate. The committee was aware that the extrapolation function had a significant effect on the model results. It noted that the log-logistic function predicted that 2–5% of people would survive for 5 years (company model, EGFR-expressing population), and some would survive for as long as 15 years. The Weibull function predicted lower long-term survival rates (the 5‑year survival rates were about 0.5% in the ERG's analysis, EGFR-expressing population). The committee was aware that the model included people with advanced or metastatic squamous NSCLC, for whom the prognosis is usually poor, and that in the SQUIRE trial 90% of people had metastases at 2 or more sites; the committee queried whether it was clinically plausible that people would survive for as long as the log-logistic model predicted. It heard from the clinical experts that a small number of people in this population would be expected to survive for 5 years, but that it was very rare for people to survive for 15 years. The committee considered that the most appropriate function for extrapolating overall survival was uncertain, but concluded that the results based on the Weibull function were likely to be more clinically plausible than the log-logistic function, and so the Weibull function was the more appropriate function to use for decision-making. The committee noted that the company applied its extrapolation from the end of the trial data onwards. It heard from the ERG that this approach meant that the model had been strongly influenced by the later stages of the survival data, when very few patients remained in the analysis, so the data were uncertain. The ERG suggested applying the extrapolation from an earlier time point. The committee agreed that applying the extrapolation from the end of the survival data (when the curves were highly uncertain) was not appropriate. However, the committee noted that the ERG chose an earlier time point to start the extrapolation, using the time at which at least 20 patients remained in the analysis. The committee noted that the choice of this earlier time point was arbitrary. The committee was also aware that in exploratory analyses (presented in the ERG's addendum), changing the starting point of the extrapolation had inconsistent effects on the model results: as the starting point of the extrapolation moved earlier, the cost effectiveness of necitumumab first decreased but then increased. The committee agreed that it was not appropriate to start the extrapolation from the end of the survival data (as in the company's model). It recognised that the most appropriate starting point for the extrapolation was uncertain, but concluded that it would have to be at an earlier time point when more patients remained in the analysis. The committee noted that the company incorporated quality of life into the economic model by applying utility values to each health state. The utility values for the pre-progression states were based on EQ‑5D data from the SQUIRE trial, pooled between the necitumumab and gemcitabine plus cisplatin treatment groups. The committee noted that the company also incorporated the effects of adverse events on quality of life, by applying utility decrements to each event. It noted that the ERG had some concerns about the values used, and understood that the company had not explored a possible alternative approach in which adverse events would have been captured by using different utility values for each treatment. The committee was aware that quality of life did not seem to differ between the 2 treatment groups in the SQUIRE trial (see section 4.6), and was also aware that the effects of adverse events on the model results were small. The committee concluded that the company's approach to capturing quality of life in the economic model was acceptable. The committee noted that the costs of the EGFR-expression tests that would need to be introduced alongside necitumumab treatment (see section 4.3) were not included in the company's model. The company's response to the factual accuracy check of the ERG report stated that EGFR-expression testing costs £42 per test.The committee considered that these costs should be included, even though they would have a small effect on the model results. The committee concluded that the costs of EGFR-expression testing should have been included. The committee considered the most plausible ICER for necitumumab compared with gemcitabine plus cisplatin. It had previously concluded that the EGFR-expressing (whole trial) population was the most appropriate for decision-making (see section 4.10), and so considered results for this population only. It noted that in the company's analysis for this population – based on a log-logistic extrapolation function applied from the end of the survival data – necitumumab was associated with an ICER of £110,248 per QALY gained compared with gemcitabine plus cisplatin. The ERG's preferred analysis for this population used a Weibull extrapolation function applied from before the end of the survival data (when at least 20 patients remained in the analysis), and in this analysis the ICER was £169,612 per QALY gained. It was aware that the most appropriate function and starting point for the extrapolation were uncertain, although the Weibull function was likely to be more clinically plausible than the log-logistic function and applying the extrapolation from the end of the survival data was inappropriate (see sections 4.11 and 4.12). The committee considered that, although uncertain, the ERG's analysis more closely matched its preferred assumptions than the company's analysis. The committee concluded that the most plausible ICER for necitumumab compared with gemcitabine plus cisplatin was between £110,000 and £170,000 per QALY gained, and was likely to be towards the upper end of this range. The committee considered the innovative nature of necitumumab. It heard from the patient and clinical experts that there have been few improvements in the treatment of squamous NSCLC in the last 20 years, and that there is an important unmet need for people with this condition. It understood that the survival benefit associated with necitumumab, although small, was clinically significant and important for people with squamous NSCLC. The committee concluded that necitumumab is innovative, but there were no additional benefits associated with this treatment that had not been captured in the economic analysis. The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy. For this advice to be applied, all the following criteria must be met. The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are sufficiently robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The committee noted the evidence presented by the company, which showed that people with advanced or metastatic squamous NSCLC have a life expectancy of less than 24 months: it noted that the median survival in people in the gemcitabine plus cisplatin group of the SQUIRE trial (EGFR-expressing population) was 9.99 months, although the mean survival predicted by the economic model was higher (the value is commercial in confidence). The committee concluded that people for whom necitumumab is indicated have a short life expectancy, so this criterion was met. The committee considered that the extension to life associated with necitumumab was uncertain. The median overall-survival gain in the SQUIRE trial (EGFR-expressing population) was 1.74 months. However, the mean overall-survival gain predicted by the economic model was strongly influenced by the function and starting point of the overall-survival extrapolation. The committee was aware that in the ERG's analysis, the overall-survival gain associated with necitumumab was 2.25 months. It noted that the gain would be larger if a log-logistic function were used or the extrapolation were started at a different time point; the overall-survival gain increased to 2.84 months when a log-logistic function was applied from the time when at least 20 patients remained in the analysis. Noting the important uncertainties in the survival gain, the committee was not convinced that there was sufficiently robust evidence (based on plausible and objective assumptions) to accept that necitumumab met the extension to life criterion, even when taking into account the life expectancy for this population. The committee concluded that necitumumab did not meet the criteria to be considered a life-extending, end-of-life treatment. Taking into account the most plausible ICER for necitumumab (between £110,000 and £170,000 per QALY gained; see section 4.15), the innovative nature of necitumumab and the fact that necitumumab did not meet the criteria to be considered a life-extending, end-of-life treatment, the committee concluded that necitumumab was not recommended as a cost-effective use of NHS resources. The committee discussed the new arrangements for the Cancer Drugs Fund recently agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee heard from the company that necitumumab may be considered for funding through the Cancer Drugs Fund. However, because of the timing of this appraisal, the company had not had an opportunity to present a case for including necitumumab in the Cancer Drugs Fund. The committee considered that the most plausible ICER for necitumumab (see section 4.15), and all of the ICERs presented for the EGFR-expressing (whole trial) population, were substantially higher than the range normally considered a cost-effective use of NHS resources, and so necitumumab did not have the plausible potential for satisfying the criteria for routine use. The committee also considered that although there were uncertainties in the evidence for this appraisal, the clinical-effectiveness evidence from SQUIRE was relatively mature (see section 4.4) and there were no clinical uncertainties that could be addressed by collecting outcome data from people in the NHS, which could be used to inform a subsequent update of the guidance. The committee concluded that necitumumab did not meet the criteria to be considered for use in the Cancer Drugs Fund. The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal. # Summary of appraisal committee's key conclusions TA411 Appraisal title: Necitumumab for untreated advanced or metastatic, squamous non-small-cell lung cancer Section Key conclusion Necitumumab, in combination with gemcitabine and cisplatin, is not recommended within its marketing authorisation for adults with locally advanced or metastatic epidermal growth factor receptor (EGFR)-expressing squamous non-small-cell lung cancer (NSCLC) that has not been treated with chemotherapy. Necitumumab provides small but clinically important improvements in overall survival compared with gemcitabine plus cisplatin. The most plausible incremental cost-effectiveness ratio (ICER) for necitumumab compared with gemcitabine plus cisplatin was £110,000–£170,000 per quality-adjusted life year (QALY) gained, and was likely to be towards the upper end of this range. Necitumumab is innovative, but does not meet the criteria to be considered a life-extending, end-of-life treatment. Necitumumab did not meet the criteria to be considered for use in the Cancer Drugs Fund. Current practice Clinical need of patients, including the availability of alternative treatments The committee heard that squamous NSCLC causes distressing and debilitating symptoms, and there have been few advances in treatment in the last 20 years. The committee concluded that there is an important unmet need for people with this condition. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee understood that the survival benefit associated with necitumumab, although small, was clinically significant and important for people with squamous NSCLC. It concluded that necitumumab is innovative, but there were no additional benefits that had not been captured in the economic analysis. What is the position of the treatment in the pathway of care for the condition? Necitumumab has a marketing authorisation, in combination with gemcitabine and cisplatin, for treating locally advanced or metastatic EGFR-expressing squamous NSCLC, in adults who have not had chemotherapy for this condition. The committee understood that this condition is usually treated with a platinum drug in combination with gemcitabine, vinorelbine, docetaxel or paclitaxel. Adverse reactions The most common adverse reactions associated with necitumumab include skin reactions, venous thromboembolic events and laboratory abnormalities. The committee concluded that the adverse effects associated with necitumumab were likely to be manageable in clinical practice. Evidence for clinical effectiveness Availability, nature and quality of evidence The key clinical-effectiveness evidence for necitumumab was taken from the SQUIRE trial. The committee considered that the data from SQUIRE were relatively mature, and concluded that the SQUIRE trial was of good quality. The committee considered that the results of the network meta-analysis, comparing necitumumab with other chemotherapies, were uncertain and it was difficult to draw conclusions from this analysis. Relevance to general clinical practice in the NHS The committee heard that the population of the SQUIRE trial reflects clinical practice in England. It understood that evidence from all regions would be representative of people in England. The committee concluded that the results of SQUIRE would be generalisable to clinical practice. Uncertainties generated by the evidence The committee was aware that necitumumab did not seem to improve quality of life, although it did not worsen quality of life. It heard that pain, breathlessness and quality of life improved in people with highly symptomatic disease, but this was a post-hoc analysis and so the results were uncertain. The committee concluded that it was uncertain whether necitumumab improves quality of life. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The committee noted that the company presented evidence from 4 populations within the SQUIRE trial, based on geographical region and EGFR expression. The committee concluded that it was appropriate to consider the results from the EGFR-expressing populations because they are consistent with the marketing authorisation for necitumumab. The committee noted important limitations in the western European populations, and noted the clinical experts' views. It concluded that the western European populations were not appropriate for decision-making. The committee concluded that the most appropriate population for decision-making was the EGFR-expressing (whole trial) population. Estimate of the size of the clinical effectiveness including strength of supporting evidence Necitumumab was associated with statistically significant improvements in overall survival and progression-free survival compared with gemcitabine plus cisplatin: the median overall-survival gain was 1.74 months (hazard ratio 0.79; 95% confidence interval 0.69 to 0.92; p=0.002; EGFR-expressing population). The committee concluded that necitumumab offers small but clinically important improvements in overall survival. Evidence for cost effectiveness Availability and nature of evidence The company's economic model used a state-transition structure with a lifetime time horizon. The committee concluded that the company's economic model was suitable for decision-making. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee considered that the most appropriate function for extrapolating overall survival was uncertain. It concluded that the Weibull function was likely to be more clinically plausible than the log-logistic function. The committee noted that the company applied its extrapolation from the end of the trial data onwards, and agreed that this was not appropriate. It recognised that the most appropriate starting point for the extrapolation was uncertain, but concluded that it would have to be at an earlier time point when more patients remained in the analysis. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee noted that the company incorporated quality of life into the economic model by applying utility values to each health state, using EQ‑5D data from the SQUIRE trial. The committee concluded that the company's approach to capturing quality of life in the economic model was acceptable. The committee concluded that there were no additional benefits associated with necitumumab that had not been captured in the economic analysis. Are there specific groups of people for whom the technology is particularly cost effective? The committee noted that the company presented results for 4 populations; it concluded that the EGFR-expressing (whole trial) population was the most appropriate population for decision-making. What are the key drivers of cost effectiveness? The committee was aware that the population and the extrapolation function had substantial effects on the economic model results, and changing the starting point of the extrapolation had inconsistent effects on the results. Most likely cost-effectiveness estimate (given as an ICER) The committee concluded that the most plausible ICER for necitumumab compared with gemcitabine plus cisplatin was between £110,000 and £170,000 per QALY gained, and was likely to be towards the upper end of this range. Additional factors taken into account Patient access schemes (PPRS) The company has agreed a patient access scheme with the Department of Health. If necitumumab had been recommended, this scheme would provide a confidential simple discount to the list price of necitumumab. End-of-life considerations The committee noted that the median survival in people in the gemcitabine plus cisplatin group of the SQUIRE trial (EGFR-expressing population) was 9.99 months, although the mean survival predicted by the economic model was higher. The committee concluded that people for whom necitumumab is indicated have a short life expectancy. The committee considered that the extension to life associated with necitumumab was uncertain. It was not convinced that there was sufficiently robust evidence that necitumumab was associated with an extension to life of more than 3 months. The committee concluded that necitumumab did not meet the criteria to be considered a life-extending, end-of-life treatment. Cancer Drugs Fund The committee noted that all of the ICERs for the EGFR-expressing (whole trial) population were substantially higher than the range normally considered cost effective, and so necitumumab did not have the plausible potential for satisfying the criteria for routine use. It considered that there were no clinical uncertainties that could be addressed by collecting outcome data from people in the NHS, which could be used to inform a subsequent update of the guidance. The committee concluded that necitumumab did not meet the criteria to be considered for use in the Cancer Drugs Fund. Equalities considerations and social value judgements No equality issues were identified.	{'Recommendations': 'Necitumumab, in combination with gemcitabine and cisplatin, is not recommended within its marketing authorisation for adults with locally advanced or metastatic epidermal growth factor receptor (EGFR)-expressing squamous non-small-cell lung cancer that has not been treated with chemotherapy.\n\nThis guidance is not intended to affect the position of patients whose treatment with necitumumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology ': 'Description of the technology\n\nNecitumumab (Portrazza, Eli Lilly) is a fully human monoclonal antibody, which inhibits the epidermal growth factor receptor (EGFR).\n\nMarketing authorisation\n\nNecitumumab has a marketing authorisation in the UK, in combination with gemcitabine and cisplatin chemotherapy, for treating locally advanced or metastatic EGFR-expressing squamous non-small-cell lung cancer (NSCLC), in adults who have not had chemotherapy for this condition.\n\nAdverse reactions\n\nThe most common adverse reactions associated with necitumumab include skin reactions, venous thromboembolic events and laboratory abnormalities (hypomagnesaemia and albumin-corrected hypocalcaemia). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nNecitumumab is given by intravenous infusion, at a dose of 800\xa0mg on days\xa01 and 8 of each 3‑week cycle.\n\nPrice\n\nNecitumumab is available at a list price of £1,450 per 800‑mg vial (excluding VAT; company submission). This equates to £2,900 per cycle, and an average of £30,740 per course (excluding the cost of gemcitabine and cisplatin; based on an average of 4.6\xa0cycles per course for induction therapy and 6\xa0cycles per course for maintenance therapy).\n\nThe company has agreed a patient access scheme with the Department of Health. If necitumumab had been recommended, this scheme would provide a simple discount to the list price of necitumumab with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.', 'Evidence': 'The appraisal committee (section\xa05) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of necitumumab, having considered evidence on the nature of squamous non-small-cell lung cancer (NSCLC) and the value placed on the benefits of necitumumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee heard from the clinical and patient experts that squamous NSCLC causes many distressing and debilitating symptoms, and typically has a poor prognosis. It heard that it is important for people with this condition to be able to function as fully as possible, for as long as possible, and that even a small extension to life would be very significant. The clinical and patient experts stated that there have been very few advances in first-line treatment of squamous NSCLC in the last 20\xa0years. The committee concluded that there is an important unmet need for people with advanced or metastatic squamous NSCLC who have not had previous chemotherapy.\n\nThe committee understood that previously untreated advanced or metastatic squamous NSCLC is usually treated with chemotherapy comprising a platinum drug in combination with gemcitabine, vinorelbine, docetaxel or paclitaxel (most commonly gemcitabine). The clinical experts stated that these platinum-based regimens were all similar in efficacy. Given that gemcitabine combinations are the most commonly used regimens and that necitumumab has a marketing authorisation in combination with gemcitabine plus cisplatin, the committee concluded that gemcitabine plus cisplatin was the most important comparator for necitumumab in this appraisal.\n\nThe committee noted that necitumumab has a marketing authorisation for treating tumours that express the epidermal growth factor receptor (EGFR), and queried whether tests for EGFR expression are routinely carried out in clinical practice. The clinical experts stated that, although EGFR-mutation testing was common for lung cancer (particularly non‑squamous NSCLC), EGFR-expression testing was not widely used and would need to be introduced for people with squamous NSCLC if necitumumab were recommended. The experts stated that this test is already used for other cancers and so would be straightforward to implement for lung cancer. The committee heard from the clinical experts that differentiating between EGFR-expressing and non‑expressing tumours (that is, those with an H‑score above\xa00 or equal to\xa00 respectively) was appropriate, although the relevance of testing for different levels of EGFR expression (for example, high or low expression based on an H‑score above or below\xa0200) was less certain. The committee concluded that it would be necessary to test tumours for EGFR expression in people with advanced or metastatic squamous NSCLC if necitumumab were to be introduced into clinical practice.\n\n# Clinical effectiveness\n\nThe committee noted that the key clinical-effectiveness evidence for necitumumab was taken from the SQUIRE trial: a randomised, phase\xa0III study comparing necitumumab (in combination with gemcitabine plus cisplatin for induction therapy, followed by maintenance therapy with necitumumab alone; referred to in this document as the necitumumab group) with gemcitabine plus cisplatin. The committee noted that this trial included people with an Eastern Cooperative Oncology Group (ECOG) performance status of\xa00 to\xa02; 9% of people in the trial had a performance status of\xa02. It heard from the clinical experts that this was an advantage of the SQUIRE trial compared with previous trials in lung cancer, because people with a performance status of\xa02 are often excluded from trials, yet they comprise up to a quarter of people with advanced or metastatic squamous NSCLC in clinical practice. It also noted that 83% of the trial population was male, and heard from the clinical experts that this reflects the gender balance seen in clinical practice in England. The committee noted that patients were followed up for an average of more than 2\xa0years, and that more than three-quarters of patients died during the study, and so considered that the data were relatively mature. The committee concluded that the SQUIRE trial was of good quality and that the results would be generalisable to clinical practice in England.\n\nThe committee noted that the company presented evidence from 4\xa0populations within the SQUIRE trial: the intention-to-treat population (ITT, n=1,093); patients having treatment in western Europe (n=348); patients with EGFR-expressing tumours in the whole-trial population (n=935; referred to in this document as 'EGFR-expressing [whole trial]'); and patients with EGFR-expressing tumours in the western European population (n=300; referred to in this document as 'EGFR-expressing western European'). The committee discussed in detail the most appropriate population to inform decision-making.\n\nIt noted that necitumumab has a marketing authorisation for treating EGFR-expressing tumours. The European Medicines Agency granted this marketing authorisation because people with tumours that did not express EGFR did not appear to benefit from necitumumab. Most people in the SQUIRE trial had EGFR-expressing tumours (about 95% of people for whom tumour samples were available for analysis, and about 85% of the population overall), and the patient characteristics were well balanced between treatment groups in these populations. The committee noted that, in the SQUIRE trial, subgroups based on high or low EGFR expression (H‑score above or below\xa0200) were prespecified; but, the EGFR-expressing populations were based on an H‑score above\xa00, and this was not prespecified in the trial. The committee concluded that, although the EGFR-expressing populations were not prespecified, it was appropriate to use the results from these groups to inform decision-making because they are consistent with the marketing authorisation for necitumumab.\n\nThe committee heard from the clinical experts that it is helpful to identify populations that closely match clinical practice in England. However, the committee also noted that, on balance, the clinical experts considered that the whole-trial populations were likely to be more appropriate for decision-making than the western European groups. The committee agreed that there were important limitations in the analyses of the western European populations. It noted the concerns raised by the evidence review group (ERG), in particular that these populations were relatively small post-hoc subgroups with a high risk of bias and that there was no statistically significant interaction between subgroups based on region; it considered that these were important limitations. It also heard from the ERG that there was limited clinical justification for why the effectiveness of necitumumab may differ between regions, although it understood from 1\xa0of the clinical experts that there may be some reasons why differences in effectiveness between regions could theoretically arise (for example, if people are diagnosed at different stages of disease or if there is varying effectiveness of a drug in people with different family origins). However, the committee understood that the ERG's clinical adviser considered that evidence from all geographical regions would be representative of people in England. The committee was aware that the overall survival in people with squamous NSCLC treated with necitumumab was similar in the ITT and western European populations, and that the apparent differences between the populations in overall-survival benefit were caused by lower survival in the gemcitabine plus cisplatin group of the western European populations. The committee was also aware that, in the western European populations, there were differences between the necitumumab and gemcitabine plus cisplatin treatment groups in the number of people with an ECOG performance status of\xa02. It heard from the clinical experts that performance status can strongly influence survival outcomes, and so considered that this imbalance may have influenced the outcomes in these populations. Because of the important limitations in these populations (including the high risk of bias and the potential influence of performance status on the outcomes), and taking into account the clinical experts' view that the whole-trial populations were more appropriate, the committee concluded that the western European populations were not appropriate for decision-making.The committee concluded that the most appropriate population on which to base its considerations was the EGFR-expressing (whole trial) population.\n\nThe committee noted that in the EGFR-expressing (whole trial) population, necitumumab was associated with statistically significant improvements in overall survival and progression-free survival compared with gemcitabine plus cisplatin: the median overall-survival gain associated with necitumumab was 1.74\xa0months (hazard ratio 0.79; 95% confidence interval 0.69 to 0.92; p=0.002). The clinical experts stated that the median overall-survival gain was small, but the hazard ratio showed that the results were highly clinically significant. The experts also highlighted that this hazard ratio is consistent with views, published in a recent article from the American Society of Clinical Oncology, on what constitutes a clinically meaningful treatment effect in lung cancer, and is similar to the hazard ratios seen in past clinical trials that have led to changes in practice. The patient expert emphasised that even small improvements in survival are very important for people with squamous NSCLC. The committee was reassured that the overall-survival benefit associated with necitumumab was consistent across prespecified subgroups, including in people with an ECOG performance status of\xa02. However, the committee was aware that necitumumab did not seem to be associated with improvements in quality of life, and understood the importance of improving quality of life for people with squamous NSCLC. The clinical experts emphasised that adding necitumumab to an established chemotherapy regimen did not worsen quality of life. The committee also heard from a clinical expert that a recently published subgroup analysis suggested that pain, breathlessness and quality of life improved in people with highly symptomatic disease. However, the committee was aware that this was a post-hoc analysis and so was subject to uncertainty. The committee concluded that it was uncertain whether necitumumab improves quality of life, but it is still an effective treatment option and offers small but clinically important improvements in overall survival compared with gemcitabine plus cisplatin.\n\nThe committee considered the effectiveness of necitumumab compared with other platinum-based chemotherapies presented in the company's network meta-analysis. This analysis suggested that necitumumab was associated with improved overall survival and progression-free survival compared with all regimens included in the analysis, although the 95% credible intervals were wide and many of them crossed\xa01. The committee noted important limitations in the network meta-analysis raised by both the company and the ERG, including limitations in the quantity and quality of evidence informing the analysis, the large number of links in the network, differences between the trial populations, and concerns about the choice of an unadjusted fixed-effects model. The committee considered that the results of the network meta-analysis were uncertain and it was difficult to draw conclusions from this analysis. It recalled that the platinum-combination regimens commonly used for squamous NSCLC are similar in effectiveness (see section\xa04.2), and therefore concluded that it was sufficient to consider the clinical effectiveness of necitumumab compared with gemcitabine plus cisplatin using the direct evidence from the SQUIRE trial.\n\nThe committee noted that in the SQUIRE trial, necitumumab was associated with a risk of hypomagnesaemia. The committee was also aware that the marketing authorisation for necitumumab in the US includes a warning about a risk of cardiopulmonary arrest. The committee acknowledged that the link between these 2\xa0effects was unproven, and that the trial population included people with several comorbidities (including hypertension), but considered that both hypomagnesaemia and cardiopulmonary arrest may be important adverse effects of necitumumab. The committee was reassured by the clinical experts that hypomagnesaemia is a well-known effect of antibodies that target EGFR, and also chemotherapies such as cisplatin, and that magnesium levels are routinely monitored in people having chemotherapy for lung cancer. The committee concluded that the adverse effects associated with necitumumab were likely to be manageable in clinical practice.\n\n# Cost effectiveness\n\nThe committee noted that the company's economic model used a state-transition structure with a lifetime time horizon, and costs and benefits were discounted at a rate of 3.5% per year. The committee noted that the ERG considered that the model was appropriately structured and well implemented, and the committee concluded that the company's economic model was suitable for decision-making.\n\nAs in the clinical-effectiveness evidence, the committee noted that the company also presented results for 4\xa0populations (ITT, western Europe, EGFR-expressing [whole trial], and EGFR-expressing western European). In each population, necitumumab was compared with gemcitabine plus cisplatin and other platinum-based regimens using direct and indirect evidence respectively. The committee noted that the company considered the EGFR-expressing western European population to be the most generalisable to people in England and therefore the relevant population for its base case. The committee was aware that the population had a substantial effect on the economic model results: in the company's base case (EGFR-expressing western European population), necitumumab was associated with an incremental cost-effectiveness ratio (ICER) compared with gemcitabine plus cisplatin of £57,725 per quality-adjusted life year (QALY) gained, whereas in the EGFR-expressing (whole trial) population the ICER was £110,248 per QALY gained primarily due to the smaller QALY gain with necitumumab in the EGFR-expressing (whole trial) population. The committee recalled its considerations on the clinical-effectiveness evidence (see sections\xa04.5 and\xa04.7), and considered that it was appropriate to take the same approach for the cost-effectiveness evidence. That is, the committee concluded that the EGFR-expressing (whole trial) population was the most appropriate population on which to base its considerations, and that comparing necitumumab with gemcitabine plus cisplatin using direct evidence was appropriate for decision-making.\n\nThe committee noted that the company extrapolated the overall-survival results from the SQUIRE trial to the lifetime time horizon of the model using a log-logistic function. The ERG commented that the clinical plausibility of the log-logistic extrapolation was uncertain, and proposed that a Weibull function may be more appropriate. The committee was aware that the extrapolation function had a significant effect on the model results. It noted that the log-logistic function predicted that 2–5% of people would survive for 5\xa0years (company model, EGFR-expressing [whole trial] population), and some would survive for as long as 15\xa0years. The Weibull function predicted lower long-term survival rates (the 5‑year survival rates were about 0.5% in the ERG's analysis, EGFR-expressing [whole trial] population). The committee was aware that the model included people with advanced or metastatic squamous NSCLC, for whom the prognosis is usually poor, and that in the SQUIRE trial 90% of people had metastases at 2\xa0or more sites; the committee queried whether it was clinically plausible that people would survive for as long as the log-logistic model predicted. It heard from the clinical experts that a small number of people in this population would be expected to survive for 5\xa0years, but that it was very rare for people to survive for 15\xa0years. The committee considered that the most appropriate function for extrapolating overall survival was uncertain, but concluded that the results based on the Weibull function were likely to be more clinically plausible than the log-logistic function, and so the Weibull function was the more appropriate function to use for decision-making.\n\nThe committee noted that the company applied its extrapolation from the end of the trial data onwards. It heard from the ERG that this approach meant that the model had been strongly influenced by the later stages of the survival data, when very few patients remained in the analysis, so the data were uncertain. The ERG suggested applying the extrapolation from an earlier time point. The committee agreed that applying the extrapolation from the end of the survival data (when the curves were highly uncertain) was not appropriate. However, the committee noted that the ERG chose an earlier time point to start the extrapolation, using the time at which at least 20\xa0patients remained in the analysis. The committee noted that the choice of this earlier time point was arbitrary. The committee was also aware that in exploratory analyses (presented in the ERG's addendum), changing the starting point of the extrapolation had inconsistent effects on the model results: as the starting point of the extrapolation moved earlier, the cost effectiveness of necitumumab first decreased but then increased. The committee agreed that it was not appropriate to start the extrapolation from the end of the survival data (as in the company's model). It recognised that the most appropriate starting point for the extrapolation was uncertain, but concluded that it would have to be at an earlier time point when more patients remained in the analysis.\n\nThe committee noted that the company incorporated quality of life into the economic model by applying utility values to each health state. The utility values for the pre-progression states were based on EQ‑5D data from the SQUIRE trial, pooled between the necitumumab and gemcitabine plus cisplatin treatment groups. The committee noted that the company also incorporated the effects of adverse events on quality of life, by applying utility decrements to each event. It noted that the ERG had some concerns about the values used, and understood that the company had not explored a possible alternative approach in which adverse events would have been captured by using different utility values for each treatment. The committee was aware that quality of life did not seem to differ between the 2\xa0treatment groups in the SQUIRE trial (see section\xa04.6), and was also aware that the effects of adverse events on the model results were small. The committee concluded that the company's approach to capturing quality of life in the economic model was acceptable.\n\nThe committee noted that the costs of the EGFR-expression tests that would need to be introduced alongside necitumumab treatment (see section\xa04.3) were not included in the company's model. The company's response to the factual accuracy check of the ERG report stated that EGFR-expression testing costs £42 per test.The committee considered that these costs should be included, even though they would have a small effect on the model results. The committee concluded that the costs of EGFR-expression testing should have been included.\n\nThe committee considered the most plausible ICER for necitumumab compared with gemcitabine plus cisplatin. It had previously concluded that the EGFR-expressing (whole trial) population was the most appropriate for decision-making (see section\xa04.10), and so considered results for this population only. It noted that in the company's analysis for this population – based on a log-logistic extrapolation function applied from the end of the survival data – necitumumab was associated with an ICER of £110,248 per QALY gained compared with gemcitabine plus cisplatin. The ERG's preferred analysis for this population used a Weibull extrapolation function applied from before the end of the survival data (when at least 20\xa0patients remained in the analysis), and in this analysis the ICER was £169,612 per QALY gained. It was aware that the most appropriate function and starting point for the extrapolation were uncertain, although the Weibull function was likely to be more clinically plausible than the log-logistic function and applying the extrapolation from the end of the survival data was inappropriate (see sections\xa04.11 and\xa04.12). The committee considered that, although uncertain, the ERG's analysis more closely matched its preferred assumptions than the company's analysis. The committee concluded that the most plausible ICER for necitumumab compared with gemcitabine plus cisplatin was between £110,000 and £170,000 per QALY gained, and was likely to be towards the upper end of this range.\n\nThe committee considered the innovative nature of necitumumab. It heard from the patient and clinical experts that there have been few improvements in the treatment of squamous NSCLC in the last 20\xa0years, and that there is an important unmet need for people with this condition. It understood that the survival benefit associated with necitumumab, although small, was clinically significant and important for people with squamous NSCLC. The committee concluded that necitumumab is innovative, but there were no additional benefits associated with this treatment that had not been captured in the economic analysis.\n\nThe committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are sufficiently robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe committee noted the evidence presented by the company, which showed that people with advanced or metastatic squamous NSCLC have a life expectancy of less than 24\xa0months: it noted that the median survival in people in the gemcitabine plus cisplatin group of the SQUIRE trial (EGFR-expressing [whole trial] population) was 9.99\xa0months, although the mean survival predicted by the economic model was higher (the value is commercial in confidence). The committee concluded that people for whom necitumumab is indicated have a short life expectancy, so this criterion was met. The committee considered that the extension to life associated with necitumumab was uncertain. The median overall-survival gain in the SQUIRE trial (EGFR-expressing [whole trial] population) was 1.74\xa0months. However, the mean overall-survival gain predicted by the economic model was strongly influenced by the function and starting point of the overall-survival extrapolation. The committee was aware that in the ERG's analysis, the overall-survival gain associated with necitumumab was 2.25\xa0months. It noted that the gain would be larger if a log-logistic function were used or the extrapolation were started at a different time point; the overall-survival gain increased to 2.84\xa0months when a log-logistic function was applied from the time when at least 20\xa0patients remained in the analysis. Noting the important uncertainties in the survival gain, the committee was not convinced that there was sufficiently robust evidence (based on plausible and objective assumptions) to accept that necitumumab met the extension to life criterion, even when taking into account the life expectancy for this population. The committee concluded that necitumumab did not meet the criteria to be considered a life-extending, end-of-life treatment.\n\nTaking into account the most plausible ICER for necitumumab (between £110,000 and £170,000 per QALY gained; see section\xa04.15), the innovative nature of necitumumab and the fact that necitumumab did not meet the criteria to be considered a life-extending, end-of-life treatment, the committee concluded that necitumumab was not recommended as a cost-effective use of NHS resources.\n\nThe committee discussed the new arrangements for the Cancer Drugs Fund recently agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee heard from the company that necitumumab may be considered for funding through the Cancer Drugs Fund. However, because of the timing of this appraisal, the company had not had an opportunity to present a case for including necitumumab in the Cancer Drugs Fund. The committee considered that the most plausible ICER for necitumumab (see section\xa04.15), and all of the ICERs presented for the EGFR-expressing (whole trial) population, were substantially higher than the range normally considered a cost-effective use of NHS resources, and so necitumumab did not have the plausible potential for satisfying the criteria for routine use. The committee also considered that although there were uncertainties in the evidence for this appraisal, the clinical-effectiveness evidence from SQUIRE was relatively mature (see section\xa04.4) and there were no clinical uncertainties that could be addressed by collecting outcome data from people in the NHS, which could be used to inform a subsequent update of the guidance. The committee concluded that necitumumab did not meet the criteria to be considered for use in the Cancer Drugs Fund.\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA411\n\nAppraisal title: Necitumumab for untreated advanced or metastatic, squamous non-small-cell lung cancer\n\nSection\n\nKey conclusion\n\nNecitumumab, in combination with gemcitabine and cisplatin, is not recommended within its marketing authorisation for adults with locally advanced or metastatic epidermal growth factor receptor (EGFR)-expressing squamous non-small-cell lung cancer (NSCLC) that has not been treated with chemotherapy.\n\nNecitumumab provides small but clinically important improvements in overall survival compared with gemcitabine plus cisplatin.\n\nThe most plausible incremental cost-effectiveness ratio (ICER) for necitumumab compared with gemcitabine plus cisplatin was £110,000–£170,000 per quality-adjusted life year (QALY) gained, and was likely to be towards the upper end of this range.\n\nNecitumumab is innovative, but does not meet the criteria to be considered a life-extending, end-of-life treatment.\n\nNecitumumab did not meet the criteria to be considered for use in the Cancer Drugs Fund.\n\n, 4.6, 4.15, 4.16, 4.18, 4.20\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard that squamous NSCLC causes distressing and debilitating symptoms, and there have been few advances in treatment in the last 20\xa0years. The committee concluded that there is an important unmet need for people with this condition.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee understood that the survival benefit associated with necitumumab, although small, was clinically significant and important for people with squamous NSCLC. It concluded that necitumumab is innovative, but there were no additional benefits that had not been captured in the economic analysis.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nNecitumumab has a marketing authorisation, in combination with gemcitabine and cisplatin, for treating locally advanced or metastatic EGFR-expressing squamous NSCLC, in adults who have not had chemotherapy for this condition.\n\nThe committee understood that this condition is usually treated with a platinum drug in combination with gemcitabine, vinorelbine, docetaxel or paclitaxel.\n\n, 4.2\n\nAdverse reactions\n\nThe most common adverse reactions associated with necitumumab include skin reactions, venous thromboembolic events and laboratory abnormalities.\n\nThe committee concluded that the adverse effects associated with necitumumab were likely to be manageable in clinical practice.\n\n, 4.8\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe key clinical-effectiveness evidence for necitumumab was taken from the SQUIRE trial. The committee considered that the data from SQUIRE were relatively mature, and concluded that the SQUIRE trial was of good quality.\n\nThe committee considered that the results of the network meta-analysis, comparing necitumumab with other chemotherapies, were uncertain and it was difficult to draw conclusions from this analysis.\n\n, 4.7\n\nRelevance to general clinical practice in the NHS\n\nThe committee heard that the population of the SQUIRE trial reflects clinical practice in England. It understood that evidence from all regions would be representative of people in England. The committee concluded that the results of SQUIRE would be generalisable to clinical practice.\n\n, 4.5\n\nUncertainties generated by the evidence\n\nThe committee was aware that necitumumab did not seem to improve quality of life, although it did not worsen quality of life. It heard that pain, breathlessness and quality of life improved in people with highly symptomatic disease, but this was a post-hoc analysis and so the results were uncertain. The committee concluded that it was uncertain whether necitumumab improves quality of life.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee noted that the company presented evidence from 4\xa0populations within the SQUIRE trial, based on geographical region and EGFR expression.\n\nThe committee concluded that it was appropriate to consider the results from the EGFR-expressing populations because they are consistent with the marketing authorisation for necitumumab.\n\nThe committee noted important limitations in the western European populations, and noted the clinical experts' views. It concluded that the western European populations were not appropriate for decision-making.\n\nThe committee concluded that the most appropriate population for decision-making was the EGFR-expressing (whole trial) population.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nNecitumumab was associated with statistically significant improvements in overall survival and progression-free survival compared with gemcitabine plus cisplatin: the median overall-survival gain was 1.74\xa0months (hazard ratio 0.79; 95% confidence interval 0.69 to 0.92; p=0.002; EGFR-expressing [whole-trial] population). The committee concluded that necitumumab offers small but clinically important improvements in overall survival.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company's economic model used a state-transition structure with a lifetime time horizon. The committee concluded that the company's economic model was suitable for decision-making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee considered that the most appropriate function for extrapolating overall survival was uncertain. It concluded that the Weibull function was likely to be more clinically plausible than the log-logistic function.\n\nThe committee noted that the company applied its extrapolation from the end of the trial data onwards, and agreed that this was not appropriate. It recognised that the most appropriate starting point for the extrapolation was uncertain, but concluded that it would have to be at an earlier time point when more patients remained in the analysis.\n\n, 4.12\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that the company incorporated quality of life into the economic model by applying utility values to each health state, using EQ‑5D data from the SQUIRE trial. The committee concluded that the company's approach to capturing quality of life in the economic model was acceptable.\n\nThe committee concluded that there were no additional benefits associated with necitumumab that had not been captured in the economic analysis.\n\n, 4.16\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee noted that the company presented results for 4\xa0populations; it concluded that the EGFR-expressing (whole trial) population was the most appropriate population for decision-making.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee was aware that the population and the extrapolation function had substantial effects on the economic model results, and changing the starting point of the extrapolation had inconsistent effects on the results.\n\n–4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that the most plausible ICER for necitumumab compared with gemcitabine plus cisplatin was between £110,000 and £170,000 per QALY gained, and was likely to be towards the upper end of this range.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. If necitumumab had been recommended, this scheme would provide a confidential simple discount to the list price of necitumumab.\n\n\n\nEnd-of-life considerations\n\nThe committee noted that the median survival in people in the gemcitabine plus cisplatin group of the SQUIRE trial (EGFR-expressing [whole trial] population) was 9.99\xa0months, although the mean survival predicted by the economic model was higher. The committee concluded that people for whom necitumumab is indicated have a short life expectancy.\n\nThe committee considered that the extension to life associated with necitumumab was uncertain. It was not convinced that there was sufficiently robust evidence that necitumumab was associated with an extension to life of more than 3\xa0months.\n\nThe committee concluded that necitumumab did not meet the criteria to be considered a life-extending, end-of-life treatment.\n\n\n\nCancer Drugs Fund\n\nThe committee noted that all of the ICERs for the EGFR-expressing (whole trial) population were substantially higher than the range normally considered cost effective, and so necitumumab did not have the plausible potential for satisfying the criteria for routine use.\n\nIt considered that there were no clinical uncertainties that could be addressed by collecting outcome data from people in the NHS, which could be used to inform a subsequent update of the guidance.\n\nThe committee concluded that necitumumab did not meet the criteria to be considered for use in the Cancer Drugs Fund.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified.\n\n–"}	https://www.nice.org.uk/guidance/ta411	Evidence-based recommendations on necitumumab (Portrazza) for treating locally advanced or metastatic epidermal growth factor receptor (EGFR)-expressing squamous non-small-cell lung cancer in adults who have not had chemotherapy.
de02a5c8382d09456647dd56c29871c1b1cad199	nice	Radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases	Radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases Evidence-based recommendations on radium‑223 dichloride (Xofigo) for treating hormone-relapsed prostate cancer with bone metastases in adults. # Recommendations Radium‑223 dichloride is recommended as an option for treating hormone-relapsed prostate cancer, symptomatic bone metastases and no known visceral metastases in adults, only if: they have already had docetaxel or docetaxel is contraindicated or is not suitable for them.The drug is only recommended if the company provides radium‑223 dichloride with the discount agreed in the patient access scheme. This guidance is not intended to affect the position of patients whose treatment with radium‑223 dichloride was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology Description of the technology Radium‑223 dichloride (Xofigo, Bayer) is a radiopharmaceutical agent designed to deliver alpha radiation to bone metastases without affecting normal bone marrow. Marketing authorisation The marketing authorisation for radium‑223 dichloride (hereafter referred to as radium‑223) is 'for the treatment of adults with castration‑resistant prostate cancer, symptomatic bone metastases and no known visceral metastases'. Adverse reactions The summary of product characteristics lists the following adverse reactions for radium‑223: thrombocytopenia, diarrhoea, vomiting, nausea, neutropenia, pancytopenia, leukopenia, injection-site reactions and lymphopenia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Recommended dose and schedule Radium‑223 dichloride is administered by intravenous injection at a recommended dose of 55 kBq/kg body weight every 4 weeks for 6 injections. Price The company's submission states that radium‑223 is available at a radioactivity of 6.6 MBq in a 6‑ml vial at a list price of £4,040 (excluding VAT). The company estimates the cost of a full course of treatment to be £24,240. The company (Bayer's) that holds the marketing authorisation for radium‑223 has agreed a patient access scheme with the Department of Health that makes radium‑223 available with a discount applied to all invoices. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.# The company's submission The appraisal committee (see section 6) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases. It focused on updated cost-effectiveness analyses for the subgroup who have not had docetaxel and for whom docetaxel is not suitable. In brief, the key clinical evidence in the company's submission came from ALSYMPCA, a randomised double-blind placebo-controlled trial comparing radium‑223 with placebo in people with hormone-refractory prostate cancer with painful bone metastases. It included people who had previously had docetaxel and people who had not, and the primary endpoint was overall survival. The trial collected quality-of-life data, which was assessed using the Functional Assessment of Cancer Therapy – Prostate (FACT‑P) and EuroQoL‑5 dimensions (EQ‑5D) questionnaires. See the committee papers for full details of the evidence, and the history for full details of the evidence used for NICE's original technology appraisal guidance on radium‑223 dichloride for treating hormone-relapsed prostate cancer with bone metastases.# Committee discussion during the original appraisal The appraisal committee reviewed the data available on the clinical and cost effectiveness of radium‑223, having considered evidence on the nature of hormone-relapsed prostate cancer with bone metastases and the value placed on the benefits of radium‑223 by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee considered the clinical need for treatment in people with hormone-relapsed prostate cancer with bone metastases. It heard from the patient experts that bone metastases are very distressing for patients and their families, particularly as a result of bone pain and fatigue, which have a profound impact on patients' quality of life. It also noted the comments from consultees that bone metastases affect mobility and that full-time care would often be needed for people to carry out daily activities. The patient experts stressed the need for a treatment option that could potentially provide relief from bone pain and other effects of bone metastases, thereby significantly improving quality of life. They also emphasised that radium‑223 would target the specific part of the body where bone metastases have occurred, unlike chemotherapy, and this was considered to outweigh the potential adverse events associated with treatment. The committee recognised the need for alternative treatment options with the potential to improve quality of life in people with bone metastases associated with hormone-relapsed prostate cancer, and concluded that radium‑223 could potentially be a treatment option. The committee discussed the relevant comparators for this appraisal, noting that the final scope specified abiraterone and best supportive care (for people who have and have not had docetaxel), and docetaxel (for people who have not had docetaxel) as comparators. The committee heard from the clinical experts that abiraterone is not an appropriate comparator for people who have not had docetaxel because the people who would have radium‑223 were distinct from those who would be considered for abiraterone. This is because the marketing authorisation for abiraterone in this setting is for people with asymptomatic or mildly symptomatic disease in whom chemotherapy is not yet clinically indicated; the marketing authorisation for radium‑223 is for people with symptomatic disease. The committee concluded that abiraterone was not an appropriate comparator for radium‑223 for people who have not had docetaxel. The committee understood that the company had not presented a comparison of radium‑223 with docetaxel for people who have not had docetaxel therapy on the basis that radium‑223 is not proposed to be offered to people for whom docetaxel would be suitable. It heard from the clinical experts that people for whom docetaxel is suitable would not be offered treatment with radium‑223 because docetaxel would always be the preferred treatment option. However, in response to consultation it was highlighted that this was not the case because in the ALSYMPCA trial, patients could be offered radium‑223 if they declined to take docetaxel. The committee also noted that radium‑223 was available through the Cancer Drugs Fund at the time of this appraisal for people who declined to have docetaxel in addition to people for whom it is not suitable. The committee considered this to mean that people for whom docetaxel is suitable can decide whether to have docetaxel or radium‑223, and therefore it concluded that docetaxel is an appropriate comparator for this group of people. The committee heard from clinical experts that there are people for whom docetaxel is contraindicated or unsuitable, and who would typically have best supportive care in clinical practice. The clinical experts stated that this group of people could be considered for treatment with radium‑223. However, they emphasised that people in this group are difficult to define and that making such a treatment decision needed an assessment of multiple factors such as age, wellbeing and comorbidities. The committee accepted the views of the clinical experts that there is a clinically recognised group for whom radium‑223 treatment is suitable, because docetaxel is contraindicated or unsuitable. It concluded that, for this group of people, best supportive care is the most relevant comparator. The committee went on to discuss the relevant comparators for people who have had docetaxel therapy. The committee heard from the clinical experts that abiraterone was used when the disease has progressed and that radium‑223 would be an alternative option to abiraterone in people who have had prior docetaxel therapy. However, the clinical experts explained that the number of people who could have radium‑223 may be limited because of the complexities associated with administering a radioactive treatment, in which case abiraterone would be considered instead. The clinical experts also stated that, in clinical practice, the choice of whether to use radium‑223 rather than abiraterone depended on whether the bone metastases were symptomatic and whether the alkaline phosphatase (ALP) level was increasing because radium‑223 specifically targets areas of bone metastases. The committee acknowledged that radium‑223 would be an alternative option to abiraterone in people who have had docetaxel therapy, and concluded that abiraterone is the relevant comparator for radium‑223 in this group of people. # Clinical effectiveness during the original appraisal The committee considered the clinical effectiveness of radium‑223 and noted that the key clinical evidence in the company's submission came from the ALSYMPCA trial, which compared radium‑223 plus best supportive care with placebo plus best supportive care. The committee discussed the characteristics of the patients in ALSYMPCA and the generalisability of the results to UK clinical practice. It noted that people with visceral metastases were excluded from ALSYMPCA and that people of African-Caribbean origin, in whom the risk of developing prostate cancer is higher, were under-represented in the trial. It heard from the clinical experts that the trial was generalisable to the wider UK population because visceral metastasis was rare among patients with bone metastases. The clinical experts also stated that people with visceral metastases were excluded from the trial because they have a worse prognosis than people with bone metastases alone, and the survival benefit with treatment in patients with visceral metastases would be minimal. The clinical experts stated that people of African-Caribbean origin may have been under-represented because they have a higher incidence of visceral and lymph node metastases, and would not have been eligible to participate in the trial. The committee also heard from the clinical experts that there was no plausible reason why the drug would work differently in people of different ethnic origins. The committee concluded that ALSYMPCA was relevant to UK clinical practice for people without visceral metastases. The committee noted that patients in the ALSYMPCA trial comprised people who had previously had docetaxel and people who had not. It further noted that the group who had not had docetaxel included people who had refused docetaxel or who had not had access to it, in addition to patients for whom docetaxel was unsuitable. It was aware that about 87% of people in the trial had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, indicating that they would have been fit enough to have docetaxel. The committee heard from clinical experts that assessment of ECOG status was subjective and that there were people in the trial for whom docetaxel was not suitable regardless of their performance status. The committee heard from the clinical experts that uptake of docetaxel at the time of ALSYMPCA was variable and that clinical practice has changed in the last 5 years. The clinical experts explained that most people in ALSYMPCA had docetaxel because it was one of the few treatments available at the time, and that some of those people would not have docetaxel in clinical practice now. They also explained that patients who were not treated with docetaxel at that time may now be able to have docetaxel in clinical practice. The committee considered that a significant proportion of the patients in the group who did not have docetaxel would now be eligible for docetaxel in clinical practice, and thus docetaxel is a relevant comparator. However, the company had not submitted evidence comparing radium‑223 with docetaxel for people who have not had previous docetaxel therapy and for whom docetaxel is suitable. Therefore, the committee concluded that any discussion on the group of people who have not previously had docetaxel would be limited to those for whom docetaxel is contraindicated or unsuitable. The committee examined the clinical-effectiveness data from ALSYMPCA for radium‑223 plus best supportive care compared with placebo plus best supportive care. It noted that radium‑223 was associated with a statistically significant median overall survival benefit of 3.6 months for all patients in the study, and that the median overall survival benefit in the subgroups who had and who had not had prior docetaxel were 3.1 months and 4.6 months respectively. However, noting that not all patients in ALSYMPCA who had not had prior docetaxel were genuinely unable to have it, the committee questioned whether the 4.6 months' overall survival gain in the trial could be generalised to the population in UK clinical practice for whom docetaxel is contraindicated or unsuitable. It noted the company's response to consultation that site-specific data from ALSYMPCA suggested that most patients would have had access to docetaxel and so the reason for not having docetaxel would have been as a result of it being unsuitable for them. The committee also noted that, for all patients in the study, radium‑223 was associated with statistically significant reductions in median time to first skeletal-related event (SRE), median time to prostate-specific antigen (PSA), and total ALP progression. The committee considered the evidence review group's (ERG's) comment that the SRE results could have been confounded by bisphosphonate use during follow-up in ALSYMPCA. However, it accepted the views of the clinical experts that radium‑223 and bisphosphonates had different mechanisms of action, and that people would be expected to benefit from radium‑223 treatment regardless of using bisphosphonates. The committee also noted that radium‑223 was associated with health-related quality-of-life benefits compared with placebo. The committee concluded that radium‑223 plus best supportive care was more effective in treating hormone-relapsed prostate cancer with bone metastases compared with best supportive care alone. The committee considered the adverse-event profile associated with radium‑223 plus best supportive care compared with placebo plus best supportive care in ALSYMPCA. It noted that bone pain was the most common adverse event in the trial, occurring with a higher frequency in the placebo group than in the radium‑223 group. It also noted that the most frequently observed adverse reactions in the radium‑223 group, occurring in 10% of patients or more, were diarrhoea, nausea, vomiting and thrombocytopenia. However, the committee was aware that the incidence of treatment-emergent adverse events leading to trial discontinuation or death was consistently higher in the placebo group than in the radium‑223 group. The committee noted the statements submitted by consultees that evidence from ALSYMPCA showed that radium‑223 has a low risk of adverse effects compared with current radiopharmaceuticals such as strontium‑89. The committee concluded that the current evidence indicates that radium‑223 has an acceptable adverse-event profile. The committee considered the company's indirect comparison of radium‑223 and abiraterone. Having previously concluded that abiraterone was only an appropriate comparator for people who have had docetaxel therapy, the committee did not consider it relevant to discuss the indirect comparison for people who had not had docetaxel therapy. The committee noted that the network of evidence in the post-docetaxel setting was limited to 2 trials: the abiraterone trial COU‑AA‑301 and the subgroup of people who had had docetaxel in ALSYMPCA; each provided direct comparisons with best supportive care. The committee noted that there were some differences between the trials, particularly in the definitions of progression, median PSA scores and the statistical handling of censored data. The committee commented that, despite these differences, the patient populations across the prior-docetaxel populations were more similar in terms of ECOG status, bone metastases and median overall survival, than those across the no-prior-docetaxel populations. The committee also heard from clinical experts that, although few patients in COU‑AA‑301 had visceral metastases compared with no patients in ALSYMPCA, the patient populations in the trials for the prior-docetaxel populations were generally similar. On the balance of the available evidence, the committee concluded that it was appropriate to compare radium‑223 with abiraterone in people who have previously had docetaxel using the indirect comparison. The committee examined the results of the indirect treatment comparison in the prior-docetaxel group. It noted that the point estimates for the hazard ratios were 1.04 for overall survival and 0.91 for progression-free survival, suggesting that radium‑223 was more effective in prolonging overall survival and less effective in delaying disease progression compared with abiraterone. However, it noted that the differences were not statistically significant. The committee, while recognising the uncertainty around using the point estimates of the hazard ratios, and while acknowledging the ERG's comments to treat the results with caution, concluded that it would be reasonable to assume that radium‑223 and abiraterone had similar effectiveness in delaying disease progression and prolonging survival. # Cost effectiveness during the original appraisal The committee considered the company's economic analysis and the ERG's critique of the analysis. The committee had previously concluded that abiraterone was an appropriate comparator only in people who had previously had docetaxel, and that best supportive care was the only relevant comparator for people in whom docetaxel is contraindicated or unsuitable. It had also concluded that docetaxel was a relevant comparator for people who can have it. However, given that the company did not submit evidence comparing radium‑223 with docetaxel, the committee could only consider the cost effectiveness of radium‑223 compared with abiraterone and best supportive care for the relevant populations stated. The committee discussed the assumptions used to model the clinical outcomes. It noted that, for the comparison of radium‑223 with best supportive care, the company presented analyses using PSA, ALP and ECOG as the measure of disease progression. The committee heard from the clinical experts that, although PSA concentrations are related to tumour burden, they do not necessarily correlate well with the presence or extent of bone metastases. The committee also heard that ECOG was a crude and subjective assessment of disease progression that did not reflect disease progression well. The committee understood that ECOG status has an impact on quality of life, but not on the natural history of disease or resource use, and that ECOG status may deteriorate because of comorbidities rather than just prostate cancer. The clinical experts indicated that, because the level of ALP activity is associated with bone turnover, it is the most appropriate biochemical measure of disease progression and correlates better with progression of bone metastases and their symptoms. The committee noted that the company had assessed progression-free survival for the comparison with abiraterone according to PSA progression only. The committee understood that there were no data reported on ALP progression in the abiraterone trials and that time to ECOG deterioration was defined differently between ALSYMPCA and the abiraterone trials. The committee accepted PSA progression for the comparison with abiraterone, but concluded that ALP progression was the most appropriate method that it would consider in its decision-making for analyses comparing radium‑223 with best supportive care. The committee considered the appropriateness of the 5‑year time horizon used in the economic model. It noted that some people were still alive in the model at the end of the 5‑year time horizon, particularly for the comparison of radium‑223 with best supportive care, even though the Kaplan–Meier data showed that the number of people surviving at the end of the 3‑year follow-up period in ALSYMPCA was 0 for the radium‑223 arm and 2 for the placebo arm. The committee heard from the company that clinical advice suggested that about 5% of patients would still be alive after 3 years, and that it had extrapolated from this to 5 years. It also heard from the clinical experts that, although average life expectancy would be around 18 months, it was not unreasonable to assume that some people with bone metastases would survive up to 5 years, particularly people who have had docetaxel. The committee understood that the survival figures from the trial could reflect loss to follow-up as well as death, and it was possible that some patients were alive at the end of the trial. The committee noted that the NICE guide to the methods of technology appraisal 2013 indicates a preference for a lifetime time horizon when alternative technologies lead to differences in survival or benefits that persist for the remainder of a person's life. It also noted the ERG's comment that overall survival should fall to 0 at the end of the time horizon, given that all patients are expected to die eventually, and it was concerned that the company's analysis excluded terminal care costs in the radium‑223 arm because a greater proportion of people were still alive after 5 years than in the placebo arm. The committee concluded that the company's choice of a 5‑year time horizon was not in line with the NICE reference case and that a lifetime time horizon would have been more appropriate to capture all relevant costs and benefits. It also concluded that appropriate modelling of a lifetime time horizon would need careful consideration of the face validity of any methods used to extrapolate survival, and that truncation of the model time horizon may not be needed if more appropriate methods for extrapolation were used. The committee discussed the parametric distributions used by the company to model the survival data. The committee understood from the company that it had used the log-normal distribution based on the best fitting approach for the best supportive care comparison because all the data came from ALSYMPCA, for which it had patient-level data and because the survival data were relatively mature. However, it noted that, although the log-normal distribution provided the best fit for the analyses comparing radium‑223 with abiraterone, the company used the Weibull distribution on the basis that it provided a more conservative assumption of survival. The company also explained that, because the abiraterone data were based on hazard ratios derived from published studies and because the indirect comparison used hazard ratios, it considered it more appropriate to use a proportional hazards model. The committee understood that the number of people surviving after 5 years, predicted by the Weibull distribution, was more in line with estimates from the clinical experts, although it also considered the argument for using a log-normal distribution to be valid. It noted that the impact of the choice of parametric distribution resulted in an incremental cost-effectiveness ratio (ICER) in a range of £40,700 per quality-adjusted life year (QALY) gained using the log-normal distribution and up to £67,500 per QALY gained using the Weibull distribution. The committee previously concluded that the company's approach was inconsistent and that both the log-normal and Weibull distributions should be considered in its decision-making. However, the committee noted that, as part of its additional analysis for the no-prior-docetaxel group, the company used the log-normal distribution to model survival for both the trial and extrapolation period, and after 3 years (156 weeks; the trial observation period) the weekly mortality rate was doubled, increasing the base-case ICER from £40,700 to £42,200 per QALY gained. The committee noted that only 1 person was at risk after 3 years, and it considered that doubling the weekly probability of mortality at a time-point when more people were at risk would be more informative. It noted that, when the ERG used a time-point of 2 years (104 weeks) in an exploratory analysis, the ICER increased from £42,200 to £45,400 per QALY gained. The committee concluded that the ERG's approach of doubling the probability of mortality after 2 years was more reasonable than extrapolation at a time-point when virtually no person was at risk. The committee further concluded that, in general, there was uncertainty in the company's approach of modelling overall survival, including the choice of parametric distribution used. The committee considered the ERG's critique of the company's additional evidence submitted in response to consultation. It noted the ERG's comments that the company's additional evidence overlooked the revisions specified in the original ERG report relating to the correction of the cohort flow calculation and revising the costs of second-line care to include all data in the radium‑223 arm. The committee understood that the ERG's correction used the formula as described in the company's original submission (figure 27 of its appendix) because this was not implemented correctly in the model. The committee noted that these changes increased the base-case ICER for radium‑223 compared with best supportive care for the no-prior-docetaxel subgroup (using ALP as the measure of progression) from £40,700 to £56,500 per QALY gained, mostly because of the correction of the cohort flow calculation. The committee heard from the company that it did not agree with the ERG's approach to correcting the cohort flow calculation. The company accepted that there were some missing data; it was therefore difficult to know when disease progression occurred in the trial. The committee considered that there was a range of issues involved, such as how the survival curves were modelled (see section 4.13), and not just the uncertainty relating to the cohort flow calculation. The committee agreed that the calculation of the cohort flow was an important issue and, while there was uncertainty relating to the most appropriate approach, the committee noted the significant effect on the ICER when applying the company's formula to model cohort flow. The committee considered the utilities applied by the company in the economic model. It was aware that, in response to consultation, the company had re-analysed the EuroQoL‑5 dimensions (EQ‑5D) data for its revised economic analysis. The committee noted that the company's method excluded the baseline EQ‑5D responses. It understood from the ERG that, although excluding the baseline values was reasonable, this method may overestimate the effect of treatment because the model assumes that treatment effects apply from the first cycle of treatment. The committee noted from the ERG's sensitivity analyses that including baseline EQ‑5D responses worsened the cost-effectiveness estimate. The committee heard from the clinical experts that, if quality of life is different for each treatment arm, then it is reasonable to adjust for baseline values and this can be done by excluding them. The committee noted that in some cases the company had used an arm-specific utility, and in other cases it used estimates that were pooled across arms, depending on whether the estimate was statistically significant. The committee agreed with the ERG's approach to use point estimates, rather than the average between the arms, when there was no statistically significant difference between these. It noted that this had only a modest effect on the cost-effectiveness estimate. The committee considered the duration of the quality-of-life benefit associated with radium‑223 compared with best supportive care. It had some concerns about the company's assumption that a quality-of-life increment from radium‑223 over best supportive care for a given health state would continue indefinitely. The committee heard from the clinical experts that it is not implausible for the quality-of-life benefit to extend over a long period of time as a result of suppressing the disease with radium‑223. Despite this, the committee considered that the company's assumption of a lifetime benefit was unlikely and that the benefit probably diminished over time. However, it also considered that the ERG's assumption of a 24‑week point was arbitrary and may be conservative. It noted the company's additional analysis for the comparison of radium‑223 with best supportive care for people who have not previously had docetaxel, where quality-of-life values were equalised between the arms after week 26 and up to 104 weeks. The committee was aware that the company had used utility values based on data from all patients in the ALSYMPCA study, rather than from the no-prior-docetaxel group. It agreed with the ERG that utility values from the no-prior-docetaxel group were the most appropriate to use, and when applied to the base case (using ALP-defined progression and incorporating a lifelong quality-of-life increment from radium‑223 over best supportive care) increased the ICER from £40,700 to £49,600 per QALY gained. The committee noted that assuming a utility benefit lasting 104 weeks and applying utility values specific to the no-prior-docetaxel group increased the ICER from £40,700 to £52,400 per QALY gained using a 5‑year time horizon. It also noted that using the same time horizon, applying utility values specific to the no-prior-docetaxel group and assuming a utility benefit lasting 26 weeks increased the ICER from £40,700 to £62,000 per QALY gained. The committee concluded that, although the quality-of-life benefits with radium‑223 compared with best supportive care could extend beyond 24 weeks, the duration of this benefit is uncertain, but would likely diminish over time and could not be assumed to extend over a person's lifetime. The committee considered the costs used in the model. It considered the concerns highlighted by the ERG on the possible double counting of SREs and adverse-event costs, the costing of first SREs only and the cost of pathological fractures in the model. However, it noted from the ERG's exploratory analyses in the original model that changes to these parameters had minimal impact on the base-case ICER. The committee noted that the total cost of radium‑223 was based on the average number of injections used in ALSYMPCA rather than the recommended dose of 6 injections, but it accepted the company's rationale that this reflected the number of doses on which the efficacy data were based. The committee considered the company's additional evidence relating to medical resource use from the ALSYMPCA study. It noted that the additional data were based on an abstract and that it suggested that, for the no-prior-docetaxel group, there were 4.58 fewer hospital days for radium‑223 compared with best supportive care. The committee considered that the abstract contained very little information about the numbers of patients and the duration of the outcome measures. It noted that NICE and the ERG had previously requested that the company provide the ALSYMPCA resource-use data, and that the company had stated that it would not be helpful for the purposes of economic modelling because the data collected were protocol-driven rather than representing clinical practice. The committee noted the very limited amount of information provided in the abstract and, given the company statement that the information on resource use would not be helpful for the purposes of economic analysis, the committee concluded that it could not consider these data further. The committee also discussed whether treatment waste was incorporated into the cost estimates. It heard from the company that there would be no radium‑223 waste because the treatment for each patient would be ordered, based on their weight, and prepared in advance. However, the committee was concerned that injections would be wasted if a patient did not attend for treatment, particularly given patient comorbidities and potential difficulties in getting to specialist centres. It heard from a clinical expert that, in her clinical practice, a patient is seen at an additional appointment 1 week before ordering the treatment to ensure that person is well enough to travel, which was a method of preventing waste. The committee was uncertain how many clinics used this approach; it noted that it would mean an additional cost for the appointment that would offset potential savings from reduced waste. The committee noted that the company had also assumed no waste for abiraterone. It noted the company's comments in response to consultation, which stated that the potential for waste was small and that the company refunds wasted doses if a patient is unable to attend the hospital because of illness or death. The committee considered that it could not take this into account because this was not a formal arrangement between the company and the NHS. It noted the consultation comment from the company that treatment waste is very rare and has happened less than 5 times in the past year, suggesting that this does not warrant a formal agreement. The committee also noted the comments from a consultee that some centres seemed unaware of arrangements to refund the cost of wasted doses and that the number of doses not used was far higher than 2 in the period since radium‑223 was made available in the UK. The committee considered that a transparent formal arrangement would be needed to eliminate any uncertainty and to ensure that all centres would have access to the company's proposed approach. The committee concluded that there was added uncertainty in the assumptions about waste, but it agreed that the true costs of treatment waste were difficult to estimate. It also concluded that incorporating waste into the comparison of radium‑223 with best supportive care would worsen the cost-effectiveness estimates for that comparison, although the magnitude of the impact is unknown. The committee discussed the costs associated with administering radium‑223. The committee noted that, for radium‑223, the company had used the administration costs for chemotherapy and in its response to consultation, the company highlighted the ease of administering radium‑223 with the cost of administration being no greater than intravenous chemotherapy. It was concerned whether this was appropriate given that radium‑223 is a radiopharmaceutical. It heard from the clinical experts who stated that the costs of preparing and administering radium‑223 were similar to those of chemotherapy even though it is a radiopharmaceutical; the exception to this is the need for nuclear medicine resources, which the clinical experts stated were available in most oncology centres. The committee noted comments from consultation that suggested that a significant number of people could be expected to be suitable for this treatment and that there were costs associated with a radiopharmaceutical product such as radium‑223 that had not been taken into account, for example, resourcing for radiopharmacy, radiation protection and training. The committee heard from the company that, although a nuclear medicines physician is needed to give radium‑223, radium‑223 is an alpha emitter and it is less toxic and harmful compared with other radiopharmaceuticals. In addition, the company stated that radium‑223 is given on an outpatient basis, unlike other radiopharmaceuticals, and therefore would not need additional resources beyond what is available for other radiopharmaceuticals. The committee noted a further consultation comment that, in addition to alpha emissions, radium‑223 and its daughter products emit a range of gamma and beta emissions, and that the risk of hospitalisation for reasons other than administration cannot be discounted. Another consultee commented that the implementation period for radium‑223 should be extended if there is no existing radium‑223 service. However, the committee heard from the company that, because radium‑223 has been available through the Cancer Drugs Fund for some time, most centres are already established, and this would allow access to the technology for most patients in England. The committee noted that it had not received any data or information that would help quantify any additional costs and so it concluded that the potential additional cost to the NHS of providing treatment with radium‑223 was uncertain. The committee also concluded that it had not seen any evidence to suggest that the implementation period for radium‑223 should be extended. The committee noted that the company had assumed, in addition to routine follow-up visits, an additional £161 monthly administration cost for abiraterone. It did not consider it appropriate to include an additional administration cost for abiraterone because the clinical experts stated that this would have been captured in the costs estimated for routine monitoring and follow-up visits. The committee noted the ERG's exploratory analysis that estimated the monthly cost of abiraterone based on 4 weeks rather than 4.33 weeks used by the company. It heard from the clinical experts that the monthly dose for chemotherapy is typically calculated in weekly increments and should be based on 4 weeks rather than a calendar month. The committee concluded that the company's estimated costs for abiraterone may have been overestimated. The committee considered whether radium‑223 could be considered a cost-effective use of NHS resources compared with best supportive care for those people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable. It noted that the company's base-case ICER for radium‑223 compared with best supportive care in this group using ALP-defined progression was £38,200 per QALY gained. It further noted that the ERG's adjustments to the model increased the base-case ICER to £40,700 per QALY gained. The committee considered that there was uncertainty about the utility values (see section 4.15 and section 4.16), and noted that the company should have applied the values derived from the no-prior-docetaxel population rather than from all patients in the ALSYMPCA study. This increased the base-case ICER further from £40,700 per QALY gained to £49,600 per QALY gained. The committee was aware that this estimate incorporated a sustained lifelong quality-of-life benefit for radium‑223 compared with best supportive care. The committee considered that a diminishing benefit, which would not extend over a lifetime, was a more likely scenario and noted this increased the ICER from £49,600 per QALY gained to £52,400 per QALY gained and up to £62,000 per QALY gained (see section 4.16). The committee considered that doubling the weekly probability of mortality at a time earlier than 3 years, making an adjustment to the calculation of the cohort flow in line with the company's formula and accounting for radium‑223 waste (see sections 4.13, 4.14 and 4.19) would increase the ICER further. The committee noted that none of the analyses presented explored the impact of all these uncertainties simultaneously; however, it considered that the effects would be additive. Therefore, it concluded that the most plausible ICER for radium‑223 compared with best supportive care for those people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable was likely to be above £50,000 per QALY gained; this is above the range normally considered cost effective: £20,000–£30,000 per QALY gained. The committee considered whether radium‑223 could be considered a cost-effective use of NHS resources compared with abiraterone for the prior-docetaxel subgroup. It was aware that abiraterone was available with a confidential patient access scheme discount, and noted that the company and the ERG presented analyses using several assumed discounts for abiraterone. The committee noted that the analysis that most closely matched the actual patient access scheme discount for abiraterone showed that radium‑223 dominated abiraterone using the ERG's preferred assumptions, which included removing the administration cost for abiraterone. The committee considered the effect of several scenarios explored by the ERG, and noted that radium‑223 dominated abiraterone in most of these scenarios. The committee acknowledged that there was uncertainty in these analyses. It noted that there were marginal differences in QALYs, which meant small differences in costs had a dramatic effect on the results. It considered that exploratory analyses around most of the assumptions had minimal impact on the ICER. It was also aware that data on ALP were not reported for the abiraterone trial, which meant that the PSA progression was used. It was aware from the discussions with the clinical experts that PSA does not correlate well with the presence or extent of bone metastases; therefore, it considered that the use of PSA progression may have biased any analysis against radium‑223, as shown in the various comparisons with best supportive care. The committee considered that, if radium‑223 were to be recommended in the group of people who had previously had treatment with docetaxel, it would be an additional treatment option to abiraterone. The committee decided to take a pragmatic approach of judging the uncertainty based on all the above factors in addition to the actual results of the ERG's exploratory analyses. On that basis, it concluded that the most plausible ICER will fall within the acceptable range and that radium‑223 could be considered a cost-effective treatment option compared with abiraterone for the prior-docetaxel subgroup. Therefore, radium‑223 should be recommended as an option for people with hormone-relapsed prostate cancer, symptomatic bone metastases and no known visceral metastases who have previously had docetaxel. The committee discussed whether radium‑223 for hormone-relapsed prostate cancer with bone metastases fulfilled the criteria for a life-extending, end-of-life treatment for people in whom docetaxel is contraindicated or unsuitable, which are that: the treatment is indicated for patients with a short life expectancy, normally less than 24 months there is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment the treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The committee noted that the median survival of people who had had placebo in ALSYMPCA was 11.5 months, which is less than 24 months. The committee noted from ALSYMPCA trial data that there was a median gain of 4.6 months compared with best supportive care for people who had not had prior docetaxel. The mean estimates from the model using the log-normal distribution also showed that the overall survival gain for radium‑223 compared with best supportive care was more than 3 months, but the actual figures were designated academic in confidence by the company. The committee noted that the company had estimated 1,807 people to be eligible for treatment in 2014, and had estimated that this would rise to 1,972 people by 2018. The committee, noting that these figures were considerably less than 7,000, considered that the population size criterion had been met. The committee concluded that, for people who have not had prior docetaxel and for whom docetaxel is contraindicated or unsuitable, the first 3 criteria for end-of-life had been met. Having concluded that the end-of-life criteria were met for people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable, the committee discussed whether radium‑223 could be considered a cost-effective use of NHS resources for this population. The committee acknowledged the uncertainties about several assumptions in the model: the calculation of the cohort flow, the modelling of overall survival, utilities and treatment waste. Given the committee considered that the most plausible ICER was likely to be above £50,000 per QALY gained (section 4.22), it concluded that the magnitude of additional weight that would need to be assigned to the QALY benefits in this patient group would be too great for radium‑223 to be considered a cost-effective use of NHS resources. Therefore, the committee concluded that radium‑223 could not be recommended for those people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable. The committee was unable to make any recommendations for radium‑223 for people who can have docetaxel because no evidence was submitted by the company. The committee discussed how innovative radium‑223 is in its potential to make a significant and substantial impact on health-related benefits. It agreed that radium‑223 is novel and specifically targets areas of increased bone turnover, and so offers a step change in treating hormone-relapsed prostate cancer with bone metastases. However, it considered that this was already captured in the QALY calculation. The committee noted the company's comment that the reduction in fatigue associated with radium‑223 treatment as shown in the Functional Assessment of Cancer Therapy – Prostate (FACT‑P) may not have been captured in the EQ‑5D based QALY calculation. However, it noted that the QALY calculation was based on both EQ‑5D and time trade-off estimates. It considered that fatigue was already captured in the QALY calculation through the other dimensions of the EQ‑5D, and that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The committee concluded that the innovative aspects of radium‑223 were already incorporated in the economic analyses. The committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism, when appraising radium‑223. The committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of radium‑223. It therefore concluded that the PPRS Payment Mechanism was not relevant for its consideration of the cost effectiveness of radium‑223. The committee examined whether the recommendations had an impact on NICE's duties under the equalities legislation. The committee noted the comments from some consultees that prostate cancer was more common in men aged 60 years and older, and in men of African-Caribbean origin. It also noted the comments from clinical experts that the complexities associated with the delivery of radioactive isotopes could potentially limit access to radium‑223 treatment for people who live in areas where there are no specialist cancer centres able to administer the treatment. The committee discussed whether these issues had an impact on NICE's duties under the equalities legislation. It considered that these were not issues that could be addressed by a technology appraisal. The committee also noted the consultation comment that patients for whom docetaxel was unsuitable because of a comorbidity or disability would not have the opportunity to have radium‑223. The committee emphasised that its recommendation for radium‑223 for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable was made because radium‑223 was not cost effective in this population. Given the high ICER and uncertainties (see sections 4.22 and 4.26), the committee agreed that the recommendation could be justified and was in line with the committee's role in applying the cost-effectiveness criteria, and was a proportionate means of achieving a legitimate aim. The committee could not identify any special factors that would justify making a positive recommendation for this population even with the high ICER. It concluded that there was no need to alter or add to its recommendations. # Cancer Drugs Fund reconsideration This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases. Specifically, because the original appraisal recommended radium‑223 only for the people who had previously had docetaxel, the Cancer Drugs Fund subsequently offered radium‑223 to people who had not had docetaxel. The committee considered the company's updated cost-utility analysis for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. In its revised analysis, the company: re-analysed data on time to progression defined by serum ALP and data on time to an SRE from ALSYMPCA to address the issue related to the flow of the cohort through the model used a longer time horizon of 10 years used subgroup-specific utilities for the group who had not had prior docetaxel from ALSYMPCA used data on medical resource use from ALSYMPCA used Ford et al. (2013) to derive the costs of treating SREs updated all other unit costs data to 2015 values presented scenario analyses to address areas of uncertainty.In addition, the company provided new evidence defining the group of people for whom docetaxel is not suitable. ## Definition of the population The committee discussed the company's criteria for defining the people for whom docetaxel is not suitable. It noted that these criteria were based on a consensus agreement by 6 oncologists, 1 of whom attended the committee meeting, and included: contraindications to docetaxel such as hypersensitivity to the active substance, a neutrophil count of less than 1.5x109/litre, or severe liver impairment a platelet count of less than 100x109/litre -ngoing treatment with an immunosuppressant for any condition an ECOG performance status of 3 or greater comorbidities and an ECOG performance status of 2 or greater comorbidities, including: a Charleston comorbidity score of 5 or above severe chronic obstructive pulmonary disease symptomatic heart failure history of bowel disease peripheral neuropathy -ngoing treatment for tuberculosis recurrent pancreatitis poor liver function poorly controlled diabetes poor peripheral circulation splenectomy plus prophylactic antibiotics recurrent sepsis poor cognition or social support, which results in inability to understand treatment and provide consent. The committee recognised that many of the criteria listed were also exclusion criteria for ALSYMPCA, suggesting the possibility that there is no evidence of efficacy of radium‑223 in these people. It heard from the clinical expert that there was no clinical or biological reason why the efficacy of radium‑223 would differ based on suitability for docetaxel. The committee also questioned whether it was reasonable to offer radium‑223 to people who cannot take docetaxel given the special warnings and adverse events included in the summary of products characteristics for radium‑223. While the committee recognised that some people, for example, those with absolute neutropenia, would not be offered either treatment, the clinical experts confirmed that there are people who cannot take docetaxel but who can take radium‑223, such as people with renal impairment, people taking immunosuppressants and those with poor performance status. The clinical expert also pointed out that radium‑223 might be more suitable for people with cognitive impairment. The committee accepted the comments from the clinical experts, and concluded that there is a clinically recognised group for whom radium‑223 would be suitable because docetaxel is contraindicated or unsuitable. ## Definition of the comparator The committee recognised that the population for whom docetaxel was not suitable differed from the population for whom chemotherapy is not yet clinically indicated. The committee discussed the appropriate comparator. It noted that, in the original appraisal, it deemed this to be best supportive care. The committee also heard from the clinical expert that docetaxel is a very effective treatment for people for whom it is suitable; the committee was not presented with evidence comparing radium‑223 with docetaxel in this group of people. The committee concluded that best supportive care remained the appropriate comparator for people for whom docetaxel is not suitable. ## Revised analysis The committee considered whether the company's revised analysis sufficiently addressed the committee's concerns in the original technology appraisal of radium‑223. It noted that the company re-analysed data on progression and SREs from ALSYMPCA and, in the analyses, people who died were considered to have had an event and were no longer censored. It heard from the ERG that this corrected the issues related to the flow of the cohort through the model. The committee agreed that using a longer time horizon of 10 years was preferable because it captured all the necessary differences in costs and benefits associated with treatment. It also agreed that applying subgroup-specific utilities and updating the costs of treating SREs was in line with its conclusions in the original appraisal. The committee heard from the ERG that the company's revisions resulted in fixing a bug in the model that played a major role in reducing the company's base-case ICER from £40,700 per QALY gained in the original appraisal to £26,000 in the revised analysis. The committee concluded that these revisions were appropriate. The committee noted that, in the company's revised base case, the company did not take into account the committee's preferred assumptions identified in the original appraisal about modelling of survival and duration of utility benefit. Looking at the company's scenario analyses, the committee noted that doubling the weekly rate of mortality after 104 weeks, as preferred by the committee in the original appraisal, increased the company's base-case ICER from £26,000 to £33,700 per QALY gained. The committee was aware that the company also explored the effect of capping the utility benefits associated with radium‑223 using different time points, rather than assuming that the benefit lasted indefinitely. For the worst case scenario, in which the company assumed the benefit would last only up to 24 weeks, the ICER increased to £32,200 per QALY gained. The committee concluded that the company's base case did not include all the committee's preferred assumptions and chose to consider the scenario analyses. The committee recalled that it did not accept the data on medical resource use included in the company's revised base case in its original appraisal. It was aware that the ERG excluded these data, and made other corrections, when revising the company's base case. The committee noted that the ERG's revisions increased the ICER from the company's new base-case estimate of £26,000 per QALY gained to £31,200 per QALY gained. It heard from the ERG that the abstract used to estimate the costs contained very little information, and including these costs could lead to double counting of costs already included in the model. The committee heard from the company that it had fixed some of the issues related to double counting, but the company and clinical expert accepted that some residual double counting may remain and also that the model may have excluded additional cost savings associated with radium‑223 in reducing hospital admissions. Having noted that the data on resource use came from an unpublished abstract (albeit data from ALSYMPCA), the committee considered that the evidence was not transparent, and so could not assess the analyses behind the data. The committee accepted that there may have been residual double counting of costs and concluded that the medical resource-use data should be excluded from the analysis. The committee understood that there were concerns about treatment waste in the original appraisal. It noted the company's comment that it refunded the hospitals on the 12 occasions when the treatment was not used in 2016, resulting in refunds for less than 0.5% of doses supplied in 2016. The company and the clinical expert explained to the committee that treatment waste was rare, and that the hospitals are aware of the arrangements by the company to refund wasted doses. The committee recognised that this is not a formal arrangement with the NHS, and that treatment waste could have cost implications for the NHS. The company stated that the arrangement has been communicated to hospitals and will continue to be communicated. The committee also heard from the company that incorporating waste into the economic analysis would probably increase the total cost of radium‑223 by approximately 0.5% based on experience in clinical practice. Having heard from the company and the clinical expert, the committee concluded that the potential for waste was not common and is not a key driver of the cost-effectiveness result. It also concluded that the company's arrangement to refund waste should be communicated appropriately to the relevant treatment centres. The committee considered the most plausible ICER for radium‑223. It had previously concluded that the medical resource-use data should be excluded; therefore, the ERG's estimate of £31,200 per QALY gained was more appropriate than the company's estimate of £26,000 per QALY gained. When the rate of mortality was doubled after 104 weeks, the ERG's estimate increased to £39,300 per QALY gained. The committee noted that the company and the ERG both provided a scenario that combined capping utility benefit at 52 weeks and doubling mortality after 104 weeks. This increased the ERG's estimate further from £39,300 to £47,900 per QALY gained. The committee noted that, if the benefit lasted for longer than 52 weeks but did not extend over a life time, the ICER would be lower than £47,900 per QALY gained. The committee noted that using the Weibull distribution rather than log-normal to extrapolate survival increased the ICER further to £56,200 per QALY gained. The committee recalled its discussions on the appropriate distribution for extrapolating survival in the original appraisal (see section 4.13). It was aware that the company's approach of doubling the rate of mortality was an attempt to minimise the uncertainty from using the log-normal distribution. The committee had previously concluded that the company's approach of modelling overall survival was uncertain, including the choice of parametric distribution. The committee noted that its concerns in the original appraisal also applied to the revised analysis. Therefore, it decided that it would consider both Weibull and log-normal distributions. On the balance of the evidence, the committee concluded that the most plausible ICER for radium‑223 plus best supportive care compared with best supportive care alone for people who are not suitable for docetaxel would be below £50,000 per QALY gained, even when accounting for waste. The committee was aware that it had previously concluded that radium‑223 was considered a life-extending end-of-life treatment for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. Therefore the committee concluded that radium‑223 was a cost-effective use of NHS resources and should be recommended for this group of people. The committee also concluded that clinicians and patients would need to take into account several factors including comorbidities (see sections 4.31, 4.32 and 4.33) to identify people for whom docetaxel is not suitable, but for whom radium‑223 is suitable. # Summary of appraisal committee's key conclusions TA412 Appraisal title: Radium‑223 dichloride for treating hormone-relapsed prostate cancer with bone metastases Section Key conclusions (Cancer Drugs Fund reconsideration of TA376) Radium‑223 dichloride is recommended as an option for treating hormone-relapsed prostate cancer, symptomatic bone metastases and no known visceral metastases in adults, only if they have had treatment with docetaxel, or docetaxel is contraindicated or is not suitable for them. The drug is only recommended if the company provides radium‑223 dichloride with the discount agreed in the patient access scheme. The committee concluded that radium‑223 plus best supportive care was more effective in treating hormone-relapsed prostate cancer with bone metastases compared with best supportive care alone, and that it would be reasonable to assume that radium‑223 and abiraterone had similar effectiveness in delaying disease progression and prolonging survival. On the balance of the evidence presented for the Cancer Drugs Fund reconsideration of TA376, the committee concluded that the most plausible incremental cost-effectiveness ratio (ICER) for radium‑223 compared with best supportive care alone for people in whom docetaxel is unsuitable would be below £50,000 per quality-adjusted life year (QALY) gained, even when accounting for waste. The committee agreed that radium‑223 is a life-extending end-of-life treatment for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. Therefore, it concluded that radium‑223 was a cost-effective use of NHS resources in this group of people. The committee also concluded that clinicians and patients would need to take into account several factors, including comorbidities, to identify the people for whom docetaxel is not suitable, but for whom radium‑223 is suitable. For the comparison with abiraterone in the subgroup who have previously had docetaxel, the committee decided to take a pragmatic approach of judging the uncertainty based on multiple factors and concluded that the most plausible ICER would fall within the acceptable range and that radium‑223 could be considered cost effective. Current practice (TA376) Clinical need of patients, including the availability of alternative treatments The committee heard from the patient experts that bone metastases are very distressing for patients and their families, particularly as a result of bone pain and fatigue, which have a profound impact on patients' quality of life. It also noted the comments from consultees that bone metastases affect mobility and that full-time care would often be needed for people to carry out daily activities. The committee recognised the need for alternative treatment options with the potential to improve quality of life in people with bone metastases associated with hormone-relapsed prostate cancer, and concluded that radium‑223 could potentially be a treatment option. The technology (TA376) Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The committee agreed that radium‑223 is novel and specifically targets areas of increased bone turnover, and so offers a step change in treating hormone-relapsed prostate cancer with bone metastases. However, it considered that this was already captured in the QALY calculation. What is the position of the treatment in the pathway of care for the condition? The committee heard from clinical experts that people who have not had previous docetaxel therapy, and for whom docetaxel is suitable would not be offered treatment with radium‑223 because docetaxel would always be the preferred treatment option. However, in response to consultation it was highlighted that this was not the case because in the ALSYMPCA trial, patients could be offered radium‑223 if they declined to take docetaxel. The committee accepted the views of the clinical experts that there is a clinically recognised group who have not had previous docetaxel and for whom radium‑223 treatment is suitable, because docetaxel is contraindicated or unsuitable. Radium‑223 is also an option alongside abiraterone in the second-line setting in people who have had docetaxel. The clinical experts stated that the choice to use radium‑223 rather than abiraterone in this setting depended on whether the bone metastases were symptomatic and whether the alkaline phosphatase (ALP) level was increasing, given that radium‑223 specifically targets areas of bone metastases. Adverse reactions The committee concluded that the current evidence indicates that radium‑223 has an acceptable adverse-event profile. Evidence for clinical effectiveness (TA376) Availability, nature and quality of evidence The committee noted that the key clinical evidence in the company's submission came from the ALSYMPCA trial, which compared radium‑223 plus best supportive care with placebo plus best supportive care. The committee noted that the network of evidence in the post-docetaxel setting was limited to 2 trials: the abiraterone trial COU‑AA‑301 and the subgroup of people who had had docetaxel in ALSYMPCA; each provided direct comparisons with best supportive care. On the balance of the available evidence, the committee concluded that it was appropriate to compare radium‑223 with abiraterone in people who have previously had docetaxel using the indirect comparison. Relevance to general clinical practice in the NHS The committee concluded that ALSYMPCA was relevant to UK clinical practice for people without visceral metastases. Uncertainties generated by the evidence The committee noted that in ALSYMPCA, the group who had not had docetaxel included people who had refused docetaxel or who had not had access to it, in addition to patients for whom docetaxel was unsuitable. The committee noted that for people who have had prior docetaxel therapy there were some differences between the trials included in the indirect comparison, particularly in the definitions of progression, median prostate-specific antigen (PSA) scores and the statistical handling of censored data. The committee noted that the differences in the hazard ratios for overall survival and progression-free survival were not statistically significant. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None. Estimate of the size of the clinical effectiveness including strength of supporting evidence The committee noted that radium‑223 was associated with a statistically significant median overall survival benefit of 3.6 months across all patients, and that the median overall survival benefit in the subgroups who had and who had not had prior docetaxel were 3.1 months and 4.6 months respectively. However, noting that that not all patients in ALSYMPCA who had not had docetaxel were genuinely unable to have it, the committee questioned whether the 4.6 months' overall survival gain in the trial could be generalised to the population in UK clinical practice for whom docetaxel is contraindicated or unsuitable. The committee also noted that across all patients, radium‑223 was associated with statistically significant reductions in median time to first skeletal‑related event, median time to PSA, and total ALP progression. It also noted that radium‑223 was associated with health-related quality-of-life benefits compared with placebo. The committee, while recognising the uncertainties generated by the indirect comparison, concluded that it would be reasonable to assume that radium‑223 and abiraterone had similar effectiveness in delaying disease progression and prolonging survival. Evidence for cost effectiveness (TA376) Availability and nature of evidence Given that the company did not submit evidence comparing radium‑223 with docetaxel, the committee could only consider the cost effectiveness of radium‑223 compared with best supportive care for people in whom docetaxel is contraindicated or unsuitable, and for radium‑223 compared with abiraterone in people who have previously had docetaxel. Uncertainties around and plausibility of assumptions and inputs in the economic model The committee concluded that the company's choice of a 5‑year time horizon was not in line with the NICE reference case and that a lifetime time horizon would have been more appropriate to capture all relevant costs and benefits. The committee accepted PSA progression for the comparison with abiraterone in the absence of any other alternative measure of progression, but for the comparison with best supportive care, it considered that ALP progression was the most appropriate measure of progression on which to base its decision. The committee noted that only 1 person was at risk of death after 3 years and it considered that doubling the weekly probability of mortality at a time-point when more people were at risk would be more informative. The committee further concluded that in general, there was uncertainty in the company's approach of modelling overall survival, including the choice of parametric distribution used. The committee agreed that the calculation of the cohort flow was an important issue and there was uncertainty relating to the most appropriate approach. The committee concluded that although the quality-of-life benefits with radium‑223 compared with best supportive care could extend beyond 24 weeks, the duration of this benefit is uncertain, but would likely diminish over time and could not be assumed to extend over a person's lifetime. The committee noted that there was added uncertainty in the assumptions about waste, which had not been accounted for either radium‑223 or abiraterone. It agreed that the true costs of treatment waste were difficult to estimate but concluded that incorporating waste into the comparison of radium‑223 with best supportive care would worsen the cost-effectiveness estimates for that comparison. The committee had not received any data or information that would help quantify any additional costs and so it concluded that the potential additional cost to the NHS of providing treatment with radium‑223 was uncertain. The committee noted that the company had assumed, in addition to routine follow-up visits, an additional £161 monthly administration cost for abiraterone, and that it had calculated the cost of abiraterone based on calendar months rather than 4 weeks. It concluded that the company's estimated costs for abiraterone may have been overestimated. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The committee considered that fatigue was already captured in the QALY calculation through the other dimensions of the EQ‑5D, and that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Therefore, the committee concluded that the innovative aspects of radium‑223 were already incorporated in the economic analyses. Are there specific groups of people for whom the technology is particularly cost effective? None. What are the key drivers of cost effectiveness? For the comparison with abiraterone, there were marginal differences in QALYs, which meant small differences in costs had a large effect on the results. For the comparison of radium‑223 with best supportive care, the assumptions around the modelling of survival, calculation of the cohort flow and the duration of quality-of-life benefits were the key drivers of the cost-effectiveness results. Most likely cost-effectiveness estimate (given as an ICER) (TA376) The committee concluded that the most plausible ICER for radium‑223 compared with best supportive care for those people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable was likely to be above £50,000 per QALY gained. The committee was unable to make any recommendations for radium‑223 for people who can have docetaxel because no evidence was submitted by the company. The committee took a pragmatic approach of judging uncertainties based on multiple factors and concluded that the most plausible ICER for radium‑223 compared with abiraterone would fall within the acceptable range. Additional factors taken into account (TA376) Patient access schemes (PPRS) The company (Bayer) that holds the marketing authorisation for radium‑223 has agreed a patient access scheme with the Department of Health that makes radium‑223 available with a discount applied to all invoices. The level of the discount is commercial in confidence. Abiraterone, a comparator in this appraisal, is available to the NHS through a simple discount patient access scheme, for which the level of the discount is confidential and cannot be disclosed. The committee considered whether it should take into account the consequences of the PPRS 2014, and in particular the PPRS Payment Mechanism. It concluded that the PPRS Payment Mechanism was not relevant for its consideration of the cost effectiveness of radium‑223. End-of-life considerations (TA376) The committee concluded that for people who have not had prior docetaxel and for whom docetaxel is contraindicated or unsuitable, the end-of-life criteria of short life expectancy, extension to life, and small population size, had all been met. The committee acknowledged the uncertainties about several assumptions in the model: the calculation of the cohort flow, the modelling of overall survival, utilities and treatment waste. Given the committee considered that the most plausible ICER was likely to be above £50,000 per QALY gained, it concluded that the magnitude of additional weight that would need to be assigned to the QALY benefits in this patient group would be too great for radium‑223 to be considered a cost-effective use of NHS resources. Therefore, the committee concluded that radium‑223 could not be recommended for those people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. The committee was unable to make any recommendations for people who can have docetaxel because no evidence was presented by the company. Equalities considerations and social value judgements (TA376) The committee noted the potential equality issues from some consultees and clinical experts regarding prevalence of prostate cancer, availability of specialist cancer centres to administer treatment and the lack of treatment with radium‑223 for people whom docetaxel was unsuitable because of a comorbidity or disability. The committee considered that prevalence and availability of treatment centres were not issues that can be addressed by a technology appraisal. The committee also emphasised that its decision on radium‑223 for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable was made because radium‑223 was not cost effective in this population. It concluded that there was no need to alter or add to its recommendations. Cancer Drugs Fund reconsideration of TA376 The committee concluded that there is a clinically recognised group for whom radium‑223 would be suitable because docetaxel is contraindicated or unsuitable. The committee concluded that best supportive care remained the appropriate comparator for people for whom docetaxel is not suitable. On the balance of the evidence, the committee concluded that the most plausible ICER for radium‑223 plus best supportive care compared with best supportive care alone among people for whom docetaxel is not suitable would be below £50,000 per QALY gained, even when accounting for waste. The committee concluded that radium‑223 was a cost-effective use of NHS resources and should be recommended for this group of people. The committee also concluded that clinicians and patients would need to take into account several factors, including comorbidities to identify the people for whom docetaxel is not suitable, but for whom radium‑223 is suitable.	{'Recommendations': 'Radium‑223 dichloride is recommended as an option for treating hormone-relapsed prostate cancer, symptomatic bone metastases and no known visceral metastases in adults, only if:\n\nthey have already had docetaxel or\n\ndocetaxel is contraindicated or is not suitable for them.The drug is only recommended if the company provides radium‑223 dichloride with the discount agreed in the patient access scheme.\n\nThis guidance is not intended to affect the position of patients whose treatment with radium‑223 dichloride was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nRadium‑223 dichloride (Xofigo, Bayer) is a radiopharmaceutical agent designed to deliver alpha radiation to bone metastases without affecting normal bone marrow.\n\nMarketing authorisation\n\nThe marketing authorisation for radium‑223 dichloride (hereafter referred to as radium‑223) is 'for the treatment of adults with castration‑resistant prostate cancer, symptomatic bone metastases and no known visceral metastases'.\n\nAdverse reactions\n\nThe summary of product characteristics lists the following adverse reactions for radium‑223: thrombocytopenia, diarrhoea, vomiting, nausea, neutropenia, pancytopenia, leukopenia, injection-site reactions and lymphopenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nRadium‑223 dichloride is administered by intravenous injection at a recommended dose of 55\xa0kBq/kg body weight every 4\xa0weeks for 6\xa0injections.\n\nPrice\n\nThe company's submission states that radium‑223 is available at a radioactivity of 6.6\xa0MBq in a 6‑ml vial at a list price of £4,040 (excluding VAT). The company estimates the cost of a full course of treatment to be £24,240. The company (Bayer's) that holds the marketing authorisation for radium‑223 has agreed a patient access scheme with the Department of Health that makes radium‑223 available with a discount applied to all invoices. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.", "The company's submission": "The appraisal committee (see section\xa06) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases. It focused on updated cost-effectiveness analyses for the subgroup who have not had docetaxel and for whom docetaxel is not suitable.\n\nIn brief, the key clinical evidence in the company's submission came from ALSYMPCA, a randomised double-blind placebo-controlled trial comparing radium‑223 with placebo in people with hormone-refractory prostate cancer with painful bone metastases. It included people who had previously had docetaxel and people who had not, and the primary endpoint was overall survival. The trial collected quality-of-life data, which was assessed using the Functional Assessment of Cancer Therapy – Prostate (FACT‑P) and EuroQoL‑5 dimensions (EQ‑5D) questionnaires. See the committee papers for full details of the evidence, and the history for full details of the evidence used for NICE's original technology appraisal guidance on radium‑223 dichloride for treating hormone-relapsed prostate cancer with bone metastases.", 'Committee discussion during the original appraisal': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of radium‑223, having considered evidence on the nature of hormone-relapsed prostate cancer with bone metastases and the value placed on the benefits of radium‑223 by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee considered the clinical need for treatment in people with hormone-relapsed prostate cancer with bone metastases. It heard from the patient experts that bone metastases are very distressing for patients and their families, particularly as a result of bone pain and fatigue, which have a profound impact on patients' quality of life. It also noted the comments from consultees that bone metastases affect mobility and that full-time care would often be needed for people to carry out daily activities. The patient experts stressed the need for a treatment option that could potentially provide relief from bone pain and other effects of bone metastases, thereby significantly improving quality of life. They also emphasised that radium‑223 would target the specific part of the body where bone metastases have occurred, unlike chemotherapy, and this was considered to outweigh the potential adverse events associated with treatment. The committee recognised the need for alternative treatment options with the potential to improve quality of life in people with bone metastases associated with hormone-relapsed prostate cancer, and concluded that radium‑223 could potentially be a treatment option.\n\nThe committee discussed the relevant comparators for this appraisal, noting that the final scope specified abiraterone and best supportive care (for people who have and have not had docetaxel), and docetaxel (for people who have not had docetaxel) as comparators. The committee heard from the clinical experts that abiraterone is not an appropriate comparator for people who have not had docetaxel because the people who would have radium‑223 were distinct from those who would be considered for abiraterone. This is because the marketing authorisation for abiraterone in this setting is for people with asymptomatic or mildly symptomatic disease in whom chemotherapy is not yet clinically indicated; the marketing authorisation for radium‑223 is for people with symptomatic disease. The committee concluded that abiraterone was not an appropriate comparator for radium‑223 for people who have not had docetaxel. The committee understood that the company had not presented a comparison of radium‑223 with docetaxel for people who have not had docetaxel therapy on the basis that radium‑223 is not proposed to be offered to people for whom docetaxel would be suitable. It heard from the clinical experts that people for whom docetaxel is suitable would not be offered treatment with radium‑223 because docetaxel would always be the preferred treatment option. However, in response to consultation it was highlighted that this was not the case because in the ALSYMPCA trial, patients could be offered radium‑223 if they declined to take docetaxel. The committee also noted that radium‑223 was available through the Cancer Drugs Fund at the time of this appraisal for people who declined to have docetaxel in addition to people for whom it is not suitable. The committee considered this to mean that people for whom docetaxel is suitable can decide whether to have docetaxel or radium‑223, and therefore it concluded that docetaxel is an appropriate comparator for this group of people. The committee heard from clinical experts that there are people for whom docetaxel is contraindicated or unsuitable, and who would typically have best supportive care in clinical practice. The clinical experts stated that this group of people could be considered for treatment with radium‑223. However, they emphasised that people in this group are difficult to define and that making such a treatment decision needed an assessment of multiple factors such as age, wellbeing and comorbidities. The committee accepted the views of the clinical experts that there is a clinically recognised group for whom radium‑223 treatment is suitable, because docetaxel is contraindicated or unsuitable. It concluded that, for this group of people, best supportive care is the most relevant comparator.\n\nThe committee went on to discuss the relevant comparators for people who have had docetaxel therapy. The committee heard from the clinical experts that abiraterone was used when the disease has progressed and that radium‑223 would be an alternative option to abiraterone in people who have had prior docetaxel therapy. However, the clinical experts explained that the number of people who could have radium‑223 may be limited because of the complexities associated with administering a radioactive treatment, in which case abiraterone would be considered instead. The clinical experts also stated that, in clinical practice, the choice of whether to use radium‑223 rather than abiraterone depended on whether the bone metastases were symptomatic and whether the alkaline phosphatase (ALP) level was increasing because radium‑223 specifically targets areas of bone metastases. The committee acknowledged that radium‑223 would be an alternative option to abiraterone in people who have had docetaxel therapy, and concluded that abiraterone is the relevant comparator for radium‑223 in this group of people.\n\n# Clinical effectiveness during the original appraisal\n\nThe committee considered the clinical effectiveness of radium‑223 and noted that the key clinical evidence in the company's submission came from the ALSYMPCA trial, which compared radium‑223 plus best supportive care with placebo plus best supportive care. The committee discussed the characteristics of the patients in ALSYMPCA and the generalisability of the results to UK clinical practice. It noted that people with visceral metastases were excluded from ALSYMPCA and that people of African-Caribbean origin, in whom the risk of developing prostate cancer is higher, were under-represented in the trial. It heard from the clinical experts that the trial was generalisable to the wider UK population because visceral metastasis was rare among patients with bone metastases. The clinical experts also stated that people with visceral metastases were excluded from the trial because they have a worse prognosis than people with bone metastases alone, and the survival benefit with treatment in patients with visceral metastases would be minimal. The clinical experts stated that people of African-Caribbean origin may have been under-represented because they have a higher incidence of visceral and lymph node metastases, and would not have been eligible to participate in the trial. The committee also heard from the clinical experts that there was no plausible reason why the drug would work differently in people of different ethnic origins. The committee concluded that ALSYMPCA was relevant to UK clinical practice for people without visceral metastases.\n\nThe committee noted that patients in the ALSYMPCA trial comprised people who had previously had docetaxel and people who had not. It further noted that the group who had not had docetaxel included people who had refused docetaxel or who had not had access to it, in addition to patients for whom docetaxel was unsuitable. It was aware that about 87% of people in the trial had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, indicating that they would have been fit enough to have docetaxel. The committee heard from clinical experts that assessment of ECOG status was subjective and that there were people in the trial for whom docetaxel was not suitable regardless of their performance status. The committee heard from the clinical experts that uptake of docetaxel at the time of ALSYMPCA was variable and that clinical practice has changed in the last 5\xa0years. The clinical experts explained that most people in ALSYMPCA had docetaxel because it was one of the few treatments available at the time, and that some of those people would not have docetaxel in clinical practice now. They also explained that patients who were not treated with docetaxel at that time may now be able to have docetaxel in clinical practice. The committee considered that a significant proportion of the patients in the group who did not have docetaxel would now be eligible for docetaxel in clinical practice, and thus docetaxel is a relevant comparator. However, the company had not submitted evidence comparing radium‑223 with docetaxel for people who have not had previous docetaxel therapy and for whom docetaxel is suitable. Therefore, the committee concluded that any discussion on the group of people who have not previously had docetaxel would be limited to those for whom docetaxel is contraindicated or unsuitable.\n\nThe committee examined the clinical-effectiveness data from ALSYMPCA for radium‑223 plus best supportive care compared with placebo plus best supportive care. It noted that radium‑223 was associated with a statistically significant median overall survival benefit of 3.6\xa0months for all patients in the study, and that the median overall survival benefit in the subgroups who had and who had not had prior docetaxel were 3.1\xa0months and 4.6\xa0months respectively. However, noting that not all patients in ALSYMPCA who had not had prior docetaxel were genuinely unable to have it, the committee questioned whether the 4.6\xa0months' overall survival gain in the trial could be generalised to the population in UK clinical practice for whom docetaxel is contraindicated or unsuitable. It noted the company's response to consultation that site-specific data from ALSYMPCA suggested that most patients would have had access to docetaxel and so the reason for not having docetaxel would have been as a result of it being unsuitable for them. The committee also noted that, for all patients in the study, radium‑223 was associated with statistically significant reductions in median time to first skeletal-related event (SRE), median time to prostate-specific antigen (PSA), and total ALP progression. The committee considered the evidence review group's (ERG's) comment that the SRE results could have been confounded by bisphosphonate use during follow-up in ALSYMPCA. However, it accepted the views of the clinical experts that radium‑223 and bisphosphonates had different mechanisms of action, and that people would be expected to benefit from radium‑223 treatment regardless of using bisphosphonates. The committee also noted that radium‑223 was associated with health-related quality-of-life benefits compared with placebo. The committee concluded that radium‑223 plus best supportive care was more effective in treating hormone-relapsed prostate cancer with bone metastases compared with best supportive care alone.\n\nThe committee considered the adverse-event profile associated with radium‑223 plus best supportive care compared with placebo plus best supportive care in ALSYMPCA. It noted that bone pain was the most common adverse event in the trial, occurring with a higher frequency in the placebo group than in the radium‑223 group. It also noted that the most frequently observed adverse reactions in the radium‑223 group, occurring in 10% of patients or more, were diarrhoea, nausea, vomiting and thrombocytopenia. However, the committee was aware that the incidence of treatment-emergent adverse events leading to trial discontinuation or death was consistently higher in the placebo group than in the radium‑223 group. The committee noted the statements submitted by consultees that evidence from ALSYMPCA showed that radium‑223 has a low risk of adverse effects compared with current radiopharmaceuticals such as strontium‑89. The committee concluded that the current evidence indicates that radium‑223 has an acceptable adverse-event profile.\n\nThe committee considered the company's indirect comparison of radium‑223 and abiraterone. Having previously concluded that abiraterone was only an appropriate comparator for people who have had docetaxel therapy, the committee did not consider it relevant to discuss the indirect comparison for people who had not had docetaxel therapy. The committee noted that the network of evidence in the post-docetaxel setting was limited to 2\xa0trials: the abiraterone trial COU‑AA‑301 and the subgroup of people who had had docetaxel in ALSYMPCA; each provided direct comparisons with best supportive care. The committee noted that there were some differences between the trials, particularly in the definitions of progression, median PSA scores and the statistical handling of censored data. The committee commented that, despite these differences, the patient populations across the prior-docetaxel populations were more similar in terms of ECOG status, bone metastases and median overall survival, than those across the no-prior-docetaxel populations. The committee also heard from clinical experts that, although few patients in COU‑AA‑301 had visceral metastases compared with no patients in ALSYMPCA, the patient populations in the trials for the prior-docetaxel populations were generally similar. On the balance of the available evidence, the committee concluded that it was appropriate to compare radium‑223 with abiraterone in people who have previously had docetaxel using the indirect comparison.\n\nThe committee examined the results of the indirect treatment comparison in the prior-docetaxel group. It noted that the point estimates for the hazard ratios were 1.04 for overall survival and 0.91 for progression-free survival, suggesting that radium‑223 was more effective in prolonging overall survival and less effective in delaying disease progression compared with abiraterone. However, it noted that the differences were not statistically significant. The committee, while recognising the uncertainty around using the point estimates of the hazard ratios, and while acknowledging the ERG's comments to treat the results with caution, concluded that it would be reasonable to assume that radium‑223 and abiraterone had similar effectiveness in delaying disease progression and prolonging survival.\n\n# Cost effectiveness during the original appraisal\n\nThe committee considered the company's economic analysis and the ERG's critique of the analysis. The committee had previously concluded that abiraterone was an appropriate comparator only in people who had previously had docetaxel, and that best supportive care was the only relevant comparator for people in whom docetaxel is contraindicated or unsuitable. It had also concluded that docetaxel was a relevant comparator for people who can have it. However, given that the company did not submit evidence comparing radium‑223 with docetaxel, the committee could only consider the cost effectiveness of radium‑223 compared with abiraterone and best supportive care for the relevant populations stated.\n\nThe committee discussed the assumptions used to model the clinical outcomes. It noted that, for the comparison of radium‑223 with best supportive care, the company presented analyses using PSA, ALP and ECOG as the measure of disease progression. The committee heard from the clinical experts that, although PSA concentrations are related to tumour burden, they do not necessarily correlate well with the presence or extent of bone metastases. The committee also heard that ECOG was a crude and subjective assessment of disease progression that did not reflect disease progression well. The committee understood that ECOG status has an impact on quality of life, but not on the natural history of disease or resource use, and that ECOG status may deteriorate because of comorbidities rather than just prostate cancer. The clinical experts indicated that, because the level of ALP activity is associated with bone turnover, it is the most appropriate biochemical measure of disease progression and correlates better with progression of bone metastases and their symptoms. The committee noted that the company had assessed progression-free survival for the comparison with abiraterone according to PSA progression only. The committee understood that there were no data reported on ALP progression in the abiraterone trials and that time to ECOG deterioration was defined differently between ALSYMPCA and the abiraterone trials. The committee accepted PSA progression for the comparison with abiraterone, but concluded that ALP progression was the most appropriate method that it would consider in its decision-making for analyses comparing radium‑223 with best supportive care.\n\nThe committee considered the appropriateness of the 5‑year time horizon used in the economic model. It noted that some people were still alive in the model at the end of the 5‑year time horizon, particularly for the comparison of radium‑223 with best supportive care, even though the Kaplan–Meier data showed that the number of people surviving at the end of the 3‑year follow-up period in ALSYMPCA was 0\xa0for the radium‑223 arm and 2\xa0for the placebo arm. The committee heard from the company that clinical advice suggested that about 5% of patients would still be alive after 3\xa0years, and that it had extrapolated from this to 5\xa0years. It also heard from the clinical experts that, although average life expectancy would be around 18\xa0months, it was not unreasonable to assume that some people with bone metastases would survive up to 5\xa0years, particularly people who have had docetaxel. The committee understood that the survival figures from the trial could reflect loss to follow-up as well as death, and it was possible that some patients were alive at the end of the trial. The committee noted that the NICE guide to the methods of technology appraisal 2013 indicates a preference for a lifetime time horizon when alternative technologies lead to differences in survival or benefits that persist for the remainder of a person's life. It also noted the ERG's comment that overall survival should fall to 0\xa0at the end of the time horizon, given that all patients are expected to die eventually, and it was concerned that the company's analysis excluded terminal care costs in the radium‑223 arm because a greater proportion of people were still alive after 5\xa0years than in the placebo arm. The committee concluded that the company's choice of a 5‑year time horizon was not in line with the NICE reference case and that a lifetime time horizon would have been more appropriate to capture all relevant costs and benefits. It also concluded that appropriate modelling of a lifetime time horizon would need careful consideration of the face validity of any methods used to extrapolate survival, and that truncation of the model time horizon may not be needed if more appropriate methods for extrapolation were used.\n\nThe committee discussed the parametric distributions used by the company to model the survival data. The committee understood from the company that it had used the log-normal distribution based on the best fitting approach for the best supportive care comparison because all the data came from ALSYMPCA, for which it had patient-level data and because the survival data were relatively mature. However, it noted that, although the log-normal distribution provided the best fit for the analyses comparing radium‑223 with abiraterone, the company used the Weibull distribution on the basis that it provided a more conservative assumption of survival. The company also explained that, because the abiraterone data were based on hazard ratios derived from published studies and because the indirect comparison used hazard ratios, it considered it more appropriate to use a proportional hazards model. The committee understood that the number of people surviving after 5\xa0years, predicted by the Weibull distribution, was more in line with estimates from the clinical experts, although it also considered the argument for using a log-normal distribution to be valid. It noted that the impact of the choice of parametric distribution resulted in an incremental cost-effectiveness ratio (ICER) in a range of £40,700 per quality-adjusted life year (QALY) gained using the log-normal distribution and up to £67,500 per QALY gained using the Weibull distribution. The committee previously concluded that the company's approach was inconsistent and that both the log-normal and Weibull distributions should be considered in its decision-making. However, the committee noted that, as part of its additional analysis for the no-prior-docetaxel group, the company used the log-normal distribution to model survival for both the trial and extrapolation period, and after 3\xa0years (156\xa0weeks; the trial observation period) the weekly mortality rate was doubled, increasing the base-case ICER from £40,700 to £42,200 per QALY gained. The committee noted that only 1\xa0person was at risk after 3\xa0years, and it considered that doubling the weekly probability of mortality at a time-point when more people were at risk would be more informative. It noted that, when the ERG used a time-point of 2\xa0years (104\xa0weeks) in an exploratory analysis, the ICER increased from £42,200 to £45,400 per QALY gained. The committee concluded that the ERG's approach of doubling the probability of mortality after 2\xa0years was more reasonable than extrapolation at a time-point when virtually no person was at risk. The committee further concluded that, in general, there was uncertainty in the company's approach of modelling overall survival, including the choice of parametric distribution used.\n\nThe committee considered the ERG's critique of the company's additional evidence submitted in response to consultation. It noted the ERG's comments that the company's additional evidence overlooked the revisions specified in the original ERG report relating to the correction of the cohort flow calculation and revising the costs of second-line care to include all data in the radium‑223 arm. The committee understood that the ERG's correction used the formula as described in the company's original submission (figure\xa027 of its appendix) because this was not implemented correctly in the model. The committee noted that these changes increased the base-case ICER for radium‑223 compared with best supportive care for the no-prior-docetaxel subgroup (using ALP as the measure of progression) from £40,700 to £56,500 per QALY gained, mostly because of the correction of the cohort flow calculation. The committee heard from the company that it did not agree with the ERG's approach to correcting the cohort flow calculation. The company accepted that there were some missing data; it was therefore difficult to know when disease progression occurred in the trial. The committee considered that there was a range of issues involved, such as how the survival curves were modelled (see section\xa04.13), and not just the uncertainty relating to the cohort flow calculation. The committee agreed that the calculation of the cohort flow was an important issue and, while there was uncertainty relating to the most appropriate approach, the committee noted the significant effect on the ICER when applying the company's formula to model cohort flow.\n\nThe committee considered the utilities applied by the company in the economic model. It was aware that, in response to consultation, the company had re-analysed the EuroQoL‑5 dimensions (EQ‑5D) data for its revised economic analysis. The committee noted that the company's method excluded the baseline EQ‑5D responses. It understood from the ERG that, although excluding the baseline values was reasonable, this method may overestimate the effect of treatment because the model assumes that treatment effects apply from the first cycle of treatment. The committee noted from the ERG's sensitivity analyses that including baseline EQ‑5D responses worsened the cost-effectiveness estimate. The committee heard from the clinical experts that, if quality of life is different for each treatment arm, then it is reasonable to adjust for baseline values and this can be done by excluding them. The committee noted that in some cases the company had used an arm-specific utility, and in other cases it used estimates that were pooled across arms, depending on whether the estimate was statistically significant. The committee agreed with the ERG's approach to use point estimates, rather than the average between the arms, when there was no statistically significant difference between these. It noted that this had only a modest effect on the cost-effectiveness estimate.\n\nThe committee considered the duration of the quality-of-life benefit associated with radium‑223 compared with best supportive care. It had some concerns about the company's assumption that a quality-of-life increment from radium‑223 over best supportive care for a given health state would continue indefinitely. The committee heard from the clinical experts that it is not implausible for the quality-of-life benefit to extend over a long period of time as a result of suppressing the disease with radium‑223. Despite this, the committee considered that the company's assumption of a lifetime benefit was unlikely and that the benefit probably diminished over time. However, it also considered that the ERG's assumption of a 24‑week point was arbitrary and may be conservative. It noted the company's additional analysis for the comparison of radium‑223 with best supportive care for people who have not previously had docetaxel, where quality-of-life values were equalised between the arms after week\xa026 and up to 104\xa0weeks. The committee was aware that the company had used utility values based on data from all patients in the ALSYMPCA study, rather than from the no-prior-docetaxel group. It agreed with the ERG that utility values from the no-prior-docetaxel group were the most appropriate to use, and when applied to the base case (using ALP-defined progression and incorporating a lifelong quality-of-life increment from radium‑223 over best supportive care) increased the ICER from £40,700 to £49,600 per QALY gained. The committee noted that assuming a utility benefit lasting 104\xa0weeks and applying utility values specific to the no-prior-docetaxel group increased the ICER from £40,700 to £52,400 per QALY gained using a 5‑year time horizon. It also noted that using the same time horizon, applying utility values specific to the no-prior-docetaxel group and assuming a utility benefit lasting 26\xa0weeks increased the ICER from £40,700 to £62,000 per QALY gained. The committee concluded that, although the quality-of-life benefits with radium‑223 compared with best supportive care could extend beyond 24\xa0weeks, the duration of this benefit is uncertain, but would likely diminish over time and could not be assumed to extend over a person's lifetime.\n\nThe committee considered the costs used in the model. It considered the concerns highlighted by the ERG on the possible double counting of SREs and adverse-event costs, the costing of first SREs only and the cost of pathological fractures in the model. However, it noted from the ERG's exploratory analyses in the original model that changes to these parameters had minimal impact on the base-case ICER. The committee noted that the total cost of radium‑223 was based on the average number of injections used in ALSYMPCA rather than the recommended dose of 6\xa0injections, but it accepted the company's rationale that this reflected the number of doses on which the efficacy data were based.\n\nThe committee considered the company's additional evidence relating to medical resource use from the ALSYMPCA study. It noted that the additional data were based on an abstract and that it suggested that, for the no-prior-docetaxel group, there were 4.58\xa0fewer hospital days for radium‑223 compared with best supportive care. The committee considered that the abstract contained very little information about the numbers of patients and the duration of the outcome measures. It noted that NICE and the ERG had previously requested that the company provide the ALSYMPCA resource-use data, and that the company had stated that it would not be helpful for the purposes of economic modelling because the data collected were protocol-driven rather than representing clinical practice. The committee noted the very limited amount of information provided in the abstract and, given the company statement that the information on resource use would not be helpful for the purposes of economic analysis, the committee concluded that it could not consider these data further.\n\nThe committee also discussed whether treatment waste was incorporated into the cost estimates. It heard from the company that there would be no radium‑223 waste because the treatment for each patient would be ordered, based on their weight, and prepared in advance. However, the committee was concerned that injections would be wasted if a patient did not attend for treatment, particularly given patient comorbidities and potential difficulties in getting to specialist centres. It heard from a clinical expert that, in her clinical practice, a patient is seen at an additional appointment 1\xa0week before ordering the treatment to ensure that person is well enough to travel, which was a method of preventing waste. The committee was uncertain how many clinics used this approach; it noted that it would mean an additional cost for the appointment that would offset potential savings from reduced waste. The committee noted that the company had also assumed no waste for abiraterone. It noted the company's comments in response to consultation, which stated that the potential for waste was small and that the company refunds wasted doses if a patient is unable to attend the hospital because of illness or death. The committee considered that it could not take this into account because this was not a formal arrangement between the company and the NHS. It noted the consultation comment from the company that treatment waste is very rare and has happened less than 5\xa0times in the past year, suggesting that this does not warrant a formal agreement. The committee also noted the comments from a consultee that some centres seemed unaware of arrangements to refund the cost of wasted doses and that the number of doses not used was far higher than\xa02 in the period since radium‑223 was made available in the UK. The committee considered that a transparent formal arrangement would be needed to eliminate any uncertainty and to ensure that all centres would have access to the company's proposed approach. The committee concluded that there was added uncertainty in the assumptions about waste, but it agreed that the true costs of treatment waste were difficult to estimate. It also concluded that incorporating waste into the comparison of radium‑223 with best supportive care would worsen the cost-effectiveness estimates for that comparison, although the magnitude of the impact is unknown.\n\nThe committee discussed the costs associated with administering radium‑223. The committee noted that, for radium‑223, the company had used the administration costs for chemotherapy and in its response to consultation, the company highlighted the ease of administering radium‑223 with the cost of administration being no greater than intravenous chemotherapy. It was concerned whether this was appropriate given that radium‑223 is a radiopharmaceutical. It heard from the clinical experts who stated that the costs of preparing and administering radium‑223 were similar to those of chemotherapy even though it is a radiopharmaceutical; the exception to this is the need for nuclear medicine resources, which the clinical experts stated were available in most oncology centres. The committee noted comments from consultation that suggested that a significant number of people could be expected to be suitable for this treatment and that there were costs associated with a radiopharmaceutical product such as radium‑223 that had not been taken into account, for example, resourcing for radiopharmacy, radiation protection and training. The committee heard from the company that, although a nuclear medicines physician is needed to give radium‑223, radium‑223 is an alpha emitter and it is less toxic and harmful compared with other radiopharmaceuticals. In addition, the company stated that radium‑223 is given on an outpatient basis, unlike other radiopharmaceuticals, and therefore would not need additional resources beyond what is available for other radiopharmaceuticals. The committee noted a further consultation comment that, in addition to alpha emissions, radium‑223 and its daughter products emit a range of gamma and beta emissions, and that the risk of hospitalisation for reasons other than administration cannot be discounted. Another consultee commented that the implementation period for radium‑223 should be extended if there is no existing radium‑223 service. However, the committee heard from the company that, because radium‑223 has been available through the Cancer Drugs Fund for some time, most centres are already established, and this would allow access to the technology for most patients in England. The committee noted that it had not received any data or information that would help quantify any additional costs and so it concluded that the potential additional cost to the NHS of providing treatment with radium‑223 was uncertain. The committee also concluded that it had not seen any evidence to suggest that the implementation period for radium‑223 should be extended.\n\nThe committee noted that the company had assumed, in addition to routine follow-up visits, an additional £161 monthly administration cost for abiraterone. It did not consider it appropriate to include an additional administration cost for abiraterone because the clinical experts stated that this would have been captured in the costs estimated for routine monitoring and follow-up visits. The committee noted the ERG's exploratory analysis that estimated the monthly cost of abiraterone based on 4\xa0weeks rather than 4.33\xa0weeks used by the company. It heard from the clinical experts that the monthly dose for chemotherapy is typically calculated in weekly increments and should be based on 4\xa0weeks rather than a calendar month. The committee concluded that the company's estimated costs for abiraterone may have been overestimated.\n\nThe committee considered whether radium‑223 could be considered a cost-effective use of NHS resources compared with best supportive care for those people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable. It noted that the company's base-case ICER for radium‑223 compared with best supportive care in this group using ALP-defined progression was £38,200 per QALY gained. It further noted that the ERG's adjustments to the model increased the base-case ICER to £40,700 per QALY gained. The committee considered that there was uncertainty about the utility values (see section\xa04.15 and section\xa04.16), and noted that the company should have applied the values derived from the no-prior-docetaxel population rather than from all patients in the ALSYMPCA study. This increased the base-case ICER further from £40,700 per QALY gained to £49,600 per QALY gained. The committee was aware that this estimate incorporated a sustained lifelong quality-of-life benefit for radium‑223 compared with best supportive care. The committee considered that a diminishing benefit, which would not extend over a lifetime, was a more likely scenario and noted this increased the ICER from £49,600 per QALY gained to £52,400 per QALY gained and up to £62,000 per QALY gained (see\xa0section 4.16). The committee considered that doubling the weekly probability of mortality at a time earlier than 3\xa0years, making an adjustment to the calculation of the cohort flow in line with the company's formula and accounting for radium‑223 waste (see sections\xa04.13, 4.14 and 4.19) would increase the ICER further. The committee noted that none of the analyses presented explored the impact of all these uncertainties simultaneously; however, it considered that the effects would be additive. Therefore, it concluded that the most plausible ICER for radium‑223 compared with best supportive care for those people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable was likely to be above £50,000 per QALY gained; this is above the range normally considered cost effective: £20,000–£30,000 per QALY gained.\n\nThe committee considered whether radium‑223 could be considered a cost-effective use of NHS resources compared with abiraterone for the prior-docetaxel subgroup. It was aware that abiraterone was available with a confidential patient access scheme discount, and noted that the company and the ERG presented analyses using several assumed discounts for abiraterone. The committee noted that the analysis that most closely matched the actual patient access scheme discount for abiraterone showed that radium‑223 dominated abiraterone using the ERG's preferred assumptions, which included removing the administration cost for abiraterone. The committee considered the effect of several scenarios explored by the ERG, and noted that radium‑223 dominated abiraterone in most of these scenarios. The committee acknowledged that there was uncertainty in these analyses. It noted that there were marginal differences in QALYs, which meant small differences in costs had a dramatic effect on the results. It considered that exploratory analyses around most of the assumptions had minimal impact on the ICER. It was also aware that data on ALP were not reported for the abiraterone trial, which meant that the PSA progression was used. It was aware from the discussions with the clinical experts that PSA does not correlate well with the presence or extent of bone metastases; therefore, it considered that the use of PSA progression may have biased any analysis against radium‑223, as shown in the various comparisons with best supportive care. The committee considered that, if radium‑223 were to be recommended in the group of people who had previously had treatment with docetaxel, it would be an additional treatment option to abiraterone. The committee decided to take a pragmatic approach of judging the uncertainty based on all the above factors in addition to the actual results of the ERG's exploratory analyses. On that basis, it concluded that the most plausible ICER will fall within the acceptable range and that radium‑223 could be considered a cost-effective treatment option compared with abiraterone for the prior-docetaxel subgroup. Therefore, radium‑223 should be recommended as an option for people with hormone-relapsed prostate cancer, symptomatic bone metastases and no known visceral metastases who have previously had docetaxel.\n\nThe committee discussed whether radium‑223 for hormone-relapsed prostate cancer with bone metastases fulfilled the criteria for a life-extending, end-of-life treatment for people in whom docetaxel is contraindicated or unsuitable, which are that:\n\nthe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months\n\nthere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment\n\nthe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe committee noted that the median survival of people who had had placebo in ALSYMPCA was 11.5\xa0months, which is less than 24\xa0months. The committee noted from ALSYMPCA trial data that there was a median gain of 4.6\xa0months compared with best supportive care for people who had not had prior docetaxel. The mean estimates from the model using the log-normal distribution also showed that the overall survival gain for radium‑223 compared with best supportive care was more than 3\xa0months, but the actual figures were designated academic in confidence by the company. The committee noted that the company had estimated 1,807\xa0people to be eligible for treatment in 2014, and had estimated that this would rise to 1,972\xa0people by 2018. The committee, noting that these figures were considerably less than 7,000, considered that the population size criterion had been met. The committee concluded that, for people who have not had prior docetaxel and for whom docetaxel is contraindicated or unsuitable, the first 3\xa0criteria for end-of-life had been met.\n\nHaving concluded that the end-of-life criteria were met for people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable, the committee discussed whether radium‑223 could be considered a cost-effective use of NHS resources for this population. The committee acknowledged the uncertainties about several assumptions in the model: the calculation of the cohort flow, the modelling of overall survival, utilities and treatment waste. Given the committee considered that the most plausible ICER was likely to be above £50,000 per QALY gained (section\xa04.22), it concluded that the magnitude of additional weight that would need to be assigned to the QALY benefits in this patient group would be too great for radium‑223 to be considered a cost-effective use of NHS resources. Therefore, the committee concluded that radium‑223 could not be recommended for those people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable. The committee was unable to make any recommendations for radium‑223 for people who can have docetaxel because no evidence was submitted by the company.\n\nThe committee discussed how innovative radium‑223 is in its potential to make a significant and substantial impact on health-related benefits. It agreed that radium‑223 is novel and specifically targets areas of increased bone turnover, and so offers a step change in treating hormone-relapsed prostate cancer with bone metastases. However, it considered that this was already captured in the QALY calculation. The committee noted the company's comment that the reduction in fatigue associated with radium‑223 treatment as shown in the Functional Assessment of Cancer Therapy – Prostate (FACT‑P) may not have been captured in the EQ‑5D based QALY calculation. However, it noted that the QALY calculation was based on both EQ‑5D and time trade-off estimates. It considered that fatigue was already captured in the QALY calculation through the other dimensions of the EQ‑5D, and that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The committee concluded that the innovative aspects of radium‑223 were already incorporated in the economic analyses.\n\nThe committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism, when appraising radium‑223. The committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of radium‑223. It therefore concluded that the PPRS Payment Mechanism was not relevant for its consideration of the cost effectiveness of radium‑223.\n\nThe committee examined whether the recommendations had an impact on NICE's duties under the equalities legislation. The committee noted the comments from some consultees that prostate cancer was more common in men aged 60\xa0years and older, and in men of African-Caribbean origin. It also noted the comments from clinical experts that the complexities associated with the delivery of radioactive isotopes could potentially limit access to radium‑223 treatment for people who live in areas where there are no specialist cancer centres able to administer the treatment. The committee discussed whether these issues had an impact on NICE's duties under the equalities legislation. It considered that these were not issues that could be addressed by a technology appraisal. The committee also noted the consultation comment that patients for whom docetaxel was unsuitable because of a comorbidity or disability would not have the opportunity to have radium‑223. The committee emphasised that its recommendation for radium‑223 for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable was made because radium‑223 was not cost effective in this population. Given the high ICER and uncertainties (see sections\xa04.22 and 4.26), the committee agreed that the recommendation could be justified and was in line with the committee's role in applying the cost-effectiveness criteria, and was a proportionate means of achieving a legitimate aim. The committee could not identify any special factors that would justify making a positive recommendation for this population even with the high ICER. It concluded that there was no need to alter or add to its recommendations.\n\n# Cancer Drugs Fund reconsideration\n\nThis appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases. Specifically, because the original appraisal recommended radium‑223 only for the people who had previously had docetaxel, the Cancer Drugs Fund subsequently offered radium‑223 to people who had not had docetaxel. The committee considered the company's updated cost-utility analysis for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. In its revised analysis, the company:\n\nre-analysed data on time to progression defined by serum ALP and data on time to an SRE from ALSYMPCA to address the issue related to the flow of the cohort through the model\n\nused a longer time horizon of 10\xa0years\n\nused subgroup-specific utilities for the group who had not had prior docetaxel from ALSYMPCA\n\nused data on medical resource use from ALSYMPCA\n\nused Ford et al. (2013) to derive the costs of treating SREs\n\nupdated all other unit costs data to 2015 values\n\npresented scenario analyses to address areas of uncertainty.In addition, the company provided new evidence defining the group of people for whom docetaxel is not suitable.\n\n## Definition of the population\n\nThe committee discussed the company's criteria for defining the people for whom docetaxel is not suitable. It noted that these criteria were based on a consensus agreement by 6\xa0oncologists, 1\xa0of whom attended the committee meeting, and included:\n\ncontraindications to docetaxel such as hypersensitivity to the active substance, a neutrophil count of less than 1.5x109/litre, or severe liver impairment\n\na platelet count of less than 100x109/litre\n\nongoing treatment with an immunosuppressant for any condition\n\nan ECOG performance status of 3\xa0or greater\n\ncomorbidities and an ECOG performance status of 2\xa0or greater\n\ncomorbidities, including:\n\n\n\n\n\na Charleston comorbidity score of 5\xa0or above\n\nsevere chronic obstructive pulmonary disease\n\nsymptomatic heart failure\n\nhistory of bowel disease\n\nperipheral neuropathy\n\nongoing treatment for tuberculosis\n\nrecurrent pancreatitis\n\npoor liver function\n\npoorly controlled diabetes\n\npoor peripheral circulation\n\nsplenectomy plus prophylactic antibiotics\n\nrecurrent sepsis\n\n\n\n\n\npoor cognition or social support, which results in inability to understand treatment and provide consent.\n\nThe committee recognised that many of the criteria listed were also exclusion criteria for ALSYMPCA, suggesting the possibility that there is no evidence of efficacy of radium‑223 in these people. It heard from the clinical expert that there was no clinical or biological reason why the efficacy of radium‑223 would differ based on suitability for docetaxel. The committee also questioned whether it was reasonable to offer radium‑223 to people who cannot take docetaxel given the special warnings and adverse events included in the summary of products characteristics for radium‑223. While the committee recognised that some people, for example, those with absolute neutropenia, would not be offered either treatment, the clinical experts confirmed that there are people who cannot take docetaxel but who can take radium‑223, such as people with renal impairment, people taking immunosuppressants and those with poor performance status. The clinical expert also pointed out that radium‑223 might be more suitable for people with cognitive impairment. The committee accepted the comments from the clinical experts, and concluded that there is a clinically recognised group for whom radium‑223 would be suitable because docetaxel is contraindicated or unsuitable.\n\n## Definition of the comparator\n\nThe committee recognised that the population for whom docetaxel was not suitable differed from the population for whom chemotherapy is not yet clinically indicated. The committee discussed the appropriate comparator. It noted that, in the original appraisal, it deemed this to be best supportive care. The committee also heard from the clinical expert that docetaxel is a very effective treatment for people for whom it is suitable; the committee was not presented with evidence comparing radium‑223 with docetaxel in this group of people. The committee concluded that best supportive care remained the appropriate comparator for people for whom docetaxel is not suitable.\n\n## Revised analysis\n\nThe committee considered whether the company's revised analysis sufficiently addressed the committee's concerns in the original technology appraisal of radium‑223. It noted that the company re-analysed data on progression and SREs from ALSYMPCA and, in the analyses, people who died were considered to have had an event and were no longer censored. It heard from the ERG that this corrected the issues related to the flow of the cohort through the model. The committee agreed that using a longer time horizon of 10\xa0years was preferable because it captured all the necessary differences in costs and benefits associated with treatment. It also agreed that applying subgroup-specific utilities and updating the costs of treating SREs was in line with its conclusions in the original appraisal. The committee heard from the ERG that the company's revisions resulted in fixing a bug in the model that played a major role in reducing the company's base-case ICER from £40,700 per QALY gained in the original appraisal to £26,000 in the revised analysis. The committee concluded that these revisions were appropriate.\n\nThe committee noted that, in the company's revised base case, the company did not take into account the committee's preferred assumptions identified in the original appraisal about modelling of survival and duration of utility benefit. Looking at the company's scenario analyses, the committee noted that doubling the weekly rate of mortality after 104\xa0weeks, as preferred by the committee in the original appraisal, increased the company's base-case ICER from £26,000 to £33,700 per QALY gained. The committee was aware that the company also explored the effect of capping the utility benefits associated with radium‑223 using different time points, rather than assuming that the benefit lasted indefinitely. For the worst case scenario, in which the company assumed the benefit would last only up to 24\xa0weeks, the ICER increased to £32,200 per QALY gained. The committee concluded that the company's base case did not include all the committee's preferred assumptions and chose to consider the scenario analyses.\n\nThe committee recalled that it did not accept the data on medical resource use included in the company's revised base case in its original appraisal. It was aware that the ERG excluded these data, and made other corrections, when revising the company's base case. The committee noted that the ERG's revisions increased the ICER from the company's new base-case estimate of £26,000 per QALY gained to £31,200 per QALY gained. It heard from the ERG that the abstract used to estimate the costs contained very little information, and including these costs could lead to double counting of costs already included in the model. The committee heard from the company that it had fixed some of the issues related to double counting, but the company and clinical expert accepted that some residual double counting may remain and also that the model may have excluded additional cost savings associated with radium‑223 in reducing hospital admissions. Having noted that the data on resource use came from an unpublished abstract (albeit data from ALSYMPCA), the committee considered that the evidence was not transparent, and so could not assess the analyses behind the data. The committee accepted that there may have been residual double counting of costs and concluded that the medical resource-use data should be excluded from the analysis.\n\nThe committee understood that there were concerns about treatment waste in the original appraisal. It noted the company's comment that it refunded the hospitals on the 12\xa0occasions when the treatment was not used in 2016, resulting in refunds for less than 0.5% of doses supplied in 2016. The company and the clinical expert explained to the committee that treatment waste was rare, and that the hospitals are aware of the arrangements by the company to refund wasted doses. The committee recognised that this is not a formal arrangement with the NHS, and that treatment waste could have cost implications for the NHS. The company stated that the arrangement has been communicated to hospitals and will continue to be communicated. The committee also heard from the company that incorporating waste into the economic analysis would probably increase the total cost of radium‑223 by approximately 0.5% based on experience in clinical practice. Having heard from the company and the clinical expert, the committee concluded that the potential for waste was not common and is not a key driver of the cost-effectiveness result. It also concluded that the company's arrangement to refund waste should be communicated appropriately to the relevant treatment centres.\n\nThe committee considered the most plausible ICER for radium‑223. It had previously concluded that the medical resource-use data should be excluded; therefore, the ERG's estimate of £31,200 per QALY gained was more appropriate than the company's estimate of £26,000 per QALY gained. When the rate of mortality was doubled after 104\xa0weeks, the ERG's estimate increased to £39,300 per QALY gained. The committee noted that the company and the ERG both provided a scenario that combined capping utility benefit at 52\xa0weeks and doubling mortality after 104\xa0weeks. This increased the ERG's estimate further from £39,300 to £47,900 per QALY gained. The committee noted that, if the benefit lasted for longer than 52\xa0weeks but did not extend over a life time, the ICER would be lower than £47,900 per QALY gained. The committee noted that using the Weibull distribution rather than log-normal to extrapolate survival increased the ICER further to £56,200 per QALY gained. The committee recalled its discussions on the appropriate distribution for extrapolating survival in the original appraisal (see section\xa04.13). It was aware that the company's approach of doubling the rate of mortality was an attempt to minimise the uncertainty from using the log-normal distribution. The committee had previously concluded that the company's approach of modelling overall survival was uncertain, including the choice of parametric distribution. The committee noted that its concerns in the original appraisal also applied to the revised analysis. Therefore, it decided that it would consider both Weibull and log-normal distributions. On the balance of the evidence, the committee concluded that the most plausible ICER for radium‑223 plus best supportive care compared with best supportive care alone for people who are not suitable for docetaxel would be below £50,000 per QALY gained, even when accounting for waste.\n\nThe committee was aware that it had previously concluded that radium‑223 was considered a life-extending end-of-life treatment for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. Therefore the committee concluded that radium‑223 was a cost-effective use of NHS resources and should be recommended for this group of people. The committee also concluded that clinicians and patients would need to take into account several factors including comorbidities (see sections 4.31, 4.32 and 4.33) to identify people for whom docetaxel is not suitable, but for whom radium‑223 is suitable.\n\n# Summary of appraisal committee's key conclusions\n\nTA412\n\nAppraisal title: Radium‑223 dichloride for treating hormone-relapsed prostate cancer with bone metastases\n\nSection\n\nKey conclusions (Cancer Drugs Fund reconsideration of TA376)\n\nRadium‑223 dichloride is recommended as an option for treating hormone-relapsed prostate cancer, symptomatic bone metastases and no known visceral metastases in adults, only if they have had treatment with docetaxel, or docetaxel is contraindicated or is not suitable for them. The drug is only recommended if the company provides radium‑223 dichloride with the discount agreed in the patient access scheme.\n\n\n\nThe committee concluded that radium‑223 plus best supportive care was more effective in treating hormone-relapsed prostate cancer with bone metastases compared with best supportive care alone, and that it would be reasonable to assume that radium‑223 and abiraterone had similar effectiveness in delaying disease progression and prolonging survival.\n\n, 4.9\n\nOn the balance of the evidence presented for the Cancer Drugs Fund reconsideration of TA376, the committee concluded that the most plausible incremental cost-effectiveness ratio (ICER) for radium‑223 compared with best supportive care alone for people in whom docetaxel is unsuitable would be below £50,000 per quality-adjusted life year (QALY) gained, even when accounting for waste. The committee agreed that radium‑223 is a life-extending end-of-life treatment for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. Therefore, it concluded that radium‑223 was a cost-effective use of NHS resources in this group of people.\n\n, 4.38\n\nThe committee also concluded that clinicians and patients would need to take into account several factors, including comorbidities, to identify the people for whom docetaxel is not suitable, but for whom radium‑223 is suitable.\n\n, 4.33, 4.39\n\nFor the comparison with abiraterone in the subgroup who have previously had docetaxel, the committee decided to take a pragmatic approach of judging the uncertainty based on multiple factors and concluded that the most plausible ICER would fall within the acceptable range and that radium‑223 could be considered cost effective.\n\n\n\nCurrent practice (TA376)\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the patient experts that bone metastases are very distressing for patients and their families, particularly as a result of bone pain and fatigue, which have a profound impact on patients' quality of life. It also noted the comments from consultees that bone metastases affect mobility and that full-time care would often be needed for people to carry out daily activities.\n\nThe committee recognised the need for alternative treatment options with the potential to improve quality of life in people with bone metastases associated with hormone-relapsed prostate cancer, and concluded that radium‑223 could potentially be a treatment option.\n\n\n\nThe technology (TA376)\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee agreed that radium‑223 is novel and specifically targets areas of increased bone turnover, and so offers a step change in treating hormone-relapsed prostate cancer with bone metastases. However, it considered that this was already captured in the QALY calculation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard from clinical experts that people who have not had previous docetaxel therapy, and for whom docetaxel is suitable would not be offered treatment with radium‑223 because docetaxel would always be the preferred treatment option. However, in response to consultation it was highlighted that this was not the case because in the ALSYMPCA trial, patients could be offered radium‑223 if they declined to take docetaxel. The committee accepted the views of the clinical experts that there is a clinically recognised group who have not had previous docetaxel and for whom radium‑223 treatment is suitable, because docetaxel is contraindicated or unsuitable.\n\n\n\nRadium‑223 is also an option alongside abiraterone in the second-line setting in people who have had docetaxel. The clinical experts stated that the choice to use radium‑223 rather than abiraterone in this setting depended on whether the bone metastases were symptomatic and whether the alkaline phosphatase (ALP) level was increasing, given that radium‑223 specifically targets areas of bone metastases.\n\n\n\nAdverse reactions\n\nThe committee concluded that the current evidence indicates that radium‑223 has an acceptable adverse-event profile.\n\n\n\nEvidence for clinical effectiveness (TA376)\n\nAvailability, nature and quality of evidence\n\nThe committee noted that the key clinical evidence in the company's submission came from the ALSYMPCA trial, which compared radium‑223 plus best supportive care with placebo plus best supportive care.\n\n\n\nThe committee noted that the network of evidence in the post-docetaxel setting was limited to 2\xa0trials: the abiraterone trial COU‑AA‑301 and the subgroup of people who had had docetaxel in ALSYMPCA; each provided direct comparisons with best supportive care. On the balance of the available evidence, the committee concluded that it was appropriate to compare radium‑223 with abiraterone in people who have previously had docetaxel using the indirect comparison.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that ALSYMPCA was relevant to UK clinical practice for people without visceral metastases.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that in ALSYMPCA, the group who had not had docetaxel included people who had refused docetaxel or who had not had access to it, in addition to patients for whom docetaxel was unsuitable.\n\n\n\nThe committee noted that for people who have had prior docetaxel therapy there were some differences between the trials included in the indirect comparison, particularly in the definitions of progression, median prostate-specific antigen (PSA) scores and the statistical handling of censored data. The committee noted that the differences in the hazard ratios for overall survival and progression-free survival were not statistically significant.\n\n, 4.9\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone.\n\n-\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee noted that radium‑223 was associated with a statistically significant median overall survival benefit of 3.6\xa0months across all patients, and that the median overall survival benefit in the subgroups who had and who had not had prior docetaxel were 3.1\xa0months and 4.6\xa0months respectively. However, noting that that not all patients in ALSYMPCA who had not had docetaxel were genuinely unable to have it, the committee questioned whether the 4.6\xa0months' overall survival gain in the trial could be generalised to the population in UK clinical practice for whom docetaxel is contraindicated or unsuitable.\n\nThe committee also noted that across all patients, radium‑223 was associated with statistically significant reductions in median time to first skeletal‑related event, median time to PSA, and total ALP progression. It also noted that radium‑223 was associated with health-related quality-of-life benefits compared with placebo.\n\n\n\nThe committee, while recognising the uncertainties generated by the indirect comparison, concluded that it would be reasonable to assume that radium‑223 and abiraterone had similar effectiveness in delaying disease progression and prolonging survival.\n\n\n\nEvidence for cost effectiveness (TA376)\n\nAvailability and nature of evidence\n\nGiven that the company did not submit evidence comparing radium‑223 with docetaxel, the committee could only consider the cost effectiveness of radium‑223 compared with best supportive care for people in whom docetaxel is contraindicated or unsuitable, and for radium‑223 compared with abiraterone in people who have previously had docetaxel.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee concluded that the company's choice of a 5‑year time horizon was not in line with the NICE reference case and that a lifetime time horizon would have been more appropriate to capture all relevant costs and benefits.\n\n\n\nThe committee accepted PSA progression for the comparison with abiraterone in the absence of any other alternative measure of progression, but for the comparison with best supportive care, it considered that ALP progression was the most appropriate measure of progression on which to base its decision.\n\n\n\nThe committee noted that only 1\xa0person was at risk of death after 3\xa0years and it considered that doubling the weekly probability of mortality at a time-point when more people were at risk would be more informative. The committee further concluded that in general, there was uncertainty in the company's approach of modelling overall survival, including the choice of parametric distribution used.\n\n\n\nThe committee agreed that the calculation of the cohort flow was an important issue and there was uncertainty relating to the most appropriate approach.\n\n\n\nThe committee concluded that although the quality-of-life benefits with radium‑223 compared with best supportive care could extend beyond 24\xa0weeks, the duration of this benefit is uncertain, but would likely diminish over time and could not be assumed to extend over a person's lifetime.\n\n\n\nThe committee noted that there was added uncertainty in the assumptions about waste, which had not been accounted for either radium‑223 or abiraterone. It agreed that the true costs of treatment waste were difficult to estimate but concluded that incorporating waste into the comparison of radium‑223 with best supportive care would worsen the cost-effectiveness estimates for that comparison.\n\n\n\nThe committee had not received any data or information that would help quantify any additional costs and so it concluded that the potential additional cost to the NHS of providing treatment with radium‑223 was uncertain.\n\n\n\nThe committee noted that the company had assumed, in addition to routine follow-up visits, an additional £161 monthly administration cost for abiraterone, and that it had calculated the cost of abiraterone based on calendar months rather than 4\xa0weeks. It concluded that the company's estimated costs for abiraterone may have been overestimated.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee considered that fatigue was already captured in the QALY calculation through the other dimensions of the EQ‑5D, and that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Therefore, the committee concluded that the innovative aspects of radium‑223 were already incorporated in the economic analyses.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone.\n\n-\n\nWhat are the key drivers of cost effectiveness?\n\nFor the comparison with abiraterone, there were marginal differences in QALYs, which meant small differences in costs had a large effect on the results.\n\n\n\nFor the comparison of radium‑223 with best supportive care, the assumptions around the modelling of survival, calculation of the cohort flow and the duration of quality-of-life benefits were the key drivers of the cost-effectiveness results.\n\n, 4.14, 416\n\nMost likely cost-effectiveness estimate (given as an ICER) (TA376)\n\nThe committee concluded that the most plausible ICER for radium‑223 compared with best supportive care for those people who have not had prior docetaxel, and for whom docetaxel is contraindicated or unsuitable was likely to be above £50,000 per QALY gained.\n\n\n\nThe committee was unable to make any recommendations for radium‑223 for people who can have docetaxel because no evidence was submitted by the company.\n\n\n\nThe committee took a pragmatic approach of judging uncertainties based on multiple factors and concluded that the most plausible ICER for radium‑223 compared with abiraterone would fall within the acceptable range.\n\n\n\nAdditional factors taken into account (TA376)\n\nPatient access schemes (PPRS)\n\nThe company (Bayer) that holds the marketing authorisation for radium‑223 has agreed a patient access scheme with the Department of Health that makes radium‑223 available with a discount applied to all invoices. The level of the discount is commercial in confidence.\n\n\n\n\n\nAbiraterone, a comparator in this appraisal, is available to the NHS through a simple discount patient access scheme, for which the level of the discount is confidential and cannot be disclosed.\n\n\n\n\n\nThe committee considered whether it should take into account the consequences of the PPRS 2014, and in particular the PPRS Payment Mechanism. It concluded that the PPRS Payment Mechanism was not relevant for its consideration of the cost effectiveness of radium‑223.\n\n\n\nEnd-of-life considerations (TA376)\n\nThe committee concluded that for people who have not had prior docetaxel and for whom docetaxel is contraindicated or unsuitable, the end-of-life criteria of short life expectancy, extension to life, and small population size, had all been met.\n\n\n\nThe committee acknowledged the uncertainties about several assumptions in the model: the calculation of the cohort flow, the modelling of overall survival, utilities and treatment waste. Given the committee considered that the most plausible ICER was likely to be above £50,000 per QALY gained, it concluded that the magnitude of additional weight that would need to be assigned to the QALY benefits in this patient group would be too great for radium‑223 to be considered a cost-effective use of NHS resources. Therefore, the committee concluded that radium‑223 could not be recommended for those people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable. The committee was unable to make any recommendations for people who can have docetaxel because no evidence was presented by the company.\n\n\n\nEqualities considerations and social value judgements (TA376)\n\nThe committee noted the potential equality issues from some consultees and clinical experts regarding prevalence of prostate cancer, availability of specialist cancer centres to administer treatment and the lack of treatment with radium‑223 for people whom docetaxel was unsuitable because of a comorbidity or disability. The committee considered that prevalence and availability of treatment centres were not issues that can be addressed by a technology appraisal. The committee also emphasised that its decision on radium‑223 for people who have not had docetaxel, and for whom docetaxel is contraindicated or unsuitable was made because radium‑223 was not cost effective in this population. It concluded that there was no need to alter or add to its recommendations.\n\n\n\nCancer Drugs Fund reconsideration of TA376\n\nThe committee concluded that there is a clinically recognised group for whom radium‑223 would be suitable because docetaxel is contraindicated or unsuitable.\n\n\n\nThe committee concluded that best supportive care remained the appropriate comparator for people for whom docetaxel is not suitable.\n\n\n\nOn the balance of the evidence, the committee concluded that the most plausible ICER for radium‑223 plus best supportive care compared with best supportive care alone among people for whom docetaxel is not suitable would be below £50,000 per QALY gained, even when accounting for waste.\n\n\n\nThe committee concluded that radium‑223 was a cost-effective use of NHS resources and should be recommended for this group of people. The committee also concluded that clinicians and patients would need to take into account several factors, including comorbidities to identify the people for whom docetaxel is not suitable, but for whom radium‑223 is suitable.\n\n, 4.32, 4.33, 4.39"}	https://www.nice.org.uk/guidance/ta412	Evidence-based recommendations on radium‑223 dichloride (Xofigo) for treating hormone-relapsed prostate cancer with bone metastases in adults.
ead769badfdc14746a1cd9c3e11c91c92ba3854f	nice	Miniature lens system implantation for advanced age-related macular degeneration	Miniature lens system implantation for advanced age-related macular degeneration Evidence-based recommendations on miniature lens system implantation for advanced age-related macular degeneration. This involves implanting an artificial lens system into 1 eye only. # Recommendations Evidence on the efficacy of miniature lens system implantation for advanced age-related macular degeneration (AMD) shows that the procedure can improve both vision and quality of life in the short term. Data on short-term safety are available for limited numbers of patients. There is currently insufficient long-term evidence on both efficacy and safety. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wishing to do miniature lens system implantation for advanced AMD should take the following actions. Inform the clinical governance leads in their trusts. Ensure that patients understand the need to adapt to having a lens system implanted into 1 eye, the risk of early complications, and the uncertainties about long-term efficacy and safety. Clinicians should provide patients with clear information in an appropriate format. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having miniature lens system implantation for advanced AMD (see section 7.1). Patient selection should include detailed assessment to predict the patient's ability to cope with the changes in vision after the operation. Extensive visual rehabilitation after the procedure may be required. This procedure should only be done by experienced cataract surgeons with appropriate training in the implantation of miniature lens systems. NICE encourages further research and publication on which patients may benefit and on safety and efficacy outcomes, particularly longer-term results. NICE may update the guidance on publication of further evidence.# Indications and current treatments Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in industrialised countries. It usually occurs in older adults and is associated with degeneration of the macula – a small area at the centre of the retina responsible for central vision, and for appreciation of fine detail and colour. There are 2 main types of AMD, the most common of which is atrophic or 'dry' macular degeneration. This dry form is characterised by thinning of the macular retina. It develops slowly, causing a gradual loss in central vision. The other type is neovascular or 'wet' AMD, which is characterised by the growth of new blood vessels behind the retina, causing retinal bleeding and scarring. The new vessels are described according to whether they can be seen clearly ('classic') or poorly ('occult') on fluorescein angiography. The onset and disease progression of wet AMD is much faster than in the dry form. Both types of AMD typically affect both eyes, although 1 eye may be affected before the other. Optical aids such as magnifying glasses may help patients with dry or wet AMD to read and do tasks needing fine-detail vision. For wet AMD, there are several treatment options but most patients have repeated intravitreal injections of anti-vascular endothelial growth factor agents, with ongoing regular clinic review. There is currently no standard treatment for dry AMD.# The procedure The aim of an implantable miniature lens system is either to magnify the image on the macula, or to optically move the image onto an undamaged part of the retina. Implantation of lens systems for advanced age-related macular degeneration (AMD) is usually done under local anaesthesia. The natural lens of the eye is removed through a small incision at the limbus (the area where the cornea meets the sclera) and the new lens system is inserted. Artificial lens systems consist of either a miniature telescope prosthesis implanted in the capsular bag of the natural lens, or of 2 separate lenses with 1 lens implanted in front of and 1 lens implanted behind the iris. The technique for implantation varies according to the system being used. Generally, if a telescope prosthesis is used, a larger limbal incision may be needed. Viscoelastic fluid is used during implantation to facilitate insertion and is then removed by irrigation or aspiration. When a single miniature telescope prosthesis is used, images are magnified by the implanted lens system and focused on the macula. When a system of 2 separate lenses is used, the lenses are rotationally aligned to deflect a magnified image away from the most damaged part of the macular and towards a less damaged area. In both cases, the contralateral eye is used for peripheral vision. After implantation, patients need visual rehabilitation.# Efficacy This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a non-randomised comparative study of 217 patients with age-related macular degeneration (AMD) comparing vision in an eye with an implanted telescope lens system with the fellow eye as control, 67% (128/192) of implanted eyes gained 3 or more lines in best-corrected distance visual acuity (BCDVA) compared with 13% (24/192) of fellow eyes at 1‑year follow-up (p<0.0001). At 2‑year follow-up, 60% (103/173) of implanted eyes had gained 3 or more lines in BCDVA compared with 10% (18/174) of fellow eyes (p<0.0001). Mean BCDVA improved by 3.5 lines in implanted eyes compared with 0.8 lines in fellow eyes (p<0.0001). At 5‑year follow-up, the mean BCDVA improvement from baseline (±standard deviation) was 2.4(±2.7) lines in all patients (n=76). The subgroup analysis, in which patients were stratified by age, showed that the improvement was 2.7(±2.7) lines in those aged 65 to 75 years and 2.1(±2.9) lines in those over 75 years. In a case series of 13 eyes (10 patients) implanted with an intraocular lens system, the mean best-corrected visual acuity (BCVA) was 1.37(±0.34) logMAR preoperatively and 0.68(±0.19) logMAR at 1‑year follow-up (p<0.001). In a case series of 6 eyes (6 patients) implanted with an intraocular telescopic lens, the mean gain in distance acuity was 3.66(±1.88) lines and BCDVA had improved significantly at 6‑month follow-up (p=0.014). In the non-randomised comparative study of 217 patients with AMD comparing vision in an eye with an implanted telescope lens system with the fellow eye as control, 68% (130/192) of implanted eyes gained 3 or more lines in best-corrected near visual acuity (BCNVA) compared with 33% (64/192) of fellow eyes at 1‑year follow-up (p<0.0001). Mean BCNVA improved by 3.2 lines in implanted eyes compared with 1.8 lines in fellow eyes (p<0.0001). In the non-randomised comparative study of 217 patients, self-reported quality-of-life scores (assessed using the National Eye Institute's visual functioning questionnaire 25‑item scores ) improved by more than 7 points from baseline (p<0.01) on 7 of 8 relevant subscales (vision specific subscales and psychosocial vision targeted subscales), at 1‑year follow-up. Overall, the mean NEI-VFQ‑25 composite score improved significantly by 6.1(±14.4) points from baseline (p<0.0001). In the subgroup analysis for age stratification both age groups (65 to 75 years, and over 75 years) showed clinically significant improvement in quality of life from baseline in most subscales, but it was higher in those aged 65 to 75 years (5‑point change in individual subscale scores or composite scores is considered as clinically significant). The specialist advisers listed key efficacy outcomes as best-corrected distance visual acuity, best-corrected near visual acuity, reading speed and improvement in quality of life. Five commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Surgery was stopped in 5% (11/217) of patients because of complications such as posterior capsule rupture in 7 patients, choroidal effusion in 1 patient, choroidal haemorrhage in 2 patients and zonular dehiscence in 1 patient in a non-randomised comparative study of 217 patients. Device explantation was reported in 6% (12/206) of patients in the non-randomised comparative study of 217 patients at 2‑year follow-up. Two were removed because of surgical trauma resulting in condensation inside the telescope, 2 were removed during corneal transplantation, and 8 were removed because of patient dissatisfaction. All devices were replaced with a conventional intraocular lens. Corneal decompensation was reported in 1% (2/206) of patients in the non-randomised comparative study of 217 patients at 1‑year follow-up. Both needed device removal and corneal transplantation more than 1 year after the initial surgery. Choroidal neovascularization after telescope implantation was reported in 2% (4/206) of patients in the non-randomised comparative study of 217 patients at 2‑year follow-up. One patient had successful treatment with focal laser photocoagulation through the telescope without complications. Details about management of the neovascularization in the other 3 patients were not reported. Increased intraocular pressure (IOP) within 7 days needing treatment was reported in 28% (57/206) of patients in the non-randomised comparative study of 217 patients. Increased IOP beyond 7 days needing treatment was reported in 3% (6/206) of patients in the same study. No further details were reported. Hypopyon (treated with topical steroids) was reported in11% (4/36) of patients in a case series of 40 patients (40 eyes). No further details were reported. Posterior capsule opacification (treated successfully with a Nd-YAG laser capsulotomy) was reported in 30% (3/10) of patients in a case series of 10 patients (13 eyes). Inflammatory deposits on the device were reported in 25% (51/206) of implanted eyes and pigment deposits on the device were reported in 11% (23/206) of implanted eyes in the non-randomised comparative study of 217 patients. No further details were reported. Loss of 3 or more lines of best-corrected distance visual acuity (BCDVA) or best-corrected near visual acuity (BCNVA) occurred in less than 1% (1/173) of implanted eyes compared with 8% (13/174) of fellow control eyes (p=0.0013) in the non-randomised comparative study of 217 patients. No further details were given. In the non-randomised comparative study of 217 patients with age-related macular degeneration, comparing an implanted telescope lens system with fellow eye controls, the loss of 2 or more lines in BCDVA was significantly less frequent in implanted eyes compared with fellow eyes (2% compared with 9%; p=0.005) at 1‑year follow-up. In the subgroup analysis for age, 3 patients (9%) in each group (65 to 75 years, and over 75 years) had lost more than 2 lines of BCDVA at 60‑month follow-up. Both groups had greater vision loss in the fellow eyes (65 to 75 years, 16% ; compared with 28% in those over 75 years). Ocular adverse events were reported in the non-randomised comparative study of 217 patients up to 60 months after the procedure, including: iris prolapse in 6% (12/206) of patients, iris incarceration in 1% (3/206), iris damage in 4% (9/206), iris transillumination defects lasting more than 21 days in 5% (11/206), iritis lasting more than 30 days in 6% (12/206), iris atrophy more than 7 days after surgery in 6% (12/206), guttata in 8% (16/206) and posterior synechiae in 7% (15/206). No further details were reported. Endothelial cell density (ECD) was reduced by 20% below baseline at 3‑month follow-up and by 25% at 1 year, compared with fellow eye controls, in the non-randomised comparative study of 217 patients with age-related macular degeneration implanted with a telescope lens system. The mean cell loss from 1 year to 2 years was 2%. In the subgroup analysis for age, ECD loss was less in those aged between 65 and 75 years than in those over 75 years (35% compared with 40%) at 60‑month follow-up. The decrease in ECD was correlated with post-surgical oedema (p<0.0001), suggesting that endothelial damage occurred during surgery, rather than during the postoperative period. Transient complications reported in a case series of 40 patients included corneal oedema in 25% (9/36) of patients, fibrin at the pupil in 33% (12/36), synechias in 19% (7/36), hyphema in 11% (4/36), conjunctivitis in 6% (2/36), uveitis in 8% (3/36) and cyclitic membrane in 3% (1/36). Persistent complications included pupillary cyclitic membrane in 1 eye, synechias in 2 eyes and posterior capsular opacification in 4 eyes. Ocular pain due to mild corneal epithelial trauma was reported in 20% (2/10) of patients in a case series of 10 patients. This resolved with no complications. Other complications reported in the non-randomised comparative study of 217 patients included corneal abrasion in 5% (11/206) of patients, foreign-body sensation in 3% (7/206), anterior chamber inflammation lasting beyond 30 days in 2% (actual numbers not reported), device dislocation in 1% (3/206), sub-retinal haemorrhage in 2% (5/206), vitreous haemorrhage more than 7 days after surgery in 2% (4/206), vitreous in the anterior chamber more than 7 days after surgery in 4% (8/206) and vitreous loss in 4% (9/206). In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers reported no anecdotal adverse events. They considered that the following were theoretical adverse events: increase in falls due to the differences in magnification in each eye for devices that give larger magnification, and failure to improve vision for devices that have lower magnification.# Further information This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedures outcomes audit tool (which is for use at local discretion). For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-2074-7	{'Recommendations': "Evidence on the efficacy of miniature lens system implantation for advanced age-related macular degeneration (AMD) shows that the procedure can improve both vision and quality of life in the short term. Data on short-term safety are available for limited numbers of patients. There is currently insufficient long-term evidence on both efficacy and safety. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do miniature lens system implantation for advanced AMD should take the following actions.\n\nInform the clinical governance leads in their trusts.\n\nEnsure that patients understand the need to adapt to having a lens system implanted into 1\xa0eye, the risk of early complications, and the uncertainties about long-term efficacy and safety. Clinicians should provide patients with clear information in an appropriate format. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having miniature lens system implantation for advanced AMD (see section\xa07.1).\n\nPatient selection should include detailed assessment to predict the patient's ability to cope with the changes in vision after the operation. Extensive visual rehabilitation after the procedure may be required.\n\nThis procedure should only be done by experienced cataract surgeons with appropriate training in the implantation of miniature lens systems.\n\nNICE encourages further research and publication on which patients may benefit and on safety and efficacy outcomes, particularly longer-term results. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': "Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in industrialised countries. It usually occurs in older adults and is associated with degeneration of the macula – a small area at the centre of the retina responsible for central vision, and for appreciation of fine detail and colour. There are 2\xa0main types of AMD, the most common of which is atrophic or 'dry' macular degeneration. This dry form is characterised by thinning of the macular retina. It develops slowly, causing a gradual loss in central vision. The other type is neovascular or 'wet' AMD, which is characterised by the growth of new blood vessels behind the retina, causing retinal bleeding and scarring. The new vessels are described according to whether they can be seen clearly ('classic') or poorly ('occult') on fluorescein angiography. The onset and disease progression of wet AMD is much faster than in the dry form. Both types of AMD typically affect both eyes, although 1\xa0eye may be affected before the other.\n\nOptical aids such as magnifying glasses may help patients with dry or wet AMD to read and do tasks needing fine-detail vision. For wet AMD, there are several treatment options but most patients have repeated intravitreal injections of anti-vascular endothelial growth factor agents, with ongoing regular clinic review. There is currently no standard treatment for dry AMD.", 'The procedure': 'The aim of an implantable miniature lens system is either to magnify the image on the macula, or to optically move the image onto an undamaged part of the retina. Implantation of lens systems for advanced age-related macular degeneration (AMD) is usually done under local anaesthesia. The natural lens of the eye is removed through a small incision at the limbus (the area where the cornea meets the sclera) and the new lens system is inserted. Artificial lens systems consist of either a miniature telescope prosthesis implanted in the capsular bag of the natural lens, or of 2\xa0separate lenses with 1\xa0lens implanted in front of and 1\xa0lens implanted behind the iris.\n\nThe technique for implantation varies according to the system being used. Generally, if a telescope prosthesis is used, a larger limbal incision may be needed. Viscoelastic fluid is used during implantation to facilitate insertion and is then removed by irrigation or aspiration. When a single miniature telescope prosthesis is used, images are magnified by the implanted lens system and focused on the macula. When a system of 2\xa0separate lenses is used, the lenses are rotationally aligned to deflect a magnified image away from the most damaged part of the macular and towards a less damaged area. In both cases, the contralateral eye is used for peripheral vision. After implantation, patients need visual rehabilitation.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a non-randomised comparative study of 217\xa0patients with age-related macular degeneration (AMD) comparing vision in an eye with an implanted telescope lens system with the fellow eye as control, 67% (128/192) of implanted eyes gained 3\xa0or more lines in best-corrected distance visual acuity (BCDVA) compared with 13% (24/192) of fellow eyes at 1‑year follow-up (p<0.0001). At 2‑year follow-up, 60% (103/173) of implanted eyes had gained 3\xa0or more lines in BCDVA compared with 10% (18/174) of fellow eyes (p<0.0001). Mean BCDVA improved by 3.5\xa0lines in implanted eyes compared with 0.8\xa0lines in fellow eyes (p<0.0001). At 5‑year follow-up, the mean BCDVA improvement from baseline (±standard deviation) was 2.4(±2.7)\xa0lines in all patients (n=76). The subgroup analysis, in which patients were stratified by age, showed that the improvement was 2.7(±2.7)\xa0lines in those aged 65\xa0to 75\xa0years and 2.1(±2.9)\xa0lines in those over 75\xa0years.\n\nIn a case series of 13\xa0eyes (10\xa0patients) implanted with an intraocular lens system, the mean best-corrected visual acuity (BCVA) was 1.37(±0.34)\xa0logMAR preoperatively and 0.68(±0.19)\xa0logMAR at 1‑year follow-up (p<0.001). In a case series of 6\xa0eyes (6\xa0patients) implanted with an intraocular telescopic lens, the mean gain in distance acuity was 3.66(±1.88)\xa0lines and BCDVA had improved significantly at 6‑month follow-up (p=0.014).\n\nIn the non-randomised comparative study of 217\xa0patients with AMD comparing vision in an eye with an implanted telescope lens system with the fellow eye as control, 68% (130/192) of implanted eyes gained 3\xa0or more lines in best-corrected near visual acuity (BCNVA) compared with 33% (64/192) of fellow eyes at 1‑year follow-up (p<0.0001). Mean BCNVA improved by 3.2\xa0lines in implanted eyes compared with 1.8\xa0lines in fellow eyes (p<0.0001).\n\nIn the non-randomised comparative study of 217\xa0patients, self-reported quality-of-life scores (assessed using the National Eye Institute's visual functioning questionnaire 25‑item scores [NEI-VFQ‑25]) improved by more than 7\xa0points from baseline (p<0.01) on 7\xa0of 8\xa0relevant subscales (vision specific subscales and psychosocial vision targeted subscales), at 1‑year follow-up. Overall, the mean NEI-VFQ‑25 composite score improved significantly by 6.1(±14.4)\xa0points from baseline (p<0.0001). In the subgroup analysis for age stratification both age groups (65\xa0to\xa075\xa0years, and over 75\xa0years) showed clinically significant improvement in quality of life from baseline in most subscales, but it was higher in those aged 65\xa0to\xa075\xa0years (5‑point change in individual subscale scores or composite scores is considered as clinically significant).\n\nThe specialist advisers listed key efficacy outcomes as best-corrected distance visual acuity, best-corrected near visual acuity, reading speed and improvement in quality of life.\n\nFive commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nSurgery was stopped in 5% (11/217) of patients because of complications such as posterior capsule rupture in 7\xa0patients, choroidal effusion in 1\xa0patient, choroidal haemorrhage in 2\xa0patients and zonular dehiscence in 1\xa0patient in a non-randomised comparative study of 217\xa0patients.\n\nDevice explantation was reported in 6% (12/206) of patients in the non-randomised comparative study of 217\xa0patients at 2‑year follow-up. Two were removed because of surgical trauma resulting in condensation inside the telescope, 2\xa0were removed during corneal transplantation, and 8\xa0were removed because of patient dissatisfaction. All devices were replaced with a conventional intraocular lens.\n\nCorneal decompensation was reported in 1% (2/206) of patients in the non-randomised comparative study of 217\xa0patients at 1‑year follow-up. Both needed device removal and corneal transplantation more than 1\xa0year after the initial surgery.\n\nChoroidal neovascularization after telescope implantation was reported in 2% (4/206) of patients in the non-randomised comparative study of 217\xa0patients at 2‑year follow-up. One patient had successful treatment with focal laser photocoagulation through the telescope without complications. Details about management of the neovascularization in the other 3\xa0patients were not reported.\n\nIncreased intraocular pressure (IOP) within 7\xa0days needing treatment was reported in 28% (57/206) of patients in the non-randomised comparative study of 217\xa0patients. Increased IOP beyond 7\xa0days needing treatment was reported in 3% (6/206) of patients in the same study. No further details were reported.\n\nHypopyon (treated with topical steroids) was reported in11% (4/36) of patients in a case series of 40\xa0patients (40 eyes). No further details were reported.\n\nPosterior capsule opacification (treated successfully with a Nd-YAG laser capsulotomy) was reported in 30% (3/10) of patients in a case series of 10\xa0patients (13 eyes).\n\nInflammatory deposits on the device were reported in 25% (51/206) of implanted eyes and pigment deposits on the device were reported in 11% (23/206) of implanted eyes in the non-randomised comparative study of 217\xa0patients. No further details were reported.\n\nLoss of 3\xa0or more lines of best-corrected distance visual acuity (BCDVA) or best-corrected near visual acuity (BCNVA) occurred in less than 1% (1/173) of implanted eyes compared with 8% (13/174) of fellow control eyes (p=0.0013) in the non-randomised comparative study of 217\xa0patients. No further details were given.\n\nIn the non-randomised comparative study of 217\xa0patients with age-related macular degeneration, comparing an implanted telescope lens system with fellow eye controls, the loss of 2\xa0or more lines in BCDVA was significantly less frequent in implanted eyes compared with fellow eyes (2% compared with 9%; p=0.005) at 1‑year follow-up. In the subgroup analysis for age, 3\xa0patients (9%) in each group (65\xa0to\xa075\xa0years, and over 75\xa0years) had lost more than 2\xa0lines of BCDVA at 60‑month follow-up. Both groups had greater vision loss in the fellow eyes (65\xa0to\xa075\xa0years, 16% [n=5]; compared with 28% [n=9] in those over 75\xa0years).\n\nOcular adverse events were reported in the non-randomised comparative study of 217\xa0patients up to 60\xa0months after the procedure, including: iris prolapse in 6% (12/206) of patients, iris incarceration in 1% (3/206), iris damage in 4% (9/206), iris transillumination defects lasting more than 21\xa0days in 5% (11/206), iritis lasting more than 30\xa0days in 6% (12/206), iris atrophy more than 7\xa0days after surgery in 6% (12/206), guttata in 8% (16/206) and posterior synechiae in 7% (15/206). No further details were reported.\n\nEndothelial cell density (ECD) was reduced by 20% below baseline at 3‑month follow-up and by 25% at 1\xa0year, compared with fellow eye controls, in the non-randomised comparative study of 217\xa0patients with age-related macular degeneration implanted with a telescope lens system. The mean cell loss from 1\xa0year to 2\xa0years was 2%. In the subgroup analysis for age, ECD loss was less in those aged between 65 and 75\xa0years than in those over 75\xa0years (35% compared with 40%) at 60‑month follow-up. The decrease in ECD was correlated with post-surgical oedema (p<0.0001), suggesting that endothelial damage occurred during surgery, rather than during the postoperative period.\n\nTransient complications reported in a case series of 40\xa0patients included corneal oedema in 25% (9/36) of patients, fibrin at the pupil in 33% (12/36), synechias in 19% (7/36), hyphema in 11% (4/36), conjunctivitis in 6% (2/36), uveitis in 8% (3/36) and cyclitic membrane in 3% (1/36). Persistent complications included pupillary cyclitic membrane in 1\xa0eye, synechias in 2\xa0eyes and posterior capsular opacification in 4\xa0eyes.\n\nOcular pain due to mild corneal epithelial trauma was reported in 20% (2/10) of patients in a case series of 10\xa0patients. This resolved with no complications.\n\nOther complications reported in the non-randomised comparative study of 217\xa0patients included corneal abrasion in 5% (11/206) of patients, foreign-body sensation in 3% (7/206), anterior chamber inflammation lasting beyond 30\xa0days in 2% (actual numbers not reported), device dislocation in 1% (3/206), sub-retinal haemorrhage in 2% (5/206), vitreous haemorrhage more than 7\xa0days after surgery in 2% (4/206), vitreous in the anterior chamber more than 7\xa0days after surgery in 4% (8/206) and vitreous loss in 4% (9/206).\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers reported no anecdotal adverse events. They considered that the following were theoretical adverse events: increase in falls due to the differences in magnification in each eye for devices that give larger magnification, and failure to improve vision for devices that have lower magnification.', 'Further information': "This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedures outcomes audit tool (which is for use at local discretion).\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2074-7"}	https://www.nice.org.uk/guidance/ipg565	Evidence-based recommendations on miniature lens system implantation for advanced age-related macular degeneration. This involves implanting an artificial lens system into 1 eye only.
4374332fb0b3169077a8b73dd74e23548d1a8c09	nice	Multimorbidity: clinical assessment and management	Multimorbidity: clinical assessment and management This guideline covers optimising care for adults with multimorbidity (multiple long-term conditions) by reducing treatment burden (polypharmacy and multiple appointments) and unplanned care. It aims to improve quality of life by promoting shared decisions based on what is important to each person in terms of treatments, health priorities, lifestyle and goals. The guideline sets out which people are most likely to benefit from an approach to care that takes account of multimorbidity, how they can be identified and what the care involves. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # General principles Be aware that multimorbidity refers to the presence of 2 or more long-term health conditions, which can include: defined physical and mental health conditions such as diabetes or schizophrenia -ngoing conditions such as learning disability symptom complexes such as frailty or chronic pain sensory impairment such as sight or hearing loss alcohol and substance misuse. Be aware that the management of risk factors for future disease can be a major treatment burden for people with multimorbidity and should be carefully considered when optimising care. Be aware that the evidence for recommendations in NICE guidance on single health conditions is regularly drawn from people without multimorbidity and taking fewer prescribed regular medicines. Think carefully about the risks and benefits, for people with multimorbidity, of individual treatments recommended in guidance for single health conditions. Discuss this with the patient alongside their preferences for care and treatment. # Taking account of multimorbidity in tailoring the approach to care Consider an approach to care that takes account of multimorbidity if the person requests it or if any of the following apply: they find it difficult to manage their treatments or day-to-day activities they receive care and support from multiple services and need additional services they have both long-term physical and mental health conditions they have frailty (see section 1.4) or falls they frequently seek unplanned or emergency care (see also recommendation 1.3.2) they are prescribed multiple regular medicines (see section 1.3). # How to identify people who may benefit from an approach to care that takes account of multimorbidity Identify adults who may benefit from an approach to care that takes account of multimorbidity (as outlined in section 1.5): -pportunistically during routine care proactively using electronic health records.Use the criteria in recommendation 1.2.1 to guide this. Consider using a validated tool such as eFI, PEONY or QAdmissions, if available in primary care electronic health records, to identify adults with multimorbidity who are at risk of adverse events such as unplanned hospital admission or admission to care homes. Consider using primary care electronic health records to identify markers of increased treatment burden such as number of regular medicines a person is prescribed. Use an approach to care that takes account of multimorbidity for adults of any age who are prescribed 15 or more regular medicines, because they are likely to be at higher risk of adverse events and drug interactions. Consider an approach to care that takes account of multimorbidity for adults of any age who: are prescribed 10 to 14 regular medicines are prescribed fewer than 10 regular medicines but are at particular risk of adverse events. # How to assess frailty Consider assessing frailty in people with multimorbidity. Be cautious about assessing frailty in a person who is acutely unwell. Do not use a physical performance tool to assess frailty in a person who is acutely unwell. ## Primary care and community care settings When assessing frailty in primary and community care settings, consider using 1 of the following: an informal assessment of gait speed (for example, time taken to answer the door, time taken to walk from the waiting room) self-reported health status (that is, 'how would you rate your health status on a scale from 0 to 10?', with scores of 6 or less indicating frailty) a formal assessment of gait speed, with more than 5 seconds to walk 4 metres indicating frailty the PRISMA-7 questionnaire, with scores of 3 and above indicating frailty. ## Hospital outpatient settings When assessing frailty in hospital outpatient settings, consider using 1 of the following: self-reported health status (that is, 'how would you rate your health status on a scale from 0 to 10?', with scores of 6 or less indicating frailty) the 'Timed Up and Go' test, with times of more than 12 seconds indicating frailty a formal assessment of gait speed, with more than 5 seconds to walk 4 metres indicating frailty the PRISMA‑7 questionnaire, with scores of 3 and above indicating frailty self-reported physical activity, with frailty indicated by scores of 56 or less for men and 59 or less for women using the Physical Activity Scale for the Elderly. # Principles of an approach to care that takes account of multimorbidity When offering an approach to care that takes account of multimorbidity, focus on: how the person's health conditions and their treatments interact and how this affects quality of life the person's individual needs, preferences for treatments, health priorities, lifestyle and goals the benefits and risks of following recommendations from guidance on single health conditions improving quality of life by reducing treatment burden, adverse events, and unplanned care improving coordination of care across services. Follow these steps when delivering an approach to care that takes account of multimorbidity: Discuss the purpose of an approach to care that takes account of multimorbidity (see recommendation 1.6.2). Establish disease and treatment burden (see recommendations 1.6.3 to 1.6.5). Establish patient goals, values and priorities (see recommendations 1.6.6 to 1.6.8). Review medicines and other treatments taking into account evidence of likely benefits and harms for the individual patient and outcomes important to the person (see recommendations 1.6.9 to 1.6.16). Agree an individualised management plan with the person (see recommendation 1.6.17), including: goals and plans for future care (including advance care planning) who is responsible for coordination of care how the individualised management plan and the responsibility for coordination of care is communicated to all professionals and services involved timing of follow-up and how to access urgent care. # Delivering an approach to care that takes account of multimorbidity Follow the recommendations in the NICE guideline on patient experience in adult NHS services, which provides guidance on knowing the patient as an individual, tailoring healthcare services for each patient, continuity of care and relationships, and enabling patients to actively participate in their care. ## Discussing the purpose of an approach to care that takes account of multimorbidity Discuss with the person the purpose of the approach to care, that is, to improve quality of life. This might include reducing treatment burden and optimising care and support by identifying: ways of maximising benefit from existing treatments treatments that could be stopped because of limited benefit treatments and follow-up arrangements with a high burden medicines with a higher risk of adverse events (for example, falls, gastrointestinal bleeding, acute kidney injury) non-pharmacological treatments as possible alternatives to some medicines alternative arrangements for follow-up to coordinate or optimise the number of appointments. ## Establishing disease and treatment burden Establish disease burden by talking to people about how their health problems affect their day-to-day life. Include a discussion of: mental health how disease burden affects their wellbeing how their health problems interact and how this affects quality of life. Establish treatment burden by talking to people about how treatments for their health problems affect their day-to-day life. Include in the discussion: the number and type of healthcare appointments a person has and where these take place the number and type of medicines a person is taking and how often any harms from medicines non-pharmacological treatments such as diets, exercise programmes and psychological treatments any effects of treatment on their mental health or wellbeing. Be alert to the possibility of: depression and anxiety (consider identifying, assessing and managing these conditions in line with the NICE guideline on common mental health problems) chronic pain and the need to assess this and the adequacy of pain management. ## Establishing patient goals, values and priorities Clarify with the patient whether and how they would like their partner, family members and/or carers to be involved in key decisions about the management of their conditions. Review this regularly. If the patient agrees, share information with their partner, family members and/or carers. Encourage people with multimorbidity to clarify what is important to them, including their personal goals, values and priorities. These may include: maintaining their independence undertaking paid or voluntary work, taking part in social activities and playing an active part in family life preventing specific adverse outcomes (for example, stroke) reducing harms from medicines reducing treatment burden lengthening life. Explore the person's attitudes to their treatments and the potential benefits and harms of those treatments. Follow the recommendations on patient involvement in decisions about medicines and understanding the patient's knowledge, beliefs and concerns about medicines in the NICE guideline on medicines adherence. ## Reviewing medicines and other treatments When reviewing medicines and other treatments, use the database of treatment effects to find information on: the effectiveness of treatments the duration of treatment trials the populations included in treatment trials. Consider using a screening tool (for example, the STOPP/START tool in older people) to identify medicine-related safety concerns and medicines the person might benefit from but is not currently taking. When optimising treatment, think about any medicines or non-pharmacological treatments that might be started as well as those that might be stopped. Ask the person if treatments intended to relieve symptoms are providing benefits or causing harms. If the person is unsure of benefit or is experiencing harms from a treatment: discuss reducing or stopping the treatment plan a review to monitor effects of any changes made and decide whether any further changes to treatments are needed (including restarting a treatment). Take into account the possibility of lower overall benefit of continuing treatments that aim to offer prognostic benefit, particularly in people with limited life expectancy or frailty. Discuss with people who have multimorbidity and limited life expectancy or frailty whether they wish to continue treatments recommended in guidance on single health conditions which may offer them limited overall benefit. Discuss any changes to treatments that aim to offer prognostic benefit with the person, taking into account: their views on the likely benefits and harms from individual treatments what is important to them in terms of personal goals, values and priorities (see recommendation 1.6.7). Tell a person who has been taking bisphosphonate for osteoporosis for at least 3 years that there is no consistent evidence of: further benefit from continuing bisphosphonate for another 3 years harms from stopping bisphosphonate after 3 years of treatment.Discuss stopping bisphosphonate after 3 years and include patient choice, fracture risk and life expectancy in the discussion. ## Agreeing the individualised management plan After a discussion of disease and treatment burden and the person's, personal goals, values and priorities, develop and agree an individualised management plan with the person. Agree what will be recorded and what actions will be taken. These could include: starting, stopping or changing medicines and non-pharmacological treatments prioritising healthcare appointments anticipating possible changes to health and wellbeing assigning responsibility for coordination of care and ensuring this is communicated to other healthcare professionals and services -ther areas the person considers important to them arranging a follow-up and review of decisions made.Share copies of the management plan in an accessible format with the person and (with the person's permission) other people involved in care (including healthcare professionals, a partner, family members and/or carers). # Comprehensive assessment in hospital Start a comprehensive assessment of older people with complex needs at the point of admission and preferably in a specialist unit for older people. # Terms used in this guideline ## Multimorbidity Multimorbidity refers to the presence of 2 or more long-term health conditions, which can include: defined physical and mental health conditions such as diabetes or schizophrenia -ngoing conditions such as learning disability symptom complexes such as frailty or chronic pain sensory impairment such as sight or hearing loss alcohol and substance misuse. The management of risk factors for future disease can be a major treatment burden for people with multimorbidity and should be carefully considered when optimising care. This guideline covers the optimisation of care for: adults with 2 or more long-term physical health conditions adults with 1 or more mental health condition and at least 1 physical health condition. ## An approach to care that takes account of multimorbidity An approach to care that takes account of multimorbidity involves personalised assessment and the development of an individualised management plan. The aim is to improve quality of life by reducing treatment burden, adverse events, and unplanned or uncoordinated care. The approach takes account of a person's individual needs, preferences for treatments, health priorities and lifestyle. It aims to improve coordination of care across services, particularly if this has become fragmented. ## Individualised management plan An individualised management plan is a management plan covering clinical aspects of a person's care, such as the medicines they are taking and the services they are attending. It includes information about which areas of care are most important to the person and whether treatments have been stopped to reduce treatment burden. ## Medicines Medicines includes topical treatments such as ointments, inhalers, creams and drops, as well as medicines taken by mouth or injection. ## Comprehensive assessment of older people with complex needs A comprehensive geriatric assessment is an interdisciplinary diagnostic process to determine the medical, psychological and functional capability of someone who is frail and old. The aim is to develop a coordinated, integrated plan for treatment and long-term support.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are: Using primary care electronic health records to identify people who may benefit from an approach to care that takes account of multimorbidity may require some area-wide provision or coordination of search tools if these are not already built into clinical IT systems. Sharing copies of individualised management plans in an accessible format can be done electronically such as through the NHS Summary Care Record, with enhanced functionality now available in 99% of GP practices in England, or by ensuring that the person always has an up-to-date paper copy of their plan at home. The most appropriate healthcare professional to develop and implement the individualised management plan may vary by area and depend on the individual needs and preferences of the person with multimorbidity. However, it is important that it is clear in different areas who should generally be responsible. Putting a guideline fully into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may need to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and the business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group should develop the action plan. The group should include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Multimorbidity is usually defined as when a person has 2 or more long-term health conditions. Measuring the prevalence of multimorbidity is not straightforward because it depends on which conditions are counted. However, all recent studies show that multimorbidity is common, becomes more common as people age, and is more common in people from less affluent areas. Whereas in older people multimorbidity is largely due to higher rates of physical health conditions, in younger people and people from less affluent areas, multimorbidity is often due to a combination of physical and mental health conditions (notably depression). Multimorbidity matters because it is associated with reduced quality of life, higher mortality, polypharmacy and high treatment burden, higher rates of adverse drug events, and much greater health services use (including unplanned or emergency care). A particular issue for health services and healthcare professionals is that treatment regimens (including non-pharmacological treatments) can easily become very burdensome for people with multimorbidity, and care can become uncoordinated and fragmented. Polypharmacy in people with multimorbidity is often driven by the introduction of multiple medicines intended to prevent future morbidity and mortality. However, the case for using these medicines weakens if life expectancy is reduced by other conditions or frailty. The absolute difference made by each additional medicine may also reduce when people are taking multiple preventive medicines. The implications of multimorbidity for organisation of healthcare are highly variable depending on which conditions a person has. Groups of conditions that have closely related or concordant treatment, such as diabetes, hypertension and angina, pose fewer problems for coordination than conditions needing quite different treatment (for example, physical and mental health conditions). NICE guidelines have been developed for managing many individual diseases and conditions. The aim of this guideline is to inform patient and clinical decision-making and models of care for people with multimorbidity who would benefit from a tailored approach because of the high impact of their conditions or treatment on their quality of life or functioning. This is a particular concern for generalist medical professionals such as GPs and geriatricians and healthcare professionals such as pharmacists and nurses working in those services; the guideline is also relevant to specialist services because many of the patients they care for will have significant other conditions.# Recommendations for research The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline. # Organisation of care What is the clinical and cost effectiveness of alternative approaches to organising primary care compared with usual care for people with multimorbidity? ## Why this is important The guideline committee felt that primary care was well suited to managing multimorbidity, but agreed that this was often challenging partly because of how primary care is currently organised. However, there was inadequate high-quality research on alternative approaches to organising care for people with multimorbidity. Trials should be undertaken to examine the impact of different strategies on important clinical outcomes, quality of life and cost effectiveness. The committee believed that no single trial could likely address this research need, because there are many plausible interventions and many defined populations in which such interventions might be of value. Large, well-designed trials of alternative ways of organising general practice based primary care for people with multimorbidity would be of value in defined patient groups (for example, people with multimorbidity who find it difficult to manage their treatment or care or day-to-day activities, people with multiple providers or services involved in their care, people with both long-term physical and mental health problems, people with well-defined frailty, people frequently using unscheduled care, people prescribed multiple regular medicines, and people who are housebound or care home residents). Such trials should have clear identification and justification of the planned target population, careful piloting and optimisation, and well-described interventions. They need to be sufficiently powered to provide evidence of clinically important effects of interventions on outcomes that are relevant to patients and health and social care services (for example, quality of life, hospital and care home admission, mortality). # Holistic assessment in the community What is the clinical and cost effectiveness of a community holistic assessment and intervention for people living with high levels of multimorbidity? ## Why this is important There was low quality evidence to indicate potential benefit from community assessments based on the principles of comprehensive geriatric assessment in older people. However, the studies were conducted outside the UK and were not aimed at all adults living with multimorbidity. The guideline committee believed that there was some evidence that holistic assessment and intervention in the community may be of benefit for older people, but that the evidence was of low quality and not adequate to inform strong recommendations. Large, well-designed trials of holistic assessment and intervention in people with multimorbidity would be of value in defined patient groups in the community (for example, people in nursing homes, people who are housebound, people of all ages with well-defined frailty, people with high levels of multimorbidity or polypharmacy). Such trials must be rigorous, with clear identification and justification of the planned target population, careful piloting and optimisation, and well-described interventions. They need to be sufficiently powered to provide evidence of clinically important effects of interventions on outcomes that are relevant to patients and health and social care services (for example, quality of life, hospital and care home admission, and mortality). The guideline committee believed that no single trial could likely address this research need, since there are many plausible interventions and many defined populations in which such interventions might be of value. The committee believed that assessment should follow the principles of Comprehensive Geriatric Assessment or the Standardised Assessment of Elderly People in Europe (STEP) tool, and that interventions would likely involve a multidisciplinary team. # Stopping preventive medicines What is the clinical and cost effectiveness of stopping preventive medicines in people with multimorbidity who may not benefit from continuing them? ## Why this is important There is good evidence from randomised controlled trials of the medium term (2–10 years) benefit of medicines recommended in guidelines for preventing future morbidity or mortality, including treatments for hypertension, hyperglycaemia and osteoporosis. However, there is much less evidence about the balance of benefit and harm over longer periods of treatment. It is plausible that harms outweigh benefits in some people with multimorbidity (for example, because of higher rates of adverse events in older, frailer people prescribed multiple regular medicines, or because the expected benefit from continuing a preventive medicine is reduced when there is limited life expectancy or high risk of death from other morbidities). These people are unlikely to have been eligible or included in published trials showing initial benefit from preventive medicines. The systematic review undertaken by NICE in 2015 did not find any randomised controlled trials of stopping antihypertensive medicines in people with multimorbidity. The review found 1 small randomised controlled trial of stopping statins in people with a life expectancy of 1 year, but the committee did not consider this provided enough evidence to make a recommendation. The review found several randomised controlled trials of stopping bisphosphonates (although not clearly in populations with multimorbidity) and a recommendation was made for this, but no randomised controlled trials were found of stopping calcium and/or vitamin D. Recommendations based on robust evidence on the clinical and cost effectiveness of stopping preventive medicines in people with multimorbidity who may not benefit could have significant budgetary implications for the NHS. No ongoing trials have been identified. The guideline committee considered that 1 or more large, well-designed trials of stopping preventive medicine in people with multimorbidity would be of value in defined patient groups in the community (for example, people in nursing homes, people who are housebound, people with well-defined frailty, people with high levels of multimorbidity or polypharmacy, people with limited life expectancy). Discontinuation could either be complete (all relevant medicines) or partial (for example, reduced intensity of hypotensive or hypoglycaemic treatment). Such trials have to be sufficiently powered to provide evidence of clinically important effects of interventions on outcomes that are relevant to patients and health and social care systems (for example, quality of life, hospital and care home admission and mortality). The committee believed that given the existing evidence, it would be of greater value to evaluate the effects of stopping discrete medicines or drug classes, rather than stopping all preventive medicines at the same time. The committee also believed that no single trial could likely address this research need, since there are many medicines that could be stopped and many defined populations in which this might be of value. # Predicting life expectancy Is it possible to analyse primary care data to identify characteristics that affect life expectancy and to develop algorithms and prediction tools for patients and healthcare providers to predict reduced life expectancy? ## Why this is important Many people take preventive medicines which are likely to offer small benefits because of reduced life expectancy from other causes. Medicines and other treatments may therefore be adding to treatment burden without adding quality or length of life. The ability to identify people with reduced life expectancy could provide healthcare professionals and people with information that could inform decisions about starting or continuing long-term preventive treatments. Conversely younger people with multimorbidity and reduced life expectancy may benefit from additional preventive treatments. Because this information would be used most often in a primary care setting, the committee considered that a tool derived from information within primary care databases would be most useful.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# General principles\n\nBe aware that multimorbidity refers to the presence of 2\xa0or more long-term health conditions, which can include:\n\ndefined physical and mental health conditions such as diabetes or schizophrenia\n\nongoing conditions such as learning disability\n\nsymptom complexes such as frailty or chronic pain\n\nsensory impairment such as sight or hearing loss\n\nalcohol and substance misuse.\n\nBe aware that the management of risk factors for future disease can be a major treatment burden for people with multimorbidity and should be carefully considered when optimising care.\n\nBe aware that the evidence for recommendations in NICE guidance on single health conditions is regularly drawn from people without multimorbidity and taking fewer prescribed regular medicines.\n\nThink carefully about the risks and benefits, for people with multimorbidity, of individual treatments recommended in guidance for single health conditions. Discuss this with the patient alongside their preferences for care and treatment.\n\n# Taking account of multimorbidity in tailoring the approach to care\n\nConsider an approach to care that takes account of multimorbidity if the person requests it or if any of the following apply:\n\nthey find it difficult to manage their treatments or day-to-day activities\n\nthey receive care and support from multiple services and need additional services\n\nthey have both long-term physical and mental health conditions\n\nthey have frailty (see section 1.4) or falls\n\nthey frequently seek unplanned or emergency care (see also recommendation 1.3.2)\n\nthey are prescribed multiple regular medicines (see section 1.3).\n\n# How to identify people who may benefit from an approach to care that takes account of multimorbidity\n\nIdentify adults who may benefit from an approach to care that takes account of multimorbidity (as outlined in section 1.5):\n\nopportunistically during routine care\n\nproactively using electronic health records.Use the criteria in recommendation 1.2.1 to guide this.\n\nConsider using a validated tool such as eFI, PEONY or QAdmissions, if available in primary care electronic health records, to identify adults with multimorbidity who are at risk of adverse events such as unplanned hospital admission or admission to care homes.\n\nConsider using primary care electronic health records to identify markers of increased treatment burden such as number of regular medicines a person is prescribed.\n\nUse an approach to care that takes account of multimorbidity for adults of any age who are prescribed 15\xa0or more regular medicines, because they are likely to be at higher risk of adverse events and drug interactions.\n\nConsider an approach to care that takes account of multimorbidity for adults of any age who:\n\nare prescribed 10\xa0to\xa014 regular medicines\n\nare prescribed fewer than 10\xa0regular medicines but are at particular risk of adverse events.\n\n# How to assess frailty\n\nConsider assessing frailty in people with multimorbidity.\n\nBe cautious about assessing frailty in a person who is acutely unwell.\n\nDo not use a physical performance tool to assess frailty in a person who is acutely unwell.\n\n## Primary care and community care settings\n\nWhen assessing frailty in primary and community care settings, consider using 1\xa0of the following:\n\nan informal assessment of gait speed (for example, time taken to answer the door, time taken to walk from the waiting room)\n\nself-reported health status (that is, 'how would you rate your health status on a scale from 0\xa0to\xa010?', with scores of 6 or less indicating frailty)\n\na formal assessment of gait speed, with more than 5\xa0seconds to walk 4\xa0metres indicating frailty\n\nthe PRISMA-7 questionnaire, with scores of 3 and above indicating frailty.\n\n## Hospital outpatient settings\n\nWhen assessing frailty in hospital outpatient settings, consider using 1\xa0of the following:\n\nself-reported health status (that is, 'how would you rate your health status on a scale from 0\xa0to\xa010?', with scores of 6\xa0or less indicating frailty)\n\nthe 'Timed Up and Go' test, with times of more than 12\xa0seconds indicating frailty\n\na formal assessment of gait speed, with more than 5\xa0seconds to walk 4\xa0metres indicating frailty\n\nthe PRISMA‑7 questionnaire, with scores of\xa03\xa0and above indicating frailty\n\nself-reported physical activity, with frailty indicated by scores of 56\xa0or less for men and 59\xa0or less for women using the Physical Activity Scale for the Elderly.\n\n# Principles of an approach to care that takes account of multimorbidity\n\nWhen offering an approach to care that takes account of multimorbidity, focus on:\n\nhow the person's health conditions and their treatments interact and how this affects quality of life\n\nthe person's individual needs, preferences for treatments, health priorities, lifestyle and goals\n\nthe benefits and risks of following recommendations from guidance on single health conditions\n\nimproving quality of life by reducing treatment burden, adverse events, and unplanned care\n\nimproving coordination of care across services.\n\nFollow these steps when delivering an approach to care that takes account of multimorbidity:\n\nDiscuss the purpose of an approach to care that takes account of multimorbidity (see recommendation 1.6.2).\n\nEstablish disease and treatment burden (see recommendations 1.6.3 to 1.6.5).\n\nEstablish patient goals, values and priorities (see recommendations 1.6.6 to 1.6.8).\n\nReview medicines and other treatments taking into account evidence of likely benefits and harms for the individual patient and outcomes important to the person (see recommendations 1.6.9 to 1.6.16).\n\nAgree an individualised management plan with the person (see recommendation 1.6.17), including:\n\n\n\ngoals and plans for future care (including advance care planning)\n\nwho is responsible for coordination of care\n\nhow the individualised management plan and the responsibility for coordination of care is communicated to all professionals and services involved\n\ntiming of follow-up and how to access urgent care.\n\n\n\n# Delivering an approach to care that takes account of multimorbidity\n\nFollow the recommendations in the NICE guideline on patient experience in adult NHS services, which provides guidance on knowing the patient as an individual, tailoring healthcare services for each patient, continuity of care and relationships, and enabling patients to actively participate in their care.\n\n## Discussing the purpose of an approach to care that takes account of multimorbidity\n\nDiscuss with the person the purpose of the approach to care, that is, to improve quality of life. This might include reducing treatment burden and optimising care and support by identifying:\n\nways of maximising benefit from existing treatments\n\ntreatments that could be stopped because of limited benefit\n\ntreatments and follow-up arrangements with a high burden\n\nmedicines with a higher risk of adverse events (for example, falls, gastrointestinal bleeding, acute kidney injury)\n\nnon-pharmacological treatments as possible alternatives to some medicines\n\nalternative arrangements for follow-up to coordinate or optimise the number of appointments.\n\n## Establishing disease and treatment burden\n\nEstablish disease burden by talking to people about how their health problems affect their day-to-day life. Include a discussion of:\n\nmental health\n\nhow disease burden affects their wellbeing\n\nhow their health problems interact and how this affects quality of life.\n\nEstablish treatment burden by talking to people about how treatments for their health problems affect their day-to-day life. Include in the discussion:\n\nthe number and type of healthcare appointments a person has and where these take place\n\nthe number and type of medicines a person is taking and how often\n\nany harms from medicines\n\nnon-pharmacological treatments such as diets, exercise programmes and psychological treatments\n\nany effects of treatment on their mental health or wellbeing.\n\nBe alert to the possibility of:\n\ndepression and anxiety (consider identifying, assessing and managing these conditions in line with the NICE guideline on common mental health problems)\n\nchronic pain and the need to assess this and the adequacy of pain management.\n\n## Establishing patient goals, values and priorities\n\nClarify with the patient whether and how they would like their partner, family members and/or carers to be involved in key decisions about the management of their conditions. Review this regularly. If the patient agrees, share information with their partner, family members and/or carers. [This recommendation is adapted from the NICE guideline on patient experience in adult NHS services.]\n\nEncourage people with multimorbidity to clarify what is important to them, including their personal goals, values and priorities. These may include:\n\nmaintaining their independence\n\nundertaking paid or voluntary work, taking part in social activities and playing an active part in family life\n\npreventing specific adverse outcomes (for example, stroke)\n\nreducing harms from medicines\n\nreducing treatment burden\n\nlengthening life.\n\nExplore the person's attitudes to their treatments and the potential benefits and harms of those treatments. Follow the recommendations on patient involvement in decisions about medicines and understanding the patient's knowledge, beliefs and concerns about medicines in the NICE guideline on medicines adherence.\n\n## Reviewing medicines and other treatments\n\nWhen reviewing medicines and other treatments, use the database of treatment effects to find information on:\n\nthe effectiveness of treatments\n\nthe duration of treatment trials\n\nthe populations included in treatment trials.\n\nConsider using a screening tool (for example, the STOPP/START tool in older people) to identify medicine-related safety concerns and medicines the person might benefit from but is not currently taking. [This recommendation is adapted from the NICE guideline on medicines optimisation.]\n\nWhen optimising treatment, think about any medicines or non-pharmacological treatments that might be started as well as those that might be stopped.\n\nAsk the person if treatments intended to relieve symptoms are providing benefits or causing harms. If the person is unsure of benefit or is experiencing harms from a treatment:\n\ndiscuss reducing or stopping the treatment\n\nplan a review to monitor effects of any changes made and decide whether any further changes to treatments are needed (including restarting a treatment).\n\nTake into account the possibility of lower overall benefit of continuing treatments that aim to offer prognostic benefit, particularly in people with limited life expectancy or frailty.\n\nDiscuss with people who have multimorbidity and limited life expectancy or frailty whether they wish to continue treatments recommended in guidance on single health conditions which may offer them limited overall benefit.\n\nDiscuss any changes to treatments that aim to offer prognostic benefit with the person, taking into account:\n\ntheir views on the likely benefits and harms from individual treatments\n\nwhat is important to them in terms of personal goals, values and priorities (see recommendation 1.6.7).\n\nTell a person who has been taking bisphosphonate for osteoporosis for at least 3\xa0years that there is no consistent evidence of:\n\nfurther benefit from continuing bisphosphonate for another 3\xa0years\n\nharms from stopping bisphosphonate after 3\xa0years of treatment.Discuss stopping bisphosphonate after 3\xa0years and include patient choice, fracture risk and life expectancy in the discussion.\n\n## Agreeing the individualised management plan\n\nAfter a discussion of disease and treatment burden and the person's, personal goals, values and priorities, develop and agree an individualised management plan with the person. Agree what will be recorded and what actions will be taken. These could include:\n\nstarting, stopping or changing medicines and non-pharmacological treatments\n\nprioritising healthcare appointments\n\nanticipating possible changes to health and wellbeing\n\nassigning responsibility for coordination of care and ensuring this is communicated to other healthcare professionals and services\n\nother areas the person considers important to them\n\narranging a follow-up and review of decisions made.Share copies of the management plan in an accessible format with the person and (with the person's permission) other people involved in care (including healthcare professionals, a partner, family members and/or carers).\n\n# Comprehensive assessment in hospital\n\nStart a comprehensive assessment of older people with complex needs at the point of admission and preferably in a specialist unit for older people. [This recommendation is from the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.]\n\n# Terms used in this guideline\n\n## Multimorbidity\n\nMultimorbidity refers to the presence of 2\xa0or more long-term health conditions, which can include:\n\ndefined physical and mental health conditions such as diabetes or schizophrenia\n\nongoing conditions such as learning disability\n\nsymptom complexes such as frailty or chronic pain\n\nsensory impairment such as sight or hearing loss\n\nalcohol and substance misuse.\n\nThe management of risk factors for future disease can be a major treatment burden for people with multimorbidity and should be carefully considered when optimising care.\n\nThis guideline covers the optimisation of care for:\n\nadults with 2\xa0or more long-term physical health conditions\n\nadults with 1\xa0or more mental health condition and at least 1\xa0physical health condition.\n\n## An approach to care that takes account of multimorbidity\n\nAn approach to care that takes account of multimorbidity involves personalised assessment and the development of an individualised management plan. The aim is to improve quality of life by reducing treatment burden, adverse events, and unplanned or uncoordinated care. The approach takes account of a person's individual needs, preferences for treatments, health priorities and lifestyle. It aims to improve coordination of care across services, particularly if this has become fragmented.\n\n## Individualised management plan\n\nAn individualised management plan is a management plan covering clinical aspects of a person's care, such as the medicines they are taking and the services they are attending. It includes information about which areas of care are most important to the person and whether treatments have been stopped to reduce treatment burden.\n\n## Medicines\n\nMedicines includes topical treatments such as ointments, inhalers, creams and drops, as well as medicines taken by mouth or injection.\n\n## Comprehensive assessment of older people with complex needs\n\nA comprehensive geriatric assessment is an interdisciplinary diagnostic process to determine the medical, psychological and functional capability of someone who is frail and old. The aim is to develop a coordinated, integrated plan for treatment and long-term support.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nUsing primary care electronic health records to identify people who may benefit from an approach to care that takes account of multimorbidity may require some area-wide provision or coordination of search tools if these are not already built into clinical IT systems.\n\nSharing copies of individualised management plans in an accessible format can be done electronically such as through the NHS Summary Care Record, with enhanced functionality now available in 99% of GP practices in England, or by ensuring that the person always has an up-to-date paper copy of their plan at home.\n\nThe most appropriate healthcare professional to develop and implement the individualised management plan may vary by area and depend on the individual needs and preferences of the person with multimorbidity. However, it is important that it is clear in different areas who should generally be responsible.\n\nPutting a guideline fully into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may need to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and the business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group should develop the action plan. The group should include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': 'Multimorbidity is usually defined as when a person has 2\xa0or more long-term health conditions. Measuring the prevalence of multimorbidity is not straightforward because it depends on which conditions are counted. However, all recent studies show that multimorbidity is common, becomes more common as people age, and is more common in people from less affluent areas. Whereas in older people multimorbidity is largely due to higher rates of physical health conditions, in younger people and people from less affluent areas, multimorbidity is often due to a combination of physical and mental health conditions (notably depression).\n\nMultimorbidity matters because it is associated with reduced quality of life, higher mortality, polypharmacy and high treatment burden, higher rates of adverse drug events, and much greater health services use (including unplanned or emergency care). A particular issue for health services and healthcare professionals is that treatment regimens (including non-pharmacological treatments) can easily become very burdensome for people with multimorbidity, and care can become uncoordinated and fragmented. Polypharmacy in people with multimorbidity is often driven by the introduction of multiple medicines intended to prevent future morbidity and mortality. However, the case for using these medicines weakens if life expectancy is reduced by other conditions or frailty. The absolute difference made by each additional medicine may also reduce when people are taking multiple preventive medicines. The implications of multimorbidity for organisation of healthcare are highly variable depending on which conditions a person has. Groups of conditions that have closely related or concordant treatment, such as diabetes, hypertension and angina, pose fewer problems for coordination than conditions needing quite different treatment (for example, physical and mental health conditions).\n\nNICE guidelines have been developed for managing many individual diseases and conditions. The aim of this guideline is to inform patient and clinical decision-making and models of care for people with multimorbidity who would benefit from a tailored approach because of the high impact of their conditions or treatment on their quality of life or functioning. This is a particular concern for generalist medical professionals such as GPs and geriatricians and healthcare professionals such as pharmacists and nurses working in those services; the guideline is also relevant to specialist services because many of the patients they care for will have significant other conditions.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Organisation of care\n\nWhat is the clinical and cost effectiveness of alternative approaches to organising primary care compared with usual care for people with multimorbidity?\n\n## Why this is important\n\nThe guideline committee felt that primary care was well suited to managing multimorbidity, but agreed that this was often challenging partly because of how primary care is currently organised. However, there was inadequate high-quality research on alternative approaches to organising care for people with multimorbidity. Trials should be undertaken to examine the impact of different strategies on important clinical outcomes, quality of life and cost effectiveness. The committee believed that no single trial could likely address this research need, because there are many plausible interventions and many defined populations in which such interventions might be of value.\n\nLarge, well-designed trials of alternative ways of organising general practice based primary care for people with multimorbidity would be of value in defined patient groups (for example, people with multimorbidity who find it difficult to manage their treatment or care or day-to-day activities, people with multiple providers or services involved in their care, people with both long-term physical and mental health problems, people with well-defined frailty, people frequently using unscheduled care, people prescribed multiple regular medicines, and people who are housebound or care home residents).\n\nSuch trials should have clear identification and justification of the planned target population, careful piloting and optimisation, and well-described interventions. They need to be sufficiently powered to provide evidence of clinically important effects of interventions on outcomes that are relevant to patients and health and social care services (for example, quality of life, hospital and care home admission, mortality).\n\n# Holistic assessment in the community\n\nWhat is the clinical and cost effectiveness of a community holistic assessment and intervention for people living with high levels of multimorbidity?\n\n## Why this is important\n\nThere was low quality evidence to indicate potential benefit from community assessments based on the principles of comprehensive geriatric assessment in older people. However, the studies were conducted outside the UK and were not aimed at all adults living with multimorbidity. The guideline committee believed that there was some evidence that holistic assessment and intervention in the community may be of benefit for older people, but that the evidence was of low quality and not adequate to inform strong recommendations.\n\nLarge, well-designed trials of holistic assessment and intervention in people with multimorbidity would be of value in defined patient groups in the community (for example, people in nursing homes, people who are housebound, people of all ages with well-defined frailty, people with high levels of multimorbidity or polypharmacy).\n\nSuch trials must be rigorous, with clear identification and justification of the planned target population, careful piloting and optimisation, and well-described interventions. They need to be sufficiently powered to provide evidence of clinically important effects of interventions on outcomes that are relevant to patients and health and social care services (for example, quality of life, hospital and care home admission, and mortality).\n\nThe guideline committee believed that no single trial could likely address this research need, since there are many plausible interventions and many defined populations in which such interventions might be of value. The committee believed that assessment should follow the principles of Comprehensive Geriatric Assessment or the Standardised Assessment of Elderly People in Europe (STEP) tool, and that interventions would likely involve a multidisciplinary team.\n\n# Stopping preventive medicines\n\nWhat is the clinical and cost effectiveness of stopping preventive medicines in people with multimorbidity who may not benefit from continuing them?\n\n## Why this is important\n\nThere is good evidence from randomised controlled trials of the medium term (2–10\xa0years) benefit of medicines recommended in guidelines for preventing future morbidity or mortality, including treatments for hypertension, hyperglycaemia and osteoporosis. However, there is much less evidence about the balance of benefit and harm over longer periods of treatment. It is plausible that harms outweigh benefits in some people with multimorbidity (for example, because of higher rates of adverse events in older, frailer people prescribed multiple regular medicines, or because the expected benefit from continuing a preventive medicine is reduced when there is limited life expectancy or high risk of death from other morbidities). These people are unlikely to have been eligible or included in published trials showing initial benefit from preventive medicines. The systematic review undertaken by NICE in 2015 did not find any randomised controlled trials of stopping antihypertensive medicines in people with multimorbidity. The review found 1\xa0small randomised controlled trial of stopping statins in people with a life expectancy of 1\xa0year, but the committee did not consider this provided enough evidence to make a recommendation. The review found several randomised controlled trials of stopping bisphosphonates (although not clearly in populations with multimorbidity) and a recommendation was made for this, but no randomised controlled trials were found of stopping calcium and/or vitamin\xa0D. Recommendations based on robust evidence on the clinical and cost effectiveness of stopping preventive medicines in people with multimorbidity who may not benefit could have significant budgetary implications for the NHS. No ongoing trials have been identified.\n\nThe guideline committee considered that 1\xa0or more large, well-designed trials of stopping preventive medicine in people with multimorbidity would be of value in defined patient groups in the community (for example, people in nursing homes, people who are housebound, people with well-defined frailty, people with high levels of multimorbidity or polypharmacy, people with limited life expectancy). Discontinuation could either be complete (all relevant medicines) or partial (for example, reduced intensity of hypotensive or hypoglycaemic treatment). Such trials have to be sufficiently powered to provide evidence of clinically important effects of interventions on outcomes that are relevant to patients and health and social care systems (for example, quality of life, hospital and care home admission and mortality). The committee believed that given the existing evidence, it would be of greater value to evaluate the effects of stopping discrete medicines or drug classes, rather than stopping all preventive medicines at the same time. The committee also believed that no single trial could likely address this research need, since there are many medicines that could be stopped and many defined populations in which this might be of value.\n\n# Predicting life expectancy\n\nIs it possible to analyse primary care data to identify characteristics that affect life expectancy and to develop algorithms and prediction tools for patients and healthcare providers to predict reduced life expectancy?\n\n## Why this is important\n\nMany people take preventive medicines which are likely to offer small benefits because of reduced life expectancy from other causes. Medicines and other treatments may therefore be adding to treatment burden without adding quality or length of life. The ability to identify people with reduced life expectancy could provide healthcare professionals and people with information that could inform decisions about starting or continuing long-term preventive treatments. Conversely younger people with multimorbidity and reduced life expectancy may benefit from additional preventive treatments. Because this information would be used most often in a primary care setting, the committee considered that a tool derived from information within primary care databases would be most useful."}	https://www.nice.org.uk/guidance/ng56	This guideline covers optimising care for adults with multimorbidity (multiple long-term conditions) by reducing treatment burden (polypharmacy and multiple appointments) and unplanned care. It aims to improve quality of life by promoting shared decisions based on what is important to each person in terms of treatments, health priorities, lifestyle and goals. The guideline sets out which people are most likely to benefit from an approach to care that takes account of multimorbidity, how they can be identified and what the care involves.
ad0400a90e7c806aec1cf8853dbc764a02034da6	nice	Harmful sexual behaviour among children and young people	Harmful sexual behaviour among children and young people This guideline covers children and young people who display harmful sexual behaviour, including those on remand or serving community or custodial sentences. It aims to ensure these problems don’t escalate and possibly lead to them being charged with a sexual offence. It also aims to ensure no-one is unnecessarily referred to specialist services. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Multi-agency approach ## Multi-agency, multidisciplinary team Ensure multi-agency, multidisciplinary teams promote continuity of care and, wherever possible, ensure the child or young person has contact with the same staff over time, so they can develop trust in their care team. Ensure young people who are nearly 18 are prepared for the transition to adult services by developing links between child and adult services. See NICE's guideline on transition from child to adult services. Ensure multi-agency, multidisciplinary teams: have links to clinical and non-clinical services and can make prompt referrals collaborate with specialists when children and young people have difficult or complex needs (for example, those with neurodevelopmental or learning disabilities or conduct disorders) establish relationships with statutory, community and voluntary organisations that work with at-risk children and young people, to provide a broad range of support services meet regularly to plan, implement and evaluate care pathways for the children and young people whose care they are overseeing understand that the care plan is the responsibility of the whole multi-agency team and not individual practitioners. ## Multi-agency, multidisciplinary working Use established mechanisms, such as local multi-agency safeguarding arrangements, to develop local safeguarding policies and procedures and agree a harmful sexual behaviour operational framework between agencies. (See Department for Education's Working together to safeguard children, Ofsted's Early help: whose responsibility?, Children Act 1989 and Children Act 2004.) Local multi-agency safeguarding arrangements should ensure: Lead agencies are identified to commission specialist harmful sexual behaviour services. Thresholds are established for when to refer a child or young person for an early help assessment or to specialist harmful sexual behaviour services. Named safeguarding leads and practitioners working in relevant services are told what the referral thresholds are. This includes those working in education, children's social services, health and youth criminal justice (such as young offender teams and youth justice boards) and voluntary sector organisations. Named safeguarding leads working in universal services use locally agreed resources as part of their policy and procedures to determine whether a child or young person should be referred for an early help assessment. (See recommendation 1.3.4 for examples of resources.) Children's social services have access to policies and procedures for training staff to deal with concerns about a child or young person's sexualised behaviour. The multi-agency team should agree which service is responsible when children and young people are referred for assessment. Consider one of the following for the lead role: child health services such as child and adolescent mental health services (CAMHS) children's social services voluntary sector organisations such as Barnardo's or the NSPCC. Consider a range of care pathways based on the 5 core domains identified in the NSPCC harmful sexual behaviour framework. The designated lead practitioner responsible for coordinating the care plan (see recommendation 1.3.2) should request a review of the care plan via the multi-agency, multidisciplinary team meeting if: the child or young person's needs are not being met or the referral and assessment procedure is unnecessarily delayed. ## Information sharing Agree a protocol for information sharing between all agencies. Base this on local safeguarding and child protection procedures and address legal and confidentiality issues. Ensure the designated lead practitioner responsible for coordinating the care plan can access information on the child or young person's family situation and factors that may affect parenting capacity and attachment (see recommendation 1.4.2). Do this as part of the assessment process (See NICE's guideline on children's attachment and recommendations on sexualised behaviour in NICE's guideline on when to suspect child maltreatment.) Ensure information is collected and shared in a sensitive and professional manner, as set out in the Caldicott Guardian information standards. If there is a need to share information with other agencies and carers to inform risk management, do this in consultation with the multidisciplinary team. # Named safeguarding leads in universal services Immediately inform your organisation's named safeguarding lead when a child or young person displays sexualised behaviour that is not appropriate for their age or developmental stage (for tools, see recommendation 1.3.4). Possible signs of problems include: using sexualised language such as adult slang to talk about sex sexualised behaviour such as sexting or sharing and sending sexual images using mobile or online technology viewing pornography that is inappropriate for age and developmental status (see the Brook Organisation information on pornography and the law). Immediately inform your organisation's named safeguarding lead when a child or young person displays sexualised behaviour that is always inappropriate, regardless of age, such as public masturbation. Named safeguarding leads should use locally agreed resources to assess concerns about the sexual behaviour of a child or young person. See recommendation 1.3.4. Named safeguarding leads concerned about a child or young person's sexual behaviour should contact their local children's social services to discuss their concerns and determine whether a referral is appropriate. # Early help assessment Children's social services should refer children and young people who display inappropriate sexualised behaviour for an early help assessment, in line with local thresholds and referral procedures (see recommendation 1.1.5). Focus on the child or young person as an individual and not on the presenting behaviour. At point of referral, early help professionals should identify a designated lead practitioner in the multi-agency, multidisciplinary team (see recommendation 1.1.6) who will: act as a single point of contact for the child or family coordinate early help and subsequent assessments and develop the care plan to avoid unnecessary or repetitious assessments that may be stigmatising coordinate delivery of the agreed actions involve children, young people and their families and carers in the design and delivery of early help services, as appropriate reduce overlap and inconsistency in services provided. Early help professionals should be familiar with the child or young person's health and social care record and have access to neonatal and early health information, if necessary. This includes information on developmental delays or a diagnosis of autism spectrum condition, for example. Use a locally agreed tool as part of the early help assessment that accounts for the severity of the behaviour, to avoid unnecessary and potentially stigmatising referrals. Examples of tools include: The Brook Sexual Behaviours Traffic Light Tool. This helps identify a range of sexual behaviours between infancy and adulthood and distinguishes between 3 levels, using a traffic light system to indicate the level of seriousness. Models that place a child or young person's sexual behaviour on a continuum indicating various levels of seriousness, such as Hackett's model (Hackett S Children and young people with harmful sexual behaviours, in Children behaving badly?: Peer violence between children and young people ; John Wiley & Sons: Chichester). Take account of the child or young person's age, developmental status and gender and, if relevant, any neurodevelopmental or learning disabilities. Recognise that inappropriate sexualised behaviour is often an expression of a range of problems or underlying vulnerabilities. Use the early help assessment to identify whether the child or young person has unmet needs that can be met by universal services. See Ofsted's Early help: whose responsibility? and Department for Education's Working together to safeguard children. Also: For preschool children, see the recommendations in NICE's guideline on social and emotional wellbeing: early years. For children and young people in primary and secondary education, see the recommendations in NICE's guideline on social, emotional and mental wellbeing in primary and secondary education. Ensure services support children and young people of all ages. See the principles of care recommendations in NICE's guideline on children's attachment, NICE's guideline on looked-after children and young people, and: For children and young people who may have a conduct disorder, see NICE's guideline on antisocial behaviour and conduct disorders in children and young people. For children and young people who may have experienced trauma, see the sections on specific recognition issues for children and management of PTSD in children and young treatment in NICE's guideline on post-traumatic stress disorder. If harmful sexual behaviour is displayed, refer to harmful sexual behaviour services, child protection services and the criminal justice system, if necessary. # Risk assessment for children and young people referred to harmful sexual behaviour services Children's social care services and NHS England should identify services employing staff with the skills to undertake a specialist assessment of risk for children and young people displaying harmful sexual behaviour. This may include: child health services such as CAMHS children's social services voluntary sector organisations such as the NSPCC or Barnardo's -rganisations within the criminal justice system such as youth offender teams and youth justice boards. Professionals responsible for specialist harmful sexual behaviour assessments should access any additional information they need. This includes incident reports of any behaviour that is causing concern. Get this information from the child or young person's: social care history educational records health records youth offending and youth justice records police records. Consider the child or young person's developmental age, neurodevelopmental disabilities, learning disabilities and gender as part of the assessment. Do this in collaboration with other specialist services, if relevant. Professionals responsible for assessing risk should use risk assessment tools suitable for the child or young person's developmental age and gender. For example, when assessing: Pre-adolescent children or those aged under 12, consider psychometric measures and questionnaires such as the Child Behaviour Checklist (Achenbach T Manual for the Child Behaviour Checklist/4–18 and 1991 Profile; Burlington: University of Vermont) and the Child Sexual Behaviour Inventory (Friedrich W Child Sexual Behaviour Inventory: professional manual; Odessa, Florida; Psychological Assessment Procedures). Children under 12 who have not been charged with a sexual offence, consider the relevant elements of AIM plus clinical judgement. Children aged 10 to 12 who have been charged with an offence, consider the relevant elements of AIM plus clinical judgement. Adolescent boys, consider tools such as J‑SOAP‑II, ERASOR or AIM2, plus clinical judgement. # Engaging with families and carers before an intervention begins Consider family or social factors that may contribute to the child or young person's harmful sexual behaviour, particularly if there is evidence of abuse within the family. See NICE's guideline on child maltreatment. Think about the impact a child or young person's harmful sexual behaviour may have on all family members. If the person at the receiving end of the harmful sexual behaviour is another child within the family, provide support for the family or a referral as needed (see NICE's guideline on child abuse and neglect). Consider the following before providing an intervention: Meeting families and carers to discuss any concerns they may have, including any potential barriers to attendance. Providing families and carers with information about the intervention and including them, when appropriate. Adopting a flexible approach to accommodate the child or young person's social activities. # Developing and managing a care plan for children and young people displaying harmful sexual behaviour ## General principles Recognise that children and young people with learning and neurodevelopmental disabilities have specific needs. Consider providing short and more frequent sessions for them. Work with specialists in these areas to provide the intervention. Help children and young people develop a strong sense of personal identity that does not include harmful sexual behaviour. This includes helping them to maintain their cultural and religious beliefs. ## Developing and managing a care plan Develop a care plan using an established risk assessment model, such as J‑SOAP‑II, ERASOR, AIM assessment for under‑12s, or AIM2, and a recognised treatment model such as the Good Lives Model, AIM or AIM2. The plan should: recognise the needs and strengths of the child or young person and the risks they may pose support them, their families and carers include clearly defined therapeutic goals include a safety plan that is agreed with the child or young person, their parents or carers and support network. Ensure the care plan: Encourages and supports children and young people to participate in a range of peer, school and community activities to help build a sense of belonging. Includes supervised social activities that promote self-esteem, develop resilience and encourage socially appropriate behaviour. Ensure the care plan is reviewed by the multidisciplinary team, and with the child or young person and their parent or carers at 3- to 6‑monthly intervals, or if there is a significant change in circumstances. # Developing interventions for children and young people displaying harmful sexual behaviour Structure interventions, but make them flexible enough to meet changing needs and the developmental status and age of the child or young person. Include regular progress reviews by practitioners delivering the intervention. Base interventions on: A comprehensive assessment of the child or young person's family and social context. This includes: their placement (for example, home, foster care, residential care, secure children's home or other custodial settings). Developmental stage, gender, learning ability, culture and religion. Factors that may have contributed to the harmful sexual behaviour, such as their background, past care or any trauma they may have experienced. The harmful sexual behaviour itself. Consider including the following elements: safety planning to reduce the risk they pose to others and themselves engagement and working that takes account of their denial of the behaviour sex and relationships education including consent, boundaries and social and moral considerations empathy development how to make good choices to keep themselves and others safe sexually emotional and self-regulation life story work understanding of their harmful sexual behaviour victimisation peer and social relationships community reintegration for those who have spent time in residential or secure units support to make future plans. Use recognised treatment resources or guided interventions such as: AIM assessment and intervention model for boys and girls. This includes components for: children aged under 12 who have not committed a criminal offence, and children aged 10 to 12 who have committed an offence (10 is the age of criminal responsibility in England). AIM2 assessment and intervention model for boys aged 12 to 18 within or outside the criminal justice system. This also has a component aimed at girls in the same age group and for those with learning disabilities. But note: the 'level of supervision' scale for young females (12 to 18 years) is likely to misrepresent the level of risk. A degree of caution is also advised when using it to predict sexual reoffending in young people with learning disabilities. Barnardo's Cymru Taith project for girls – assessment and treatment workbook. The California Evidence-Based Clearinghouse for Child Welfare Children with problematic sexual behaviour cognitive-behavioural treatment program: preschool program and school-age program. Good Lives Model, a strengths-based programme. NSPCC manualised treatment programme Change for good (McCrory E, Walker-Rhymes P A treatment manual for adolescents displaying harmful sexual behaviour: change for good; London: Jessica Kingsley) aimed at boys aged 12 to 18 in residential care. NSPCC harmful sexual behaviour programme Turn the page, a guided intervention that follows certain key principles for boys and girls aged 5 to 18 and those with learning disabilities. This is suitable as a community-based approach. Use therapeutic approaches such as: cognitive behavioural therapy multisystemic therapy for problematic sexual behaviour psychotherapeutic approaches strengths-based approaches systemic therapy (a type of family therapy). Consider 1 or more of the following modes of delivery: individual therapy group therapy family therapy. Deliver interventions in community and family settings, if it has been assessed as safe to do so. Work alongside care staff when delivering interventions in residential, secure or custodial settings. Ensure the care plan includes safety planning to reduce the risk the child or young person may pose to others in the same environment. Consider including family members when delivering interventions in residential, secure or custodial settings. Do this only if it is safe and has been agreed as part of the care plan (see recommendation 1.6.4). ## Children and young people not living with their birth parents Ensure links with their family of origin or community are maintained if it is in the best interests of the child or young person. Maintain links with birth parents if safe and appropriate. ## Children and young people who have been abused by a family member If it is in the best interests of the child or young person, consider family reconciliation, re-integration and restorative approaches, if it is safe and appropriate. ## Looked after children and young people Ensure the intervention supports carers. This includes giving them advice on how to respond to the risks presented by children and young people in their care. ## Working with parents and carers Encourage caring relationships between the child or young person and their family and carer, if it is safe to do so. Recognise that looked after children and young people may have problems arising from insecure attachment, making the relationship with their carer very challenging (see NICE's guideline on children's attachment). Help carers create a sense of belonging and trust to ensure the child or young person feels safe, valued and protected. Consider including the following elements in the programme: how to work with parents and carers in denial about their child's harmful sexual behaviour support to come to terms with harmful sexual behaviour and its impact how to understand harmful sexual behaviour risk indicators maintaining safety plans, including ongoing supervision addressing the parent-child relationship, if needed communications and problem solving behaviour management.See NICE's guidelines on: challenging behaviour and learning disabilities, sections 1.5 to 1.11 autism in under 19s: support and management, recommendations 1.4.1 to 1.4.13, and section 1.5 violence and aggression: short-term management in mental health, health and community settings. # Supporting a return to the community for 'accommodated' children and young people Provide ongoing support when children and young people in residential homes, secure children homes or young offenders' institutions move back into the community or return to the family home. This includes continuity of care for those who need this type of support. # Terms used in this guideline This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary. ## Children In this guideline, 'children' refers to anyone under 10. ## Harmful sexual behaviour This guideline uses the NSPCC definition of harmful sexual behaviour: 'One or more children engaging in sexual discussions or acts that are inappropriate for their age or stage of development. These can range from using sexually explicit words and phrases to full penetrative sex with other children or adults (NSPCC's advice on sexual behaviour in children). ## Multi-agency safeguarding arrangements Responsibility for join up rests with three safeguarding partners (local authority, clinical commissioning group for an area, and chief officer of police for a police area) who have a shared and equal duty to work together to safeguard and promote the welfare of all children in a local area. ## Risk assessment tool In this guideline, this term is used for tools that estimate the risk of sexual re‑offending or the level of supervision needed, and help users decide what action to take. It includes tools such as J‑SOAP‑II and ERASOR, which are North American tools designed to assess the risk of sexual reoffending. The AIM assessment model was developed in the UK and considers the level of management and supervision needed for people displaying harmful sexual behaviour. ## Young people In this guideline, 'young people' refers to those aged 10 to 18. It includes those on remand and those serving community or custodial sentences. The guideline also includes people aged up to 25 who display harmful sexual behaviour and have special educational needs or a disability. This age extension is in light of the Children and Families Act 2014.# Context Research indicates that many children and young people charged with criminal offences relating to harmful sexual behaviour had previously been referred to children's services. But their sexual behaviour was either not recognised or dismissed (Criminal Justice Joint Inspection's Examining multi-agency responses to children and young people who sexually offend). Data indicate that children and young people with learning disabilities are over-represented among those in the criminal justice system (Criminal Justice Joint Inspection's Examining multi-agency responses to children and young people who sexually offend; Department of Health's needs and effective treatment of young people who sexually abuse: current evidence). However, few studies have been done with children and young people with learning disabilities. Little is known about prepubescent children or young people whose sexual behaviour has not reached a level that would be regarded as criminal. There is also a lack of understanding of where these children and young people fit into the social care system, making it difficult to provide an effective response (Department of Health's needs and effective treatment of young people who sexually abuse: current evidence). Evidence suggests that sexualised behaviours in children and young people can be an expression of other problems or underlying vulnerabilities. It also suggests that early help assessments, without involving specialist harmful sexual behaviour services, can help. But there is little evidence of effectiveness on interventions addressing harmful sexual behaviour. This guideline covers children and young people under 18 who display harmful sexual behaviour. It includes those on remand and those serving community or custodial sentences. It also includes people up to the age of 25 who have special educational needs or a disability, as set out the Children and Families Act 2014. This guideline does not deal with the consequences of sexual abuse. NICE has published a guideline on child abuse and neglect.# Committee discussion Links to evidence sources are given in square brackets. See evidence reviews for details. # Background This guideline uses the NSPCC definition of harmful sexual behaviour: 'One or more children engaging in sexual discussions or acts that are inappropriate for their age or stage of development. These can range from using sexually explicit words and phrases to full penetrative sex with other children or adults.' (NSPCC's advice on sexual behaviour in children). Using the term 'harmful sexual behaviour' avoids labelling young children as sexual offenders, but it does not reflect the diversity of children and young people who engage in sexualised behaviours. It is critical to differentiate between sexually abusive behaviour and behaviours that are detrimental to the child or young person's development. Sexually abusive behaviours are coercive and involve forcing others to comply with an action. This can include oral, anal and vaginal penetration. Whereas behaviours that affect individual development could include, for example, compulsive masturbation or addiction to online pornography. Such behaviours may result in stigmatisation and victimisation, as well as making others feel uncomfortable. There has been significant debate about how to describe children and young people displaying sexualised behaviour without labelling them as sex offenders. Difficulties in defining such behaviour are compounded by a general lack of knowledge of childhood sexuality and what constitutes normal sexual development. The focus of this guideline is on children and young people who are sole perpetrators of harmful sexual activities, directed either towards themselves or other individuals. It does not focus on activities such as child sexual exploitation and peer-on-peer or gang-related sexual violence. The Department for Education's Working together to safeguard children definition of sexual abuse (which covers physical, emotional and sexual abuse, and neglect) acknowledges that children can commit acts of sexual abuse. But it does not acknowledge that children and young people's sexual behaviour is on a continuum. The NSPCC's definition of harmful sexual behaviour acknowledges that children and young people's sexual behaviour is on a continuum. It defines harmful sexual behaviour as acts that are inappropriate for age or stage of development and are important factors when assessing and intervening with this group. Children and young people's sexual behaviour problems are diverse. Various terms have been used to refer to children and young people who engage in developmentally unexpected sexual behaviours. These include: abuse-reactive, sexually reactive, sexually aggressive, sexualised children, children who molest, sexually abusive children and young sexual offenders. The committee agreed with evidence from expert paper 1, and members' own experience, that many children and young people's display of harmful sexual behaviour will naturally come to an end as they mature. But members also agreed that concerns about a child or young person's sexualised behaviour should always be followed up and assessed. Little is known about the number of prepubescent children who continue with harmful sexual activities as they get older. What is known is that only a small number go on to commit more serious sexual offences. In addition, the committee recognised the need to distinguish between chronological and developmental age when deciding how to assess and then intervene with this group. The committee also agreed that it is important to distinguish between prepubescent children and adolescents for assessment purposes. Some behaviours may be considered normal in prepubescent children, for example, but would be of concern if they continue into adolescence. Likewise, behaviours that would be considered normal in adolescents may be regarded as highly unusual in prepubescent children and therefore merit a need for referral. In addition, the committee recognised the need to distinguish between these groups in the context of the criminal justice system in England, where 10 is the age of criminal responsibility. The committee also noted that the Children Act 1989 defines a child as someone who has not reached 18 and that young people enter the adult criminal justice system at age 18. The committee noted that young people with ongoing or long-term health or social care needs may need to move into adult services at age 18 or 25, if they have special educational needs or disabilities. It agreed that these transitions need to be managed as part of the harmful sexual behaviour assessment and intervention process. The committee discussed the fact that pornography is now more readily available thanks to new technology, but no evidence was found in the systematic search of the literature. Expert testimony confirmed a significant gap in the literature on how pornography influences sexual behaviour . So the committee agreed to make a research recommendation on this. See also the section on gaps in the evidence, numbers 10 to 12. # Section 1.1 Multi-agency approach ## Multi-agency, multidisciplinary team The discussion below explains how we made recommendations 1.1.1 to 1.1.3. The committee acknowledged a number of statutory arrangements are relevant for children and young people displaying harmful sexual behaviour. This includes: Section 10 of the Children Act 2004. This makes local authorities responsible for promoting interagency cooperation to improve the welfare of children in need. Ofsted's Early help: whose responsibility? and the Department for Education's Working together to safeguard children give local safeguarding children boards statutory responsibilities for children in need of protection and those with highly complex needs. Safeguarding boards are also responsible for developing thresholds for action. The committee acknowledged that the involvement of health agencies will vary, because support is provided in a multi-agency context. The committee discussed the role of children and adolescent mental health services (CAMHS) in this area. Members noted that, in their experience, referral thresholds to CAMHS vary and that not all CAMHS services would take referrals for children and young people displaying harmful sexual behaviour. The committee also noted that there is no coherent national commissioning framework on harmful sexual behaviour for people living in secure accommodation and few secure children's homes or young offender institutions offer these services. The committee recognised these recommendations were not based on evidence of effectiveness or cost effectiveness. Rather, they were framed by the Department for Education and Ofsted guidance on interagency working and were generated by consensus from their own experience and from 2 expert testimonies . From the committee's experience, interagency assessments would be a suitable route for developing multi-agency approaches. These could use, for example, the Common Assessment Framework (see 'Working together to safeguard children'), the local children safeguarding board and the Ministry of Housing, Communities and Local Government's Troubled Families Programme. There was no evidence of effectiveness on the multi-agency approach but the committee agreed with the conclusions from 8 qualitative studies (3 high quality, 3 moderate quality and 2 low quality). These stated that early assessment should be 'joined up' with any subsequent therapeutic interventions, to ensure continuity between assessment and intervention . Based on their own experiences, members also agreed that a lack of effective interagency working is often a key factor in serious case reviews (see Department for Education's New learning from serious case reviews: a 2-year report for 2009 to 2011). The committee agreed that failures in interagency working could have a serious 'knock on' effect and lead to a limited response to referrals. This may also have implications for cost effectiveness: failure to provide services may leave the behaviour unchecked and eventual entry into the criminal justice system. The latter would be expensive and is also likely to result in harm to others. The committee reflected on expert testimony that described regional arrangements for harmful sexual behaviour services as well as agreements across agencies . Practitioners working with children and young people with complex needs, such as autism spectrum condition or conduct disorder, need access to specialists working in harmful sexual behaviour services. It would not be possible to agree interagency care plans without a multidisciplinary team of professionals who meet regularly to agree and evaluate outcomes. The committee agreed that the practice of closing a social work file on a child or young person once they have been referred to harmful sexual behaviour services is not helpful. Members described how, in some instances, referrals to harmful sexual behaviour services were declined because specialist services do not have the resources to deal with the child or young person's additional needs. They agreed there was a need for greater recognition that a range of agencies is usually needed to provide support. The committee agreed that if nobody took lead responsibility for assessment and referral this could have a serious impact on delivery of the care plan. The 'knock-on' effect could be further harm to the child or young person, or risk of harm to others. Many local safeguarding children boards and child protection committees across the UK now include harmful sexual behaviours in their interagency procedures and policy documents. Many also offer short courses on young sexual abusers as part of their interagency training programmes. The committee agreed that failure to provide local expertise using a coordinated, multi-agency approach will mean children and young people displaying more serious behaviour are likely to receive ad hoc assessments and interventions. Sometimes this might result in out-of-area placements that could prove expensive. It could also lead to delays in providing a more effective intervention in the child or young person's locality and at an earlier stage. ## Multi-agency, multidisciplinary working The discussion below explains how we made recommendations 1.1.4 to 1.1.8. Committee members discussed their experience of working across agencies and disciplines within the harmful sexual behaviour service sector. Their experiences were generally positive, but they knew that there was room for improvement in many locations. There was no empirical evidence of effectiveness or cost effectiveness. The committee agreed that children and young people who display harmful sexual behaviour are likely to have complex needs that can only be met by numerous health and social care agencies working together. Members agreed that a well-established multi-agency response is likely to lead to multiple cost savings to society. This includes: savings from otherwise lost educational and employment opportunities during the child or young person's life savings from preventing harm to others. The committee agreed that local safeguarding children boards should implement NICE recommendations in this area and should identify lead agencies to commission and develop harmful sexual behaviour services. The committee noted that various services are needed to respond to this group of children and young people, and that a statutory response is not always necessary. It agreed that the safeguarding needs of children and young people referred for an early help assessment should be a priority, with the results used to determine whether a statutory or criminal justice response is needed. (For victims of sexual abuse, see Home Office and Department for Education's Reporting and acting on child abuse and neglect.) It recommended that a variety of referral and care pathways should be in place. The committee heard testimony on the NSPCC harmful sexual behaviour framework . It aims to improve local interagency working and coordination while recognising the resource constraints that local areas face. Members agreed that local authorities should offer a range of care pathways based on the 5 core domains of the framework to create a consistent approach across services. Currently there is no national strategy or overarching service delivery framework for harmful sexual behaviour. The NSPCC framework was developed by a wide range of partners and is being tested in a number of local authority areas. The committee agreed that, in line with 'Working together to safeguard children', local safeguarding children boards should set thresholds for when to refer a child or young person for early help assessment or specialist harmful sexual behaviour services. The committee saw local safeguarding children boards as a potential vehicle for ensuring a coordinated approach to meeting the needs of this group. This would have the benefit of making use of existing services to improve multiagency working. The committee recommended that local safeguarding children boards should ensure local policies and procedures are in place to train staff in children's social services to deal with concerns about a child or young person's sexualised behaviour. Concerns may be raised by professionals working in universal services or members of the public. Local safeguarding children boards should recommend resources for professionals working in universal services to consult when there are concerns over a child or young person's sexualised behaviour. The committee agreed that these recommendations are informed by government guidance and form the basis of current health and social care practice. It also agreed that a brief consultation (or triage meeting) over the phone or face-to-face with a concerned parent or teacher and a specialist practitioner could sometimes be enough. ## Information sharing The discussion below explains how we made recommendations 1.1.9 to 1.1.12. The committee agreed that information sharing between agencies remains a contentious issue. Members also agreed that fears about sharing information should not stand in the way of the need to promote the welfare and protect the safety of children. (See Department for Education's Information sharing: advice for practitioners providing safeguarding services to children, young people, parents and carers.) The committee recognised that the recommendations were not based on evidence of effectiveness but reflected the committee's experience of serious case reviews (see Department for Education's New learning from serious case reviews: a 2-year report for 2009 to 2011). The issues are also highlighted in the Department for Education's report 'Working together to safeguard children.' Seven qualitative studies reported there is reluctance among practitioners to share assessments (2 high quality, 4 moderate, 1 low) . The committee also discussed the need for clear, effective protocols that are regularly evaluated. In particular, these protocols should highlight the adverse consequences of not sharing information – a point repeatedly made in serious case reviews, including cases of violent or sexual assault and rape. There was no cost effectiveness evidence for this set of recommendations. Using information-sharing protocols is regarded as good practice, as outlined in 'Working together to safeguard children'. The committee considered that the resource impact of setting up and agreeing information sharing protocols would be negligible, particularly compared with: the negative consequences associated with poor information sharing and interagency working identified in case reviews the costs and quality-adjusted life year (QALY) losses attributed to sexual offences and rape in the economic modelling report. In addition, information sharing using a locally agreed approach does not have a significant resource impact because it uses established pathways and protocols, as set out in 'Working together to safeguard children'. # Section 1.2 Named safeguarding leads in universal services The discussion below explains how we made recommendations 1.2.1 to 1.2.4. ## Current practice Any professional working in universal services who is concerned about the sexualised behaviour of a child or young person has a responsibility to notify their organisation's named safeguarding professional. Named safeguarding leads should discuss their concerns with children's social services so a decision can be made about whether referral for an early help assessment is needed (see Ofsted's Early help: whose responsibility?). The committee noted, however, that members were aware of instances where such behaviour had been ignored and children had been harmed. ## Evidence of effectiveness No evidence of effectiveness was identified for this section. The recommendations are linked to the Department for Education's guidance 'Working together to safeguard children'. This requires professionals in universal services and those providing services to adults working with children to identify emerging problems and share this with other professionals involved in early identification and assessment of harmful sexual behaviour. It requires them to discuss concerns and referrals through agreed routes so appropriate referrals are made, to reduce risk of stigmatisation. The committee agreed that professionals working in universal services should use locally agreed resources to identify if a child or young person's behaviour is a cause for concern . # Section 1.3 Early help assessment The discussion below explains how we made recommendations 1.3.1 to 1.3.10. See also the section on gaps in the evidence, number 2. ## Current practice The principles of early help assessment are discussed in the Department for Education's guidance 'Working together to safeguard children' (see current practice in the section on multi-agency, multidisciplinary team of the committee discussion). This type of assessment is key to identifying and addressing needs not being met by universal services. For example, it can identify the need for: targeted services specialist harmful sexual behaviour assessment referral to the child protection team referral to the criminal justice system. Other helpful tools include: Department for Education's use of whole family assessment to identify families with multiple problems, and Youth Justice Board for England and Wales' AssetPlus, previously known as the Youth Offending Asset assessment. In their experience, members said that early help professionals and professionals not trained to work with people displaying harmful sexual behaviour need more information and resources to identify such behaviour. That is because referrals to children's services are based on a generic practice model and not one that specialises in harmful sexual behaviour. ## Evidence for effectiveness The committee agreed that an early help assessment using, for example, the Common Assessment Framework, can help identify what additional help the child or young person and their family need, apart from that provided by universal health and social care services. The early help assessment provides a model for gathering and recording information about the child or young person's strengths and needs, based on discussions with the family. It can also form the basis for their care plan. The committee agreed that the early help assessment should be done by a lead professional who supports the child and family, acts as an advocate on their behalf, and coordinates the delivery of services. The decision on who should lead should be made on a case-by-case basis, with input from the child or young person and their family. It could be a GP, family support worker, school nurse, social worker or health visitor. The committee agreed that it should be made clear which agencies are responsible for children and young people who do not fall under the remit of child protection, or who do not need harmful sexual behaviour services but do have unmet needs. The committee agreed that a locally agreed identification tool should be used as part of the early help assessment for a child or young person displaying sexualised behaviour that is a cause for concern . The committee based these recommendations on government guidance on early help (see 'Working together to safeguard children'). It also included expert testimony that recognised the need for early help to prevent escalation . There is no evidence on how effective tools are at identifying harmful sexual behaviour, but the committee agreed that a tool should be used as part of the early help assessment. This will help to identify harmful sexual behaviour and improve decision making. The aim would be to screen for age and developmentally inappropriate sexualised behaviour and language to decide whether to refer on to specialist harmful sexual behaviour services. Tools commonly referred to in the literature, or used in practice, include: the Brook Traffic Light Tool and Hackett's continuum model of children and young people's sexual behaviours, patterns and cycles . ## Evidence for cost effectiveness There was no cost effectiveness evidence for this set of recommendations. The committee did not make it a priority for modelling. It considered the cost impact to be negligible because it is widely considered to be good working practice (see resource impact section below). ## Additional factors taken into account The committee considered that such assessments could prevent the escalation of sexualised behaviour. This, in turn, could prevent the need for specialist harmful sexual behaviour services, a statutory assessment under the Children Act 1989 or involvement of the criminal justice system. The committee agreed that interagency assessments should use a joined-up process that focuses on outcomes. Assessments should acknowledge chronological age and developmental status, and what constitutes healthy sexual behaviour among children and young people. This is particularly true when discussing children and young people with a neurodevelopmental disorder such as autism or a learning disability. The committee also agreed that often, as children and young people mature, they stop displaying harmful sexual behaviour. However, their life chances may still be impaired (because of their previous behaviour or related factors). So they may need ongoing assessment and input, particularly in relation to educational and employment opportunities . The committee acknowledged that those working with children and young people displaying inappropriate sexualised behaviour need a greater understanding of the benefits of an early help assessment. However, members also wanted to ensure that unnecessary assessments and referrals do not occur that may be stigmatising, so they included caution around this area in the recommendations. Sexual behaviours exist on a continuum that ranges from normal and developmentally appropriate to highly abnormal and violent . There is little evidence on interventions that address behaviours that fall short of thresholds needing a response from specialist harmful sexual behaviour services or the criminal justice system. Locating sexual behaviour on a continuum that is related to development age is an important part of the assessment process, and can help practitioners and families make distinctions between different sexual behaviours. The committee acknowledged that using assessment tools with prepubescent age groups that were designed for older groups could be harmful. The committee agreed with expert paper 7. This recommends that when assessing children and young people displaying sexualised behaviour, practitioners should distinguish between children and young people in general and those with special educational needs and learning disabilities, or with autism. It noted that although the latter form a significant minority, there is a lack of tools for assessing their behaviour. The committee agreed that using a tool to identify the sexual behaviour of children and young people would help make practitioners aware that this behaviour exists on a continuum. It would also help determine whether a referral to specialist services is necessary. Members recognised that if the tool is not designed for the subgroup being assessed, the results may not be accurate. ## Resource impact and implementation issues Use of early help assessment is regarded as good working practice. It provides a shared assessment and planning framework for all children's services in England. Because of this, the committee does not consider these recommendations will have any additional resource impact, except in areas that are not following good practice. The committee believed that early identification and intervention would be cost effective by preventing escalation of the behaviour and avoiding involvement of the criminal justice system. # Section 1.4 Risk assessment for children and young people referred to harmful sexual behaviour services The discussion below explains how we made recommendations 1.4.1 to 1.4.7. See also the section on gaps in the evidence, number 2. ## Current practice Risk assessment tools are used to assess specific risks and needs arising from a child or young person's harmful sexual behaviour. In the UK, different models are used depending on whether they come into contact with child welfare, mental health or the criminal justice system. When children and young people are charged by the Crown Prosecution Service for harmful sexual behaviour, the offence cannot be discussed with them while the case continues. But an assessment can still take place. The committee discussed the AIM assessment model, which was originally developed for practitioners in the criminal justice system, but could be used in the community . The committee was told that current practice is dominated by AIM2 designed primarily for boys and young men aged 12 to 18. The AIM model considers the level of management and supervision needed, together with the person's development and intervention needs. Members were also told that although the AIM assessment model has led to a more standardised approach, it is unclear how it might be applied outside the criminal justice system. Members noted that the AIM model for under‑12s is used to assess: children under 12 children between 10 and 12 whose harmful sexual behaviour needs a criminal justice response (10 being the age of criminal responsibility in England). Members noted that AIM2 is used mainly to assess males aged 12 to 18 and: Focuses on factors linked to the risk of harmful sexual behaviours. Brings together elements from the more general approach outlined in the Department of Health's Framework for the assessment of children in need and their families (this guidance was subsumed into 'Working together to safeguard children' and is no longer current) and the Youth Offending Asset assessment (Youth Justice Board for England and Wales) now AssetPlus. Takes into account clinical factors. The committee also discussed whether AIM2 could be used with young females and young people with learning disabilities. Members agreed this should be on a more limited basis. The developers of AIM2 do not recommend using the 'level of supervision' scale for young females, as it is likely to misrepresent the level of risk. A degree of caution is also advised when using AIM2 to predict sexual reoffending in young people with learning disabilities. At this stage the committee agreed the evidence available was too limited to make recommendations in these areas. It noted that further research is needed on assessing risk in all children and young people (see research recommendation 5). ## Evidence for effectiveness The committee considered the evidence of effectiveness for various risk assessment tools in terms of predicting sexual and non-sexual re-offending. It noted that 10 of the 11 quantitative studies in the evidence review were based on adolescent boys with a mean age of 15 who had been convicted of sexual offences. Only 1 study included girls and a younger age group (boys 12.3 years and girls 11.9 years) who had recently begun to display harmful sexual behaviour . All the studies were from North America, which may limit their applicability in the UK. They were all at risk of bias from the methods used. The committee considered: J‑SOAP‑II (5 low to moderate quality studies on future sexual re-offending). The evidence was inconsistent: 3 predicted sexual re-offending, 2 did not . ERASOR (4 moderate to high quality studies). Three predicted sexual re‑offending, 1 did not . Adapted AIM and AIM2 (2 moderate quality studies on future sexual re-offending). Both studies predicted that adolescents with and without learning disabilities who were previously known to sexually offend would reoffend . J‑SORRAT‑II (2 studies, 1 low and 1 moderate quality). One study found it was able to predict future sexual re-offending among adolescent males convicted of a sexual offence, the other found no effect . The committee noted that although the evidence is contradictory for J‑SOAP‑II and ERASOR , the tools look promising for assessing young people's risk of sexual and non-sexual reoffending. The committee agreed that although the evidence from adapted AIM and AIM2 studies is limited , they are promising tools and are relevant because they were developed in the UK. Only limited attempts have been made to test their predictive validity . AIM2 is also now being used (with caution) for girls and for those with learning disabilities. So the committee recommended further research on AIM2. So the committee was unable to make a strong recommendation for the use of AIM for under‑12s or AIM2. The committee agreed that the J‑SORRATT‑II was still undergoing research and was not used outside North America, so it could not currently recommend its use as a risk assessment tool . There was no evidence that tools focusing on strengths (BERS-2) enhance the accuracy of ERASOR to predict sexual re-offending among adolescent young men who have committed a sexual offence . The committee also considered evidence from 2 quantitative studies (moderate quality) on the SAVRY and YLS/CMI tools. It noted that SAVRY was unable to predict sexual or non-sexual reoffending for adolescent males convicted of a sexual offence . The YLS/CMI tool did not predict sexual reoffending but did predict non-sexual violence, and any potential for non-sexual re-offending . The committee considered 11 qualitative studies: 3 papers were rated high, 6 moderate and 2 low quality. Two moderate quality studies stated that AIM2 offered a more standardised approach to assessment, and encouraged better cooperation between young offender teams and social care departments in the UK. But practitioners reported frustration because they were not properly trained to use it. In addition, there was some confusion about its purpose and how the findings might be applied in practice . The committee discussed the literature on risk assessment tools to predict future sexual violence. Members agreed it is limited because the number of re-offenders recruited into research studies is too small for the research designs needed to validate tools. This means that most UK agencies are using largely under-tested models to underpin their assessments of risk and need. So further research is urgently needed (see research recommendation 5). ## Evidence for cost effectiveness There was no cost effectiveness evidence for this set of recommendations. The committee agreed that a good initial assessment is vital when making decisions about therapeutic interventions, treatment placements and care plans. ## Additional factors taken into account There are no fully validated models or frameworks to suggest what core elements should be included in risk assessment tools. The quantitative evidence on sexual abuse was largely drawn from North America. It reported on small clinical populations of relatively high-risk young people referred for specialist treatment. The assessment models used were adapted from models used for male adults convicted of a sexual offence. Assessing the risk of sexual re-offending among young people is particularly challenging because of the enormous changes they undergo at this age. The committee also noted a key finding from research that indicates that many young people who engage in offending behaviours stop them as they mature (Moffitt T Adolescence-limited and life course persistent anti-social behaviour: a developmental taxonomy; Psychological Review 100: 674–701). The committee noted 2 specific risk trajectories evident in samples of young sexual abusers: general antisocial behaviours and harmful sexual behaviour. Most young people charged with sexual offences do not re-offend sexually, although the rate of non-sexual re-offending is substantially higher than average. The committee agreed that risk assessment tools should consider a range of key elements, including the factors that led to the behaviour. The tools should also address the need for ongoing support and re-assessment . The committee discussed risk assessment tools for different subgroups and acknowledged the lack of tools and models for different population groups. The committee agreed that risk assessment tools and models designed for adolescents convicted of a sexual offence should not be used with prepubescent children displaying harmful sexual behaviour. There are few empirical studies of assessment tools and interventions directed at the small proportion of girls and young women who sexually abuse others . Research has indicated that females convicted of a sexual offence differ from males in various ways. For example, harmful sexual behaviour in girls is more likely to be motivated by aggression against them. The committee acknowledged the valuable work being done in this area by Barnardo's Cymru Taith project. Evidence paper 4 discussed how boys and girls with harmful sexual behaviour are treated differently. For example, boys are more likely to be removed from mainstream school. ## Trade-off between benefits and harms Benefits include the adoption of a consistent approach to assessment. In addition, using locally agreed tools allows practitioners from different agencies and professional backgrounds to share information. However, potential harm could come from the fact that the assessment of the level of risk is not accurate. On the one hand, this could lead to an over-punitive or over-restrictive approach. On the other, it could sometimes mean the child or young person does not get the support they need to prevent further harmful sexual behaviour, so exposing them to risk – to themselves and others. ## Resource impact and implementation issues The committee noted that AIM for under‑12s and AIM2 were developed for the UK, but have to be paid for and involve specialist training. In comparison, J‑SOAP‑II, and ERASOR are free and specialist training is not needed, so they would have less impact on training needs and resources. But their applicability in England is unknown. Overall, the committee could not recommend 1 tool over another and noted that most effectiveness evidence came from North America. Internationally, the 2 tools with the highest degree of empirical support are ERASOR and J‑SOAP‑II, although the evidence for predicting sexual re-offending is not consistent across studies. Further studies are needed on larger samples. Also, studies are needed to compare the use of different models with the same samples. In the absence of more consistent evidence, the committee agreed that it might be best if practitioners use AIM2, ERASOR, or J‑SOAP‑II for assessing risk. If time allows, the committee recognised that there may be benefits if the ERASOR and J‑SOAP‑II are used together to compare the use of these two models over time. In each case, the developers also recommend that practitioners use their own clinical judgement. Only the most promising tools were included in the recommendations as examples of what was available. But the committee agreed that, given the uncertainty in the evidence base more research is needed (see research recommendation 5). The committee also agreed by consensus that in their expert opinion children's social services and NHS England are best placed to identify who should undertake a risk assessment and these names were added to recommendation 1.4.1. # Section 1.5 Engaging with families and carers before an intervention begins The discussion below explains how we made recommendations 1.5.1 to 1.5.4. ## Current practice Not all practitioners meet with families and carers before an intervention begins. ## Evidence for effectiveness There was no quantitative evidence of effectiveness on the role of practitioners. Six qualitative studies and 2 expert testimonies identified key features and approaches that practitioners could use to reduce barriers to services and improve communications between the practitioner and children, young people, parents and carers . The committee agreed that before an intervention begins, practitioners must consider whether the child or young person has been abused within the family or the victim is another family member. (See also NICE's guidelines on when to suspect child maltreatment and child abuse and neglect.) The committee agreed with 2 high quality qualitative studies that offering families and carers the opportunity to meet the programme practitioner before an intervention starts may help to overcome any fears about getting involved in and continuing with the programme . The committee agreed with 2 qualitative studies (moderate to high quality) that family and carer participation and support is crucial to getting young people involved with interventions. It also helps reinforce intervention messages in the home . The committee agreed with 2 qualitative studies of moderate to high quality on the need for practitioners to accommodate a child or young person's changing needs and offer a flexible service to accommodate their social activities to maintain their interest . The committee agreed with 3 high quality qualitative studies and expert papers 9 and 10 that the therapist's relationship with the child or young person is vital if an intervention is to be effective . Members also agreed that, in their experience, interventions were only as good as the person providing them. ## Evidence for cost effectiveness There was no cost effectiveness evidence for this set of recommendations, but the committee agreed that encouraging practitioners to meet beforehand is likely to improve the outcome of the intervention. So they are likely to be cost effective and potentially cost saving. ## Trade-off between benefits and harms The committee agreed that the main benefit would be greater involvement with the intervention and improved outcomes for the child or young person, their family and carers. ## Resource impact and implementation issues The committee agreed that this recommendation would have a resource impact, particularly in terms of arranging meetings that are not part of the therapeutic intervention. But members agreed that increasing attendance and improving the relationship between the child or young person and the practitioner could lead to better outcomes and offset any resource implications. # Section 1.6 Developing and managing a care plan for children and young people displaying harmful behaviour The discussion below explains how we made recommendations 1.6.1 to 1.6.5. ## Current practice Practice may vary. But good practice involves using a care plan based on the results of the assessment of the child or young person's risks and needs. ## Evidence of effectiveness Based on members' own experience, the committee agreed that care planning should be based on the results of the needs and risk assessment and should include the use of recognised resources. ## Resource impact and implementation issues The committee believed that these recommendations would not result in increased costs but would probably improve outcomes . # Section 1.7 Developing interventions for children and young people displaying harmful sexual behaviour The discussion below explains how we made recommendations 1.7.1 to 1.7.15. See also the section on gaps in the evidence (number 1). ## Current practice Current practice is often based on cognitive behavioural therapy models used to treat adult men who have sexually offended. Developed originally in the US, these models came to prominence in the UK probation and prison services from the late 1980s. ## Evidence for effectiveness The evidence of effectiveness was from North America and may be only partially applicable to a UK population. The interventions reviewed mainly focused on those convicted of a sexual offence in treatment settings and will have limited applicability to children and young people outside the criminal justice system. Many types of intervention are used to help children and young people displaying harmful sexual behaviour but not all of them have been evaluated. The committee considered evidence statements covering 13 quantitative studies (4 randomised controlled trials, 3 controlled studies and 6 before-and-after studies). It noted that although the studies were grouped for analysis according to type of intervention, many included elements drawn from a range of approaches. This included cognitive behavioural therapy (CBT) and multisystemic therapy. It also considered qualitative evidence from 26 studies (11 low, 9 moderate, 6 high quality studies). Of the 13 quantitative studies, 9 (2 randomised controlled trials, 1 controlled study and 6 before-and-after studies) of variable quality reported on the effectiveness of CBT-based approaches. These comprise a range of components delivered to both individuals and groups and focus on the sexually abusive behaviour. Four papers reported on 3 studies of multisystemic therapy. Two randomised controlled trials and 1 controlled study (ranging from low to moderate quality) reported that multisystemic therapy significantly reduced the risk of adolescent sexual re-offending compared with CBT or usual care. One controlled study (moderate quality) using adventure-based therapy (Legacy) for adolescent boys convicted of a sexual offence, reported no difference between the intervention and control group for re-offending rates for violent sexual offences. The committee considered the evidence on CBT interventions from 4 low to moderate quality quantitative studies. These were abuse-focused and targeted the sexual behaviour of juveniles convicted of sexual offences using 1 or several components of CBT. This included: satiation therapy, a method for reducing deviant sexual arousal verbal satiation – repeatedly talking about deviant sexual fantasies to reduce sexual arousal from such fantasies vicarious sensitisation, a form of conditioning used to treat teenage boys who have displayed harmful sexual behaviour towards younger children cognitive restructuring therapy to help people to think differently about a situation, event, thought, or belief. The committee noted the positive direction of all 4 studies but agreed that, on balance and from members' expert opinion and experience, it could not recommend these types of interventions . The committee agreed with evidence from 3 low to moderate quality qualitative studies that stigma and ostracism may arise if a child or young person is labelled as a sex offender. It was keen to highlight that children and young people with harmful sexual behaviour are not 'mini adult sex offenders' and that offering interventions that are abuse-focused is potentially stigmatising . The committee considered a study of moderate quality that compared CBT with dynamic play therapy with boys (61%) and girls (39%) aged 5 to 12. This targeted a range of harmful behaviours and included families and carers. It reported no significant difference between the 2 approaches. Both improved the children's ability to socialise while reducing their behavioural, affective and sexual behaviour problems . The committee agreed the positive outcomes were likely to have resulted from the types of components that were included in each approach. This included: behaviour modification and psychoeducational principles in the CBT group; and client-centred and psychodynamic play therapy principles in the play therapy group . The committee also considered evidence on 2 CBT programmes for young people displaying a range of harmful behaviours and personality disorders: SAFE‑T (Sexual Abuse, Family Education and Treatment Programme) and Thought Change System. Both interventions included family members and carers. (The evidence comprised 2 low to moderate quality quantitative studies.) Both reported a decrease in harmful behaviours, with the SAFE‑T programme reporting a 72% reduction in re-offending rates for sexual assault . The committee considered the evidence of effectiveness for multisystemic therapy compared with CBT-based usual care for adolescents convicted of sexual offences. Two moderate quality quantitative studies found that significantly fewer people from the multisystemic therapy group had been re-arrested for sexual offences at follow-up than from the comparison group . One moderate quality quantitative study found that multisystemic therapy for adolescents charged with sexual offences led to a reduction in deviant sexual interests when compared with CBT-based usual care . Two moderate quality quantitative studies reported improvements in problem sexual behaviour, psychiatric symptoms, antisocial behaviour, family and peer relations and school performance among adolescents charged with sexual offences, compared with CBT-based usual care . Multisystemic therapy focuses on the family, which means its use will be limited because a significant number of children and young people who display harmful sexual behaviour are in out-of-home placements. Its main goal is to reduce the risk of re-offending by enhancing family and peer relationships. A big benefit is that carers become better at identifying friends who were having a negative influence on their adolescents and advising their children to stop associating with them. Research suggests, however, that multisystemic therapy may not be as effective with all subgroups of young people who display harmful sexual behaviour. For example, there is a strong link between antisocial peer groups and young people whose harmful sexual behaviour is often directed towards peers and accompanied by other non-sexual criminality. This group is different from those whose harmful sexual behaviour targets younger, prepubescent children. The latter are less likely to have a social life or strong peer friendship groups. The committee heard expert testimony on the ongoing trial of Multi-systemic therapy – problematic sexual behaviour in the UK and agreed that this may, in future, offer more conclusive results . It noted that previous evaluations of the programme in the US were positive, and had been carried out by its designers. The committee noted the results from 1 moderate quality study that evaluated an adventure-based programme (Legacy). This reported no difference for re-arrest rates for violent sex offences between groups but appears to be beneficial in reducing future risks of non-sexual reoffending . Drawing on expert papers 2 and 5, members agreed that the duration and intensity of interventions should be adapted for those with learning disabilities. (For example, by having more frequent, shorter sessions, or longer sessions as necessary, or fewer participants in group sessions.) The committee agreed with the evidence from 1 moderate quantitative study and 3 moderate to high quality qualitative studies that understanding the factors that lead to harmful sexual behaviour is an important part of relapse prevention and making future plans . The committee agreed that victim empathy is a contested component of harmful sexual behaviour interventions . The committee also agreed with the results from 6 qualitative studies (3 low, 1 moderate, 2 high) that interventions involving children and young people in supervised social activities helps promote self-esteem and socially appropriate behaviour . The committee noted the evidence from 1 moderate quantitative study and 2 low to moderate qualitative studies highlighting the concerns of families and young people about not getting support to maintain their progress. The committee agreed this was an important component of services . The committee agreed with 14 qualitative studies (11 low, 1 moderate, 2 high quality) that reported that communication skills, social skills training and anger management or 'emotional regulation' are important components of any intervention . The committee noted the results from 3 qualitative studies (1 high, 1 moderate, 1 low) that showed that group interventions (for both the child and young person and their family and carer) can reduce their sense of isolation and provide valuable support. But members also noted that it may be problematic for those who find it difficult to talk in front of others . In addition, they noted the difficulties involved in treating perpetrators of harmful sexual behaviour alongside their victims, as highlighted in 4 qualitative studies (2 moderate, 2 low) . ## Evidence for cost effectiveness The committee made the recommendations on cognitive behavioural therapy, multisystemic therapy and play therapy a priority for economic modelling. The model results showed a cost per QALY of under £20,000, but the committee questioned these estimates and thought that not all these therapies would in fact be cost effective. This is particularly true for children and young people who did not need a custodial sentence. That is because the studies that underpinned the modelling were from North America, where comparators are different. Given that the multisystemic therapy trial in the UK has yet to report, the committee suggested that it would be prudent to continue with current approaches – but make them work better by following the recommendations outlined in this guideline. Getting better results at the same cost would automatically be cost effective. If the current trial shows that more expensive methods are more effective than current methods, the approach advocated here (continuing with current practice) could be revised. ## Additional factors taken into account The sexual behaviour of children and young people exists on a continuum that ranges from normal and developmentally appropriate to highly abnormal and violent. Various approaches are needed to address these different behaviours. But there is little evidence on interventions that address behaviours that fall short of thresholds needing a response from the criminal justice system. The qualitative studies identified programmes offering relapse prevention, anger management (emotional restraint), victim empathy, communication and social skills training. They also documented the emergence of family-level interventions and the role of the therapist as important components. The committee noted that mode of delivery (such as face-to-face or in groups) should be based on the needs and circumstances of the child or young person, as highlighted in the assessment and using clinical judgement. The qualitative studies also highlighted the components of an intervention that participants, their families and professionals feel have value. But it is not clear which components are most effective for different groups. The committee agreed that having to choose between cognitive behavioural therapy and multisystemic therapy is not realistic and that there are advantages to both (this includes the fact that effectiveness can depend on the family circumstances). In the absence of clear evidence, the committee recommended continued use of these therapies. The evidence reported was based on small numbers of participants (and conducted by developers of the intervention in the case of multisystemic therapy). Members agreed that more research, with a low risk of bias and relevant to UK practice, is needed (see research recommendation 3). Members acknowledged that multisystemic therapy is a more complex approach that needs the child or young person to be living in the family home or in a stable foster family situation (for at least 18 months in the case of multisystemic therapy Problematic Sexual Behaviour). As a significant proportion of children and young people displaying harmful sexual behaviour may not be living in a family situation this approach may not work. In that respect, cognitive behavioural therapy might be a more pragmatic solution but, the downside is that it needs more follow-up once the intervention has ended. The committee did not put the list of interventions in order of priority, because the results of the child or young person's assessment should help practitioners decide what type of intervention to offer. Members agreed that what was needed was a 'toolbox' of approaches that could be tailored to individual needs. From their own experience, they agreed that comprehensive, multicomponent interventions that focus on the child or young person's family and background are more promising than those that focus solely on the abusive behaviour. The committee also discussed looked after children and young people displaying harmful sexual behaviour and the need for foster carers to be adequately trained. It heard testimony from expert paper 10 that young people in the care system with harmful sexual behaviour often experience multiple placement moves. This, in turn, can affect the child's willingness to form attachments and makes therapeutic interventions more challenging. # Section 1.8 Supporting a return to the community for 'accommodated' children and young people The discussion below explains how we made recommendation 1.8.1. ## Current practice The Glebe House model, a specialist children's home, is an example of residential practice in this area. It is based on a therapeutic community model for adolescent males with a known history of harmful sexual behaviours. The committee noted that the Glebe House model is not usual practice in this area, and that the types of interventions offered at Glebe House are very different from those offered by custodial services. Young people in a young offender's institution serving a custodial sentence for a sexual offence do not always receive harmful sexual behaviour services. Local youth offending teams should provide this service but it can take months to arrange. That's because it may involve transferring the person to a young offender's institution that offers specialist services. It is not uncommon for a transfer from one custodial setting to another to take place a few months before the release date. The committee noted that even where harmful sexual behaviour services are commissioned, the threshold for provision varies and is occasionally too high. For example, young people who receive a custodial sentence for harmful sexual behaviour may not be offered these services if their sentence is under 6 months. Youth Justice Board statistics for 2014/15 show that the average time, from the date of an offence being committed until completion of court proceedings, is 66 days. But for sexual offences this rises to 295 days – so many would not be eligible for support by the time they are sentenced. In addition, young people aged between 12 and 17 who receive a 12‑month detention training order would not be eligible. That is because half the sentence will be spent in custody and the other half will be supervised by the youth offending team in the community. However, the Wakefield harmful sexual behaviour model allows all young people displaying harmful sexual behaviour, whether or not it is part of the offence, to be referred. This is also regardless of the length of time they spend in custody and whether or not they receive a custodial or community sentence. In this model, any agency involved with the young person can refer and self-referrals are also accepted. Everyone is offered a consultation plus a transition package, regardless of whether they are discharged into the community or transferred to adult prison. ## Evidence for effectiveness The committee noted that a small number of children and young people displaying harmful sexual behaviour may warrant placement in a specialist residential or secure setting. It drew on evidence from expert paper 6 as an example of a specialist children's home that uses a therapeutic community model. The committee agreed that, if possible, residential settings should draw on the values and approaches of a therapeutic model originally developed in the field of social psychiatry by Rapoport and Roscow (Community as doctor ; New York: Arno Press). This is based on 5 social psychology principles: attachment, containment, communication, involvement and agency. The committee agreed that interventions in residential settings should be based on the principles outlined in this guideline, including the principles and approaches set out in section 1.6 and section 1.7. The committee agreed that residential settings should also provide a range of services, including ongoing support, to enable a child or young person to successfully integrate back into the community. In addition, if it is in the best interests of the child or young person, out-of-home care should not undermine relationships with their family. The committee referred to evidence previously noted for sections 1.7 and to ES1.6 and ES1.28. # Evidence reviews Details of the evidence discussed are in evidence reviews, reports and papers from experts in the area. The evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from. Evidence statement (ES) ES1.1 indicates that the linked statement is numbered 1 in review 1. ES2.1 indicates that the linked statement is numbered 1 in review 2. EP1 indicates expert paper 1 'Definitions, epidemiology and natural history of HSB'. EP2 indicates expert paper 2 'Developmental pathways towards sexually harmful behaviour and emerging personality disorder traits in childhood'. EP3 indicates expert paper 3 'Harmful sexual behaviour of children'. EP4 indicates expert paper 4 'Girls who display harmful sexual behaviour – developing assessment tools and intervention resources'. EP5 indicates expert paper 5 'Glebe House'. EP6 indicates expert paper 6 'Turn the page'. EP7 indicates expert paper 7 'Harmful sexual behaviour – children and young people with learning difficulties who display harmful sexual behaviour'. EP8 indicates expert paper 8 'AIM project'. EP9 indicates expert paper 9 'Service user expert testimony'. EP10 indicates expert paper 10 'Practitioner and advocate expert testimony'. EP11 indicates expert paper 11 'Pornography and its impact on harmful sexual behaviour'. EP12 indicates expert paper 12 'The development of an operational framework for children and young people who sexually harm'. EP13 indicates expert paper 13 'An overview of policy and practice'. EP14 indicates expert paper 14 'MST PSB trial'. If the committee considered other evidence, it is linked to the appropriate recommendation below. Section 1.1: ES2.9; EP1, EP9, EP10 Section 1.2: ES2.1, ES2.13; EP1, EP7; Department for Education's 'Working together to safeguard children.' Section 1.3: ES2.1; EP7, EP12 Section 1.4: ES1.6, ES1.28, ES2.2, ES2.3, ES2.4, ES2.5, ES2.6, ES2.7, ES2.8, ES2.10, ES2.14; EP3, EP4, EP7, EP8 Section 1.5: ES1.16, ES1.18, ES1.20, ES1.21, ES1.22, ES1.23, ES1.24; EP1, EP9, EP10 Section 1.6: ES1.6, ES1.17, ES1.28, ES2.2, ES2.3, ES2.4, ES2.5, ES2.6, ES2.7, ES2.11, ES2.13; EP3, EP4, EP8 Section 1.7: ES1.6, ES1.7, ES1.8, ES1.10, ES1.11, ES1.12, ES1.13, ES1.14, ES1.15, ES1.16, ES1.17, ES1.19, ES1.25, ES1.26, ES1.27, ES1.28; EP2, EP3, EP5, EP9, EP10, EP14 Section 1.8: ES1.6, ES1.15, ES1.28; EP5, EP9, EP10 ## Gaps in the evidence The committee's assessment of the evidence on harmful sexual behaviour and stakeholder comments identified a number of gaps. These are set out below. . A comparison of the effectiveness of therapeutic approaches such as cognitive behavioural therapy and multisystemic therapy for children and young people who display harmful sexual behaviour and their family and carers. (Source ER1) . Evidence of effectiveness for recognised assessment and treatment models, such as the Good Lives Model and AIM2, for children and young people who display harmful sexual behaviour. (Source ER1) . Empirically evaluated tools to assess need and predict the risk of harmful sexual behaviour among children and young people in the community including: different age groups (that is, children under 10 and children and young people aged 10 and older). those with neurodevelopmental or learning disabilities those from black and minority ethnic communities those at the less severe end of the harmful sexual behaviour spectrum. (Source ER2) . Evidence on interventions aimed at younger children (prepubescent or under 10) who display sexualised behaviour that is of concern. (Source ER1) . Evidence on actuarial models used to assess children and young people who display harmful sexual behaviour. (Source ER1) . Rates for continued problematic sexual behaviours following prepubescence. (Source EP1) . Factors that encourage children and young people to go on to commit more serious sexual offences. (Source EP1) . Evidence of the impact that pornography and new technologies have on harmful sexual behaviour such as sexting, the posting of sexual images and grooming. (Source EP11)# Recommendations for research The guideline committee has made the following recommendations for research. # Long-term outcomes for children and young people displaying harmful sexual behaviour What are the long-term outcomes for children and young people displaying harmful sexual behaviour, when should practitioners intervene and what potentially modifiable factors have the most important impact? ## Why this is important Longitudinal evidence spanning the life-course of children and young people who display harmful sexual behaviour is needed to understand when to intervene. This is particularly true for children and young people whose sexual behaviour does not warrant an intervention from harmful sexual behaviour services or the criminal justice system. There is a lack of evidence on thresholds for intervening, including evidence on modifiable risk and protective factors that prevent the behaviour escalating. We also need evidence on quality-of-life measures. As a result, we should be able to avoid mislabelling younger children as 'sexual offenders' and subjecting them to intrusive and stigmatising interventions. # Effective interventions for children and young people displaying harmful sexual behaviour What interventions are effective with children and young people displaying harmful sexual behaviour? ## Why this is important Most of the evidence on interventions is inconclusive. It comes from small clinical populations of adolescent males convicted of sexual offences. More research is needed on the effectiveness of current interventions and to understand how to avoid children and young people who display sexualised behaviour being taken into the criminal justice system. This includes research on: prepubescent children young women children and young people with neurodevelopmental and learning disabilities minority ethnic and migrant communities looked after children (including those in non-family-based settings). children and young people in the criminal justice system (community and custody). Evidence on interventions for looked-after children needs to include those in non-family-based settings and in unstable foster care. For this group, there is also a lack of evidence on interventions to promote placement stability and permanence, as well as on interventions specifically relating to harmful sexual behaviour. The former is needed because a stable home life may help reduce the risk of harmful sexual behaviour. Evidence of effective interventions could help target resources more effectively and ensure programmes are tailored to meet children and young people's differing needs. # Effective interventions for the families and carers of children and young people displaying harmful sexual behaviour What type of therapeutic interventions are effective when working with the family and carers of children and young people who display harmful sexual behaviour? ## Why this is important Evidence on effective interventions for families and carers of children and young people who display harmful sexual behaviour is equivocal. Evidence of effectiveness for the 2 most common approaches – cognitive behavioural therapy and multisystemic therapy – and other therapies is very limited. Further research is needed to help practitioners tailor interventions according to need. # Early interventions to prevent problems escalating What interventions are effective in diverting children and young people away from further harmful sexual behaviour before a legal response is needed? ## Why this is important There is a need for more evidence on what is effective in diverting children and young people away from further harmful sexual behaviour at the earliest stages of its development. Research is needed on missed opportunities to intervene and what the trajectory has been for those children and young people who were missed. Such evidence could help ensure children and young people receive timely support to prevent an escalation of the behaviour. # Assessment models for different groups of children and young people How effective are the models currently used for assessing the needs of, and level of risk for, children and young people from different population groups who display harmful sexual behaviour? ## Why this is important Assessment is at the heart of effective intervention planning and risk management. Without good assessment models, levels of risk may be misclassified. To date, risk assessment tools have mainly been used on small clinical populations of adolescent males who have sexually offended and there is a need for assessment tools for other groups of children and young people. Assessment results are also a basis for needs assessment and decisions about therapeutic interventions, treatment placements and care plans. For those in the criminal justice system, an assessment provides a clear guide to sentencing and multiagency management (for example, multi-agency public protection arrangements). Lack of evidence on current assessment models means that we know little about: problems caused by mislabelling a child or young person impact of the assessment process on the child and young person and their families and carers treatment outcomes. # Electronic media How does the use of electronic media affect harmful sexual behaviour? ## Why this is important The reasons behind the growth in online grooming, the viewing of online pornography, and the making and distributing of sexual images is poorly understood. There have been few studies into the links between aggressive behaviour, sexual offending and the use of electronic media. Longitudinal studies are needed to understand the impact electronic media has on sexual behaviour and on the general values, attitudes, beliefs and behaviour of children and young people. Research is also needed on its long-term impact on children and young people's social and psychological development. Such research could provide evidence on how best to assess, intervene and manage the risks associated with the use of electronic media in this area.# Glossary # Cognitive behavioural therapy Cognitive behaviour therapy for people displaying harmful sexual behaviour typically includes: identifying previous circumstances leading to sexual arousal, accepting responsibility for offensive behaviour, social skills training, empathy and relapse prevention. # Cognitive restructuring therapy Methods that help people to think differently about a situation, event, thought, or belief. # Common Assessment Framework Early help assessments, such as the Common Assessment Framework, identify what help the child and family need to prevent their needs escalating to a point where intervention would be needed via a statutory assessment under the Children Act 1989. # Conduct disorder A serious behavioural problem that can last a long time and can affect a child or young person's ability to lead a normal life. Common signs and symptoms include: aggressive behaviour towards people or animals destructive behaviour towards other people's property lying and stealing playing truant from school. For older children and adolescents, this can also include smoking, drinking alcohol, substance abuse and engaging in unprotected sexual activities. # Developmental age A child or young person's social, emotional, physical and intellectual maturity compared with typical behaviours and characteristics for their chronological age. # Early help assessments Early help assessments identify what help a child and family may need to prevent their needs escalating. They are for children and families who may need targeted support from several agencies. # Guided interventions Guided interventions offer practitioners a set of key principles on which to base interventions. # Multisystemic therapy Multisystemic therapy is an intensive community- and home-based approach to a broad set of adolescent problem behaviours, including harmful sexual behaviour. The emphasis is on interventions that target specific, well-defined problems. The aim is to empower carers to address family members' needs. # Neurodevelopmental disorders Disorders that typically appear early in a child's development, often before they enter school. They are characterised by impairments in personal, social, academic, or occupational functioning. Examples are: learning disability, autism spectrum condition, speech and language disorders and ADHD (attention deficit hyperactivity disorder). # Prepubescent A child who has not yet reached puberty. # Problematic sexual behaviour Unusual and socially unexpected behaviour. It may not involve victimisation and consent issues may be unclear but it may make others uncomfortable or interfere with the child or young person's healthy psychosexual development. # Safeguarding All organisations that work with or come into contact with children and young people should have safeguarding policies and procedures to ensure that they all, regardless of their age, gender, religion or ethnicity, can be protected from harm. # Satiation therapy A procedure that involves the pairing of prolonged masturbation (1 hour) with a verbal commentary by the patient of his or her deviant sexual fantasies. # Sexually abusive A term mainly used to describe sexual behaviours initiated by a child or young person in which there is an element of manipulation or coercion, or the subject of the behaviour is unable to give informed consent. # Strengths-based programmes Strengths-based programmes are a collaboration between the person and the services supporting them. Programmes consider not only factors that are of concern but build on the person's capabilities and strengths. # Universal services Universal services are those services provided to all children and young people such as schools, health visiting, GPs. # Youth criminal justice The youth criminal justice system is for those aged 10 to 17 years: people aged 18 go through the adult criminal justice system. For other public health and social care terms, see the Think Local, Act Personal's Care and Support Jargon Buster.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Multi-agency approach\n\n## Multi-agency, multidisciplinary team\n\nEnsure multi-agency, multidisciplinary teams promote continuity of care and, wherever possible, ensure the child or young person has contact with the same staff over time, so they can develop trust in their care team.\n\nEnsure young people who are nearly\xa018 are prepared for the transition to adult services by developing links between child and adult services. See NICE's guideline on transition from child to adult services.\n\nEnsure multi-agency, multidisciplinary teams:\n\nhave links to clinical and non-clinical services and can make prompt referrals\n\ncollaborate with specialists when children and young people have difficult or complex needs (for example, those with neurodevelopmental or learning disabilities or conduct disorders)\n\nestablish relationships with statutory, community and voluntary organisations that work with at-risk children and young people, to provide a broad range of support services\n\nmeet regularly to plan, implement and evaluate care pathways for the children and young people whose care they are overseeing\n\nunderstand that the care plan is the responsibility of the whole multi-agency team and not individual practitioners.\n\n## Multi-agency, multidisciplinary working\n\nUse established mechanisms, such as local multi-agency safeguarding arrangements, to develop local safeguarding policies and procedures and agree a harmful sexual behaviour operational framework between agencies. (See Department for Education's Working together to safeguard children, Ofsted's Early help: whose responsibility?, Children Act 1989 and Children Act\xa02004.)\n\nLocal multi-agency safeguarding arrangements should ensure:\n\nLead agencies are identified to commission specialist harmful sexual behaviour services.\n\nThresholds are established for when to refer a child or young person for an early help assessment or to specialist harmful sexual behaviour services.\n\nNamed safeguarding leads and practitioners working in relevant services are told what the referral thresholds are. This includes those working in education, children's social services, health and youth criminal justice (such as young offender teams and youth justice boards) and voluntary sector organisations.\n\nNamed safeguarding leads working in universal services use locally agreed resources as part of their policy and procedures to determine whether a child or young person should be referred for an early help assessment. (See recommendation\xa01.3.4 for examples of resources.)\n\nChildren's social services have access to policies and procedures for training staff to deal with concerns about a child or young person's sexualised behaviour.\n\nThe multi-agency team should agree which service is responsible when children and young people are referred for assessment. Consider one of the following for the lead role:\n\nchild health services such as child and adolescent mental health services (CAMHS)\n\nchildren's social services\n\nvoluntary sector organisations such as Barnardo's or the NSPCC.\n\nConsider a range of care pathways based on the 5\xa0core domains identified in the NSPCC harmful sexual behaviour framework.\n\nThe designated lead practitioner responsible for coordinating the care plan (see recommendation\xa01.3.2) should request a review of the care plan via the multi-agency, multidisciplinary team meeting if:\n\nthe child or young person's needs are not being met or\n\nthe referral and assessment procedure is unnecessarily delayed.\n\n## Information sharing\n\nAgree a protocol for information sharing between all agencies. Base this on local safeguarding and child protection procedures and address legal and confidentiality issues.\n\nEnsure the designated lead practitioner responsible for coordinating the care plan can access information on the child or young person's family situation and factors that may affect parenting capacity and attachment (see recommendation\xa01.4.2). Do this as part of the assessment process (See NICE's guideline on children's attachment and recommendations on sexualised behaviour in NICE's guideline on when to suspect child maltreatment.)\n\nEnsure information is collected and shared in a sensitive and professional manner, as set out in the Caldicott Guardian information standards.\n\nIf there is a need to share information with other agencies and carers to inform risk management, do this in consultation with the multidisciplinary team.\n\n# Named safeguarding leads in universal services\n\nImmediately inform your organisation's named safeguarding lead when a child or young person displays sexualised behaviour that is not appropriate for their age or developmental stage (for tools, see recommendation\xa01.3.4). Possible signs of problems include:\n\nusing sexualised language such as adult slang to talk about sex\n\nsexualised behaviour such as sexting or sharing and sending sexual images using mobile or online technology\n\nviewing pornography that is inappropriate for age and developmental status (see the Brook Organisation information on pornography and the law).\n\nImmediately inform your organisation's named safeguarding lead when a child or young person displays sexualised behaviour that is always inappropriate, regardless of age, such as public masturbation.\n\nNamed safeguarding leads should use locally agreed resources to assess concerns about the sexual behaviour of a child or young person. See recommendation\xa01.3.4.\n\nNamed safeguarding leads concerned about a child or young person's sexual behaviour should contact their local children's social services to discuss their concerns and determine whether a referral is appropriate.\n\n# Early help assessment\n\nChildren's social services should refer children and young people who display inappropriate sexualised behaviour for an early help assessment, in line with local thresholds and referral procedures (see recommendation\xa01.1.5). Focus on the child or young person as an individual and not on the presenting behaviour.\n\nAt point of referral, early help professionals should identify a designated lead practitioner in the multi-agency, multidisciplinary team (see recommendation\xa01.1.6) who will:\n\nact as a single point of contact for the child or family\n\ncoordinate early help and subsequent assessments and develop the care plan to avoid unnecessary or repetitious assessments that may be stigmatising\n\ncoordinate delivery of the agreed actions\n\ninvolve children, young people and their families and carers in the design and delivery of early help services, as appropriate\n\nreduce overlap and inconsistency in services provided.\n\nEarly help professionals should be familiar with the child or young person's health and social care record and have access to neonatal and early health information, if necessary. This includes information on developmental delays or a diagnosis of autism spectrum condition, for example.\n\nUse a locally agreed tool as part of the early help assessment that accounts for the severity of the behaviour, to avoid unnecessary and potentially stigmatising referrals. Examples of tools include:\n\nThe Brook Sexual Behaviours Traffic Light Tool. This helps identify a range of sexual behaviours between infancy and adulthood and distinguishes between 3\xa0levels, using a traffic light system to indicate the level of seriousness.\n\nModels that place a child or young person's sexual behaviour on a continuum indicating various levels of seriousness, such as Hackett's model (Hackett S Children and young people with harmful sexual behaviours, in Children behaving badly?: Peer violence between children and young people [eds Barter C and Berridge D]; John Wiley & Sons: Chichester).\n\nTake account of the child or young person's age, developmental status and gender and, if relevant, any neurodevelopmental or learning disabilities.\n\nRecognise that inappropriate sexualised behaviour is often an expression of a range of problems or underlying vulnerabilities.\n\nUse the early help assessment to identify whether the child or young person has unmet needs that can be met by universal services. See Ofsted's Early help: whose responsibility? and Department for Education's Working together to safeguard children. Also:\n\nFor preschool children, see the recommendations\xa0in NICE's guideline on social and emotional wellbeing: early years.\n\nFor children and young people in primary and secondary education, see the recommendations in NICE's guideline on social, emotional and mental wellbeing in primary and secondary education.\n\nEnsure services support children and young people of all ages. See the principles of care recommendations in NICE's guideline on children's attachment, NICE's guideline on looked-after children and young people, and:\n\nFor children and young people who may have a conduct disorder, see NICE's guideline on antisocial behaviour and conduct disorders in children and young people.\n\nFor children and young people who may have experienced trauma, see the sections on specific recognition issues for children and management of PTSD in children and young treatment in NICE's guideline on post-traumatic stress disorder.\n\nIf harmful sexual behaviour is displayed, refer to harmful sexual behaviour services, child protection services and the criminal justice system, if necessary.\n\n# Risk assessment for children and young people referred to harmful sexual behaviour services\n\nChildren's social care services and NHS England should identify services employing staff with the skills to undertake a specialist assessment of risk for children and young people displaying harmful sexual behaviour. This may include:\n\nchild health services such as CAMHS\n\nchildren's social services\n\nvoluntary sector organisations such as the NSPCC or Barnardo's\n\norganisations within the criminal justice system such as youth offender teams and youth justice boards.\n\nProfessionals responsible for specialist harmful sexual behaviour assessments should access any additional information they need. This includes incident reports of any behaviour that is causing concern. Get this information from the child or young person's:\n\nsocial care history\n\neducational records\n\nhealth records\n\nyouth offending and youth justice records\n\npolice records.\n\nConsider the child or young person's developmental age, neurodevelopmental disabilities, learning disabilities and gender as part of the assessment. Do this in collaboration with other specialist services, if relevant.\n\nProfessionals responsible for assessing risk should use risk assessment tools suitable for the child or young person's developmental age and gender. For example, when assessing:\n\nPre-adolescent children or those aged under\xa012, consider psychometric measures and questionnaires such as the Child Behaviour Checklist (Achenbach T Manual for the Child Behaviour Checklist/4–18 and 1991 Profile; Burlington: University of Vermont) and the Child Sexual Behaviour Inventory (Friedrich W Child Sexual Behaviour Inventory: professional manual; Odessa, Florida; Psychological Assessment Procedures).\n\nChildren under\xa012 who have not been charged with a sexual offence, consider the relevant elements of AIM plus clinical judgement.\n\nChildren aged 10\xa0to\xa012 who have been charged with an offence, consider the relevant elements of AIM plus clinical judgement.\n\nAdolescent boys, consider tools such as J‑SOAP‑II, ERASOR or AIM2, plus clinical judgement.\n\n# Engaging with families and carers before an intervention begins\n\nConsider family or social factors that may contribute to the child or young person's harmful sexual behaviour, particularly if there is evidence of abuse within the family. See NICE's guideline on child maltreatment.\n\nThink about the impact a child or young person's harmful sexual behaviour may have on all family members.\n\nIf the person at the receiving end of the harmful sexual behaviour is another child within the family, provide support for the family or a referral as needed (see NICE's guideline on child abuse and neglect).\n\nConsider the following before providing an intervention:\n\nMeeting families and carers to discuss any concerns they may have, including any potential barriers to attendance.\n\nProviding families and carers with information about the intervention and including them, when appropriate.\n\nAdopting a flexible approach to accommodate the child or young person's social activities.\n\n# Developing and managing a care plan for children and young people displaying harmful sexual behaviour\n\n## General principles\n\nRecognise that children and young people with learning and neurodevelopmental disabilities have specific needs. Consider providing short and more frequent sessions for them. Work with specialists in these areas to provide the intervention.\n\nHelp children and young people develop a strong sense of personal identity that does not include harmful sexual behaviour. This includes helping them to maintain their cultural and religious beliefs.\n\n## Developing and managing a care plan\n\nDevelop a care plan using an established risk assessment model, such as J‑SOAP‑II, ERASOR, AIM assessment for under‑12s, or AIM2, and a recognised treatment model such as the Good Lives Model, AIM or AIM2. The plan should:\n\nrecognise the needs and strengths of the child or young person and the risks they may pose\n\nsupport them, their families and carers\n\ninclude clearly defined therapeutic goals\n\ninclude a safety plan that is agreed with the child or young person, their parents or carers and support network.\n\nEnsure the care plan:\n\nEncourages and supports children and young people to participate in a range of peer, school and community activities to help build a sense of belonging.\n\nIncludes supervised social activities that promote self-esteem, develop resilience and encourage socially appropriate behaviour.\n\nEnsure the care plan is reviewed by the multidisciplinary team, and with the child or young person and their parent or carers at 3- to\xa06‑monthly intervals, or if there is a significant change in circumstances.\n\n# Developing interventions for children and young people displaying harmful sexual behaviour\n\nStructure interventions, but make them flexible enough to meet changing needs and the developmental status and age of the child or young person. Include regular progress reviews by practitioners delivering the intervention.\n\nBase interventions on:\n\nA comprehensive assessment of the child or young person's family and social context. This includes: their placement (for example, home, foster care, residential care, secure children's home or other custodial settings).\n\nDevelopmental stage, gender, learning ability, culture and religion.\n\nFactors that may have contributed to the harmful sexual behaviour, such as their background, past care or any trauma they may have experienced.\n\nThe harmful sexual behaviour itself.\n\nConsider including the following elements:\n\nsafety planning to reduce the risk they pose to others and themselves\n\nengagement and working that takes account of their denial of the behaviour\n\nsex and relationships education including consent, boundaries and social and moral considerations\n\nempathy development\n\nhow to make good choices to keep themselves and others safe sexually\n\nemotional and self-regulation\n\nlife story work\n\nunderstanding of their harmful sexual behaviour\n\nvictimisation\n\npeer and social relationships\n\ncommunity reintegration for those who have spent time in residential or secure units\n\nsupport to make future plans.\n\nUse recognised treatment resources or guided interventions such as:\n\nAIM assessment and intervention model for boys and girls. This includes components for:\n\n\n\nchildren aged under\xa012 who have not committed a criminal offence, and\n\nchildren aged 10\xa0to\xa012 who have committed an offence (10\xa0is the age of criminal responsibility in England).\n\n\n\nAIM2 assessment and intervention model for boys aged 12\xa0to\xa018 within or outside the criminal justice system. This also has a component aimed at girls in the same age group and for those with learning disabilities. But note: the 'level of supervision' scale for young females (12\xa0to\xa018\xa0years) is likely to misrepresent the level of risk. A degree of caution is also advised when using it to predict sexual reoffending in young people with learning disabilities.\n\nBarnardo's Cymru Taith project for girls – assessment and treatment workbook.\n\nThe California Evidence-Based Clearinghouse for Child Welfare Children with problematic sexual behaviour cognitive-behavioural treatment program: preschool program and school-age program.\n\nGood Lives Model, a strengths-based programme.\n\nNSPCC manualised treatment programme Change for good (McCrory E, Walker-Rhymes P A treatment manual for adolescents displaying harmful sexual behaviour: change for good; London: Jessica Kingsley) aimed at boys aged 12\xa0to\xa018 in residential care.\n\nNSPCC harmful sexual behaviour programme Turn the page, a guided intervention that follows certain key principles for boys and girls aged 5\xa0to\xa018 and those with learning disabilities. This is suitable as a community-based approach.\n\nUse therapeutic approaches such as:\n\ncognitive behavioural therapy\n\nmultisystemic therapy for problematic sexual behaviour\n\npsychotherapeutic approaches\n\nstrengths-based approaches\n\nsystemic therapy (a type of family therapy).\n\nConsider 1\xa0or more of the following modes of delivery:\n\nindividual therapy\n\ngroup therapy\n\nfamily therapy.\n\nDeliver interventions in community and family settings, if it has been assessed as safe to do so.\n\nWork alongside care staff when delivering interventions in residential, secure or custodial settings. Ensure the care plan includes safety planning to reduce the risk the child or young person may pose to others in the same environment.\n\nConsider including family members when delivering interventions in residential, secure or custodial settings. Do this only if it is safe and has been agreed as part of the care plan (see recommendation\xa01.6.4).\n\n## Children and young people not living with their birth parents\n\nEnsure links with their family of origin or community are maintained if it is in the best interests of the child or young person. Maintain links with birth parents if safe and appropriate.\n\n## Children and young people who have been abused by a family member\n\nIf it is in the best interests of the child or young person, consider family reconciliation, re-integration and restorative approaches, if it is safe and appropriate.\n\n## Looked after children and young people\n\nEnsure the intervention supports carers. This includes giving them advice on how to respond to the risks presented by children and young people in their care.\n\n## Working with parents and carers\n\nEncourage caring relationships between the child or young person and their family and carer, if it is safe to do so. Recognise that looked after children and young people may have problems arising from insecure attachment, making the relationship with their carer very challenging (see NICE's guideline on children's attachment).\n\nHelp carers create a sense of belonging and trust to ensure the child or young person feels safe, valued and protected.\n\nConsider including the following elements in the programme:\n\nhow to work with parents and carers in denial about their child's harmful sexual behaviour\n\nsupport to come to terms with harmful sexual behaviour and its impact\n\nhow to understand harmful sexual behaviour risk indicators\n\nmaintaining safety plans, including ongoing supervision\n\naddressing the parent-child relationship, if needed\n\ncommunications and problem solving\n\nbehaviour management.See NICE's guidelines on:\n\nchallenging behaviour and learning disabilities, sections\xa01.5 to\xa01.11\n\nautism in under\xa019s: support and management, recommendations\xa01.4.1 to 1.4.13, and section\xa01.5\n\nviolence and aggression: short-term management in mental health, health and community settings.\n\n# Supporting a return to the community for 'accommodated' children and young people\n\nProvide ongoing support when children and young people in residential homes, secure children homes or young offenders' institutions move back into the community or return to the family home. This includes continuity of care for those who need this type of support.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.\n\n## Children\n\nIn this guideline, 'children' refers to anyone under\xa010.\n\n## Harmful sexual behaviour\n\nThis guideline uses the NSPCC definition of harmful sexual behaviour: 'One or more children engaging in sexual discussions or acts that are inappropriate for their age or stage of development. These can range from using sexually explicit words and phrases to full penetrative sex with other children or adults (NSPCC's advice on sexual behaviour in children).\n\n## Multi-agency safeguarding arrangements\n\nResponsibility for join up rests with three safeguarding partners (local authority, clinical commissioning group for an area, and chief officer of police for a police area) who have a shared and equal duty to work together to safeguard and promote the welfare of all children in a local area.\n\n## Risk assessment tool\n\nIn this guideline, this term is used for tools that estimate the risk of sexual re‑offending or the level of supervision needed, and help users decide what action to take. It includes tools such as J‑SOAP‑II and ERASOR, which are North American tools designed to assess the risk of sexual reoffending. The AIM assessment model was developed in the UK and considers the level of management and supervision needed for people displaying harmful sexual behaviour.\n\n## Young people\n\nIn this guideline, 'young people' refers to those aged 10\xa0to\xa018. It includes those on remand and those serving community or custodial sentences. The guideline also includes people aged up to\xa025 who display harmful sexual behaviour and have special educational needs or a disability. This age extension is in light of the Children and Families Act\xa02014.", 'Context': "Research indicates that many children and young people charged with criminal offences relating to harmful sexual behaviour had previously been referred to children's services. But their sexual behaviour was either not recognised or dismissed (Criminal Justice Joint Inspection's Examining multi-agency responses to children and young people who sexually offend).\n\nData indicate that children and young people with learning disabilities are over-represented among those in the criminal justice system (Criminal Justice Joint Inspection's Examining multi-agency responses to children and young people who sexually offend; Department of Health's needs and effective treatment of young people who sexually abuse: current evidence). However, few studies have been done with children and young people with learning disabilities.\n\nLittle is known about prepubescent children or young people whose sexual behaviour has not reached a level that would be regarded as criminal. There is also a lack of understanding of where these children and young people fit into the social care system, making it difficult to provide an effective response (Department of Health's needs and effective treatment of young people who sexually abuse: current evidence).\n\nEvidence suggests that sexualised behaviours in children and young people can be an expression of other problems or underlying vulnerabilities. It also suggests that early help assessments, without involving specialist harmful sexual behaviour services, can help. But there is little evidence of effectiveness on interventions addressing harmful sexual behaviour.\n\nThis guideline covers children and young people under\xa018 who display harmful sexual behaviour. It includes those on remand and those serving community or custodial sentences. It also includes people up to the age of\xa025 who have special educational needs or a disability, as set out the Children and Families Act 2014. This guideline does not deal with the consequences of sexual abuse. NICE has published a guideline on child abuse and neglect.", 'Committee discussion': "Links to evidence sources are given in square brackets. See evidence reviews for details.\n\n# Background\n\nThis guideline uses the NSPCC definition of harmful sexual behaviour: 'One or more children engaging in sexual discussions or acts that are inappropriate for their age or stage of development. These can range from using sexually explicit words and phrases to full penetrative sex with other children or adults.' (NSPCC's advice on sexual behaviour in children).\n\nUsing the term 'harmful sexual behaviour' avoids labelling young children as sexual offenders, but it does not reflect the diversity of children and young people who engage in sexualised behaviours.\n\nIt is critical to differentiate between sexually abusive behaviour and behaviours that are detrimental to the child or young person's development. Sexually abusive behaviours are coercive and involve forcing others to comply with an action. This can include oral, anal and vaginal penetration. Whereas behaviours that affect individual development could include, for example, compulsive masturbation or addiction to online pornography. Such behaviours may result in stigmatisation and victimisation, as well as making others feel uncomfortable.\n\nThere has been significant debate about how to describe children and young people displaying sexualised behaviour without labelling them as sex offenders. Difficulties in defining such behaviour are compounded by a general lack of knowledge of childhood sexuality and what constitutes normal sexual development.\n\nThe focus of this guideline is on children and young people who are sole perpetrators of harmful sexual activities, directed either towards themselves or other individuals. It does not focus on activities such as child sexual exploitation and peer-on-peer or gang-related sexual violence.\n\nThe Department for Education's Working together to safeguard children definition of sexual abuse (which covers physical, emotional and sexual abuse, and neglect) acknowledges that children can commit acts of sexual abuse. But it does not acknowledge that children and young people's sexual behaviour is on a continuum. The NSPCC's definition of harmful sexual behaviour acknowledges that children and young people's sexual behaviour is on a continuum. It defines harmful sexual behaviour as acts that are inappropriate for age or stage of development and are important factors when assessing and intervening with this group.\n\nChildren and young people's sexual behaviour problems are diverse. Various terms have been used to refer to children and young people who engage in developmentally unexpected sexual behaviours. These include: abuse-reactive, sexually reactive, sexually aggressive, sexualised children, children who molest, sexually abusive children and young sexual offenders.\n\nThe committee agreed with evidence from expert paper\xa01, and members' own experience, that many children and young people's display of harmful sexual behaviour will naturally come to an end as they mature. But members also agreed that concerns about a child or young person's sexualised behaviour should always be followed up and assessed.\n\nLittle is known about the number of prepubescent children who continue with harmful sexual activities as they get older. What is known is that only a small number go on to commit more serious sexual offences. In addition, the committee recognised the need to distinguish between chronological and developmental age when deciding how to assess and then intervene with this group.\n\nThe committee also agreed that it is important to distinguish between prepubescent children and adolescents for assessment purposes. Some behaviours may be considered normal in prepubescent children, for example, but would be of concern if they continue into adolescence. Likewise, behaviours that would be considered normal in adolescents may be regarded as highly unusual in prepubescent children and therefore merit a need for referral.\n\nIn addition, the committee recognised the need to distinguish between these groups in the context of the criminal justice system in England, where 10\xa0is the age of criminal responsibility. The committee also noted that the Children Act 1989 defines a child as someone who has not reached\xa018 and that young people enter the adult criminal justice system at age\xa018.\n\nThe committee noted that young people with ongoing or long-term health or social care needs may need to move into adult services at age 18\xa0or\xa025, if they have special educational needs or disabilities. It agreed that these transitions need to be managed as part of the harmful sexual behaviour assessment and intervention process.\n\nThe committee discussed the fact that pornography is now more readily available thanks to new technology, but no evidence was found in the systematic search of the literature. Expert testimony confirmed a significant gap in the literature on how pornography influences sexual behaviour [EP11]. So the committee agreed to make a research recommendation on this.\n\nSee also the section on gaps in the evidence, numbers\xa010\xa0to\xa012.\n\n# Section 1.1 Multi-agency approach\n\n## Multi-agency, multidisciplinary team\n\nThe discussion below explains how we made recommendations 1.1.1 to\xa01.1.3.\n\nThe committee acknowledged a number of statutory arrangements are relevant for children and young people displaying harmful sexual behaviour. This includes:\n\nSection 10 of the Children Act 2004. This makes local authorities responsible for promoting interagency cooperation to improve the welfare of children in need.\n\nOfsted's Early help: whose responsibility? and the Department for Education's Working together to safeguard children give local safeguarding children boards statutory responsibilities for children in need of protection and those with highly complex needs. Safeguarding boards are also responsible for developing thresholds for action.\n\nThe committee acknowledged that the involvement of health agencies will vary, because support is provided in a multi-agency context.\n\nThe committee discussed the role of children and adolescent mental health services (CAMHS) in this area. Members noted that, in their experience, referral thresholds to CAMHS vary and that not all CAMHS services would take referrals for children and young people displaying harmful sexual behaviour.\n\nThe committee also noted that there is no coherent national commissioning framework on harmful sexual behaviour for people living in secure accommodation and few secure children's homes or young offender institutions offer these services.\n\nThe committee recognised these recommendations were not based on evidence of effectiveness or cost effectiveness. Rather, they were framed by the Department for Education and Ofsted guidance on interagency working and were generated by consensus from their own experience and from 2\xa0expert testimonies [EP9 and EP10].\n\nFrom the committee's experience, interagency assessments would be a suitable route for developing multi-agency approaches. These could use, for example, the Common Assessment Framework (see 'Working together to safeguard children'), the local children safeguarding board and the Ministry of Housing, Communities and Local Government's Troubled Families Programme.\n\nThere was no evidence of effectiveness on the multi-agency approach but the committee agreed with the conclusions from 8\xa0qualitative studies (3\xa0high quality, 3\xa0moderate quality and 2\xa0low quality). These stated that early assessment should be 'joined up' with any subsequent therapeutic interventions, to ensure continuity between assessment and intervention [ES2.11, ES2.12].\n\nBased on their own experiences, members also agreed that a lack of effective interagency working is often a key factor in serious case reviews (see Department for Education's New learning from serious case reviews: a 2-year report for 2009 to 2011).\n\nThe committee agreed that failures in interagency working could have a serious 'knock on' effect and lead to a limited response to referrals. This may also have implications for cost effectiveness: failure to provide services may leave the behaviour unchecked and eventual entry into the criminal justice system. The latter would be expensive and is also likely to result in harm to others.\n\nThe committee reflected on expert testimony that described regional arrangements for harmful sexual behaviour services as well as agreements across agencies [EP10 and EP13].\n\nPractitioners working with children and young people with complex needs, such as autism spectrum condition or conduct disorder, need access to specialists working in harmful sexual behaviour services. It would not be possible to agree interagency care plans without a multidisciplinary team of professionals who meet regularly to agree and evaluate outcomes.\n\nThe committee agreed that the practice of closing a social work file on a child or young person once they have been referred to harmful sexual behaviour services is not helpful. Members described how, in some instances, referrals to harmful sexual behaviour services were declined because specialist services do not have the resources to deal with the child or young person's additional needs. They agreed there was a need for greater recognition that a range of agencies is usually needed to provide support.\n\nThe committee agreed that if nobody took lead responsibility for assessment and referral this could have a serious impact on delivery of the care plan. The 'knock-on' effect could be further harm to the child or young person, or risk of harm to others.\n\nMany local safeguarding children boards and child protection committees across the UK now include harmful sexual behaviours in their interagency procedures and policy documents. Many also offer short courses on young sexual abusers as part of their interagency training programmes.\n\nThe committee agreed that failure to provide local expertise using a coordinated, multi-agency approach will mean children and young people displaying more serious behaviour are likely to receive ad hoc assessments and interventions. Sometimes this might result in out-of-area placements that could prove expensive. It could also lead to delays in providing a more effective intervention in the child or young person's locality and at an earlier stage.\n\n## Multi-agency, multidisciplinary working\n\nThe discussion below explains how we made recommendations 1.1.4 to\xa01.1.8.\n\nCommittee members discussed their experience of working across agencies and disciplines within the harmful sexual behaviour service sector. Their experiences were generally positive, but they knew that there was room for improvement in many locations.\n\nThere was no empirical evidence of effectiveness or cost effectiveness.\n\nThe committee agreed that children and young people who display harmful sexual behaviour are likely to have complex needs that can only be met by numerous health and social care agencies working together. Members agreed that a well-established multi-agency response is likely to lead to multiple cost savings to society. This includes:\n\nsavings from otherwise lost educational and employment opportunities during the child or young person's life\n\nsavings from preventing harm to others.\n\nThe committee agreed that local safeguarding children boards should implement NICE recommendations in this area and should identify lead agencies to commission and develop harmful sexual behaviour services.\n\nThe committee noted that various services are needed to respond to this group of children and young people, and that a statutory response is not always necessary. It agreed that the safeguarding needs of children and young people referred for an early help assessment should be a priority, with the results used to determine whether a statutory or criminal justice response is needed. (For victims of sexual abuse, see Home Office and Department for Education's Reporting and acting on child abuse and neglect.) It recommended that a variety of referral and care pathways should be in place.\n\nThe committee heard testimony on the NSPCC harmful sexual behaviour framework [EP12]. It aims to improve local interagency working and coordination while recognising the resource constraints that local areas face. Members agreed that local authorities should offer a range of care pathways based on the 5\xa0core domains of the framework to create a consistent approach across services.\n\nCurrently there is no national strategy or overarching service delivery framework for harmful sexual behaviour. The NSPCC framework was developed by a wide range of partners and is being tested in a number of local authority areas.\n\nThe committee agreed that, in line with 'Working together to safeguard children', local safeguarding children boards should set thresholds for when to refer a child or young person for early help assessment or specialist harmful sexual behaviour services.\n\nThe committee saw local safeguarding children boards as a potential vehicle for ensuring a coordinated approach to meeting the needs of this group. This would have the benefit of making use of existing services to improve multiagency working.\n\nThe committee recommended that local safeguarding children boards should ensure local policies and procedures are in place to train staff in children's social services to deal with concerns about a child or young person's sexualised behaviour. Concerns may be raised by professionals working in universal services or members of the public.\n\nLocal safeguarding children boards should recommend resources for professionals working in universal services to consult when there are concerns over a child or young person's sexualised behaviour.\n\nThe committee agreed that these recommendations are informed by government guidance and form the basis of current health and social care practice. It also agreed that a brief consultation (or triage meeting) over the phone or face-to-face with a concerned parent or teacher and a specialist practitioner could sometimes be enough.\n\n## Information sharing\n\nThe discussion below explains how we made recommendations 1.1.9 to\xa01.1.12.\n\nThe committee agreed that information sharing between agencies remains a contentious issue. Members also agreed that fears about sharing information should not stand in the way of the need to promote the welfare and protect the safety of children. (See Department for Education's Information sharing: advice for practitioners providing safeguarding services to children, young people, parents and carers.)\n\nThe committee recognised that the recommendations were not based on evidence of effectiveness but reflected the committee's experience of serious case reviews (see Department for Education's New learning from serious case reviews: a 2-year report for 2009 to 2011). The issues are also highlighted in the Department for Education's report 'Working together to safeguard children.' Seven qualitative studies reported there is reluctance among practitioners to share assessments (2\xa0high quality, 4\xa0moderate, 1\xa0low) [ES2.13].\n\nThe committee also discussed the need for clear, effective protocols that are regularly evaluated. In particular, these protocols should highlight the adverse consequences of not sharing information – a point repeatedly made in serious case reviews, including cases of violent or sexual assault and rape.\n\nThere was no cost effectiveness evidence for this set of recommendations.\n\nUsing information-sharing protocols is regarded as good practice, as outlined in 'Working together to safeguard children'.\n\nThe committee considered that the resource impact of setting up and agreeing information sharing protocols would be negligible, particularly compared with:\n\nthe negative consequences associated with poor information sharing and interagency working identified in case reviews\n\nthe costs and quality-adjusted life year (QALY) losses attributed to sexual offences and rape in the economic modelling report.\n\nIn addition, information sharing using a locally agreed approach does not have a significant resource impact because it uses established pathways and protocols, as set out in 'Working together to safeguard children'.\n\n# Section 1.2 Named safeguarding leads in universal services\n\nThe discussion below explains how we made recommendations 1.2.1 to\xa01.2.4.\n\n## Current practice\n\nAny professional working in universal services who is concerned about the sexualised behaviour of a child or young person has a responsibility to notify their organisation's named safeguarding professional. Named safeguarding leads should discuss their concerns with children's social services so a decision can be made about whether referral for an early help assessment is needed (see Ofsted's Early help: whose responsibility?).\n\nThe committee noted, however, that members were aware of instances where such behaviour had been ignored and children had been harmed.\n\n## Evidence of effectiveness\n\nNo evidence of effectiveness was identified for this section. The recommendations are linked to the Department for Education's guidance 'Working together to safeguard children'. This requires professionals in universal services and those providing services to adults working with children to identify emerging problems and share this with other professionals involved in early identification and assessment of harmful sexual behaviour. It requires them to discuss concerns and referrals through agreed routes so appropriate referrals are made, to reduce risk of stigmatisation.\n\nThe committee agreed that professionals working in universal services should use locally agreed resources to identify if a child or young person's behaviour is a cause for concern [ES2.1].\n\n# Section 1.3 Early help assessment\n\nThe discussion below explains how we made recommendations 1.3.1 to\xa01.3.10.\n\nSee also the section on gaps in the evidence, number\xa02.\n\n## Current practice\n\nThe principles of early help assessment are discussed in the Department for Education's guidance 'Working together to safeguard children' (see current practice in the section on multi-agency, multidisciplinary team of the committee discussion). This type of assessment is key to identifying and addressing needs not being met by universal services. For example, it can identify the need for:\n\ntargeted services\n\nspecialist harmful sexual behaviour assessment\n\nreferral to the child protection team\n\nreferral to the criminal justice system.\n\nOther helpful tools include: Department for Education's use of whole family assessment to identify families with multiple problems, and Youth Justice Board for England and Wales' AssetPlus, previously known as the Youth Offending Asset assessment.\n\nIn their experience, members said that early help professionals and professionals not trained to work with people displaying harmful sexual behaviour need more information and resources to identify such behaviour. That is because referrals to children's services are based on a generic practice model and not one that specialises in harmful sexual behaviour.\n\n## Evidence for effectiveness\n\nThe committee agreed that an early help assessment using, for example, the Common Assessment Framework, can help identify what additional help the child or young person and their family need, apart from that provided by universal health and social care services. The early help assessment provides a model for gathering and recording information about the child or young person's strengths and needs, based on discussions with the family. It can also form the basis for their care plan.\n\nThe committee agreed that the early help assessment should be done by a lead professional who supports the child and family, acts as an advocate on their behalf, and coordinates the delivery of services. The decision on who should lead should be made on a case-by-case basis, with input from the child or young person and their family. It could be a GP, family support worker, school nurse, social worker or health visitor.\n\nThe committee agreed that it should be made clear which agencies are responsible for children and young people who do not fall under the remit of child protection, or who do not need harmful sexual behaviour services but do have unmet needs.\n\nThe committee agreed that a locally agreed identification tool should be used as part of the early help assessment for a child or young person displaying sexualised behaviour that is a cause for concern [ES2.1, ES2.13].\n\nThe committee based these recommendations on government guidance on early help (see 'Working together to safeguard children'). It also included expert testimony that recognised the need for early help to prevent escalation [EP12 and EP13].\n\nThere is no evidence on how effective tools are at identifying harmful sexual behaviour, but the committee agreed that a tool should be used as part of the early help assessment. This will help to identify harmful sexual behaviour and improve decision making. The aim would be to screen for age and developmentally inappropriate sexualised behaviour and language to decide whether to refer on to specialist harmful sexual behaviour services.\n\nTools commonly referred to in the literature, or used in practice, include: the Brook Traffic Light Tool and Hackett's continuum model of children and young people's sexual behaviours, patterns and cycles [ES2.1].\n\n## Evidence for cost effectiveness\n\nThere was no cost effectiveness evidence for this set of recommendations. The committee did not make it a priority for modelling. It considered the cost impact to be negligible because it is widely considered to be good working practice (see resource impact section below).\n\n## Additional factors taken into account\n\nThe committee considered that such assessments could prevent the escalation of sexualised behaviour. This, in turn, could prevent the need for specialist harmful sexual behaviour services, a statutory assessment under the Children Act 1989 or involvement of the criminal justice system.\n\nThe committee agreed that interagency assessments should use a joined-up process that focuses on outcomes.\n\nAssessments should acknowledge chronological age and developmental status, and what constitutes healthy sexual behaviour among children and young people. This is particularly true when discussing children and young people with a neurodevelopmental disorder such as autism or a learning disability.\n\nThe committee also agreed that often, as children and young people mature, they stop displaying harmful sexual behaviour. However, their life chances may still be impaired (because of their previous behaviour or related factors). So they may need ongoing assessment and input, particularly in relation to educational and employment opportunities [EP1].\n\nThe committee acknowledged that those working with children and young people displaying inappropriate sexualised behaviour need a greater understanding of the benefits of an early help assessment. However, members also wanted to ensure that unnecessary assessments and referrals do not occur that may be stigmatising, so they included caution around this area in the recommendations.\n\nSexual behaviours exist on a continuum that ranges from normal and developmentally appropriate to highly abnormal and violent [EP1]. There is little evidence on interventions that address behaviours that fall short of thresholds needing a response from specialist harmful sexual behaviour services or the criminal justice system.\n\nLocating sexual behaviour on a continuum that is related to development age is an important part of the assessment process, and can help practitioners and families make distinctions between different sexual behaviours.\n\nThe committee acknowledged that using assessment tools with prepubescent age groups that were designed for older groups could be harmful.\n\nThe committee agreed with expert paper\xa07. This recommends that when assessing children and young people displaying sexualised behaviour, practitioners should distinguish between children and young people in general and those with special educational needs and learning disabilities, or with autism. It noted that although the latter form a significant minority, there is a lack of tools for assessing their behaviour.\n\nThe committee agreed that using a tool to identify the sexual behaviour of children and young people would help make practitioners aware that this behaviour exists on a continuum. It would also help determine whether a referral to specialist services is necessary. Members recognised that if the tool is not designed for the subgroup being assessed, the results may not be accurate.\n\n## Resource impact and implementation issues\n\nUse of early help assessment is regarded as good working practice. It provides a shared assessment and planning framework for all children's services in England. Because of this, the committee does not consider these recommendations will have any additional resource impact, except in areas that are not following good practice.\n\nThe committee believed that early identification and intervention would be cost effective by preventing escalation of the behaviour and avoiding involvement of the criminal justice system.\n\n# Section 1.4 Risk assessment for children and young people referred to harmful sexual behaviour services\n\nThe discussion below explains how we made recommendations 1.4.1 to\xa01.4.7.\n\nSee also the section on gaps in the evidence, number\xa02.\n\n## Current practice\n\nRisk assessment tools are used to assess specific risks and needs arising from a child or young person's harmful sexual behaviour. In the UK, different models are used depending on whether they come into contact with child welfare, mental health or the criminal justice system.\n\nWhen children and young people are charged by the Crown Prosecution Service for harmful sexual behaviour, the offence cannot be discussed with them while the case continues. But an assessment can still take place.\n\nThe committee discussed the AIM assessment model, which was originally developed for practitioners in the criminal justice system, but could be used in the community [EP8]. The committee was told that current practice is dominated by AIM2 designed primarily for boys and young men aged 12\xa0to\xa018. The AIM model considers the level of management and supervision needed, together with the person's development and intervention needs. Members were also told that although the AIM assessment model has led to a more standardised approach, it is unclear how it might be applied outside the criminal justice system.\n\nMembers noted that the AIM model for under‑12s is used to assess:\n\nchildren under\xa012\n\nchildren between 10\xa0and\xa012 whose harmful sexual behaviour needs a criminal justice response (10\xa0being the age of criminal responsibility in England).\n\nMembers noted that AIM2 is used mainly to assess males aged 12\xa0to\xa018 and:\n\nFocuses on factors linked to the risk of harmful sexual behaviours.\n\nBrings together elements from the more general approach outlined in the Department of Health's Framework for the assessment of children in need and their families (this guidance was subsumed into 'Working together to safeguard children' and is no longer current) and the Youth Offending Asset assessment (Youth Justice Board for England and Wales) now AssetPlus.\n\nTakes into account clinical factors.\n\nThe committee also discussed whether AIM2 could be used with young females and young people with learning disabilities. Members agreed this should be on a more limited basis. The developers of AIM2 do not recommend using the 'level of supervision' scale for young females, as it is likely to misrepresent the level of risk. A degree of caution is also advised when using AIM2 to predict sexual reoffending in young people with learning disabilities. At this stage the committee agreed the evidence available was too limited to make recommendations in these areas. It noted that further research is needed on assessing risk in all children and young people (see research recommendation\xa05).\n\n## Evidence for effectiveness\n\nThe committee considered the evidence of effectiveness for various risk assessment tools in terms of predicting sexual and non-sexual re-offending. It noted that 10\xa0of the 11\xa0quantitative studies in the evidence review were based on adolescent boys with a mean age of\xa015 who had been convicted of sexual offences.\n\nOnly 1\xa0study included girls and a younger age group (boys 12.3\xa0years and girls 11.9\xa0years) who had recently begun to display harmful sexual behaviour [ES2.3]. All the studies were from North America, which may limit their applicability in the UK. They were all at risk of bias from the methods used.\n\nThe committee considered:\n\nJ‑SOAP‑II (5\xa0low to moderate quality studies on future sexual re-offending). The evidence was inconsistent: 3\xa0predicted sexual re-offending, 2\xa0did not [ES2.3].\n\nERASOR (4\xa0moderate to high quality studies). Three predicted sexual re‑offending, 1\xa0did not [ES2.5].\n\nAdapted AIM and AIM2 (2\xa0moderate quality studies on future sexual re-offending). Both studies predicted that adolescents with and without learning disabilities who were previously known to sexually offend would reoffend [ES2.2].\n\nJ‑SORRAT‑II (2\xa0studies, 1\xa0low and 1\xa0moderate quality). One study found it was able to predict future sexual re-offending among adolescent males convicted of a sexual offence, the other found no effect [ES2.8].\n\nThe committee noted that although the evidence is contradictory for J‑SOAP‑II and ERASOR [ES2.3, ES2.4, ES2.5, ES2.6, ES2.7], the tools look promising for assessing young people's risk of sexual and non-sexual reoffending.\n\nThe committee agreed that although the evidence from adapted AIM and AIM2 studies is limited [ES2.2, EP8], they are promising tools and are relevant because they were developed in the UK. Only limited attempts have been made to test their predictive validity [ES2.2].\n\nAIM2 is also now being used (with caution) for girls and for those with learning disabilities. So the committee recommended further research on AIM2.\n\nSo the committee was unable to make a strong recommendation for the use of AIM for under‑12s or AIM2.\n\nThe committee agreed that the J‑SORRATT‑II was still undergoing research and was not used outside North America, so it could not currently recommend its use as a risk assessment tool [ES2.8].\n\nThere was no evidence that tools focusing on strengths (BERS-2) enhance the accuracy of ERASOR to predict sexual re-offending among adolescent young men who have committed a sexual offence [ES2.7].\n\nThe committee also considered evidence from 2\xa0quantitative studies (moderate quality) on the SAVRY and YLS/CMI tools. It noted that SAVRY was unable to predict sexual or non-sexual reoffending for adolescent males convicted of a sexual offence [ES2.9]. The YLS/CMI tool did not predict sexual reoffending but did predict non-sexual violence, and any potential for non-sexual re-offending [ES2.10].\n\nThe committee considered 11\xa0qualitative studies: 3\xa0papers were rated high, 6\xa0moderate and 2\xa0low quality. Two moderate quality studies stated that AIM2 offered a more standardised approach to assessment, and encouraged better cooperation between young offender teams and social care departments in the UK. But practitioners reported frustration because they were not properly trained to use it. In addition, there was some confusion about its purpose and how the findings might be applied in practice [ES2.14].\n\nThe committee discussed the literature on risk assessment tools to predict future sexual violence. Members agreed it is limited because the number of re-offenders recruited into research studies is too small for the research designs needed to validate tools. This means that most UK agencies are using largely under-tested models to underpin their assessments of risk and need. So further research is urgently needed (see research recommendation\xa05).\n\n## Evidence for cost effectiveness\n\nThere was no cost effectiveness evidence for this set of recommendations. The committee agreed that a good initial assessment is vital when making decisions about therapeutic interventions, treatment placements and care plans.\n\n## Additional factors taken into account\n\nThere are no fully validated models or frameworks to suggest what core elements should be included in risk assessment tools.\n\nThe quantitative evidence on sexual abuse was largely drawn from North America. It reported on small clinical populations of relatively high-risk young people referred for specialist treatment. The assessment models used were adapted from models used for male adults convicted of a sexual offence.\n\nAssessing the risk of sexual re-offending among young people is particularly challenging because of the enormous changes they undergo at this age. The committee also noted a key finding from research that indicates that many young people who engage in offending behaviours stop them as they mature (Moffitt T Adolescence-limited and life course persistent anti-social behaviour: a developmental taxonomy; Psychological Review 100: 674–701).\n\nThe committee noted 2\xa0specific risk trajectories evident in samples of young sexual abusers: general antisocial behaviours and harmful sexual behaviour. Most young people charged with sexual offences do not re-offend sexually, although the rate of non-sexual re-offending is substantially higher than average.\n\nThe committee agreed that risk assessment tools should consider a range of key elements, including the factors that led to the behaviour. The tools should also address the need for ongoing support and re-assessment [ES1.6, ES1.28].\n\nThe committee discussed risk assessment tools for different subgroups and acknowledged the lack of tools and models for different population groups.\n\nThe committee agreed that risk assessment tools and models designed for adolescents convicted of a sexual offence should not be used with prepubescent children displaying harmful sexual behaviour.\n\nThere are few empirical studies of assessment tools and interventions directed at the small proportion of girls and young women who sexually abuse others [EP4]. Research has indicated that females convicted of a sexual offence differ from males in various ways. For example, harmful sexual behaviour in girls is more likely to be motivated by aggression against them. The committee acknowledged the valuable work being done in this area by Barnardo's Cymru Taith project.\n\nEvidence paper\xa04 discussed how boys and girls with harmful sexual behaviour are treated differently. For example, boys are more likely to be removed from mainstream school.\n\n## Trade-off between benefits and harms\n\nBenefits include the adoption of a consistent approach to assessment. In addition, using locally agreed tools allows practitioners from different agencies and professional backgrounds to share information.\n\nHowever, potential harm could come from the fact that the assessment of the level of risk is not accurate. On the one hand, this could lead to an over-punitive or over-restrictive approach. On the other, it could sometimes mean the child or young person does not get the support they need to prevent further harmful sexual behaviour, so exposing them to risk – to themselves and others.\n\n## Resource impact and implementation issues\n\nThe committee noted that AIM for under‑12s and AIM2 were developed for the UK, but have to be paid for and involve specialist training. In comparison, J‑SOAP‑II, and ERASOR are free and specialist training is not needed, so they would have less impact on training needs and resources. But their applicability in England is unknown.\n\nOverall, the committee could not recommend 1\xa0tool over another and noted that most effectiveness evidence came from North America. Internationally, the 2\xa0tools with the highest degree of empirical support are ERASOR and J‑SOAP‑II, although the evidence for predicting sexual re-offending is not consistent across studies. Further studies are needed on larger samples. Also, studies are needed to compare the use of different models with the same samples.\n\nIn the absence of more consistent evidence, the committee agreed that it might be best if practitioners use AIM2, ERASOR, or J‑SOAP‑II for assessing risk. If time allows, the committee recognised that there may be benefits if the ERASOR and J‑SOAP‑II are used together to compare the use of these two models over time. In each case, the developers also recommend that practitioners use their own clinical judgement.\n\nOnly the most promising tools were included in the recommendations as examples of what was available. But the committee agreed that, given the uncertainty in the evidence base more research is needed (see research recommendation\xa05).\n\nThe committee also agreed by consensus that in their expert opinion children's social services and NHS England are best placed to identify who should undertake a risk assessment and these names were added to recommendation\xa01.4.1.\n\n# Section 1.5 Engaging with families and carers before an intervention begins\n\nThe discussion below explains how we made recommendations 1.5.1 to\xa01.5.4.\n\n## Current practice\n\nNot all practitioners meet with families and carers before an intervention begins.\n\n## Evidence for effectiveness\n\nThere was no quantitative evidence of effectiveness on the role of practitioners. Six qualitative studies and 2\xa0expert testimonies identified key features and approaches that practitioners could use to reduce barriers to services and improve communications between the practitioner and children, young people, parents and carers [EP9 and EP10].\n\nThe committee agreed that before an intervention begins, practitioners must consider whether the child or young person has been abused within the family or the victim is another family member. (See also NICE's guidelines on when to suspect child maltreatment and child abuse and neglect.)\n\nThe committee agreed with 2\xa0high quality qualitative studies that offering families and carers the opportunity to meet the programme practitioner before an intervention starts may help to overcome any fears about getting involved in and continuing with the programme [ES1.23, ES1.24].\n\nThe committee agreed with 2\xa0qualitative studies (moderate to high quality) that family and carer participation and support is crucial to getting young people involved with interventions. It also helps reinforce intervention messages in the home [ES1.20].\n\nThe committee agreed with 2\xa0qualitative studies of moderate to high quality on the need for practitioners to accommodate a child or young person's changing needs and offer a flexible service to accommodate their social activities to maintain their interest [ES1.16, ES1.22].\n\nThe committee agreed with 3\xa0high quality qualitative studies and expert papers\xa09 and\xa010 that the therapist's relationship with the child or young person is vital if an intervention is to be effective [ES1.21]. Members also agreed that, in their experience, interventions were only as good as the person providing them.\n\n## Evidence for cost effectiveness\n\nThere was no cost effectiveness evidence for this set of recommendations, but the committee agreed that encouraging practitioners to meet beforehand is likely to improve the outcome of the intervention. So they are likely to be cost effective and potentially cost saving.\n\n## Trade-off between benefits and harms\n\nThe committee agreed that the main benefit would be greater involvement with the intervention and improved outcomes for the child or young person, their family and carers.\n\n## Resource impact and implementation issues\n\nThe committee agreed that this recommendation would have a resource impact, particularly in terms of arranging meetings that are not part of the therapeutic intervention. But members agreed that increasing attendance and improving the relationship between the child or young person and the practitioner could lead to better outcomes and offset any resource implications.\n\n# Section 1.6 Developing and managing a care plan for children and young people displaying harmful behaviour\n\nThe discussion below explains how we made recommendations 1.6.1 to\xa01.6.5.\n\n## Current practice\n\nPractice may vary. But good practice involves using a care plan based on the results of the assessment of the child or young person's risks and needs.\n\n## Evidence of effectiveness\n\nBased on members' own experience, the committee agreed that care planning should be based on the results of the needs and risk assessment and should include the use of recognised resources.\n\n## Resource impact and implementation issues\n\nThe committee believed that these recommendations would not result in increased costs but would probably improve outcomes [ES1.15].\n\n# Section 1.7 Developing interventions for children and young people displaying harmful sexual behaviour\n\nThe discussion below explains how we made recommendations 1.7.1 to\xa01.7.15.\n\nSee also the section on gaps in the evidence (number\xa01).\n\n## Current practice\n\nCurrent practice is often based on cognitive behavioural therapy models used to treat adult men who have sexually offended. Developed originally in the US, these models came to prominence in the UK probation and prison services from the late 1980s.\n\n## Evidence for effectiveness\n\nThe evidence of effectiveness was from North America and may be only partially applicable to a UK population. The interventions reviewed mainly focused on those convicted of a sexual offence in treatment settings and will have limited applicability to children and young people outside the criminal justice system.\n\nMany types of intervention are used to help children and young people displaying harmful sexual behaviour but not all of them have been evaluated.\n\nThe committee considered evidence statements covering 13\xa0quantitative studies (4\xa0randomised controlled trials, 3\xa0controlled studies and 6\xa0before-and-after studies). It noted that although the studies were grouped for analysis according to type of intervention, many included elements drawn from a range of approaches. This included cognitive behavioural therapy (CBT) and multisystemic therapy. It also considered qualitative evidence from 26\xa0studies (11\xa0low, 9\xa0moderate, 6\xa0high quality studies).\n\nOf the 13\xa0quantitative studies, 9 (2\xa0randomised controlled trials, 1\xa0controlled study and 6\xa0before-and-after studies) of variable quality reported on the effectiveness of CBT-based approaches. These comprise a range of components delivered to both individuals and groups and focus on the sexually abusive behaviour.\n\nFour papers reported on 3\xa0studies of multisystemic therapy. Two randomised controlled trials and 1\xa0controlled study (ranging from low to moderate quality) reported that multisystemic therapy significantly reduced the risk of adolescent sexual re-offending compared with CBT or usual care.\n\nOne controlled study (moderate quality) using adventure-based therapy (Legacy) for adolescent boys convicted of a sexual offence, reported no difference between the intervention and control group for re-offending rates for violent sexual offences.\n\nThe committee considered the evidence on CBT interventions from 4\xa0low to moderate quality quantitative studies. These were abuse-focused and targeted the sexual behaviour of juveniles convicted of sexual offences using 1\xa0or several components of CBT. This included:\n\nsatiation therapy, a method for reducing deviant sexual arousal\n\nverbal satiation – repeatedly talking about deviant sexual fantasies to reduce sexual arousal from such fantasies\n\nvicarious sensitisation, a form of conditioning used to treat teenage boys who have displayed harmful sexual behaviour towards younger children\n\ncognitive restructuring therapy to help people to think differently about a situation, event, thought, or belief.\n\nThe committee noted the positive direction of all 4\xa0studies but agreed that, on balance and from members' expert opinion and experience, it could not recommend these types of interventions [ER1, ES1.1, ES1.2, ES1.3, ES1.4, ES1.5].\n\nThe committee agreed with evidence from 3\xa0low to moderate quality qualitative studies that stigma and ostracism may arise if a child or young person is labelled as a sex offender. It was keen to highlight that children and young people with harmful sexual behaviour are not 'mini adult sex offenders' and that offering interventions that are abuse-focused is potentially stigmatising [ES1.25].\n\nThe committee considered a study of moderate quality that compared CBT with dynamic play therapy with boys (61%) and girls (39%) aged 5\xa0to\xa012. This targeted a range of harmful behaviours and included families and carers. It reported no significant difference between the 2\xa0approaches. Both improved the children's ability to socialise while reducing their behavioural, affective and sexual behaviour problems [ES1.7].\n\nThe committee agreed the positive outcomes were likely to have resulted from the types of components that were included in each approach. This included: behaviour modification and psychoeducational principles in the CBT group; and client-centred and psychodynamic play therapy principles in the play therapy group [ES1.7].\n\nThe committee also considered evidence on 2\xa0CBT programmes for young people displaying a range of harmful behaviours and personality disorders: SAFE‑T (Sexual Abuse, Family Education and Treatment Programme) and Thought Change System. Both interventions included family members and carers. (The evidence comprised 2\xa0low to moderate quality quantitative studies.)\n\nBoth reported a decrease in harmful behaviours, with the SAFE‑T programme reporting a 72% reduction in re-offending rates for sexual assault [ES1.6 and ES1.8].\n\nThe committee considered the evidence of effectiveness for multisystemic therapy compared with CBT-based usual care for adolescents convicted of sexual offences.\n\nTwo moderate quality quantitative studies found that significantly fewer people from the multisystemic therapy group had been re-arrested for sexual offences at follow-up than from the comparison group [ES2.9].\n\nOne moderate quality quantitative study found that multisystemic therapy for adolescents charged with sexual offences led to a reduction in deviant sexual interests when compared with CBT-based usual care [ES1.10]. Two moderate quality quantitative studies reported improvements in problem sexual behaviour, psychiatric symptoms, antisocial behaviour, family and peer relations and school performance among adolescents charged with sexual offences, compared with CBT-based usual care [ES1.11, ES1.12, ES1.13].\n\nMultisystemic therapy focuses on the family, which means its use will be limited because a significant number of children and young people who display harmful sexual behaviour are in out-of-home placements. Its main goal is to reduce the risk of re-offending by enhancing family and peer relationships. A big benefit is that carers become better at identifying friends who were having a negative influence on their adolescents and advising their children to stop associating with them.\n\nResearch suggests, however, that multisystemic therapy may not be as effective with all subgroups of young people who display harmful sexual behaviour. For example, there is a strong link between antisocial peer groups and young people whose harmful sexual behaviour is often directed towards peers and accompanied by other non-sexual criminality. This group is different from those whose harmful sexual behaviour targets younger, prepubescent children. The latter are less likely to have a social life or strong peer friendship groups.\n\nThe committee heard expert testimony on the ongoing trial of Multi-systemic therapy – problematic sexual behaviour in the UK and agreed that this may, in future, offer more conclusive results [EP14]. It noted that previous evaluations of the programme in the US were positive, and had been carried out by its designers.\n\nThe committee noted the results from 1\xa0moderate quality study that evaluated an adventure-based programme (Legacy). This reported no difference for re-arrest rates for violent sex offences between groups but appears to be beneficial in reducing future risks of non-sexual reoffending [ES1.14].\n\nDrawing on expert papers\xa02 and\xa05, members agreed that the duration and intensity of interventions should be adapted for those with learning disabilities. (For example, by having more frequent, shorter sessions, or longer sessions as necessary, or fewer participants in group sessions.)\n\nThe committee agreed with the evidence from 1\xa0moderate quantitative study and 3\xa0moderate to high quality qualitative studies that understanding the factors that lead to harmful sexual behaviour is an important part of relapse prevention and making future plans [ES1.6, ES1.17].\n\nThe committee agreed that victim empathy is a contested component of harmful sexual behaviour interventions [ES1.18].\n\nThe committee also agreed with the results from 6\xa0qualitative studies (3\xa0low, 1\xa0moderate, 2\xa0high) that interventions involving children and young people in supervised social activities helps promote self-esteem and socially appropriate behaviour [ES1.15].\n\nThe committee noted the evidence from 1\xa0moderate quantitative study and 2\xa0low to moderate qualitative studies highlighting the concerns of families and young people about not getting support to maintain their progress. The committee agreed this was an important component of services [ES1.6, ES1.28].\n\nThe committee agreed with 14\xa0qualitative studies (11\xa0low, 1\xa0moderate, 2\xa0high quality) that reported that communication skills, social skills training and anger management or 'emotional regulation' are important components of any intervention [ES1.19, ES1.27].\n\nThe committee noted the results from 3\xa0qualitative studies (1\xa0high, 1\xa0moderate, 1\xa0low) that showed that group interventions (for both the child and young person and their family and carer) can reduce their sense of isolation and provide valuable support. But members also noted that it may be problematic for those who find it difficult to talk in front of others [ES1.26]. In addition, they noted the difficulties involved in treating perpetrators of harmful sexual behaviour alongside their victims, as highlighted in 4\xa0qualitative studies (2\xa0moderate, 2\xa0low) [ES1.25].\n\n## Evidence for cost effectiveness\n\nThe committee made the recommendations on cognitive behavioural therapy, multisystemic therapy and play therapy a priority for economic modelling. The model results showed a cost per QALY of under £20,000, but the committee questioned these estimates and thought that not all these therapies would in fact be cost effective. This is particularly true for children and young people who did not need a custodial sentence. That is because the studies that underpinned the modelling were from North America, where comparators are different.\n\nGiven that the multisystemic therapy trial in the UK has yet to report, the committee suggested that it would be prudent to continue with current approaches – but make them work better by following the recommendations outlined in this guideline. Getting better results at the same cost would automatically be cost effective.\n\nIf the current trial shows that more expensive methods are more effective than current methods, the approach advocated here (continuing with current practice) could be revised.\n\n## Additional factors taken into account\n\nThe sexual behaviour of children and young people exists on a continuum that ranges from normal and developmentally appropriate to highly abnormal and violent. Various approaches are needed to address these different behaviours. But there is little evidence on interventions that address behaviours that fall short of thresholds needing a response from the criminal justice system.\n\nThe qualitative studies identified programmes offering relapse prevention, anger management (emotional restraint), victim empathy, communication and social skills training. They also documented the emergence of family-level interventions and the role of the therapist as important components. The committee noted that mode of delivery (such as face-to-face or in groups) should be based on the needs and circumstances of the child or young person, as highlighted in the assessment and using clinical judgement.\n\nThe qualitative studies also highlighted the components of an intervention that participants, their families and professionals feel have value. But it is not clear which components are most effective for different groups.\n\nThe committee agreed that having to choose between cognitive behavioural therapy and multisystemic therapy is not realistic and that there are advantages to both (this includes the fact that effectiveness can depend on the family circumstances).\n\nIn the absence of clear evidence, the committee recommended continued use of these therapies. The evidence reported was based on small numbers of participants (and conducted by developers of the intervention in the case of multisystemic therapy). Members agreed that more research, with a low risk of bias and relevant to UK practice, is needed (see research recommendation\xa03).\n\nMembers acknowledged that multisystemic therapy is a more complex approach that needs the child or young person to be living in the family home or in a stable foster family situation (for at least 18\xa0months in the case of multisystemic therapy Problematic Sexual Behaviour). As a significant proportion of children and young people displaying harmful sexual behaviour may not be living in a family situation this approach may not work. In that respect, cognitive behavioural therapy might be a more pragmatic solution but, the downside is that it needs more follow-up once the intervention has ended.\n\nThe committee did not put the list of interventions in order of priority, because the results of the child or young person's assessment should help practitioners decide what type of intervention to offer. Members agreed that what was needed was a 'toolbox' of approaches that could be tailored to individual needs. From their own experience, they agreed that comprehensive, multicomponent interventions that focus on the child or young person's family and background are more promising than those that focus solely on the abusive behaviour.\n\nThe committee also discussed looked after children and young people displaying harmful sexual behaviour and the need for foster carers to be adequately trained. It heard testimony from expert paper\xa010 that young people in the care system with harmful sexual behaviour often experience multiple placement moves. This, in turn, can affect the child's willingness to form attachments and makes therapeutic interventions more challenging.\n\n# Section 1.8 Supporting a return to the community for 'accommodated' children and young people\n\nThe discussion below explains how we made recommendation\xa01.8.1.\n\n## Current practice\n\nThe Glebe House model, a specialist children's home, is an example of residential practice in this area. It is based on a therapeutic community model for adolescent males with a known history of harmful sexual behaviours. The committee noted that the Glebe House model is not usual practice in this area, and that the types of interventions offered at Glebe House are very different from those offered by custodial services.\n\nYoung people in a young offender's institution serving a custodial sentence for a sexual offence do not always receive harmful sexual behaviour services. Local youth offending teams should provide this service but it can take months to arrange. That's because it may involve transferring the person to a young offender's institution that offers specialist services. It is not uncommon for a transfer from one custodial setting to another to take place a few months before the release date.\n\nThe committee noted that even where harmful sexual behaviour services are commissioned, the threshold for provision varies and is occasionally too high. For example, young people who receive a custodial sentence for harmful sexual behaviour may not be offered these services if their sentence is under 6\xa0months.\n\nYouth Justice Board statistics for 2014/15 show that the average time, from the date of an offence being committed until completion of court proceedings, is 66\xa0days. But for sexual offences this rises to 295\xa0days – so many would not be eligible for support by the time they are sentenced. In addition, young people aged between 12\xa0and\xa017 who receive a 12‑month detention training order would not be eligible. That is because half the sentence will be spent in custody and the other half will be supervised by the youth offending team in the community.\n\nHowever, the Wakefield harmful sexual behaviour model allows all young people displaying harmful sexual behaviour, whether or not it is part of the offence, to be referred. This is also regardless of the length of time they spend in custody and whether or not they receive a custodial or community sentence.\n\nIn this model, any agency involved with the young person can refer and self-referrals are also accepted. Everyone is offered a consultation plus a transition package, regardless of whether they are discharged into the community or transferred to adult prison.\n\n## Evidence for effectiveness\n\nThe committee noted that a small number of children and young people displaying harmful sexual behaviour may warrant placement in a specialist residential or secure setting. It drew on evidence from expert paper\xa06 as an example of a specialist children's home that uses a therapeutic community model.\n\nThe committee agreed that, if possible, residential settings should draw on the values and approaches of a therapeutic model originally developed in the field of social psychiatry by Rapoport and Roscow (Community as doctor ; New York: Arno Press). This is based on 5\xa0social psychology principles: attachment, containment, communication, involvement and agency.\n\nThe committee agreed that interventions in residential settings should be based on the principles outlined in this guideline, including the principles and approaches set out in section\xa01.6 and section\xa01.7.\n\nThe committee agreed that residential settings should also provide a range of services, including ongoing support, to enable a child or young person to successfully integrate back into the community. In addition, if it is in the best interests of the child or young person, out-of-home care should not undermine relationships with their family. The committee referred to evidence previously noted for sections\xa01.7 and to ES1.6 and ES1.28.\n\n# Evidence reviews\n\nDetails of the evidence discussed are in evidence reviews, reports and papers from experts in the area.\n\nThe evidence statements are short summaries of evidence. Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement (ES) ES1.1 indicates that the linked statement is numbered 1 in review 1. ES2.1 indicates that the linked statement is numbered 1 in review 2. EP1 indicates expert paper 1 'Definitions, epidemiology and natural history of HSB'. EP2 indicates expert paper 2 'Developmental pathways towards sexually harmful behaviour and emerging personality disorder traits in childhood'. EP3 indicates expert paper 3 'Harmful sexual behaviour of children'. EP4 indicates expert paper 4 'Girls who display harmful sexual behaviour – developing assessment tools and intervention resources'. EP5 indicates expert paper 5 'Glebe House'. EP6 indicates expert paper 6 'Turn the page'. EP7 indicates expert paper 7 'Harmful sexual behaviour – children and young people with learning difficulties who display harmful sexual behaviour'. EP8 indicates expert paper 8 'AIM project'. EP9 indicates expert paper 9 'Service user expert testimony'. EP10 indicates expert paper 10 'Practitioner and advocate expert testimony'. EP11 indicates expert paper 11 'Pornography and its impact on harmful sexual behaviour'. EP12 indicates expert paper 12 'The development of an operational framework for children and young people who sexually harm'. EP13 indicates expert paper 13 'An overview of policy and practice'. EP14 indicates expert paper 14 'MST PSB trial'.\n\nIf the committee considered other evidence, it is linked to the appropriate recommendation below.\n\nSection 1.1: ES2.9; EP1, EP9, EP10\n\nSection 1.2: ES2.1, ES2.13; EP1, EP7; Department for Education's 'Working together to safeguard children.'\n\nSection 1.3: ES2.1; EP7, EP12\n\nSection 1.4: ES1.6, ES1.28, ES2.2, ES2.3, ES2.4, ES2.5, ES2.6, ES2.7, ES2.8, ES2.10, ES2.14; EP3, EP4, EP7, EP8\n\nSection 1.5: ES1.16, ES1.18, ES1.20, ES1.21, ES1.22, ES1.23, ES1.24; EP1, EP9, EP10\n\nSection 1.6: ES1.6, ES1.17, ES1.28, ES2.2, ES2.3, ES2.4, ES2.5, ES2.6, ES2.7, ES2.11, ES2.13; EP3, EP4, EP8\n\nSection 1.7: ES1.6, ES1.7, ES1.8, ES1.10, ES1.11, ES1.12, ES1.13, ES1.14, ES1.15, ES1.16, ES1.17, ES1.19, ES1.25, ES1.26, ES1.27, ES1.28; EP2, EP3, EP5, EP9, EP10, EP14\n\nSection 1.8: ES1.6, ES1.15, ES1.28; EP5, EP9, EP10\n\n## Gaps in the evidence\n\nThe committee's assessment of the evidence on harmful sexual behaviour and stakeholder comments identified a number of gaps. These are set out below.\n\n. A comparison of the effectiveness of therapeutic approaches such as cognitive behavioural therapy and multisystemic therapy for children and young people who display harmful sexual behaviour and their family and carers.\n\n(Source ER1)\n\n. Evidence of effectiveness for recognised assessment and treatment models, such as the Good Lives Model and AIM2, for children and young people who display harmful sexual behaviour.\n\n(Source ER1)\n\n. Empirically evaluated tools to assess need and predict the risk of harmful sexual behaviour among children and young people in the community including:\n\ndifferent age groups (that is, children under\xa010 and children and young people aged 10\xa0and older).\n\nthose with neurodevelopmental or learning disabilities\n\nthose from black and minority ethnic communities\n\nthose at the less severe end of the harmful sexual behaviour spectrum.\n\n(Source ER2)\n\n. Evidence on interventions aimed at younger children (prepubescent or under\xa010) who display sexualised behaviour that is of concern.\n\n(Source ER1)\n\n. Evidence on actuarial models used to assess children and young people who display harmful sexual behaviour.\n\n(Source ER1)\n\n. Rates for continued problematic sexual behaviours following prepubescence.\n\n(Source EP1)\n\n. Factors that encourage children and young people to go on to commit more serious sexual offences.\n\n(Source EP1)\n\n. Evidence of the impact that pornography and new technologies have on harmful sexual behaviour such as sexting, the posting of sexual images and grooming.\n\n(Source EP11)", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Long-term outcomes for children and young people displaying harmful sexual behaviour\n\nWhat are the long-term outcomes for children and young people displaying harmful sexual behaviour, when should practitioners intervene and what potentially modifiable factors have the most important impact?\n\n## Why this is important\n\nLongitudinal evidence spanning the life-course of children and young people who display harmful sexual behaviour is needed to understand when to intervene. This is particularly true for children and young people whose sexual behaviour does not warrant an intervention from harmful sexual behaviour services or the criminal justice system.\n\nThere is a lack of evidence on thresholds for intervening, including evidence on modifiable risk and protective factors that prevent the behaviour escalating. We also need evidence on quality-of-life measures.\n\nAs a result, we should be able to avoid mislabelling younger children as 'sexual offenders' and subjecting them to intrusive and stigmatising interventions.\n\n# Effective interventions for children and young people displaying harmful sexual behaviour\n\nWhat interventions are effective with children and young people displaying harmful sexual behaviour?\n\n## Why this is important\n\nMost of the evidence on interventions is inconclusive. It comes from small clinical populations of adolescent males convicted of sexual offences. More research is needed on the effectiveness of current interventions and to understand how to avoid children and young people who display sexualised behaviour being taken into the criminal justice system. This includes research on:\n\nprepubescent children\n\nyoung women\n\nchildren and young people with neurodevelopmental and learning disabilities\n\nminority ethnic and migrant communities\n\nlooked after children (including those in non-family-based settings).\n\nchildren and young people in the criminal justice system (community and custody).\n\nEvidence on interventions for looked-after children needs to include those in non-family-based settings and in unstable foster care. For this group, there is also a lack of evidence on interventions to promote placement stability and permanence, as well as on interventions specifically relating to harmful sexual behaviour. The former is needed because a stable home life may help reduce the risk of harmful sexual behaviour.\n\nEvidence of effective interventions could help target resources more effectively and ensure programmes are tailored to meet children and young people's differing needs.\n\n# Effective interventions for the families and carers of children and young people displaying harmful sexual behaviour\n\nWhat type of therapeutic interventions are effective when working with the family and carers of children and young people who display harmful sexual behaviour?\n\n## Why this is important\n\nEvidence on effective interventions for families and carers of children and young people who display harmful sexual behaviour is equivocal. Evidence of effectiveness for the 2\xa0most common approaches – cognitive behavioural therapy and multisystemic therapy – and other therapies is very limited. Further research is needed to help practitioners tailor interventions according to need.\n\n# Early interventions to prevent problems escalating\n\nWhat interventions are effective in diverting children and young people away from further harmful sexual behaviour before a legal response is needed?\n\n## Why this is important\n\nThere is a need for more evidence on what is effective in diverting children and young people away from further harmful sexual behaviour at the earliest stages of its development. Research is needed on missed opportunities to intervene and what the trajectory has been for those children and young people who were missed. Such evidence could help ensure children and young people receive timely support to prevent an escalation of the behaviour.\n\n# Assessment models for different groups of children and young people\n\nHow effective are the models currently used for assessing the needs of, and level of risk for, children and young people from different population groups who display harmful sexual behaviour?\n\n## Why this is important\n\nAssessment is at the heart of effective intervention planning and risk management. Without good assessment models, levels of risk may be misclassified. To date, risk assessment tools have mainly been used on small clinical populations of adolescent males who have sexually offended and there is a need for assessment tools for other groups of children and young people. Assessment results are also a basis for needs assessment and decisions about therapeutic interventions, treatment placements and care plans.\n\nFor those in the criminal justice system, an assessment provides a clear guide to sentencing and multiagency management (for example, multi-agency public protection arrangements).\n\nLack of evidence on current assessment models means that we know little about:\n\nproblems caused by mislabelling a child or young person\n\nimpact of the assessment process on the child and young person and their families and carers\n\ntreatment outcomes.\n\n# Electronic media\n\nHow does the use of electronic media affect harmful sexual behaviour?\n\n## Why this is important\n\nThe reasons behind the growth in online grooming, the viewing of online pornography, and the making and distributing of sexual images is poorly understood. There have been few studies into the links between aggressive behaviour, sexual offending and the use of electronic media.\n\nLongitudinal studies are needed to understand the impact electronic media has on sexual behaviour and on the general values, attitudes, beliefs and behaviour of children and young people. Research is also needed on its long-term impact on children and young people's social and psychological development. Such research could provide evidence on how best to assess, intervene and manage the risks associated with the use of electronic media in this area.", 'Glossary': "# Cognitive behavioural therapy\n\nCognitive behaviour therapy for people displaying harmful sexual behaviour typically includes: identifying previous circumstances leading to sexual arousal, accepting responsibility for offensive behaviour, social skills training, empathy and relapse prevention.\n\n# Cognitive restructuring therapy\n\nMethods that help people to think differently about a situation, event, thought, or belief.\n\n# Common Assessment Framework\n\nEarly help assessments, such as the Common Assessment Framework, identify what help the child and family need to prevent their needs escalating to a point where intervention would be needed via a statutory assessment under the Children Act 1989.\n\n# Conduct disorder\n\nA serious behavioural problem that can last a long time and can affect a child or young person's ability to lead a normal life. Common signs and symptoms include:\n\naggressive behaviour towards people or animals\n\ndestructive behaviour towards other people's property\n\nlying and stealing\n\nplaying truant from school.\n\nFor older children and adolescents, this can also include smoking, drinking alcohol, substance abuse and engaging in unprotected sexual activities.\n\n# Developmental age\n\nA child or young person's social, emotional, physical and intellectual maturity compared with typical behaviours and characteristics for their chronological age.\n\n# Early help assessments\n\nEarly help assessments identify what help a child and family may need to prevent their needs escalating. They are for children and families who may need targeted support from several agencies.\n\n# Guided interventions\n\nGuided interventions offer practitioners a set of key principles on which to base interventions.\n\n# Multisystemic therapy\n\nMultisystemic therapy is an intensive community- and home-based approach to a broad set of adolescent problem behaviours, including harmful sexual behaviour. The emphasis is on interventions that target specific, well-defined problems. The aim is to empower carers to address family members' needs.\n\n# Neurodevelopmental disorders\n\nDisorders that typically appear early in a child's development, often before they enter school. They are characterised by impairments in personal, social, academic, or occupational functioning. Examples are: learning disability, autism spectrum condition, speech and language disorders and ADHD (attention deficit hyperactivity disorder).\n\n# Prepubescent\n\nA child who has not yet reached puberty.\n\n# Problematic sexual behaviour\n\nUnusual and socially unexpected behaviour. It may not involve victimisation and consent issues may be unclear but it may make others uncomfortable or interfere with the child or young person's healthy psychosexual development.\n\n# Safeguarding\n\nAll organisations that work with or come into contact with children and young people should have safeguarding policies and procedures to ensure that they all, regardless of their age, gender, religion or ethnicity, can be protected from harm.\n\n# Satiation therapy\n\nA procedure that involves the pairing of prolonged masturbation (1\xa0hour) with a verbal commentary by the patient of his or her deviant sexual fantasies.\n\n# Sexually abusive\n\nA term mainly used to describe sexual behaviours initiated by a child or young person in which there is an element of manipulation or coercion, or the subject of the behaviour is unable to give informed consent.\n\n# Strengths-based programmes\n\nStrengths-based programmes are a collaboration between the person and the services supporting them. Programmes consider not only factors that are of concern but build on the person's capabilities and strengths.\n\n# Universal services\n\nUniversal services are those services provided to all children and young people such as schools, health visiting, GPs.\n\n# Youth criminal justice\n\nThe youth criminal justice system is for those aged 10\xa0to\xa017 years: people aged\xa018 go through the adult criminal justice system.\n\nFor other public health and social care terms, see the Think Local, Act Personal's Care and Support Jargon Buster."}	https://www.nice.org.uk/guidance/ng55	This guideline covers children and young people who display harmful sexual behaviour, including those on remand or serving community or custodial sentences. It aims to ensure these problems don’t escalate and possibly lead to them being charged with a sexual offence. It also aims to ensure no-one is unnecessarily referred to specialist services.
b8b1b8feb5b2d7c71b8b809201aaab8c76c4e441	nice	Mental health problems in people with learning disabilities: prevention, assessment and management	Mental health problems in people with learning disabilities: prevention, assessment and management This guideline covers preventing, assessing and managing mental health problems in people with learning disabilities in all settings (including health, social care, education, and forensic and criminal justice). It aims to improve assessment and support for mental health conditions, and help people with learning disabilities and their families and carers to be involved in their care. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we used words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Using this guideline with other NICE guidelines ## Improving the experience of care Use this guideline with: the NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services, to improve the experience of care for adults with learning disabilities and mental health problems recommendations for improving the experience of care for children and young people in the NICE guidelines on specific mental health problems the NICE guideline on challenging behaviour and learning disabilities if relevant. ## Interventions for mental health problems in people with learning disabilities Use this guideline with the NICE guidelines on specific mental health problems and other NICE guidelines on mental health services. Take into account: differences in the presentation of mental health problems communication needs (see recommendation 1.3.1) decision-making capacity (see recommendation 1.3.2) the degree of learning disabilities the treatment setting (for example, primary or secondary care services, mental health or learning disabilities services, in the community or the person's home) interventions specifically for people with learning disabilities (see the section on social and physical environment interventions and the sections on psychological, pharmacological and occupational interventions). # Organisation and delivery of care and support ## Organising effective care A designated leadership team of healthcare professionals, educational staff, social care practitioners and health and local authority commissioners should develop and implement service delivery systems in partnership with people with learning disabilities and mental health problems and (as appropriate) their family members, carers, self-advocates or care workers. The designated leadership team should ensure that care is: person-centred and integrated within a care programme negotiable, workable and understandable for people with learning disabilities and mental health problems, their family members, carers or care workers, and staff accessible and acceptable to people using the services responsive to the needs and abilities of people with learning disabilities, and that reasonable adjustments (in line with the Equality Act 2010) are made if needed regularly audited to assess effectiveness, accessibility and acceptability. The designated leadership team should ensure that care pathways: cover all health, social care, support and education services, and define the roles and responsibilities of each service have designated staff who are responsible for coordinating: how people are involved with a care pathway transition between services within and across different care pathways maintain consistency of care have protocols for sharing information: with the person with learning disabilities and a mental health problem and their family members, carers or care workers (as appropriate) with other staff (including GPs) involved in the person's care are focused on outcomes (including measures of quality, service user experience and harm) establish clear links (including access and entry points) to other care pathways (including those for physical health problems). The designated leadership team should ensure that young people with learning disabilities and mental health problems have in place plans that address their health, social, educational and recreational needs (including Education, Health and Care Plans), as part of their transition to adult services and adulthood. This planning should start when young people are aged 14 and follow the NICE guideline on transition from children's to adults' services. The designated leadership team, together with health and social care providers, should ensure that care pathways: provide access to all NICE-recommended interventions for mental health problems clearly state the responsibilities of specialist learning disabilities and specialist mental health services to ensure people's needs are met. For people with learning disabilities who need acute inpatient treatment for a serious mental illness, provide treatment: within a locally available service where possible and with staff who are skilled and knowledgeable in the care and treatment of mental health problems in people with learning disabilities. Staff working with people with learning disabilities and mental health problems should ensure they are fully informed about: the nature and degree of the learning disabilities the nature and severity of the mental health problem, and any physical health problems (including sensory impairments). All people with learning disabilities and a serious mental illness should have a key worker who: coordinates all aspects of care, including safeguarding concerns and risk management helps services communicate with the person and their family members, carers or care workers (as appropriate) clearly and promptly, in a format and language suited to the person's needs and preferences monitors the implementation of the care plan and its outcomes. Health, social care and education services should train all staff who may come into contact with people with learning disabilities to be aware: that people with learning disabilities are at increased risk of mental health problems that mental health problems may develop and present in different ways from people without learning disabilities, and the usual signs or symptoms may not be observable or reported that people with learning disabilities can develop mental health problems for the same reasons as people without learning disabilities (for example, because of financial worries, bereavement or relationship difficulties) that mental health problems are commonly overlooked in people with learning disabilities where to refer people with learning disabilities and suspected mental health problems. Health and social care services should ensure that staff who deliver interventions for people with learning disabilities and mental health problems are competent, and that they: receive regular high-quality supervision deliver interventions based on relevant manuals, if available evaluate adherence to interventions take part in the monitoring of their practice (for example, by using video and audio recording, external audit and scrutiny). Health and social care staff who deliver interventions for people with learning disabilities and mental health problems should consider using routine sessional outcome measures, including service-user-reported experience measures. # Involving people with learning disabilities, and their family members, carers or care workers, in mental health assessment and treatment ## Communication Take into account the person's communication needs and level of understanding throughout assessments, treatment and care for a mental health problem, and: speak to the person directly rather than talking about or over them use clear, straightforward and unambiguous language assess whether communication aids, an advocate or someone familiar with the person's communication methods are needed make adjustments to accommodate sensory impairments (including sight and hearing impairments) explain the content and purpose of every meeting or session use concrete examples, visual imagery, practical demonstrations and role play to explain concepts communicate at a pace that is comfortable for the person, and arrange longer or additional meetings or treatment sessions if needed use different methods and formats for communication (written, signing, visual, verbal, or a combination of these), depending on the person's preferences (see NHS England's Accessible Information Standard for guidance on ensuring people with learning disabilities receive information in formats they can understand) regularly check the person's understanding summarise and explain the conclusions of every meeting or session check that the person has communicated what they wanted. ## Consent, capacity and decision-making Assess the person's capacity to make decisions throughout assessment, care and treatment for the mental health problem on a decision-by-decision basis, in accordance with the Mental Capacity Act and supporting codes of practice (see NICE's information on making decisions about your care). Help people make decisions by ensuring that their communication needs are met (see recommendation 1.3.1) and (if appropriate) involving a family member, carer, care worker or other individual familiar with the person's communication abilities. Staff delivering care to people with learning disabilities and mental health problems should: discuss the assessment process and treatment options with the person and provide information in a format and language suited to their needs, including: potential benefits potential side effects or disadvantages the purpose of treatment -utcome measures ensure that the person understands the purpose, plan and content of any meeting or intervention before it starts, and regularly throughout address any queries or concerns that the person may have at any stage allow enough time for the person to make an informed choice if they have decision-making capacity, and if they do not then provide enough time for their family members, carers or care workers to contribute fully. ## Involving family members, carers and care workers Encourage and support family members, carers and care workers (as appropriate) to be actively involved throughout the assessment, care and treatment of the person's mental health problem, apart from in exceptional circumstances when an adult or young person with decision-making capacity has said that they do not want them involved. Give family members, carers and care workers (as appropriate) information about support and interventions in a suitable format and language, including NICE's information for the public. # Support and interventions for family members and carers Advise family members and carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers). When providing support to family members (including siblings) and carers: recognise the potential impact of living with or caring for a person with learning disabilities and a mental health problem explain how to access: family advocacy family support and information groups disability-specific support groups for family members or carers provide skills training and emotional support, or information about how to access these, to help them take part in and support interventions for the person with learning disabilities and a mental health problem. If a family member or carer also has an identified mental health problem, offer: interventions in line with the NICE guidelines on specific mental health problems or referral to a mental health professional who can provide interventions in line with NICE guidelines. # Social and physical environment interventions Health, social care and education services should consider the impact of the social and physical environment on the mental health of children and young people with learning disabilities when developing care plans, and: provide positive educational environments that are appropriate to their needs when care placements (such as birth family to foster care, foster care to adoptive placement, home to residential school/college) are required, minimise the risk of placement breakdown by taking particular care to fit these to the needs of the person. give special consideration and support to looked-after children and young people with learning disabilities and their foster parents or care workers, to reduce the child or young person's very high risk of developing mental health problems, and the risk of changes in their home and carers (see the NICE guideline on looked-after children and young people). Health, social care and education services should consider the impact of the social and physical environment on the mental health of adults with learning disabilities when developing care plans,and: support people to live where and with whom they want encourage family involvement in the person's life, if appropriate support people to get involved in activities that are interesting and meaningful to them plan for and help people with any significant changes to their living arrangements. # Annual health check The following recommendations on annual health checks for people with learning disabilities build on recommendation 1.2.1 in the NICE guideline on challenging behaviour and learning disabilities, which relates to the provision of annual physical checks by GPs to all people with learning disabilities. GPs should offer an annual health check using NHS England's learning disability annual health check electronic clinical template to all adults with learning disabilities, and all children and young people with learning disabilities who are not having annual health checks with a paediatrician. Involve a family member, carer or care worker (as appropriate), or a healthcare professional or social care practitioner who knows the person well, in the annual health check. Take into account that more time may be needed to complete health checks with people with learning disabilities. Include the following in annual health checks: a mental health review, including any known or suspected mental health problems and how they may be linked to any physical health problems a physical health review, including assessment for the conditions and impairments which are common in people with learning disabilities a review of all current interventions, including medication and related side effects, adverse events, interactions and adherence an agreed and shared care plan for managing any physical health problems (including pain). During annual health checks with adults with Down's syndrome, ask them and their family members, carers or care workers (as appropriate) about any changes that might suggest the need for an assessment of dementia, such as: any change in the person's behaviour any loss of skills (including self-care) a need for more prompting in the past few months. # Identification and referral Staff and others caring for people with learning disabilities should consider a mental health problem if a person with learning disabilities shows any changes in behaviour, for example: loss of skills or needing more prompting to use skills social withdrawal irritability avoidance agitation loss of interest in activities they usually enjoy. Staff should consider using identification questions (adjusted as needed) as recommended in the NICE guidelines on specific mental health problems to identify common mental health problems in people with learning disabilities. Paediatricians should explain to parents of children identified with learning disabilities that mental health problems are common in people with learning disabilities, and may present in different ways. If a mental health problem is suspected in a person with learning disabilities, staff should conduct a triage assessment to establish an initial formulation of the problem. This should include: a description of the problem, including its nature, severity and duration an action plan including possible referral for further assessment and interventions. Refer people with learning disabilities who have a suspected serious mental illness or suspected dementia to a psychiatrist with expertise in assessing and treating mental health problems in people with learning disabilities. # Assessment ## Conducting a mental health assessment A professional with expertise in mental health problems in people with learning disabilities should coordinate the mental health assessment, and conduct it with: the person with the mental health problem, in a place familiar to them if possible, and help them to prepare for it if needed the family members, carers, care workers and others that the person wants involved in their assessment -ther professionals (if needed) who are competent in using a range of assessment tools and methods with people with learning disabilities and mental health problems. Speak to the person on their own to find out if they have any concerns (including safeguarding concerns) that they don't want to talk about in front of their family members, carers or care workers. Before mental health assessments: agree a clear objective, and explain it to the person, their family members, carers or care workers (as appropriate), and all professionals involved explain the nature and duration of the assessment to everyone involved explain the need to ask certain sensitive questions address any queries or concerns that the person may have about the assessment process. When conducting mental health assessments, be aware: that an underlying physical health condition may be causing the problem that a physical health condition, sensory or cognitive impairment may mask an underlying mental health problem that mental health problems can present differently in people with more severe learning disabilities. When conducting mental health assessments, take into account the person's: level of distress understanding of the problem living arrangements and settings where they receive care strengths and needs. During mental health assessments: establish specific areas of need to focus on assess all potential psychopathology, and not just the symptoms and signs that the person and their family members, carers or care workers first report describe the nature, duration and severity of the presenting mental health problem take into account the person's cultural, ethnic and religious background review psychiatric and medical history, past treatments and response review physical health problems and any current medication, and refer to other specialists for review if needed review the nature and degree of the learning disabilities, and if relevant the person's developmental history assess for problems that may be associated with particular behavioural phenotypes (for example, anxiety in people with autism and psychosis in people with Prader–Willi syndrome), so that they can be treated assess the person's family and social circumstances and environment, and recent life events assess the level of drug or alcohol use as a potential problem in itself and as a factor contributing to other mental health problems establish or review a diagnosis using: a classification system such as DSM-5 or ICD-10, or those adapted for learning disabilities (for example the Diagnostic Manual – Intellectual Disability or Diagnostic Criteria for Psychiatric Disorders for Use with Adults with Learning Disabilities/Mental Retardation ) or problem specification assess whether a risk assessment is needed (see recommendation 1.8.18). Assess recent changes in behaviour using information from family members, carers, staff or others involved in the assessment as well as information from relevant records and previous assessments. Take into account the nature, quality and length of their relationship with the person. Use the results of the mental health assessment to develop a written statement (formulation) of the mental health problem, which should form the basis of the care plan (see recommendation 1.8.23) and cover: an understanding of the nature of the problem and its development precipitating and maintaining factors any protective factors the potential benefits, side effects and harms of any interventions the potential difficulties with delivering interventions the adjustments needed to deliver interventions the impact of the mental health problem and associated risk factors on providing care and treatment. Provide the person, their family members, carers or care workers (as appropriate), and all relevant professionals with a summary of the assessment: in an agreed format and language that sets out the implications for care and treatment. Give the person and their family members, carers or care workers (as appropriate) another chance to discuss the assessment after it has finished, for example at a follow-up appointment. ## Further assessment Consider conducting a further assessment that covers any areas not explored by the initial assessment, if: new information emerges about the person's mental health problem or there are significant differences between the views of the person and the views of their family members, carers, care workers or staff about the problems that the assessment has focused on. ## Assessment tools During any mental health assessment: consider using tools that have been developed or adapted for people with learning disabilities and take cost into account if more than one suitable tool is available. If using tools that have not been developed or adapted for people with learning disabilities, take this into account when interpreting the results. When conducting an assessment with a child or young person with learning disabilities, consider using tools such as the Developmental Behavior Checklist – parent version (DBC-P) or the Strengths and Difficulties Questionnaire (SDQ). When assessing depressive symptoms in an adult with learning disabilities, consider using a formal measure of depression to monitor change over time, such as the Glasgow Depression Scale (the self-report for people with milder learning disabilities or the carer supplement for people with any degree of learning disabilities). Consider supplementing an assessment of dementia with an adult with learning disabilities with: measures of symptoms, such as the Dementia Questionnaire for People with Learning Disabilities (DLD), the Down Syndrome Dementia Scale (DSDS) or the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) measures of cognitive function to monitor changes over time, such as the Test for Severe Impairment (TSI) measures of adaptive function to monitor changes over time. Complete a baseline assessment of adaptive behaviour with all adults with Down's syndrome. ## Risk assessment When conducting risk assessments with people with learning disabilities and mental health problems, assess: risk to self risk to others (including sexual offending) risk of self-neglect vulnerability to exploitation likelihood and severity of any particular risk potential triggers, causal or maintaining factors whether safeguarding protocols should be implemented. If indicated by the risk assessment, develop a risk management plan with the person and their family members, carers or care workers (as appropriate). Risk management plans should: set out individual, social or environmental interventions to reduce risk be communicated to family members, carers or care workers (as appropriate) and all relevant staff and agencies. Risk assessments and resulting risk management plans should be reviewed regularly and adjusted if risk levels change. ## Mental health assessment during a crisis Conduct an initial assessment for people who are experiencing a mental health crisis, which should: include an assessment of the person's mental health include a risk assessment (see recommendations 1.8.18 to 1.8.21) include identification of interventions to: help address the problem that caused the crisis minimise any associated risks bring stability to the individual and their immediate environment produce a crisis plan that sets out (using the least restrictive options possible) how to reduce the likelihood of further crises, and what to do if the person has another crisis. ## The mental health care plan Develop a mental health care plan with each person with learning disabilities and a mental health problem and their family members, carers or care workers (as appropriate), and integrate it into their other care plans. Base mental health care plans on the written statement (formulation) and include in them: goals agreed with the person and the steps to achieve them treatment decisions agreed outcome measures that are realistic and meaningful to the person, to monitor progress early warning signs of relapse or exacerbation of symptoms, if known risk and crisis plans, if needed (see recommendations 1.8.18 to 1.8.22) steps to minimise future problems. Ensure that the mental health care plan sets out the roles and responsibilities of everyone involved in delivering it, and that: the person can easily access all interventions and services in the plan it is communicated to everyone involved, including the person and their family members, carers or care workers (as appropriate) there is an agreement on when the plan will be reviewed. # Psychological interventions ## Delivering psychological interventions for mental health problems in people with learning disabilities For psychological interventions for mental health problems in people with learning disabilities, refer to the NICE guidelines on specific mental health problems and take into account: the principles for delivering psychological interventions (see recommendations 1.9.2 to 1.9.4) and the specific interventions recommended in this guideline (see recommendations 1.9.5 to 1.9.9). Use the mental health assessment to inform the psychological intervention and any adaptations to it, and: tailor it to their preferences, level of understanding, and strengths and needs take into account any physical, neurological, cognitive or sensory impairments and communication needs take into account the person's need for privacy (particularly when offering interventions on an outreach basis) agree how it will be delivered (for example, face-to-face or remotely by phone or computer), taking into account the person's communication needs and how suitable remote working is for them. If possible, collaborate with the person and their family members, carers or care workers (as appropriate) to: develop and agree the intervention goals develop an understanding of how the person expresses or describes emotions or distressing experiences agree the structure, frequency, duration and content of the intervention, including its timing, mode of delivery and pace agree the level of flexibility needed to effectively deliver the intervention agree how progress will be measured and how data will be collected (for example, visual representations of distress or wellbeing). Be aware that people with learning disabilities might need more structured support to practise and apply new skills to everyday life between sessions. In discussion with the person, consider: providing additional support during meetings and in the planning of activities between meetings asking a family member, carer or care worker to provide support and assistance (such as reminders) to practise new skills between meetings. ## Specific psychological interventions Consider cognitive behavioural therapy, adapted for people with learning disabilities (see recommendation 1.9.2 on intervention adaptation methods), to treat depression or subthreshold depressive symptoms in people with milder learning disabilities. Consider relaxation therapy to treat anxiety symptoms in people with learning disabilities. Consider using graded exposure techniques to treat anxiety symptoms or phobias in people with learning disabilities. Consider parent training programmes specifically designed for parents or carers of children with learning disabilities to help prevent or treat mental health problems in the child, and to support carer wellbeing. Parent training programmes should: be delivered in groups of parents or carers be accessible (for example, take place outside normal working hours or in community settings with childcare facilities) focus on developing communication and social functioning skills typically consist of 8 to 12 sessions lasting 90 minutes follow the relevant treatment manual use all of the necessary materials to ensure consistent implementation of the programme seek parent feedback. # Pharmacological interventions For pharmacological interventions for mental health problems in people with learning disabilities, refer to the NICE guidelines on specific mental health problems and take into account the principles for delivering pharmacological interventions (see recommendations 1.10.2 to 1.10.9). For guidance on adherence and the safe and effective use of medicines, see the NICE guidelines on medicines adherence and medicines optimisation. Only specialists with expertise in treating mental health problems in people with learning disabilities should start medication to treat a mental health problem in: adults with more severe learning disabilities (unless there are locally agreed protocols for shared care) children and young people with any learning disabilities. Before starting medication for a mental health problem in children, young people or adults with learning disabilities: take account of: potential medication interactions the potential impact of medication on other health conditions the potential impact of other health conditions on the medication when necessary consult with specialists (for example, neurologists providing epilepsy care when prescribing antipsychotic medication that may lower the seizure threshold), to minimise possible interactions assess the risk of non-adherence to the medication regimen or any necessary monitoring tests (for example, blood tests), and the implications for treatment establish a review schedule to reduce polypharmacy provide support to improve adherence (see the NICE guideline on medicines adherence) assess whether support from community and learning disabilities nurses is needed for physical investigations (such as blood tests) agree monitoring responsibilities, including who will carry out blood tests and other investigations, between primary and secondary care. Monitor and review the benefits and possible harms or side effects, using agreed outcome measures and taking into account communication needs. If stated in the relevant NICE guideline, use the timescales given for the specific disorder to inform the review, and adjust it to the person's needs. When deciding the initial dose and subsequent increases, aim for the lowest effective dose. Take account of both potential side effects and difficulties the person may have in reporting them, and the need to avoid sub-therapeutic doses that may not treat the mental health problem effectively. Prescribers should record: a summary of what information was provided about the medication prescribed, including side effects, to the person and their family members, carers or care workers (as appropriate) and any discussions about this when the medication will be reviewed plans for reducing or discontinuing the medication, if appropriate full details of all medication the person is taking, including the doses, frequency and purpose. For people with learning disabilities who are taking antipsychotic drugs and not experiencing psychotic symptoms: consider reducing or discontinuing long-term prescriptions of antipsychotic drugs, review the person's condition after reducing or discontinuing a prescription consider referral to a psychiatrist experienced in working with people with learning disabilities and mental health problems annually document the reasons for continuing the prescription if it is not reduced or discontinued. When switching medication, pay particular attention to discontinuation or interaction effects that may occur during titration. Only change one drug at a time, to make it easier to identify these effects. # Occupational interventions In keeping with the preferences of the person with learning disabilities and mental health problems, all staff should support them to: engage in community activities, such as going to a library or sports centre access local community resources such as libraries, cinemas, cafes and leisure centres take part in leisure activities, such as hobbies, which are meaningful to the person.Reasonable adjustments may be needed to do this (in line with the Equality Act 2010), such as a buddy system, transport, or advising local facilities on accessibility. Actively encourage adults with learning disabilities (with or without a mental health problem) to find and participate in paid or voluntary work that is meaningful to them, if they are able. Consider providing practical support to adults with learning disabilities (with or without a mental health problem) to find paid or voluntary work, including: preparing a CV identifying personal strengths and interests completing application forms preparing for interviews accompanying the person to interviews completing any pre-employment checks. Health and social care services should take account of an adult or young person's sensory, physical, cognitive and communication needs and the severity of their mental health problem (if any), and consider: helping them to identify and overcome any possible challenges during employment appointing supported employment workers to provide ongoing support to adults with learning disabilities and their employers providing information and guidance to potential employers about the benefits of recruiting people with learning disabilities assisting employers in making reasonable adjustments to help them to work (in line with the Equality Act). # Terms used in this guideline ## Carer A person who provides unpaid support to someone who is ill, having trouble coping or has disabilities. ## Care pathways Defined in this guideline as the ways different services interact with each other, and how people access and move between them. ## Care worker A person who provides paid support to someone who is ill, having trouble coping or has disabilities, in a variety of settings (including residential homes, supported living settings and day services). ## Children Aged 0 to12 years. ## Key worker A key worker (also known as a care or case coordinator) is a central point of contact for the person with a mental health problem, family members, carers and the services involved in their care. They are responsible for helping the person and family members or carers to access services and for coordinating the involvement of different services. They ensure clear communication between all people and services and have an overall view of the person's needs and the requirements of their care plan. ## Learning disabilities Learning disabilities are commonly divided into 'mild', 'moderate', 'severe' and 'profound', but these categories are based on IQ and most UK health and social care services do not measure this. Therefore, this guideline uses the terms 'milder learning disabilities' (approximating to mild and moderate learning disabilities that are often defined as an IQ of 35 to 69 and impairment of adaptive functioning with onset in childhood) and 'more severe learning disabilities' (approximating to severe and profound learning disabilities that are often defined as an IQ of 34 or below with impairment of adaptive functioning with onset in childhood). All people with learning disabilities: need additional support at school need support in some areas of adult life, such as budgeting, planning, time management, and understanding complex information need more time to learn new skills than people who don't have learning disabilities. People with milder learning disabilities: may be able to live independently and care for themselves, managing everyday tasks and working in paid employment can often communicate their needs and wishes may have some language skills may have needs that are not clear to people who do not know them well. People with more severe learning disabilities are more likely to: need support with daily activities such as dressing, washing, food preparation, and keeping themselves safe have limited or no verbal communication skills or understanding of others need support with mobility have complex health needs and sensory impairments. ## Serious mental illness Defined in this guideline as: severe and incapacitating depression or anxiety, psychosis, schizophrenia, bipolar disorder or schizoaffective disorder. ## Staff Healthcare professionals and social care practitioners, including those working in community teams for adults, children or young people (such as psychologists, psychiatrists, social workers, speech and language therapists, nurses, behavioural analysts, occupational therapists, physiotherapists and pharmacists); and education staff. ## Young people Aged 13 to 17 years.# Recommendations for research The Guideline Committee has made the following recommendations for research. The Committee's full set of research recommendations is detailed in the full guideline. # Develop case identification tools for common mental health problems Develop or adapt reliable and valid tools for the case identification of common mental health problems in people with learning disabilities, for routine use in primary care, social care and education settings. ## Why this is important Mental health problems are often overlooked and therefore untreated in people with learning disabilities. This includes common mental health problems such as depression and anxiety disorders, or dementia in Down's syndrome. As a result, the identification of mental health problems in people with learning disabilities was a priority for this guideline. While case identification tools exist and are recommended for use in the general population, no suitable tools were found that help with initial identification for people with learning disabilities. Research to develop and validate such tools would be valuable when this guideline is updated. More reliable identification should help with early intervention and provide better outcomes, and earlier identification could also reduce costs for the NHS and social care. No relevant ongoing trials were identified. Existing tools with the best psychometric properties could be adapted and validated for use with people with learning disabilities, or new tools could be developed that are appropriate for use. The tools should be readily available and useable in routine health, social care and education settings (such as by GPs or caregiving staff). Tools should first be adapted or developed for the most common mental health problems within this population: dementia, depression and anxiety in adults depression and anxiety in children and young people. A series of cohort studies are needed to validate the tools (new or existing). The studies could include the following outcomes: sensitivity and specificity predictive validity. # Psychological interventions for children and young people with internalising disorders For children and young people with learning disabilities, what psychological interventions (such as cognitive behavioural therapy and interpersonal therapy) are clinically and cost effective for treating internalising disorders? ## Why this is important There is some evidence for the use of psychological interventions for internalising disorders in children and young people within the general population, and in adults with learning disabilities. However no evidence was found to indicate which interventions for internalising disorders are effective in children and young people with learning disabilities, or what adaptations are most helpful. Psychological interventions commonly used within the general population (such as cognitive behavioural therapy and interpersonal therapy) should be adapted and tested in large randomised controlled trials. This research is crucial to improving the mental health outcomes in this population, and would have a significant impact upon updates of this guideline. Important outcomes could include: effect on the mental health problem cost effectiveness health-related quality of life. # Psychological interventions for depression and anxiety disorders in adults with mild to moderate learning disabilities For adults with milder learning disabilities, what is the clinical and cost effectiveness of psychological interventions such as cognitive behavioural therapy (modified for people with learning disabilities) for treating depression and anxiety disorders? ## Why this is important Psychological interventions such as cognitive behavioural therapy (CBT) are clinically and cost-effective treatments for anxiety and depression within the general population. While there is some evidence to suggest that these interventions may be useful in treating depression in people with learning disabilities, this is limited. Further research is also needed for CBT for anxiety disorders such as generalised anxiety disorder, obsessive compulsive disorder and post-traumatic stress disorder. The existing evidence on CBT for learning disabilities is based on small feasibility trials, with various and inconsistent adaptations across the studies. Many therapists are also reluctant to use CBT in this population. As a result, people with learning disabilities may be missing out on effective treatments. Effective treatments would reduce unnecessary suffering and impairment, improve quality of life and ultimately should reduce the demand for mental health and social care services. Modifications of CBT need to be tested in large randomised controlled trials, and any modifications should be clearly explained and documented. In order to achieve an appropriate sample size, several different services may need to cooperate. Important outcomes could include: effect on the mental health problem cost effectiveness health-related quality of life. # Pharmacological interventions for anxiety disorders in people with learning disabilities who have autism What is the clinical and cost effectiveness and safety of pharmacological interventions for anxiety disorders in people with learning disabilities who have autism? ## Why this is important Anxiety disorders are common in people with learning disabilities who have autism. However, there is no high-quality evidence on pharmacological interventions for anxiety disorders in people with learning disabilities who have autism. They may be more susceptible to adverse events, and have particular difficulty communicating side effects. There may also be differences in effectiveness compared with the general population. These uncertainties about side effects and effectiveness may contribute to the under-treatment of mental health problems in people with learning disabilities who have autism. Research is therefore needed to determine the safety and effectiveness of pharmacological interventions and make it clear what treatments are effective for anxiety in people learning disabilities who have autism. Clarity over this issue could have a substantial impact upon quality of life for people with learning disabilities who have autism and their carers, as well as reducing costs to the NHS. Randomised controlled trials should be carried out to compare the clinical and cost effectiveness of pharmacological interventions for anxiety disorders in this population. Several services may need to collaborate in order to ensure sufficient sample size. Researchers would need to take into account factors such as genotype and pharmacological treatment for other conditions when designing these trials. Important outcomes could include: effect on the mental health problem side effects cost effectiveness health-related quality of life. # Psychosocial interventions for people with more severe learning disabilities For people with more severe learning disabilities, what is the clinical and cost effectiveness of psychosocial interventions to treat mental health problems? ## Why this is important People with more severe learning disabilities whose communication is non-verbal are likely to need tailored interventions to address mental health problems. Research is particularly limited on mental health problems in people with more severe learning disabilities. Further research is needed into different types of interventions, such as social interactions and building resilience. This research would fill a need within mental health services, which are currently limited in their ability to provide effective interventions to this group. Randomised controlled trials should be carried out to compare the clinical and cost effectiveness of psychosocial interventions, which may include multiple components, to prevent and treat mental health problems in people with more severe learning disabilities. Several services may need to collaborate in order to ensure sufficient sample size. Important outcomes could include: effect on the mental health problem cost effectiveness health-related quality of life. When designing these trials, appropriate measures will need to be developed for mental health problems in people with more severe learning disabilities. # The experiences of people with learning disabilities and mental health problems in services What experience do people with learning disabilities have of services designed to prevent and treat mental health problems and how does this relate to clinical outcomes? ## Why this is important Mental health service provision for people with learning disabilities is complex and varies across the UK. There appears to be no high-quality evidence or ongoing research for any particular approach. Evidence on the experiences, aspirations and mental health of young people as they prepare for adulthood would help in the development of preventative strategies. Evidence on what service models are most effective and acceptable to people with learning disabilities would help to improve service design, staffing decisions and patient outcomes. This is also an area of national priority, as explained in the NHS Five Year Forward View. To understand what experience people with learning disabilities have of services, a series of studies covering the following should be conducted: The experiences and life course trajectories of young people (aged 13–17 years) in terms of their aspirations and goals, including whether the support they and their families get affects their mental health and their expected outcomes as they prepare for adulthood. The experience people have of mental health inpatient services (specialist learning disability services or non-specialist services), including factors that may have prevented the need for admission and how inpatient admission affects them. Studies should include economic modelling. The experience people have of being discharged from mental health inpatient services (specialist learning disability services or non-specialist services), after a stay of one year or more. In particular: the factors that may have helped them to be discharged earlier, what support is effective after discharge, and how to lower the risk of readmission. The experiences people have during a crisis, including how effective crisis support is in meeting their needs, minimising risk and helping them recover. The experiences of people with milder learning disabilities (including people on the autistic spectrum) and common mental health problems (such as anxiety or depression) in accessing community-based interventions.# Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context People of all ages with all levels of learning disabilities can be affected by mental health problems. When a person is not able to describe or express their distress, and when they have coexisting physical health problems, their mental health problems can be difficult to identify. This leads to mental health problems remaining unrecognised, which prolongs unnecessary distress. Psychosis, bipolar disorder, dementia, behaviour that challenges, and neurodevelopmental conditions such as autism and attention deficit hyperactivity disorder are all more common than in people without learning disabilities, and emotional disorders are at least as common. Some causes of learning disabilities are associated with particularly high levels of specific mental health problems (for example, affective psychosis in Prader–Willi syndrome and dementia in Down's syndrome). When people with learning disabilities experience mental health problems, the symptoms are sometimes wrongly attributed to the learning disabilities or a physical health problem rather than a change in the person's mental health. Indeed, their physical health state can contribute to mental ill health, as can the degree and cause of their learning disabilities (including behavioural phenotypes), biological factors (such as pain and polypharmacy), psychological factors (such as trauma) and social factors (such as neglect, poverty and lack of social networks). Population-based estimates suggest in the UK that 40% (28% if problem behaviours are excluded) of adults with learning disabilities experience mental health problems at any point in time. An estimated 36% (24% if problem behaviours are excluded) of children and young people with learning disabilities experience mental health problems at any point in time. These rates are much higher than for people who do not have learning disabilities. This guideline covers the identification, assessment, treatment and prevention of mental health problems in children, young people and adults with any degree of learning disabilities. In addition, there are recommendations on support for family members, carers and care workers. The guideline covers all settings (including health, social care, educational, forensic and criminal justice settings). People with learning disabilities have many needs both as individuals and related to their learning disabilities. This guideline only addresses their needs in relation to mental health problems.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we used words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Using this guideline with other NICE guidelines\n\n## Improving the experience of care\n\nUse this guideline with:\n\nthe NICE guidelines on service user experience in adult mental health and patient experience in adult NHS services, to improve the experience of care for adults with learning disabilities and mental health problems\n\nrecommendations for improving the experience of care for children and young people in the NICE guidelines on specific mental health problems\n\nthe NICE guideline on challenging behaviour and learning disabilities if relevant.\n\n## Interventions for mental health problems in people with learning disabilities\n\nUse this guideline with the NICE guidelines on specific mental health problems and other NICE guidelines on mental health services. Take into account:\n\ndifferences in the presentation of mental health problems\n\ncommunication needs (see recommendation 1.3.1)\n\ndecision-making capacity (see recommendation 1.3.2)\n\nthe degree of learning disabilities\n\nthe treatment setting (for example, primary or secondary care services, mental health or learning disabilities services, in the community or the person's home)\n\ninterventions specifically for people with learning disabilities (see the section on social and physical environment interventions and the sections on psychological, pharmacological and occupational interventions).\n\n# Organisation and delivery of care and support\n\n## Organising effective care\n\nA designated leadership team of healthcare professionals, educational staff, social care practitioners and health and local authority commissioners should develop and implement service delivery systems in partnership with people with learning disabilities and mental health problems and (as appropriate) their family members, carers, self-advocates or care workers.\n\nThe designated leadership team should ensure that care is:\n\nperson-centred and integrated within a care programme\n\nnegotiable, workable and understandable for people with learning disabilities and mental health problems, their family members, carers or care workers, and staff\n\naccessible and acceptable to people using the services\n\nresponsive to the needs and abilities of people with learning disabilities, and that reasonable adjustments (in line with the Equality Act 2010) are made if needed\n\nregularly audited to assess effectiveness, accessibility and acceptability.\n\nThe designated leadership team should ensure that care pathways:\n\ncover all health, social care, support and education services, and define the roles and responsibilities of each service\n\nhave designated staff who are responsible for coordinating:\n\n\n\nhow people are involved with a care pathway\n\ntransition between services within and across different care pathways\n\n\n\nmaintain consistency of care\n\nhave protocols for sharing information:\n\n\n\nwith the person with learning disabilities and a mental health problem and their family members, carers or care workers (as appropriate)\n\nwith other staff (including GPs) involved in the person's care\n\n\n\nare focused on outcomes (including measures of quality, service user experience and harm)\n\nestablish clear links (including access and entry points) to other care pathways (including those for physical health problems).\n\nThe designated leadership team should ensure that young people with learning disabilities and mental health problems have in place plans that address their health, social, educational and recreational needs (including Education, Health and Care Plans), as part of their transition to adult services and adulthood. This planning should start when young people are aged 14 and follow the NICE guideline on transition from children's to adults' services.\n\nThe designated leadership team, together with health and social care providers, should ensure that care pathways:\n\nprovide access to all NICE-recommended interventions for mental health problems\n\nclearly state the responsibilities of specialist learning disabilities and specialist mental health services to ensure people's needs are met.\n\nFor people with learning disabilities who need acute inpatient treatment for a serious mental illness, provide treatment:\n\nwithin a locally available service where possible and\n\nwith staff who are skilled and knowledgeable in the care and treatment of mental health problems in people with learning disabilities.\n\nStaff working with people with learning disabilities and mental health problems should ensure they are fully informed about:\n\nthe nature and degree of the learning disabilities\n\nthe nature and severity of the mental health problem, and any physical health problems (including sensory impairments).\n\nAll people with learning disabilities and a serious mental illness should have a key worker who:\n\ncoordinates all aspects of care, including safeguarding concerns and risk management\n\nhelps services communicate with the person and their family members, carers or care workers (as appropriate) clearly and promptly, in a format and language suited to the person's needs and preferences\n\nmonitors the implementation of the care plan and its outcomes.\n\nHealth, social care and education services should train all staff who may come into contact with people with learning disabilities to be aware:\n\nthat people with learning disabilities are at increased risk of mental health problems\n\nthat mental health problems may develop and present in different ways from people without learning disabilities, and the usual signs or symptoms may not be observable or reported\n\nthat people with learning disabilities can develop mental health problems for the same reasons as people without learning disabilities (for example, because of financial worries, bereavement or relationship difficulties)\n\nthat mental health problems are commonly overlooked in people with learning disabilities\n\nwhere to refer people with learning disabilities and suspected mental health problems.\n\nHealth and social care services should ensure that staff who deliver interventions for people with learning disabilities and mental health problems are competent, and that they:\n\nreceive regular high-quality supervision\n\ndeliver interventions based on relevant manuals, if available\n\nevaluate adherence to interventions\n\ntake part in the monitoring of their practice (for example, by using video and audio recording, external audit and scrutiny).\n\nHealth and social care staff who deliver interventions for people with learning disabilities and mental health problems should consider using routine sessional outcome measures, including service-user-reported experience measures.\n\n# Involving people with learning disabilities, and their family members, carers or care workers, in mental health assessment and treatment\n\n## Communication\n\nTake into account the person's communication needs and level of understanding throughout assessments, treatment and care for a mental health problem, and:\n\nspeak to the person directly rather than talking about or over them\n\nuse clear, straightforward and unambiguous language\n\nassess whether communication aids, an advocate or someone familiar with the person's communication methods are needed\n\nmake adjustments to accommodate sensory impairments (including sight and hearing impairments)\n\nexplain the content and purpose of every meeting or session\n\nuse concrete examples, visual imagery, practical demonstrations and role play to explain concepts\n\ncommunicate at a pace that is comfortable for the person, and arrange longer or additional meetings or treatment sessions if needed\n\nuse different methods and formats for communication (written, signing, visual, verbal, or a combination of these), depending on the person's preferences (see NHS England's Accessible Information Standard for guidance on ensuring people with learning disabilities receive information in formats they can understand)\n\nregularly check the person's understanding\n\nsummarise and explain the conclusions of every meeting or session\n\ncheck that the person has communicated what they wanted.\n\n## Consent, capacity and decision-making\n\nAssess the person's capacity to make decisions throughout assessment, care and treatment for the mental health problem on a decision-by-decision basis, in accordance with the Mental Capacity Act and supporting codes of practice (see NICE's information on making decisions about your care). Help people make decisions by ensuring that their communication needs are met (see recommendation 1.3.1) and (if appropriate) involving a family member, carer, care worker or other individual familiar with the person's communication abilities.\n\nStaff delivering care to people with learning disabilities and mental health problems should:\n\ndiscuss the assessment process and treatment options with the person and provide information in a format and language suited to their needs, including:\n\n\n\npotential benefits\n\npotential side effects or disadvantages\n\nthe purpose of treatment\n\noutcome measures\n\n\n\nensure that the person understands the purpose, plan and content of any meeting or intervention before it starts, and regularly throughout\n\naddress any queries or concerns that the person may have at any stage\n\nallow enough time for the person to make an informed choice if they have decision-making capacity, and if they do not then provide enough time for their family members, carers or care workers to contribute fully.\n\n## Involving family members, carers and care workers\n\nEncourage and support family members, carers and care workers (as appropriate) to be actively involved throughout the assessment, care and treatment of the person's mental health problem, apart from in exceptional circumstances when an adult or young person with decision-making capacity has said that they do not want them involved.\n\nGive family members, carers and care workers (as appropriate) information about support and interventions in a suitable format and language, including NICE's information for the public.\n\n# Support and interventions for family members and carers\n\nAdvise family members and carers about their right to carer assessment, and assessment for respite care and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).\n\nWhen providing support to family members (including siblings) and carers:\n\nrecognise the potential impact of living with or caring for a person with learning disabilities and a mental health problem\n\nexplain how to access:\n\n\n\nfamily advocacy\n\nfamily support and information groups\n\ndisability-specific support groups for family members or carers\n\n\n\nprovide skills training and emotional support, or information about how to access these, to help them take part in and support interventions for the person with learning disabilities and a mental health problem.\n\nIf a family member or carer also has an identified mental health problem, offer:\n\ninterventions in line with the NICE guidelines on specific mental health problems or\n\nreferral to a mental health professional who can provide interventions in line with NICE guidelines.\n\n# Social and physical environment interventions\n\nHealth, social care and education services should consider the impact of the social and physical environment on the mental health of children and young people with learning disabilities when developing care plans, and:\n\nprovide positive educational environments that are appropriate to their needs\n\nwhen care placements (such as birth family to foster care, foster care to adoptive placement, home to residential school/college) are required, minimise the risk of placement breakdown by taking particular care to fit these to the needs of the person.\n\ngive special consideration and support to looked-after children and young people with learning disabilities and their foster parents or care workers, to reduce the child or young person's very high risk of developing mental health problems, and the risk of changes in their home and carers (see the NICE guideline on looked-after children and young people).\n\nHealth, social care and education services should consider the impact of the social and physical environment on the mental health of adults with learning disabilities when developing care plans,and:\n\nsupport people to live where and with whom they want\n\nencourage family involvement in the person's life, if appropriate\n\nsupport people to get involved in activities that are interesting and meaningful to them\n\nplan for and help people with any significant changes to their living arrangements.\n\n# Annual health check\n\nThe following recommendations on annual health checks for people with learning disabilities build on recommendation 1.2.1 in the NICE guideline on challenging behaviour and learning disabilities, which relates to the provision of annual physical checks by GPs to all people with learning disabilities.\n\nGPs should offer an annual health check using NHS England's learning disability annual health check electronic clinical template to all adults with learning disabilities, and all children and young people with learning disabilities who are not having annual health checks with a paediatrician.\n\nInvolve a family member, carer or care worker (as appropriate), or a healthcare professional or social care practitioner who knows the person well, in the annual health check. Take into account that more time may be needed to complete health checks with people with learning disabilities.\n\nInclude the following in annual health checks:\n\na mental health review, including any known or suspected mental health problems and how they may be linked to any physical health problems\n\na physical health review, including assessment for the conditions and impairments which are common in people with learning disabilities\n\na review of all current interventions, including medication and related side effects, adverse events, interactions and adherence\n\nan agreed and shared care plan for managing any physical health problems (including pain).\n\nDuring annual health checks with adults with Down's syndrome, ask them and their family members, carers or care workers (as appropriate) about any changes that might suggest the need for an assessment of dementia, such as:\n\nany change in the person's behaviour\n\nany loss of skills (including self-care)\n\na need for more prompting in the past few months.\n\n# Identification and referral\n\nStaff and others caring for people with learning disabilities should consider a mental health problem if a person with learning disabilities shows any changes in behaviour, for example:\n\nloss of skills or needing more prompting to use skills\n\nsocial withdrawal\n\nirritability\n\navoidance\n\nagitation\n\nloss of interest in activities they usually enjoy.\n\nStaff should consider using identification questions (adjusted as needed) as recommended in the NICE guidelines on specific mental health problems to identify common mental health problems in people with learning disabilities.\n\nPaediatricians should explain to parents of children identified with learning disabilities that mental health problems are common in people with learning disabilities, and may present in different ways.\n\nIf a mental health problem is suspected in a person with learning disabilities, staff should conduct a triage assessment to establish an initial formulation of the problem. This should include:\n\na description of the problem, including its nature, severity and duration\n\nan action plan including possible referral for further assessment and interventions.\n\nRefer people with learning disabilities who have a suspected serious mental illness or suspected dementia to a psychiatrist with expertise in assessing and treating mental health problems in people with learning disabilities.\n\n# Assessment\n\n## Conducting a mental health assessment\n\nA professional with expertise in mental health problems in people with learning disabilities should coordinate the mental health assessment, and conduct it with:\n\nthe person with the mental health problem, in a place familiar to them if possible, and help them to prepare for it if needed\n\nthe family members, carers, care workers and others that the person wants involved in their assessment\n\nother professionals (if needed) who are competent in using a range of assessment tools and methods with people with learning disabilities and mental health problems.\n\nSpeak to the person on their own to find out if they have any concerns (including safeguarding concerns) that they don't want to talk about in front of their family members, carers or care workers.\n\nBefore mental health assessments:\n\nagree a clear objective, and explain it to the person, their family members, carers or care workers (as appropriate), and all professionals involved\n\nexplain the nature and duration of the assessment to everyone involved\n\nexplain the need to ask certain sensitive questions\n\naddress any queries or concerns that the person may have about the assessment process.\n\nWhen conducting mental health assessments, be aware:\n\nthat an underlying physical health condition may be causing the problem\n\nthat a physical health condition, sensory or cognitive impairment may mask an underlying mental health problem\n\nthat mental health problems can present differently in people with more severe learning disabilities.\n\nWhen conducting mental health assessments, take into account the person's:\n\nlevel of distress\n\nunderstanding of the problem\n\nliving arrangements and settings where they receive care\n\nstrengths and needs.\n\nDuring mental health assessments:\n\nestablish specific areas of need to focus on\n\nassess all potential psychopathology, and not just the symptoms and signs that the person and their family members, carers or care workers first report\n\ndescribe the nature, duration and severity of the presenting mental health problem\n\ntake into account the person's cultural, ethnic and religious background\n\nreview psychiatric and medical history, past treatments and response\n\nreview physical health problems and any current medication, and refer to other specialists for review if needed\n\nreview the nature and degree of the learning disabilities, and if relevant the person's developmental history\n\nassess for problems that may be associated with particular behavioural phenotypes (for example, anxiety in people with autism and psychosis in people with Prader–Willi syndrome), so that they can be treated\n\nassess the person's family and social circumstances and environment, and recent life events\n\nassess the level of drug or alcohol use as a potential problem in itself and as a factor contributing to other mental health problems\n\nestablish or review a diagnosis using:\n\n\n\na classification system such as DSM-5 or ICD-10, or those adapted for learning disabilities (for example the Diagnostic Manual – Intellectual Disability [DM-ID] or Diagnostic Criteria for Psychiatric Disorders for Use with Adults with Learning Disabilities/Mental Retardation [DC-LD]) or\n\nproblem specification\n\n\n\nassess whether a risk assessment is needed (see recommendation 1.8.18).\n\nAssess recent changes in behaviour using information from family members, carers, staff or others involved in the assessment as well as information from relevant records and previous assessments. Take into account the nature, quality and length of their relationship with the person.\n\nUse the results of the mental health assessment to develop a written statement (formulation) of the mental health problem, which should form the basis of the care plan (see recommendation 1.8.23) and cover:\n\nan understanding of the nature of the problem and its development\n\nprecipitating and maintaining factors\n\nany protective factors\n\nthe potential benefits, side effects and harms of any interventions\n\nthe potential difficulties with delivering interventions\n\nthe adjustments needed to deliver interventions\n\nthe impact of the mental health problem and associated risk factors on providing care and treatment.\n\nProvide the person, their family members, carers or care workers (as appropriate), and all relevant professionals with a summary of the assessment:\n\nin an agreed format and language\n\nthat sets out the implications for care and treatment.\n\nGive the person and their family members, carers or care workers (as appropriate) another chance to discuss the assessment after it has finished, for example at a follow-up appointment.\n\n## Further assessment\n\nConsider conducting a further assessment that covers any areas not explored by the initial assessment, if:\n\nnew information emerges about the person's mental health problem or\n\nthere are significant differences between the views of the person and the views of their family members, carers, care workers or staff about the problems that the assessment has focused on.\n\n## Assessment tools\n\nDuring any mental health assessment:\n\nconsider using tools that have been developed or adapted for people with learning disabilities and\n\ntake cost into account if more than one suitable tool is available.\n\nIf using tools that have not been developed or adapted for people with learning disabilities, take this into account when interpreting the results.\n\nWhen conducting an assessment with a child or young person with learning disabilities, consider using tools such as the Developmental Behavior Checklist – parent version (DBC-P) or the Strengths and Difficulties Questionnaire (SDQ).\n\nWhen assessing depressive symptoms in an adult with learning disabilities, consider using a formal measure of depression to monitor change over time, such as the Glasgow Depression Scale (the self-report for people with milder learning disabilities or the carer supplement for people with any degree of learning disabilities).\n\nConsider supplementing an assessment of dementia with an adult with learning disabilities with:\n\nmeasures of symptoms, such as the Dementia Questionnaire for People with Learning Disabilities (DLD), the Down Syndrome Dementia Scale (DSDS) or the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID)\n\nmeasures of cognitive function to monitor changes over time, such as the Test for Severe Impairment (TSI)\n\nmeasures of adaptive function to monitor changes over time.\n\nComplete a baseline assessment of adaptive behaviour with all adults with Down's syndrome.\n\n## Risk assessment\n\nWhen conducting risk assessments with people with learning disabilities and mental health problems, assess:\n\nrisk to self\n\nrisk to others (including sexual offending)\n\nrisk of self-neglect\n\nvulnerability to exploitation\n\nlikelihood and severity of any particular risk\n\npotential triggers, causal or maintaining factors\n\nwhether safeguarding protocols should be implemented.\n\nIf indicated by the risk assessment, develop a risk management plan with the person and their family members, carers or care workers (as appropriate).\n\nRisk management plans should:\n\nset out individual, social or environmental interventions to reduce risk\n\nbe communicated to family members, carers or care workers (as appropriate) and all relevant staff and agencies.\n\nRisk assessments and resulting risk management plans should be reviewed regularly and adjusted if risk levels change.\n\n## Mental health assessment during a crisis\n\nConduct an initial assessment for people who are experiencing a mental health crisis, which should:\n\ninclude an assessment of the person's mental health\n\ninclude a risk assessment (see recommendations 1.8.18 to 1.8.21)\n\ninclude identification of interventions to:\n\n\n\nhelp address the problem that caused the crisis\n\nminimise any associated risks\n\nbring stability to the individual and their immediate environment\n\n\n\nproduce a crisis plan that sets out (using the least restrictive options possible) how to reduce the likelihood of further crises, and what to do if the person has another crisis.\n\n## The mental health care plan\n\nDevelop a mental health care plan with each person with learning disabilities and a mental health problem and their family members, carers or care workers (as appropriate), and integrate it into their other care plans.\n\nBase mental health care plans on the written statement (formulation) and include in them:\n\ngoals agreed with the person and the steps to achieve them\n\ntreatment decisions\n\nagreed outcome measures that are realistic and meaningful to the person, to monitor progress\n\nearly warning signs of relapse or exacerbation of symptoms, if known\n\nrisk and crisis plans, if needed (see recommendations 1.8.18 to 1.8.22)\n\nsteps to minimise future problems.\n\nEnsure that the mental health care plan sets out the roles and responsibilities of everyone involved in delivering it, and that:\n\nthe person can easily access all interventions and services in the plan\n\nit is communicated to everyone involved, including the person and their family members, carers or care workers (as appropriate)\n\nthere is an agreement on when the plan will be reviewed.\n\n# Psychological interventions\n\n## Delivering psychological interventions for mental health problems in people with learning disabilities\n\nFor psychological interventions for mental health problems in people with learning disabilities, refer to the NICE guidelines on specific mental health problems and take into account:\n\nthe principles for delivering psychological interventions (see recommendations 1.9.2 to 1.9.4) and\n\nthe specific interventions recommended in this guideline (see recommendations 1.9.5 to 1.9.9).\n\nUse the mental health assessment to inform the psychological intervention and any adaptations to it, and:\n\ntailor it to their preferences, level of understanding, and strengths and needs\n\ntake into account any physical, neurological, cognitive or sensory impairments and communication needs\n\ntake into account the person's need for privacy (particularly when offering interventions on an outreach basis)\n\nagree how it will be delivered (for example, face-to-face or remotely by phone or computer), taking into account the person's communication needs and how suitable remote working is for them.\n\nIf possible, collaborate with the person and their family members, carers or care workers (as appropriate) to:\n\ndevelop and agree the intervention goals\n\ndevelop an understanding of how the person expresses or describes emotions or distressing experiences\n\nagree the structure, frequency, duration and content of the intervention, including its timing, mode of delivery and pace\n\nagree the level of flexibility needed to effectively deliver the intervention\n\nagree how progress will be measured and how data will be collected (for example, visual representations of distress or wellbeing).\n\nBe aware that people with learning disabilities might need more structured support to practise and apply new skills to everyday life between sessions. In discussion with the person, consider:\n\nproviding additional support during meetings and in the planning of activities between meetings\n\nasking a family member, carer or care worker to provide support and assistance (such as reminders) to practise new skills between meetings.\n\n## Specific psychological interventions\n\nConsider cognitive behavioural therapy, adapted for people with learning disabilities (see recommendation 1.9.2 on intervention adaptation methods), to treat depression or subthreshold depressive symptoms in people with milder learning disabilities.\n\nConsider relaxation therapy to treat anxiety symptoms in people with learning disabilities.\n\nConsider using graded exposure techniques to treat anxiety symptoms or phobias in people with learning disabilities.\n\nConsider parent training programmes specifically designed for parents or carers of children with learning disabilities to help prevent or treat mental health problems in the child, and to support carer wellbeing.\n\nParent training programmes should:\n\nbe delivered in groups of parents or carers\n\nbe accessible (for example, take place outside normal working hours or in community settings with childcare facilities)\n\nfocus on developing communication and social functioning skills\n\ntypically consist of 8 to 12 sessions lasting 90\xa0minutes\n\nfollow the relevant treatment manual\n\nuse all of the necessary materials to ensure consistent implementation of the programme\n\nseek parent feedback.\n\n# Pharmacological interventions\n\nFor pharmacological interventions for mental health problems in people with learning disabilities, refer to the NICE guidelines on specific mental health problems and take into account the principles for delivering pharmacological interventions (see recommendations 1.10.2 to 1.10.9).\n\nFor guidance on adherence and the safe and effective use of medicines, see the NICE guidelines on medicines adherence and medicines optimisation.\n\nOnly specialists with expertise in treating mental health problems in people with learning disabilities should start medication to treat a mental health problem in:\n\nadults with more severe learning disabilities (unless there are locally agreed protocols for shared care)\n\nchildren and young people with any learning disabilities.\n\nBefore starting medication for a mental health problem in children, young people or adults with learning disabilities:\n\ntake account of:\n\n\n\npotential medication interactions\n\nthe potential impact of medication on other health conditions\n\nthe potential impact of other health conditions on the medication\n\n\n\nwhen necessary consult with specialists (for example, neurologists providing epilepsy care when prescribing antipsychotic medication that may lower the seizure threshold), to minimise possible interactions\n\nassess the risk of non-adherence to the medication regimen or any necessary monitoring tests (for example, blood tests), and the implications for treatment\n\nestablish a review schedule to reduce polypharmacy\n\nprovide support to improve adherence (see the NICE guideline on medicines adherence)\n\nassess whether support from community and learning disabilities nurses is needed for physical investigations (such as blood tests)\n\nagree monitoring responsibilities, including who will carry out blood tests and other investigations, between primary and secondary care.\n\nMonitor and review the benefits and possible harms or side effects, using agreed outcome measures and taking into account communication needs. If stated in the relevant NICE guideline, use the timescales given for the specific disorder to inform the review, and adjust it to the person's needs.\n\nWhen deciding the initial dose and subsequent increases, aim for the lowest effective dose. Take account of both potential side effects and difficulties the person may have in reporting them, and the need to avoid sub-therapeutic doses that may not treat the mental health problem effectively.\n\nPrescribers should record:\n\na summary of what information was provided about the medication prescribed, including side effects, to the person and their family members, carers or care workers (as appropriate) and any discussions about this\n\nwhen the medication will be reviewed\n\nplans for reducing or discontinuing the medication, if appropriate\n\nfull details of all medication the person is taking, including the doses, frequency and purpose.\n\nFor people with learning disabilities who are taking antipsychotic drugs and not experiencing psychotic symptoms:\n\nconsider reducing or discontinuing long-term prescriptions of antipsychotic drugs,\n\nreview the person's condition after reducing or discontinuing a prescription\n\nconsider referral to a psychiatrist experienced in working with people with learning disabilities and mental health problems\n\nannually document the reasons for continuing the prescription if it is not reduced or discontinued.\n\nWhen switching medication, pay particular attention to discontinuation or interaction effects that may occur during titration. Only change one drug at a time, to make it easier to identify these effects.\n\n# Occupational interventions\n\nIn keeping with the preferences of the person with learning disabilities and mental health problems, all staff should support them to:\n\nengage in community activities, such as going to a library or sports centre\n\naccess local community resources such as libraries, cinemas, cafes and leisure centres\n\ntake part in leisure activities, such as hobbies, which are meaningful to the person.Reasonable adjustments may be needed to do this (in line with the Equality Act 2010), such as a buddy system, transport, or advising local facilities on accessibility.\n\nActively encourage adults with learning disabilities (with or without a mental health problem) to find and participate in paid or voluntary work that is meaningful to them, if they are able.\n\nConsider providing practical support to adults with learning disabilities (with or without a mental health problem) to find paid or voluntary work, including:\n\npreparing a CV\n\nidentifying personal strengths and interests\n\ncompleting application forms\n\npreparing for interviews\n\naccompanying the person to interviews\n\ncompleting any pre-employment checks.\n\nHealth and social care services should take account of an adult or young person's sensory, physical, cognitive and communication needs and the severity of their mental health problem (if any), and consider:\n\nhelping them to identify and overcome any possible challenges during employment\n\nappointing supported employment workers to provide ongoing support to adults with learning disabilities and their employers\n\nproviding information and guidance to potential employers about the benefits of recruiting people with learning disabilities\n\nassisting employers in making reasonable adjustments to help them to work (in line with the Equality Act).\n\n# Terms used in this guideline\n\n## Carer\n\nA person who provides unpaid support to someone who is ill, having trouble coping or has disabilities.\n\n## Care pathways\n\nDefined in this guideline as the ways different services interact with each other, and how people access and move between them.\n\n## Care worker\n\nA person who provides paid support to someone who is ill, having trouble coping or has disabilities, in a variety of settings (including residential homes, supported living settings and day services).\n\n## Children\n\nAged 0 to12\xa0years.\n\n## Key worker\n\nA key worker (also known as a care or case coordinator) is a central point of contact for the person with a mental health problem, family members, carers and the services involved in their care. They are responsible for helping the person and family members or carers to access services and for coordinating the involvement of different services. They ensure clear communication between all people and services and have an overall view of the person's needs and the requirements of their care plan.\n\n## Learning disabilities\n\nLearning disabilities are commonly divided into 'mild', 'moderate', 'severe' and 'profound', but these categories are based on IQ and most UK health and social care services do not measure this. Therefore, this guideline uses the terms 'milder learning disabilities' (approximating to mild and moderate learning disabilities that are often defined as an IQ of 35 to 69 and impairment of adaptive functioning with onset in childhood) and 'more severe learning disabilities' (approximating to severe and profound learning disabilities that are often defined as an IQ of 34 or below with impairment of adaptive functioning with onset in childhood).\n\nAll people with learning disabilities:\n\nneed additional support at school\n\nneed support in some areas of adult life, such as budgeting, planning, time management, and understanding complex information\n\nneed more time to learn new skills than people who don't have learning disabilities.\n\nPeople with milder learning disabilities:\n\nmay be able to live independently and care for themselves, managing everyday tasks and working in paid employment\n\ncan often communicate their needs and wishes\n\nmay have some language skills\n\nmay have needs that are not clear to people who do not know them well.\n\nPeople with more severe learning disabilities are more likely to:\n\nneed support with daily activities such as dressing, washing, food preparation, and keeping themselves safe\n\nhave limited or no verbal communication skills or understanding of others\n\nneed support with mobility\n\nhave complex health needs and sensory impairments.\n\n## Serious mental illness\n\nDefined in this guideline as: severe and incapacitating depression or anxiety, psychosis, schizophrenia, bipolar disorder or schizoaffective disorder.\n\n## Staff\n\nHealthcare professionals and social care practitioners, including those working in community teams for adults, children or young people (such as psychologists, psychiatrists, social workers, speech and language therapists, nurses, behavioural analysts, occupational therapists, physiotherapists and pharmacists); and education staff.\n\n## Young people\n\nAged 13 to 17\xa0years.", 'Recommendations for research': "The Guideline Committee has made the following recommendations for research. The Committee's full set of research recommendations is detailed in the full guideline.\n\n# Develop case identification tools for common mental health problems\n\nDevelop or adapt reliable and valid tools for the case identification of common mental health problems in people with learning disabilities, for routine use in primary care, social care and education settings.\n\n## Why this is important\n\nMental health problems are often overlooked and therefore untreated in people with learning disabilities. This includes common mental health problems such as depression and anxiety disorders, or dementia in Down's syndrome. As a result, the identification of mental health problems in people with learning disabilities was a priority for this guideline.\n\nWhile case identification tools exist and are recommended for use in the general population, no suitable tools were found that help with initial identification for people with learning disabilities. Research to develop and validate such tools would be valuable when this guideline is updated. More reliable identification should help with early intervention and provide better outcomes, and earlier identification could also reduce costs for the NHS and social care. No relevant ongoing trials were identified.\n\nExisting tools with the best psychometric properties could be adapted and validated for use with people with learning disabilities, or new tools could be developed that are appropriate for use. The tools should be readily available and useable in routine health, social care and education settings (such as by GPs or caregiving staff).\n\nTools should first be adapted or developed for the most common mental health problems within this population:\n\ndementia, depression and anxiety in adults\n\ndepression and anxiety in children and young people.\n\nA series of cohort studies are needed to validate the tools (new or existing). The studies could include the following outcomes:\n\nsensitivity and specificity\n\npredictive validity.\n\n# Psychological interventions for children and young people with internalising disorders\n\nFor children and young people with learning disabilities, what psychological interventions (such as cognitive behavioural therapy and interpersonal therapy) are clinically and cost effective for treating internalising disorders?\n\n## Why this is important\n\nThere is some evidence for the use of psychological interventions for internalising disorders in children and young people within the general population, and in adults with learning disabilities. However no evidence was found to indicate which interventions for internalising disorders are effective in children and young people with learning disabilities, or what adaptations are most helpful.\n\nPsychological interventions commonly used within the general population (such as cognitive behavioural therapy and interpersonal therapy) should be adapted and tested in large randomised controlled trials. This research is crucial to improving the mental health outcomes in this population, and would have a significant impact upon updates of this guideline.\n\nImportant outcomes could include:\n\neffect on the mental health problem\n\ncost effectiveness\n\nhealth-related quality of life.\n\n# Psychological interventions for depression and anxiety disorders in adults with mild to moderate learning disabilities\n\nFor adults with milder learning disabilities, what is the clinical and cost effectiveness of psychological interventions such as cognitive behavioural therapy (modified for people with learning disabilities) for treating depression and anxiety disorders?\n\n## Why this is important\n\nPsychological interventions such as cognitive behavioural therapy (CBT) are clinically and cost-effective treatments for anxiety and depression within the general population. While there is some evidence to suggest that these interventions may be useful in treating depression in people with learning disabilities, this is limited. Further research is also needed for CBT for anxiety disorders such as generalised anxiety disorder, obsessive compulsive disorder and post-traumatic stress disorder. The existing evidence on CBT for learning disabilities is based on small feasibility trials, with various and inconsistent adaptations across the studies. Many therapists are also reluctant to use CBT in this population. As a result, people with learning disabilities may be missing out on effective treatments. Effective treatments would reduce unnecessary suffering and impairment, improve quality of life and ultimately should reduce the demand for mental health and social care services.\n\nModifications of CBT need to be tested in large randomised controlled trials, and any modifications should be clearly explained and documented. In order to achieve an appropriate sample size, several different services may need to cooperate. Important outcomes could include:\n\neffect on the mental health problem\n\ncost effectiveness\n\nhealth-related quality of life.\n\n# Pharmacological interventions for anxiety disorders in people with learning disabilities who have autism\n\nWhat is the clinical and cost effectiveness and safety of pharmacological interventions for anxiety disorders in people with learning disabilities who have autism?\n\n## Why this is important\n\nAnxiety disorders are common in people with learning disabilities who have autism. However, there is no high-quality evidence on pharmacological interventions for anxiety disorders in people with learning disabilities who have autism. They may be more susceptible to adverse events, and have particular difficulty communicating side effects. There may also be differences in effectiveness compared with the general population. These uncertainties about side effects and effectiveness may contribute to the under-treatment of mental health problems in people with learning disabilities who have autism. Research is therefore needed to determine the safety and effectiveness of pharmacological interventions and make it clear what treatments are effective for anxiety in people learning disabilities who have autism. Clarity over this issue could have a substantial impact upon quality of life for people with learning disabilities who have autism and their carers, as well as reducing costs to the NHS.\n\nRandomised controlled trials should be carried out to compare the clinical and cost effectiveness of pharmacological interventions for anxiety disorders in this population. Several services may need to collaborate in order to ensure sufficient sample size. Researchers would need to take into account factors such as genotype and pharmacological treatment for other conditions when designing these trials. Important outcomes could include:\n\neffect on the mental health problem\n\nside effects\n\ncost effectiveness\n\nhealth-related quality of life.\n\n# Psychosocial interventions for people with more severe learning disabilities\n\nFor people with more severe learning disabilities, what is the clinical and cost effectiveness of psychosocial interventions to treat mental health problems?\n\n## Why this is important\n\nPeople with more severe learning disabilities whose communication is non-verbal are likely to need tailored interventions to address mental health problems. Research is particularly limited on mental health problems in people with more severe learning disabilities. Further research is needed into different types of interventions, such as social interactions and building resilience. This research would fill a need within mental health services, which are currently limited in their ability to provide effective interventions to this group.\n\nRandomised controlled trials should be carried out to compare the clinical and cost effectiveness of psychosocial interventions, which may include multiple components, to prevent and treat mental health problems in people with more severe learning disabilities. Several services may need to collaborate in order to ensure sufficient sample size. Important outcomes could include:\n\neffect on the mental health problem\n\ncost effectiveness\n\nhealth-related quality of life.\n\nWhen designing these trials, appropriate measures will need to be developed for mental health problems in people with more severe learning disabilities.\n\n# The experiences of people with learning disabilities and mental health problems in services\n\nWhat experience do people with learning disabilities have of services designed to prevent and treat mental health problems and how does this relate to clinical outcomes?\n\n## Why this is important\n\nMental health service provision for people with learning disabilities is complex and varies across the UK. There appears to be no high-quality evidence or ongoing research for any particular approach. Evidence on the experiences, aspirations and mental health of young people as they prepare for adulthood would help in the development of preventative strategies. Evidence on what service models are most effective and acceptable to people with learning disabilities would help to improve service design, staffing decisions and patient outcomes. This is also an area of national priority, as explained in the NHS Five Year Forward View.\n\nTo understand what experience people with learning disabilities have of services, a series of studies covering the following should be conducted:\n\nThe experiences and life course trajectories of young people (aged 13–17 years) in terms of their aspirations and goals, including whether the support they and their families get affects their mental health and their expected outcomes as they prepare for adulthood.\n\nThe experience people have of mental health inpatient services (specialist learning disability services or non-specialist services), including factors that may have prevented the need for admission and how inpatient admission affects them. Studies should include economic modelling.\n\nThe experience people have of being discharged from mental health inpatient services (specialist learning disability services or non-specialist services), after a stay of one year or more. In particular: the factors that may have helped them to be discharged earlier, what support is effective after discharge, and how to lower the risk of readmission.\n\nThe experiences people have during a crisis, including how effective crisis support is in meeting their needs, minimising risk and helping them recover.\n\nThe experiences of people with milder learning disabilities (including people on the autistic spectrum) and common mental health problems (such as anxiety or depression) in accessing community-based interventions.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "People of all ages with all levels of learning disabilities can be affected by mental health problems. When a person is not able to describe or express their distress, and when they have coexisting physical health problems, their mental health problems can be difficult to identify. This leads to mental health problems remaining unrecognised, which prolongs unnecessary distress. Psychosis, bipolar disorder, dementia, behaviour that challenges, and neurodevelopmental conditions such as autism and attention deficit hyperactivity disorder are all more common than in people without learning disabilities, and emotional disorders are at least as common. Some causes of learning disabilities are associated with particularly high levels of specific mental health problems (for example, affective psychosis in Prader–Willi syndrome and dementia in Down's syndrome).\n\nWhen people with learning disabilities experience mental health problems, the symptoms are sometimes wrongly attributed to the learning disabilities or a physical health problem rather than a change in the person's mental health. Indeed, their physical health state can contribute to mental ill health, as can the degree and cause of their learning disabilities (including behavioural phenotypes), biological factors (such as pain and polypharmacy), psychological factors (such as trauma) and social factors (such as neglect, poverty and lack of social networks).\n\nPopulation-based estimates suggest in the UK that 40% (28% if problem behaviours are excluded) of adults with learning disabilities experience mental health problems at any point in time. An estimated 36% (24% if problem behaviours are excluded) of children and young people with learning disabilities experience mental health problems at any point in time. These rates are much higher than for people who do not have learning disabilities.\n\nThis guideline covers the identification, assessment, treatment and prevention of mental health problems in children, young people and adults with any degree of learning disabilities. In addition, there are recommendations on support for family members, carers and care workers.\n\nThe guideline covers all settings (including health, social care, educational, forensic and criminal justice settings).\n\nPeople with learning disabilities have many needs both as individuals and related to their learning disabilities. This guideline only addresses their needs in relation to mental health problems."}	https://www.nice.org.uk/guidance/ng54	This guideline covers preventing, assessing and managing mental health problems in people with learning disabilities in all settings (including health, social care, education, and forensic and criminal justice). It aims to improve assessment and support for mental health conditions, and help people with learning disabilities and their families and carers to be involved in their care.
d79a3f796319860df48f78a6b6249852c07b24e2	nice	Transition between inpatient mental health settings and community or care home settings	Transition between inpatient mental health settings and community or care home settings This guideline covers the period before, during and after a person is admitted to, and discharged from, a mental health hospital. It aims to help people who use mental health services, and their families and carers, to have a better experience of transition by improving the way it’s planned and carried out. # Recommendations Although most of the recommendations in this guideline cover both planned and unplanned admissions, some (like those on pre-admission planning) are only applicable to planned admissions. If an admission is unplanned, then these recommendations should be applied at the soonest possible point after admission, if appropriate to the person's individual circumstances. Use this guideline alongside NICE guidance on mental health services. People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Overarching principles Ensure the aim of care and support of people in transition is person-centred and focused on recovery. Work with people as active partners in their own care and transition planning. For more information, see the section on relationships and communication in the NICE guideline on service user experience in adult mental health. Support people in transition in the least restrictive setting available (in line with the Mental Health Act Code of Practice). Record the needs and wishes of the person at each stage of transition planning and review. Identify the person's support networks. Work with the person to explore ways in which the people who support them can be involved throughout their admission and discharge. Enable the person to maintain links with their home community by: supporting them to maintain relationships with family and friends, for example, by finding ways to help with transport helping them to stay in touch with social and recreational contacts helping them to keep links with employment, education and their local community. This is particularly important if people are admitted to mental health units outside the area in which they live. Mental health services should work with primary care, local authorities and third sector organisations to ensure that people with mental health problems in transition have equal access to services. This should be based on need and irrespective of: gender sexual orientation socioeconomic status age disability cultural, ethnic and religious background whether or not they are receiving support through the Care Programme Approach whether or not they are subject to mental health legislation. Give people in transition comprehensive information about treatments and services for their mental health problems at the time they need it. If required, provide information: in large-print, braille or Easy Read format by audio or video in translation. For more information, see the section on care and support across all points on the care pathway in the NICE guideline on service user experience in adult mental health. # Before hospital admission ## Planning and assessment Mental health practitioners supporting transition should respond quickly to requests for assessment of mental health from: people with mental health problems family members carers primary care practitioners (including GPs) specialist community teams (for example, learning disability teams) staff such as hostel, housing and community support workers.Assessments for people in crisis should be prioritised. If admission is being planned for a treatment episode involve: the person who is being admitted their family members, parents or carers community accommodation and support providers. When planning treatment for people being admitted, take account of the expertise and knowledge of the person's family members, parents or carers. Allow more time and expert input to support people with complex, multiple or specific support needs to make transitions to and from services, if necessary. This may include: children and young people people with dementia, cognitive or sensory impairment people on the autistic spectrum people with learning disabilities and other additional needs people placed outside the area in which they live. For planned admissions, offer people an opportunity to visit the inpatient unit before they are admitted. This is particularly important for: children and young people people with dementia, cognitive or sensory impairment people on the autistic spectrum people with learning disabilities and other additional needs people placed outside the area in which they live. If it is not possible for the person to visit the inpatient unit that they will be admitted to in advance, consider using accessible online and printed information to support discussion about their admission. During admission planning, record a full history or update that: covers the person's cognitive, physical and mental health needs includes details of their current medication identifies the services involved in their care. For more information, see the section on medicines reconciliation in the NICE guideline on medicines optimisation. If more than 1 team is involved in a person's transition to, within and from a service, ensure there is ongoing communication between the inpatient team and other relevant teams that include: community health or social care providers, such as: the community mental health team the learning disability team teams that work with older people child and adolescent mental health services (CAMHS) housing support teams general hospital or psychiatric liaison teams. ## Crisis plans Support people who have had more than 1 admission to develop a crisis plan as part of their care planning process. This should include: relapse indicators and plans who to contact in a crisis coping strategies preferences for treatment and specific interventions advance decisions. For more information, see the section on community care in the NICE guideline on service user experience in adult mental health. # Hospital admission ## General principles Start building therapeutic relationships as early as possible to: lessen the person's sense of being coerced encourage the person to engage with treatment and recovery programmes and collaborative decision-making create a safe, contained environment reduce the risk of suicide, which is high during the first 7 days after admission. This is particularly important for people who have been admitted in crisis. Practitioners involved in admission should refer to crisis plans and advance statements when arranging care. Advance decisions must be followed in line with the Mental Capacity Act 2005. For more information on advance decisions as part of advanced care planning, see the NICE guideline on decision-making and mental capacity. At admission, offer all people access to advocacy services that take into account their: language and communication needs cultural and social needs protected characteristics (see the GOV.UK page about discrimination). Health and social care practitioners admitting someone with cognitive difficulties should try to ensure the person understands why they have been admitted. During admission, discuss with the person: any strategies for coping that they use how they can continue to use, adapt and develop positive coping strategies on the ward. Start discharge planning at admission or as early as possible when in crisis (for more information, see section 1.5). For recommendations on assessing and treating people who have been detained under the Mental Health Act, see the section on assessment and treatment in the NICE guideline on service user experience in adult mental health. For recommendations on crisis, including crisis admissions, see the section on assessment and referral in a crisis in the NICE guideline on service user experience in adult mental health. ## Out-of-area admissions If the person is being admitted outside the area in which they live, identify: a named practitioner from the person's home area who has been supporting the person a named practitioner from the ward they are being admitted to. The named practitioners from the person's home area and the ward should work together to ensure that the person's current placement lasts no longer than required. This should include reviewing the person's care plan, current placement, recovery goals and discharge plan at least every 3 months, or more frequently according to the person's needs. This could be done in person or by audio or videoconference. For people admitted to hospital outside the area in which they live, take into account the higher risk of suicide after discharge at all stages of the planning process (see the National Confidential Inquiry into Suicide and Homicide by People with Mental Illness). This should include: assessing the risk discussing with the person how services can help them to stay safe discussing with the person's family members, parents or carers how they can help the person to stay safe. ## Legal status of person being admitted The senior health professional responsible for the admission should tell the person being admitted about their legal status at the point of admission. They should: use clear language discuss rights and restrictions with the person provide written and verbal information make the discussion relevant to the ward the person is being admitted to explain whether they are under observation and what this means (see observations and restrictions). A senior health professional should ensure that discussions take place with the person being admitted to check that: they have understood the information they were given at admission they know they have a right to appeal, and that information and advocacy can be provided to support them to do so if they wish they understand that any changes to their legal status and treatment plans will be discussed as they occur. ## Observations and restrictions The admitting nurse or person responsible should tell the person what level of observation they are under and: explain what being under observation means explain clearly the reasons why the person is under observation and when, or under what circumstances, this will be reviewed explain how they will be observed and how often explain how observation will support their recovery and treatment discuss with the person how their preferences will be respected and how their rights to privacy and dignity will be protected -ffer the person an opportunity to ask questions. Ensure that restrictions, including restrictions on access to personal possessions: are relevant and reasonable in relation to the person concerned take into consideration the safety of the person and others on the ward are explained clearly to ensure the person understands: why the restrictions are in place under what circumstances they would be changed. ## Addressing personal concerns To support the person's transition to the ward the admitting nurse or person responsible should make the following items available if the person needs them: a toothbrush hygiene products nightwear. This is particularly important for people who have been admitted in crisis. Give the person verbal and written information about ward facilities and routines (see the section on hospital care in the NICE guideline on service user experience in adult mental health). At admission, a senior healthcare professional should discuss all medication and care needs with the person being admitted. This should include: physical healthcare needs pregnancy, breastfeeding or the need for emergency contraception advice about immediate addiction issues, treatment and support mental health treatment. The admitting nurse or person responsible should discuss with the person how to manage domestic and caring arrangements and liaise with the appropriate agencies. This may include: people they have a responsibility to care for, such as: children frail or ill relatives domestic arrangements, in particular: home security tenancy benefits home care service pets. On admission, ensure people (particularly children and young people) know who they can talk to if they are frightened or need support. For more information, see the section on hospital care in the NICE guideline on service user experience in adult mental health. Identify whether the person has any additional need for support, for example, with daily living activities. Work with carers and community-based services, such as specialist services for people with learning or physical disabilities, to provide support and continuity while the person is in hospital. # Support for families, parents and carers throughout admission Identify a named practitioner who will make sure that the person's family members, parents or carers receive support and timely information (see the section on sharing information with families, parents and carers). Practitioners should start to build relationships with the person's family members, parents or carers during admission. This should be done: in an empathetic, reassuring and non-judgemental way acknowledging that admission to hospital can be particularly traumatic for families and carers, particularly if it is the person's first admission. Arrange for parents to have protected time at an early point in the process of admitting their child to discuss the process with the relevant practitioners. Try to accommodate parents' or carers' working patterns and other responsibilities so that they can attend meetings (if the person they care for wants this). This should include: care planning meetings discharge planning meetings -ther meetings concerning the care of the person. ## Sharing information with families, parents and carers Respect the rights and needs of carers alongside the person's right to confidentiality. Review the person's consent to share information with family members, carers and other services during the inpatient stay. For more information, see the subsection on involving families and carers in the NICE guideline on service user experience in adult mental health. Throughout admission, give families, parents or carers clear, accessible information about: the purpose of the admission the person's condition (either general, or specific if the person agrees to this) the treatment, care and support that the person is receiving the inpatient unit, including: the ward and the wider hospital environment the practicalities of being in hospital resources that are available, including accommodation for families visiting arrangements preparing for discharge. Give families, parents and carers information about support services in their area that can address emotional, practical and other needs (this is particularly important if this is the person's first admission). Give young carers (under 18) of people in transition relevant information that they are able to understand. ## Carers' assessments Practitioners involved in admission and discharge should always take account of carers' needs, especially if the carer is likely to be a vital part of the person's support after discharge. Identify carers (including young carers) who have recognisable needs. If the carer wishes it, make a referral to the carer's local authority for a carer's assessment (in line with the Care Act 2014). Ensure a carer's assessment has been offered, or started, before the person is discharged from hospital.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. # Hospital discharge Health and social care practitioners in the hospital and community should plan discharge with the person and their family, carers or advocate. They should ensure that it is collaborative, person-centred and suitably-paced, so the person does not feel their discharge is sudden or premature. For more information, see discharge and transfer of care in the NICE guideline on service user experience in adult mental health. ## Maintaining links with the community Work with the person throughout their hospital stay to help them: keep links with their life outside the hospital (see recommendation 1.1.6) restart any activities before they are discharged. This is particularly important for people who need a long-term inpatient stay, are placed out-of-area, or who will have restricted access to the community. Before discharge offer: phased leave (the person can have trial periods out of hospital before discharge) phased return to employment or education (the person can gradually build up hours spent in employment or education). This is particularly important for people who have been in hospital for an extended period and people who have had restricted access to the community. Before discharging a person who is in education or training, arrange a planning meeting between them and a named person from the education setting to plan their return to learning. Children and young people under 18 must have continued access to education and learning throughout their hospital stay, in line with the Education Act 1996. Before the child or young person goes back into community-based education or training: identify a named worker from the education or training setting to be responsible for the transition arrange a meeting between the named worker and the child or young person to plan their return. ## Accommodation Before discharging people with mental health needs, discuss their housing arrangements to ensure they are suitable for them and plan accommodation accordingly. This should take into account any specific accommodation and observation requirements associated with risk of suicide. Give people with serious mental health issues who have recently been homeless, or are at risk of homelessness, intensive, structured support (in line with the Homelessness Reduction Act 2017) to find and keep accommodation. This should: be started before discharge continue after discharge for as long as the person needs support to stay in secure accommodation focus on joint problem-solving, housing and mental health issues. ## Helping the person to prepare for discharge Before discharge, offer a series of individualised psychoeducation sessions for people with psychotic illnesses to promote learning and awareness. Sessions should: start while the person is in hospital continue after discharge so the person can test new approaches in the community cover: symptoms and their causes what might cause the person to relapse, and how that can be prevented psychological treatment coping strategies to help the person if they become distressed risk factors how the person can be helped to look after themselves be conducted by the same practitioner throughout if possible. Consider psychoeducation sessions for all people with other diagnoses as part of planning discharge and avoiding readmission. During discharge planning, consider group psychoeducation support for carers. This should include signposting to information on the specific condition of the person they care for. Consider a staged, group-based psychological intervention for adults with bipolar disorder who have had at least 1 hospital admission and are being discharged from hospital. This should include: evaluation by a psychiatrist within 2 weeks of discharge sequential sets of group sessions led by trained practitioners that focus on, respectively: people's current mental health and recent experiences in hospital psychoeducation or cognitive behavioural therapy early warning signs and coping strategies. For people being discharged from hospital, consider a group-based, peer-delivered self-management training programme as part of recovery planning. Sessions should: continue for up to 12 weeks be delivered in groups of up to 12 members provide an opportunity for social support cover: self-help, early warning signs and coping strategies independent living skills making choices and setting goals. Consider providing peer support to people with more than 1 previous hospital admission. People giving peer support should: have experience of using mental health services be formally recruited, trained and supervised. ## Care planning to support discharge Ensure that there is a designated person responsible for writing the care plan in collaboration with the person being discharged (and their carers if the person agrees). Write the care plan in clear language. Avoid jargon and explain difficult terms. Ensure the care plan is based on the principles of recovery and describes the support arrangements for the person after they are discharged. If a person is being discharged to a care home, involve care home managers and practitioners in care planning and discharge planning. Ensure frequent, comprehensive review of the person's care plan and progress toward discharge. Send a copy of the care plan to everyone involved in providing support to the person at discharge and afterwards. It should include: possible relapse signs recovery goals who to contact where to go in a crisis budgeting and benefits handling personal budgets (if applicable) social networks educational, work-related and social activities details of medication (see the recommendations on medicines-related communication systems in the NICE guideline on medicines optimisation) details of treatment and support plan physical health needs including health promotion and information about contraception date of review of the care plan. ## Preparing for discharge Mental health practitioners should carry out a thorough assessment of the person's personal, social, safety and practical needs to support discharge. The assessment should include risk of suicide (see recommendations 1.6.6–1.6.8). It should: relate directly to the setting the person is being discharged to fully involve the person be shared with carers (if the person agrees) explore the possibility of using a personal health or social care budget and ensure the person understands about charges for social care cover aftercare support, in line with section 117 of the Mental Health Act 1983 cover aspects of the person's life including: daytime activities such as employment, education and leisure food, transport, budgeting and benefits pre-existing family and social issues and stressors that may have triggered the person's admission ways in which the person can manage their own condition suitability of accommodation. Recognise that carers' circumstances may have changed since admission, and take any changes into account when planning discharge. Before the person is discharged: let carers know about plans for discharge discuss with carers the person's progress during their hospital stay and how ready they are for discharge ensure that carers know the likely date of discharge well in advance. # Follow-up support Discuss follow-up support with the person before discharge. Arrange support according to their mental and physical health needs. This could include: contact details, for example of: a community psychiatric nurse or social worker the out-of-hours service support and plans for the first week practical help if needed employment support. Consider booking a follow-up appointment with the GP to take place within 2 weeks of the person's discharge. Give the person a written record of the appointment details. At discharge, the hospital psychiatrist should ensure that: Within 24 hours, a discharge letter is emailed to the person's GP. A copy should be given to the person and, if appropriate, the community team and other specialist services. Within 24 hours, a copy of the person's latest care plan is sent to everyone involved in their care (see recommendation 1.5.20). Within a week, a discharge summary is sent to the GP and others involved in developing the care plan, subject to the person's agreement. This should include information about why the person was admitted and how their condition has changed during the hospital stay. If the person has a learning disability, dementia or is on the autistic spectrum, the hospital team should lead communication about discharge planning with the other services that support the person in the community. This could include: -lder people's services learning disability services the home care service. If a person is being discharged to a care home, hospital and care home practitioners should exchange information about the person. An example might be a hospital practitioner accompanying a person with cognitive impairment when they return to the care home to help their transition (see also sharing information about a resident's medicines in the NICE guideline on managing medicines in care homes). In collaboration with the person, identify any risk of suicide and incorporate into care planning. Follow up a person who has been discharged within 7 days. Follow up a person who has been discharged within 48 hours if a risk of suicide has been identified. Consider contacting adults admitted for self-harm, who are not receiving treatment in the community after discharge, and providing advice on: services in the community that may be able to offer support or reassurance how to get in touch with them if they want to. ## Community treatment orders Decide whether a community treatment order (CTO) or guardianship order is needed (see the Mental Health Act Code of Practice), based on: the benefit to the person (for example, it may be helpful for people who have had repeated admissions) the purpose (for example, to support the person to follow their treatment plan) the conditions and legal basis. Ensure that the person who will be subject to the order has the opportunity to discuss why it is being imposed. Explain: the specific benefit for the person how to access advocacy (including their entitlement to an Independent Mental Health Advocate), and what this means what restrictions the order involves when it will be reviewed what will happen if the person does not comply with the order, and that this may not automatically lead to readmission. Ensure that the conditions, purpose, legal basis and intended benefit of the order are explained to families, carers and others providing support.# Terms used in this guideline # Carers A carer is someone who helps another person, usually a relative or friend, in their day-to-day life. This is not the same as someone who provides care professionally or through a voluntary organisation. # Coping strategies Coping strategies are the methods a person uses to deal with stressful situations. The term is used in this guideline to refer to ways that people recognise changes and cope with their mental illness or related symptoms. Some coping strategies can have negative consequences for a person using them or for the people around them. # Discharge letter A short document that includes the details of a person's current prescription, the reasons for any changes in medicines and their immediate medication treatment plan. # Discharge summary A summary of what happened during a person's admission and hospital stay from a medical perspective. It must include the diagnosis, outcomes of investigations, changes to treatment and the medicines started or stopped, or dosage changes and reasons why. # Observation An intervention in which a healthcare professional observes and maintains contact with a person using mental health services to ensure that person's safety and the safety of others. There are different levels of observation depending on how vulnerable to harm the person is considered to be. # Psychoeducation Education sessions for people affected by mental illness and their families and carers. Psychoeducation uses shared learning to empower people to cope better. Sessions can cover areas such as recognising symptoms and triggers, preventing relapses and developing coping strategies. Carers learn how best to support the person. Sessions should start while the person is in hospital and run beyond discharge so the person can test approaches in their home setting. # Recovery There is no single definition of recovery for people with mental health problems, but the guiding principle is the belief that it is possible for someone to regain a meaningful life, despite serious mental illness. In this guideline it is used to refer to someone achieving the best quality of life they can, while living and coping with their symptoms. It is an ongoing process whereby the person is supported to build up resilience and set goals to minimise the impact of mental health problems on their everyday life. # Therapeutic relationships Relationships based on mutual trust, kindness and respect, focusing on the person's recovery goals. For other social care terms, see the Think Local, Act Personal Care and Support Jargon Buster.# Context Poor transition between inpatient mental health settings and community or care home settings has negative effects on people using services and their families and carers. A key issue affecting transitions between inpatient mental health settings and the community is a lack of integrated and collaborative working between mental health and social care services, and between practitioners based in hospitals and those in the community. Both can result in inadequate and fragmented support for people using mental health services. People who use inpatient mental health services and their families and carers have reported a number of problem areas: delayed assessment and admission, so that the person is not treated until they are in crisis inadequate planning for – and support after – discharge, resulting in readmissions the person and their family or carers not being involved in planning admission, treatment and discharge people being discharged having no help to manage the mental health symptoms and other problems that contributed to their admission failure to give people the information, advocacy and support they need failure to arrange support to help the person reintegrate into the life they want to lead in the community (for example, returning to employment, education and social activities). The consequences of a poor transition can be very serious for the person and their family or carers. For example, the University of Manchester's National Confidential Inquiry into Suicide and Homicide by People with Mental Illness found that, between 2003 and 2013 in England, 2,368 mental health patients died by suicide in the first 3 months after being discharged from hospital (compared with 1,295 inpatient deaths in the same period). Older people are sometimes discharged to care homes when they might have been able to return to their own homes if extra support, such as home care, had been arranged in advance. The impact of poor discharge planning on young people who are not supported to reintegrate into education and training can have long‑lasting consequences for their life chances. People placed in inpatient facilities away from their home communities are particularly vulnerable to delayed discharges, because case management is difficult at a distance. Delayed discharge is an unnecessary expense to the NHS, but also has consequences for patients, who may become dependent on inpatient care, lose coping skills that they will need after discharge, and find that personal relationships are damaged, and housing or jobs lost. This guideline is about everyone who uses mental health inpatient facilities, including children, young people and adults, and people who have other health issues and care needs. It primarily covers transitions – admissions and discharges – and makes recommendations about how they might be handled in order to maximise the benefits of the treatment being offered, and continuity of care. It includes people who are admitted from, or discharged to, care homes and other community settings. The guideline also covers the preparation for discharge that takes place during the inpatient stay.# Recommendations for research The guideline committee has made the following recommendations for research. # Care and support for people with dementia What is the effect of specific interventions to support people with dementia during transition between inpatient mental health settings and community or care home settings? ## Why this is important The review did not identify any studies about transition for people with dementia from or to inpatient mental health settings. This is one of the groups identified in the equality impact assessment that need special consideration. Mental health disorders may be under-diagnosed in people with dementia due to 'diagnostic overshadowing', in which a person's symptoms may be wrongly attributed to dementia. If they are admitted to a psychiatric ward, being able to support them to communicate and function in a new environment, and to return to the community, may help ensure that they do not stay on inpatient wards longer than necessary. It is also important to consider how to achieve continuity of care if the person's usual residence is, or will be, a care home. Effectiveness studies are needed to evaluate different approaches and interventions to support people with dementia during transition between inpatient mental health settings and community or care home settings. Qualitative studies exploring views and experiences of people with dementia and their families and carers would also be welcome. # People with complex needs other than dementia What is the effect of specific interventions to support people with complex needs because of multiple diagnoses and resistance to treatment during transition between inpatient mental health settings and community or care home settings? (This includes people with physical or learning disabilities, people with personality disorder, people with complex psychosis, people with long-term severe mental illness and people on the autistic spectrum.) ## Why this is important As the population ages and people live longer, the number of people with severe and complex mental and physical care needs is increasing. They may need ongoing intensive support from rehabilitation and other mental health services to live in the community after discharge. Although they are a relatively small group, expenditure on care for people in this group accounts for around 25% of the total mental health budget. Studies are needed to evaluate different approaches and interventions to support people with complex needs during transition. Qualitative studies exploring views and experiences of people with complex needs and their families are also needed. These should include the views of staff from the receiving care home. # Children and young people in transition between settings What is the effect of specific interventions to support children and young people during transition between inpatient mental health settings and community or care home settings? Is there any particular benefit for black, Asian and minority ethnic communities? ## Why this is important Young people admitted to inpatient mental health settings may have a range of associated difficulties, and may be more likely than adults to be admitted to out-of-area or specialist units. The committee highlighted particular gaps in the evidence about children and young people during transitions. These included gaps in evidence on: child protection and safeguarding voluntary compared with involuntary admission understanding by children and young people of their status how looked-after children are best supported through transitions and reintegration into the school system after hospital discharge self-directed support or peer support for children and young people and their parents. Effectiveness studies are needed to evaluate the different approaches and interventions to support children and young people through safe and timely transitions. These need to be supplemented with views and experiences studies.	{'Recommendations ': "Although most of the recommendations in this guideline cover both planned and unplanned admissions, some (like those on pre-admission planning) are only applicable to planned admissions. If an admission is unplanned, then these recommendations should be applied at the soonest possible point after admission, if appropriate to the person's individual circumstances. Use this guideline alongside NICE guidance on mental health services.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Overarching principles\n\nEnsure the aim of care and support of people in transition is person-centred and focused on recovery.\n\nWork with people as active partners in their own care and transition planning. For more information, see the section on relationships and communication in the NICE guideline on service user experience in adult mental health.\n\nSupport people in transition in the least restrictive setting available (in line with the Mental Health Act Code of Practice).\n\nRecord the needs and wishes of the person at each stage of transition planning and review.\n\nIdentify the person's support networks. Work with the person to explore ways in which the people who support them can be involved throughout their admission and discharge.\n\nEnable the person to maintain links with their home community by:\n\nsupporting them to maintain relationships with family and friends, for example, by finding ways to help with transport\n\nhelping them to stay in touch with social and recreational contacts\n\nhelping them to keep links with employment, education and their local community. This is particularly important if people are admitted to mental health units outside the area in which they live.\n\nMental health services should work with primary care, local authorities and third sector organisations to ensure that people with mental health problems in transition have equal access to services. This should be based on need and irrespective of:\n\ngender\n\nsexual orientation\n\nsocioeconomic status\n\nage\n\ndisability\n\ncultural, ethnic and religious background\n\nwhether or not they are receiving support through the Care Programme Approach\n\nwhether or not they are subject to mental health legislation.\n\nGive people in transition comprehensive information about treatments and services for their mental health problems at the time they need it. If required, provide information:\n\nin large-print, braille or Easy Read format\n\nby audio or video\n\nin translation. For more information, see the section on care and support across all points on the care pathway in the NICE guideline on service user experience in adult mental health.\n\n# Before hospital admission\n\n## Planning and assessment\n\nMental health practitioners supporting transition should respond quickly to requests for assessment of mental health from:\n\npeople with mental health problems\n\nfamily members\n\ncarers\n\nprimary care practitioners (including GPs)\n\nspecialist community teams (for example, learning disability teams)\n\nstaff such as hostel, housing and community support workers.Assessments for people in crisis should be prioritised.\n\nIf admission is being planned for a treatment episode involve:\n\nthe person who is being admitted\n\ntheir family members, parents or carers\n\ncommunity accommodation and support providers.\n\nWhen planning treatment for people being admitted, take account of the expertise and knowledge of the person's family members, parents or carers.\n\nAllow more time and expert input to support people with complex, multiple or specific support needs to make transitions to and from services, if necessary. This may include:\n\nchildren and young people\n\npeople with dementia, cognitive or sensory impairment\n\npeople on the autistic spectrum\n\npeople with learning disabilities and other additional needs\n\npeople placed outside the area in which they live.\n\nFor planned admissions, offer people an opportunity to visit the inpatient unit before they are admitted. This is particularly important for:\n\nchildren and young people\n\npeople with dementia, cognitive or sensory impairment\n\npeople on the autistic spectrum\n\npeople with learning disabilities and other additional needs\n\npeople placed outside the area in which they live.\n\nIf it is not possible for the person to visit the inpatient unit that they will be admitted to in advance, consider using accessible online and printed information to support discussion about their admission.\n\nDuring admission planning, record a full history or update that:\n\ncovers the person's cognitive, physical and mental health needs\n\nincludes details of their current medication\n\nidentifies the services involved in their care. For more information, see the section on medicines reconciliation in the NICE guideline on medicines optimisation.\n\nIf more than 1\xa0team is involved in a person's transition to, within and from a service, ensure there is ongoing communication between the inpatient team and other relevant teams that include:\n\ncommunity health or social care providers, such as:\n\n\n\nthe community mental health team\n\nthe learning disability team\n\nteams that work with older people\n\n\n\nchild and adolescent mental health services (CAMHS)\n\nhousing support teams\n\ngeneral hospital or psychiatric liaison teams.\n\n## Crisis plans\n\nSupport people who have had more than 1\xa0admission to develop a crisis plan as part of their care planning process. This should include:\n\nrelapse indicators and plans\n\nwho to contact in a crisis\n\ncoping strategies\n\npreferences for treatment and specific interventions\n\nadvance decisions. For more information, see the section on community care in the NICE guideline on service user experience in adult mental health.\n\n# Hospital admission\n\n## General principles\n\nStart building therapeutic relationships as early as possible to:\n\nlessen the person's sense of being coerced\n\nencourage the person to engage with treatment and recovery programmes and collaborative decision-making\n\ncreate a safe, contained environment\n\nreduce the risk of suicide, which is high during the first 7\xa0days after admission. This is particularly important for people who have been admitted in crisis.\n\nPractitioners involved in admission should refer to crisis plans and advance statements when arranging care.\n\nAdvance decisions must be followed in line with the Mental Capacity Act 2005. For more information on advance decisions as part of advanced care planning, see the NICE guideline on decision-making and mental capacity.\n\nAt admission, offer all people access to advocacy services that take into account their:\n\nlanguage and communication needs\n\ncultural and social needs\n\nprotected characteristics (see the GOV.UK page about discrimination).\n\nHealth and social care practitioners admitting someone with cognitive difficulties should try to ensure the person understands why they have been admitted.\n\nDuring admission, discuss with the person:\n\nany strategies for coping that they use\n\nhow they can continue to use, adapt and develop positive coping strategies on the ward.\n\nStart discharge planning at admission or as early as possible when in crisis (for more information, see section 1.5).\n\nFor recommendations on assessing and treating people who have been detained under the Mental Health Act, see the section on assessment and treatment in the NICE guideline on service user experience in adult mental health.\n\nFor recommendations on crisis, including crisis admissions, see the section on assessment and referral in a crisis in the NICE guideline on service user experience in adult mental health.\n\n## Out-of-area admissions\n\nIf the person is being admitted outside the area in which they live, identify:\n\na named practitioner from the person's home area who has been supporting the person\n\na named practitioner from the ward they are being admitted to.\n\nThe named practitioners from the person's home area and the ward should work together to ensure that the person's current placement lasts no longer than required. This should include reviewing the person's care plan, current placement, recovery goals and discharge plan at least every 3\xa0months, or more frequently according to the person's needs. This could be done in person or by audio or videoconference.\n\nFor people admitted to hospital outside the area in which they live, take into account the higher risk of suicide after discharge at all stages of the planning process (see the National Confidential Inquiry into Suicide and Homicide by People with Mental Illness). This should include:\n\nassessing the risk\n\ndiscussing with the person how services can help them to stay safe\n\ndiscussing with the person's family members, parents or carers how they can help the person to stay safe.\n\n## Legal status of person being admitted\n\nThe senior health professional responsible for the admission should tell the person being admitted about their legal status at the point of admission. They should:\n\nuse clear language\n\ndiscuss rights and restrictions with the person\n\nprovide written and verbal information\n\nmake the discussion relevant to the ward the person is being admitted to\n\nexplain whether they are under observation and what this means (see observations and restrictions).\n\nA senior health professional should ensure that discussions take place with the person being admitted to check that:\n\nthey have understood the information they were given at admission\n\nthey know they have a right to appeal, and that information and advocacy can be provided to support them to do so if they wish\n\nthey understand that any changes to their legal status and treatment plans will be discussed as they occur.\n\n## Observations and restrictions\n\nThe admitting nurse or person responsible should tell the person what level of observation they are under and:\n\nexplain what being under observation means\n\nexplain clearly the reasons why the person is under observation and when, or under what circumstances, this will be reviewed\n\nexplain how they will be observed and how often\n\nexplain how observation will support their recovery and treatment\n\ndiscuss with the person how their preferences will be respected and how their rights to privacy and dignity will be protected\n\noffer the person an opportunity to ask questions.\n\nEnsure that restrictions, including restrictions on access to personal possessions:\n\nare relevant and reasonable in relation to the person concerned\n\ntake into consideration the safety of the person and others on the ward\n\nare explained clearly to ensure the person understands:\n\n\n\nwhy the restrictions are in place\n\nunder what circumstances they would be changed.\n\n\n\n## Addressing personal concerns\n\nTo support the person's transition to the ward the admitting nurse or person responsible should make the following items available if the person needs them:\n\na toothbrush\n\nhygiene products\n\nnightwear. This is particularly important for people who have been admitted in crisis.\n\nGive the person verbal and written information about ward facilities and routines (see the section on hospital care in the NICE guideline on service user experience in adult mental health).\n\nAt admission, a senior healthcare professional should discuss all medication and care needs with the person being admitted. This should include:\n\nphysical healthcare needs\n\npregnancy, breastfeeding or the need for emergency contraception\n\nadvice about immediate addiction issues, treatment and support\n\nmental health treatment.\n\nThe admitting nurse or person responsible should discuss with the person how to manage domestic and caring arrangements and liaise with the appropriate agencies. This may include:\n\npeople they have a responsibility to care for, such as:\n\n\n\nchildren\n\nfrail or ill relatives\n\n\n\ndomestic arrangements, in particular:\n\n\n\nhome security\n\ntenancy\n\nbenefits\n\nhome care service\n\npets.\n\n\n\nOn admission, ensure people (particularly children and young people) know who they can talk to if they are frightened or need support. For more information, see the section on hospital care in the NICE guideline on service user experience in adult mental health.\n\nIdentify whether the person has any additional need for support, for example, with daily living activities. Work with carers and community-based services, such as specialist services for people with learning or physical disabilities, to provide support and continuity while the person is in hospital.\n\n# Support for families, parents and carers throughout admission\n\nIdentify a named practitioner who will make sure that the person's family members, parents or carers receive support and timely information (see the section on sharing information with families, parents and carers).\n\nPractitioners should start to build relationships with the person's family members, parents or carers during admission. This should be done:\n\nin an empathetic, reassuring and non-judgemental way\n\nacknowledging that admission to hospital can be particularly traumatic for families and carers, particularly if it is the person's first admission.\n\nArrange for parents to have protected time at an early point in the process of admitting their child to discuss the process with the relevant practitioners.\n\nTry to accommodate parents' or carers' working patterns and other responsibilities so that they can attend meetings (if the person they care for wants this). This should include:\n\ncare planning meetings\n\ndischarge planning meetings\n\nother meetings concerning the care of the person.\n\n## Sharing information with families, parents and carers\n\nRespect the rights and needs of carers alongside the person's right to confidentiality. Review the person's consent to share information with family members, carers and other services during the inpatient stay. For more information, see the subsection on involving families and carers in the NICE guideline on service user experience in adult mental health.\n\nThroughout admission, give families, parents or carers clear, accessible information about:\n\nthe purpose of the admission\n\nthe person's condition (either general, or specific if the person agrees to this)\n\nthe treatment, care and support that the person is receiving\n\nthe inpatient unit, including:\n\n\n\nthe ward and the wider hospital environment\n\nthe practicalities of being in hospital\n\nresources that are available, including accommodation for families\n\nvisiting arrangements\n\n\n\npreparing for discharge.\n\nGive families, parents and carers information about support services in their area that can address emotional, practical and other needs (this is particularly important if this is the person's first admission).\n\nGive young carers (under\xa018) of people in transition relevant information that they are able to understand.\n\n## Carers' assessments\n\nPractitioners involved in admission and discharge should always take account of carers' needs, especially if the carer is likely to be a vital part of the person's support after discharge.\n\nIdentify carers (including young carers) who have recognisable needs. If the carer wishes it, make a referral to the carer's local authority for a carer's assessment (in line with the Care Act 2014). Ensure a carer's assessment has been offered, or started, before the person is discharged from hospital.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.\n\n# Hospital discharge\n\nHealth and social care practitioners in the hospital and community should plan discharge with the person and their family, carers or advocate. They should ensure that it is collaborative, person-centred and suitably-paced, so the person does not feel their discharge is sudden or premature. For more information, see discharge and transfer of care in the NICE guideline on service user experience in adult mental health.\n\n## Maintaining links with the community\n\nWork with the person throughout their hospital stay to help them:\n\nkeep links with their life outside the hospital (see recommendation 1.1.6)\n\nrestart any activities before they are discharged. This is particularly important for people who need a long-term inpatient stay, are placed out-of-area, or who will have restricted access to the community.\n\nBefore discharge offer:\n\nphased leave (the person can have trial periods out of hospital before discharge)\n\nphased return to employment or education (the person can gradually build up hours spent in employment or education). This is particularly important for people who have been in hospital for an extended period and people who have had restricted access to the community.\n\nBefore discharging a person who is in education or training, arrange a planning meeting between them and a named person from the education setting to plan their return to learning.\n\nChildren and young people under 18 must have continued access to education and learning throughout their hospital stay, in line with the Education Act 1996.\n\nBefore the child or young person goes back into community-based education or training:\n\nidentify a named worker from the education or training setting to be responsible for the transition\n\narrange a meeting between the named worker and the child or young person to plan their return.\n\n## Accommodation\n\nBefore discharging people with mental health needs, discuss their housing arrangements to ensure they are suitable for them and plan accommodation accordingly. This should take into account any specific accommodation and observation requirements associated with risk of suicide.\n\nGive people with serious mental health issues who have recently been homeless, or are at risk of homelessness, intensive, structured support (in line with the Homelessness Reduction Act 2017) to find and keep accommodation. This should:\n\nbe started before discharge\n\ncontinue after discharge for as long as the person needs support to stay in secure accommodation\n\nfocus on joint problem-solving, housing and mental health issues.\n\n## Helping the person to prepare for discharge\n\nBefore discharge, offer a series of individualised psychoeducation sessions for people with psychotic illnesses to promote learning and awareness. Sessions should:\n\nstart while the person is in hospital\n\ncontinue after discharge so the person can test new approaches in the community\n\ncover:\n\n\n\nsymptoms and their causes\n\nwhat might cause the person to relapse, and how that can be prevented\n\npsychological treatment\n\ncoping strategies to help the person if they become distressed\n\nrisk factors\n\nhow the person can be helped to look after themselves\n\n\n\nbe conducted by the same practitioner throughout if possible.\n\nConsider psychoeducation sessions for all people with other diagnoses as part of planning discharge and avoiding readmission.\n\nDuring discharge planning, consider group psychoeducation support for carers. This should include signposting to information on the specific condition of the person they care for.\n\nConsider a staged, group-based psychological intervention for adults with bipolar disorder who have had at least 1 hospital admission and are being discharged from hospital. This should include:\n\nevaluation by a psychiatrist within 2\xa0weeks of discharge\n\nsequential sets of group sessions led by trained practitioners that focus on, respectively:\n\n\n\npeople's current mental health and recent experiences in hospital\n\npsychoeducation or cognitive behavioural therapy\n\nearly warning signs and coping strategies.\n\n\n\nFor people being discharged from hospital, consider a group-based, peer-delivered self-management training programme as part of recovery planning. Sessions should:\n\ncontinue for up to 12\xa0weeks\n\nbe delivered in groups of up to 12\xa0members\n\nprovide an opportunity for social support\n\ncover:\n\n\n\nself-help, early warning signs and coping strategies\n\nindependent living skills\n\nmaking choices and setting goals.\n\n\n\nConsider providing peer support to people with more than 1 previous hospital admission. People giving peer support should:\n\nhave experience of using mental health services\n\nbe formally recruited, trained and supervised.\n\n## Care planning to support discharge\n\nEnsure that there is a designated person responsible for writing the care plan in collaboration with the person being discharged (and their carers if the person agrees).\n\nWrite the care plan in clear language. Avoid jargon and explain difficult terms.\n\nEnsure the care plan is based on the principles of recovery and describes the support arrangements for the person after they are discharged.\n\nIf a person is being discharged to a care home, involve care home managers and practitioners in care planning and discharge planning.\n\nEnsure frequent, comprehensive review of the person's care plan and progress toward discharge.\n\nSend a copy of the care plan to everyone involved in providing support to the person at discharge and afterwards. It should include:\n\npossible relapse signs\n\nrecovery goals\n\nwho to contact\n\nwhere to go in a crisis\n\nbudgeting and benefits\n\nhandling personal budgets (if applicable)\n\nsocial networks\n\neducational, work-related and social activities\n\ndetails of medication (see the recommendations on medicines-related communication systems in the NICE guideline on medicines optimisation)\n\ndetails of treatment and support plan\n\nphysical health needs including health promotion and information about contraception\n\ndate of review of the care plan.\n\n## Preparing for discharge\n\nMental health practitioners should carry out a thorough assessment of the person's personal, social, safety and practical needs to support discharge. The assessment should include risk of suicide (see recommendations 1.6.6–1.6.8). It should:\n\nrelate directly to the setting the person is being discharged to\n\nfully involve the person\n\nbe shared with carers (if the person agrees)\n\nexplore the possibility of using a personal health or social care budget and ensure the person understands about charges for social care\n\ncover aftercare support, in line with section 117 of the Mental Health Act 1983\n\ncover aspects of the person's life including:\n\n\n\ndaytime activities such as employment, education and leisure\n\nfood, transport, budgeting and benefits\n\npre-existing family and social issues and stressors that may have triggered the person's admission\n\nways in which the person can manage their own condition\n\nsuitability of accommodation.\n\n\n\nRecognise that carers' circumstances may have changed since admission, and take any changes into account when planning discharge.\n\nBefore the person is discharged:\n\nlet carers know about plans for discharge\n\ndiscuss with carers the person's progress during their hospital stay and how ready they are for discharge\n\nensure that carers know the likely date of discharge well in advance.\n\n# Follow-up support\n\nDiscuss follow-up support with the person before discharge. Arrange support according to their mental and physical health needs. This could include:\n\ncontact details, for example of:\n\n\n\na community psychiatric nurse or social worker\n\nthe out-of-hours service\n\n\n\nsupport and plans for the first week\n\npractical help if needed\n\nemployment support.\n\nConsider booking a follow-up appointment with the GP to take place within 2\xa0weeks of the person's discharge. Give the person a written record of the appointment details.\n\nAt discharge, the hospital psychiatrist should ensure that:\n\nWithin 24 hours, a discharge letter is emailed to the person's GP. A copy should be given to the person and, if appropriate, the community team and other specialist services.\n\nWithin 24 hours, a copy of the person's latest care plan is sent to everyone involved in their care (see recommendation 1.5.20).\n\nWithin a week, a discharge summary is sent to the GP and others involved in developing the care plan, subject to the person's agreement. This should include information about why the person was admitted and how their condition has changed during the hospital stay.\n\nIf the person has a learning disability, dementia or is on the autistic spectrum, the hospital team should lead communication about discharge planning with the other services that support the person in the community. This could include:\n\nolder people's services\n\nlearning disability services\n\nthe home care service.\n\nIf a person is being discharged to a care home, hospital and care home practitioners should exchange information about the person. An example might be a hospital practitioner accompanying a person with cognitive impairment when they return to the care home to help their transition (see also sharing information about a resident's medicines in the NICE guideline on managing medicines in care homes).\n\nIn collaboration with the person, identify any risk of suicide and incorporate into care planning.\n\nFollow up a person who has been discharged within 7\xa0days.\n\nFollow up a person who has been discharged within 48\xa0hours if a risk of suicide has been identified.\n\nConsider contacting adults admitted for self-harm, who are not receiving treatment in the community after discharge, and providing advice on:\n\nservices in the community that may be able to offer support or reassurance\n\nhow to get in touch with them if they want to.\n\n## Community treatment orders\n\nDecide whether a community treatment order (CTO) or guardianship order is needed (see the Mental Health Act Code of Practice), based on:\n\nthe benefit to the person (for example, it may be helpful for people who have had repeated admissions)\n\nthe purpose (for example, to support the person to follow their treatment plan)\n\nthe conditions and legal basis.\n\nEnsure that the person who will be subject to the order has the opportunity to discuss why it is being imposed. Explain:\n\nthe specific benefit for the person\n\nhow to access advocacy (including their entitlement to an Independent Mental Health Advocate), and what this means\n\nwhat restrictions the order involves\n\nwhen it will be reviewed\n\nwhat will happen if the person does not comply with the order, and that this may not automatically lead to readmission.\n\nEnsure that the conditions, purpose, legal basis and intended benefit of the order are explained to families, carers and others providing support.", 'Terms used in this guideline': "# Carers\n\nA carer is someone who helps another person, usually a relative or friend, in their day-to-day life. This is not the same as someone who provides care professionally or through a voluntary organisation.\n\n# Coping strategies\n\nCoping strategies are the methods a person uses to deal with stressful situations. The term is used in this guideline to refer to ways that people recognise changes and cope with their mental illness or related symptoms. Some coping strategies can have negative consequences for a person using them or for the people around them.\n\n# Discharge letter\n\nA short document that includes the details of a person's current prescription, the reasons for any changes in medicines and their immediate medication treatment plan.\n\n# Discharge summary\n\nA summary of what happened during a person's admission and hospital stay from a medical perspective. It must include the diagnosis, outcomes of investigations, changes to treatment and the medicines started or stopped, or dosage changes and reasons why.\n\n# Observation\n\nAn intervention in which a healthcare professional observes and maintains contact with a person using mental health services to ensure that person's safety and the safety of others. There are different levels of observation depending on how vulnerable to harm the person is considered to be.\n\n# Psychoeducation\n\nEducation sessions for people affected by mental illness and their families and carers. Psychoeducation uses shared learning to empower people to cope better. Sessions can cover areas such as recognising symptoms and triggers, preventing relapses and developing coping strategies. Carers learn how best to support the person. Sessions should start while the person is in hospital and run beyond discharge so the person can test approaches in their home setting.\n\n# Recovery\n\nThere is no single definition of recovery for people with mental health problems, but the guiding principle is the belief that it is possible for someone to regain a meaningful life, despite serious mental illness. In this guideline it is used to refer to someone achieving the best quality of life they can, while living and coping with their symptoms. It is an ongoing process whereby the person is supported to build up resilience and set goals to minimise the impact of mental health problems on their everyday life.\n\n# Therapeutic relationships\n\nRelationships based on mutual trust, kindness and respect, focusing on the person's recovery goals.\n\nFor other social care terms, see the Think Local, Act Personal Care and Support Jargon Buster.", 'Context': "Poor transition between inpatient mental health settings and community or care home settings has negative effects on people using services and their families and carers. A key issue affecting transitions between inpatient mental health settings and the community is a lack of integrated and collaborative working between mental health and social care services, and between practitioners based in hospitals and those in the community. Both can result in inadequate and fragmented support for people using mental health services.\n\nPeople who use inpatient mental health services and their families and carers have reported a number of problem areas:\n\ndelayed assessment and admission, so that the person is not treated until they are in crisis\n\ninadequate planning for – and support after – discharge, resulting in readmissions\n\nthe person and their family or carers not being involved in planning admission, treatment and discharge\n\npeople being discharged having no help to manage the mental health symptoms and other problems that contributed to their admission\n\nfailure to give people the information, advocacy and support they need\n\nfailure to arrange support to help the person reintegrate into the life they want to lead in the community (for example, returning to employment, education and social activities).\n\nThe consequences of a poor transition can be very serious for the person and their family or carers. For example, the University of Manchester's National Confidential Inquiry into Suicide and Homicide by People with Mental Illness found that, between 2003 and 2013 in England, 2,368 mental health patients died by suicide in the first 3\xa0months after being discharged from hospital (compared with 1,295 inpatient deaths in the same period).\n\nOlder people are sometimes discharged to care homes when they might have been able to return to their own homes if extra support, such as home care, had been arranged in advance.\n\nThe impact of poor discharge planning on young people who are not supported to reintegrate into education and training can have long‑lasting consequences for their life chances.\n\nPeople placed in inpatient facilities away from their home communities are particularly vulnerable to delayed discharges, because case management is difficult at a distance. Delayed discharge is an unnecessary expense to the NHS, but also has consequences for patients, who may become dependent on inpatient care, lose coping skills that they will need after discharge, and find that personal relationships are damaged, and housing or jobs lost.\n\nThis guideline is about everyone who uses mental health inpatient facilities, including children, young people and adults, and people who have other health issues and care needs. It primarily covers transitions – admissions and discharges – and makes recommendations about how they might be handled in order to maximise the benefits of the treatment being offered, and continuity of care. It includes people who are admitted from, or discharged to, care homes and other community settings. The guideline also covers the preparation for discharge that takes place during the inpatient stay.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Care and support for people with dementia\n\nWhat is the effect of specific interventions to support people with dementia during transition between inpatient mental health settings and community or care home settings?\n\n## Why this is important\n\nThe review did not identify any studies about transition for people with dementia from or to inpatient mental health settings. This is one of the groups identified in the equality impact assessment that need special consideration.\n\nMental health disorders may be under-diagnosed in people with dementia due to 'diagnostic overshadowing', in which a person's symptoms may be wrongly attributed to dementia. If they are admitted to a psychiatric ward, being able to support them to communicate and function in a new environment, and to return to the community, may help ensure that they do not stay on inpatient wards longer than necessary. It is also important to consider how to achieve continuity of care if the person's usual residence is, or will be, a care home.\n\nEffectiveness studies are needed to evaluate different approaches and interventions to support people with dementia during transition between inpatient mental health settings and community or care home settings. Qualitative studies exploring views and experiences of people with dementia and their families and carers would also be welcome.\n\n# People with complex needs other than dementia\n\nWhat is the effect of specific interventions to support people with complex needs because of multiple diagnoses and resistance to treatment during transition between inpatient mental health settings and community or care home settings? (This includes people with physical or learning disabilities, people with personality disorder, people with complex psychosis, people with long-term severe mental illness and people on the autistic spectrum.)\n\n## Why this is important\n\nAs the population ages and people live longer, the number of people with severe and complex mental and physical care needs is increasing. They may need ongoing intensive support from rehabilitation and other mental health services to live in the community after discharge. Although they are a relatively small group, expenditure on care for people in this group accounts for around 25% of the total mental health budget.\n\nStudies are needed to evaluate different approaches and interventions to support people with complex needs during transition. Qualitative studies exploring views and experiences of people with complex needs and their families are also needed. These should include the views of staff from the receiving care home.\n\n# Children and young people in transition between settings\n\nWhat is the effect of specific interventions to support children and young people during transition between inpatient mental health settings and community or care home settings? Is there any particular benefit for black, Asian and minority ethnic communities?\n\n## Why this is important\n\nYoung people admitted to inpatient mental health settings may have a range of associated difficulties, and may be more likely than adults to be admitted to out-of-area or specialist units.\n\nThe committee highlighted particular gaps in the evidence about children and young people during transitions. These included gaps in evidence on:\n\nchild protection and safeguarding\n\nvoluntary compared with involuntary admission\n\nunderstanding by children and young people of their status\n\nhow looked-after children are best supported through transitions and reintegration into the school system after hospital discharge\n\nself-directed support or peer support for children and young people and their parents.\n\nEffectiveness studies are needed to evaluate the different approaches and interventions to support children and young people through safe and timely transitions. These need to be supplemented with views and experiences studies."}	https://www.nice.org.uk/guidance/ng53	This guideline covers the period before, during and after a person is admitted to, and discharged from, a mental health hospital. It aims to help people who use mental health services, and their families and carers, to have a better experience of transition by improving the way it’s planned and carried out.
8a463fa928c5f87c71788c916c4fde0fbacee2ea	nice	Stable angina: management	Stable angina: management This guideline covers managing stable angina in people aged 18 and over. It outlines the importance of addressing the person’s concerns about stable angina and the roles of medical therapy and revascularisation. # Introduction Angina is pain or constricting discomfort that typically occurs in the front of the chest (but may radiate to the neck, shoulders, jaw or arms) and is brought on by physical exertion or emotional stress. Some people can have atypical symptoms, such as gastrointestinal discomfort, breathlessness or nausea. Angina is the main symptom of myocardial ischaemia and is usually caused by atherosclerotic obstructive coronary artery disease restricting blood flow and therefore oxygen delivery to the heart muscle. The Health Survey for England (2006) reported that around 8% of men and 3% of women aged between 55 and 64 years currently have or have had angina. The figures for men and women aged between 65 and 74 years are around 14% and 8% respectively. It is estimated that almost 2 million people in England currently have or have had angina. Being diagnosed with angina can have a significant impact on a person's quality of life, restricting daily work and leisure activities. Stable angina is a chronic medical condition with a low but appreciable incidence of acute coronary events and increased mortality. The aim of management is to stop or minimise symptoms, and to improve quality of life and long-term morbidity and mortality. Management options include lifestyle advice, drug treatment and revascularisation using percutaneous or surgical techniques. Analysis of the comparative efficacy of different treatments for people with stable angina is difficult because of the advances in drug treatment and revascularisation strategies over several decades. Trials of drug treatment versus coronary artery bypass surgery were carried out more than 25 years ago and showed a survival advantage with surgery in patients with severe coronary artery disease. Statins and other secondary prevention treatments were not used when the trials were carried out and these treatments have a significant effect on morbidity and mortality. Percutaneous revascularisation techniques have developed, from balloon angioplasty to bare metal stents and drug eluting stents and each is associated with reduced rates of repeat revascularisation compared with the previous technique. All trials, including trials of revascularisation strategies, have been limited to people considered suitable for the intervention rather than being representative of the whole population with angina. The recommendations in this guideline relate only to people with a diagnosis of stable angina. Coronary artery disease can also present as acute coronary syndromes, such as unstable angina or myocardial infarction. The NICE guideline on recent-onset chest pain of suspected cardiac arrest origin, covers the diagnosis of stable angina and should be read in conjunction with this guideline. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients. This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.# Guidance People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Recommendations 1.5.2 and 1.5.12 partially update recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction. The following guidance is for people who have a diagnosis of stable angina and is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # Diagnosis Diagnose stable angina according to the NICE guideline on recent-onset chest pain of suspected cardiac origin. Diagnose and manage unstable angina and NSTEMI according to the NICE guidelines on recent-onset chest pain of suspected cardiac origin, unstable angina and NSTEMI and acute coronary syndromes. # Information and support for people with stable angina Clearly explain stable angina to the person, including factors that can provoke angina (for example, exertion, emotional stress, exposure to cold, eating a heavy meal) and its long-term course and management. When relevant, involve the person's family or carers in the discussion. Encourage the person with stable angina to ask questions about their angina and its treatment. Provide opportunities for them to voice their concerns and fears. Discuss the person's, and if appropriate, their family or carer's ideas, concerns and expectations about their condition, prognosis and treatment. Explore and address any misconceptions about stable angina and its implications for daily activities, heart attack risk and life expectancy. Advise the person with stable angina to seek professional help if there is a sudden worsening in the frequency or severity of their angina. Discuss with the person the purpose and any risks and benefits of their treatment. Assess the person's need for lifestyle advice (for example about exercise, stopping smoking, diet and weight control) and psychological support, and offer interventions as necessary. Explore and address issues according to the person's needs, which may include: self-management skills such as pacing their activities and goal setting concerns about the impact of stress, anxiety or depression on angina advice about physical exertion including sexual activity. # General principles for treating people with stable angina Do not exclude people with stable angina from treatment based on their age alone. Do not investigate or treat symptoms of stable angina differently in men and women or in different ethnic groups. ## Preventing and treating episodes of angina Offer a short-acting nitrate for preventing and treating episodes of angina. Advise people with stable angina: how to administer the short-acting nitrate to use it immediately before any planned exercise or exertion that side effects such as flushing, headache and light-headedness may occur to sit down or find something to hold on to if feeling light-headed. When a short-acting nitrate is being used to treat episodes of angina, advise people: to repeat the dose after 5 minutes if the pain has not gone to call an emergency ambulance if the pain has not gone 5 minutes after taking a second dose. ## Drugs for secondary prevention of cardiovascular disease Consider aspirin 75 mg daily for people with stable angina, taking into account the risk of bleeding and comorbidities. Consider angiotensin-converting enzyme (ACE) inhibitors for people with stable angina and diabetes. Offer or continue ACE inhibitors for other conditions, in line with relevant NICE guidance. Offer statin treatment in line with the NICE guideline on lipid modification. Offer treatment for high blood pressure in line with the NICE guideline on hypertension. ## Dietary supplements Do not offer vitamin or fish oil supplements to treat stable angina. Inform people that there is no evidence that they help stable angina. # Anti-anginal drug treatment ## General recommendations Offer people optimal drug treatment for the initial management of stable angina. Optimal drug treatment consists of one or two anti-anginal drugs as necessary plus drugs for secondary prevention of cardiovascular disease. Advise people that the aim of anti-anginal drug treatment is to prevent episodes of angina and the aim of secondary prevention treatment is to prevent cardiovascular events such as heart attack and stroke. Discuss how side effects of drug treatment might affect the person's daily activities and explain why it is important to take drug treatment regularly. Patients differ in the type and amount of information they need and want. Therefore the provision of information should be individualised and is likely to include, but not be limited to: what the medicine is how the medicine is likely to affect their condition (that is, its benefits) likely or significant adverse effects and what to do if they think they are experiencing them how to use the medicine what to do if they miss a dose whether further courses of the medicine will be needed after the first prescription how to get further supplies of medicines. Review the person's response to treatment, including any side effects, 2 to 4 weeks after starting or changing drug treatment. Titrate the drug dosage against the person's symptoms up to the maximum tolerable dosage. ## Drugs for treating stable angina Offer either a beta blocker or a calcium channel blocker as first-line treatment for stable angina. Decide which drug to use based on comorbidities, contraindications and the person's preference. If the person cannot tolerate the beta blocker or calcium channel blocker, consider switching to the other option (calcium channel blocker or beta blocker). If the person's symptoms are not satisfactorily controlled on a beta blocker or a calcium channel blocker, consider either switching to the other option or using a combination of the two. When combining a calcium channel blocker with a beta blocker, use a dihydropyridine calcium channel blocker, for example, slow release nifedipine, amlodipine or felodipine. Do not routinely offer anti-anginal drugs other than beta blockers or calcium channel blockers as first-line treatment for stable angina. If the person cannot tolerate beta blockers and calcium channel blockers or both are contraindicated, consider monotherapy with one of the following drugs: a long-acting nitrate or ivabradine or nicorandil or ranolazine.Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs.Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016). For people on beta blocker or calcium channel blocker monotherapy whose symptoms are not controlled and the other option (calcium channel blocker or beta blocker) is contraindicated or not tolerated, consider one of the following as an additional drug: a long-acting nitrate or ivabradine or nicorandil or ranolazine.Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs. Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016).When combining ivabradine with a calcium channel blocker, use a dihydropyridine calcium channel blocker, for example, slow release nifedipine, amlodipine, or felodipine. Do not offer a third anti-anginal drug to people whose stable angina is controlled with two anti-anginal drugs. Consider adding a third anti-anginal drug only when: the person's symptoms are not satisfactorily controlled with two anti-anginal drugs and the person is waiting for revascularisation or revascularisation is not considered appropriate or acceptable.Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs. # Investigation and revascularisation ## People with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment Consider revascularisation (coronary artery bypass graft or percutaneous coronary intervention ) for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment. Offer coronary angiography to guide treatment strategy for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment. Additional non-invasive or invasive functional testing may be required to evaluate angiographic findings and guide treatment decisions. Offer CABG to people with stable angina and suitable coronary anatomy when: their symptoms are not satisfactorily controlled with optimal medical treatment and revascularisation is considered appropriate and PCI is not appropriate. Offer PCI to people with stable angina and suitable coronary anatomy when: their symptoms are not satisfactorily controlled with optimal medical treatment and revascularisation is considered appropriate and CABG is not appropriate. When either procedure would be appropriate, explain to the person the risks and benefits of PCI and CABG for people with anatomically less complex disease whose symptoms are not satisfactorily controlled with optimal medical treatment. If the person does not express a preference, take account of the evidence that suggests that PCI may be the more cost-effective procedure in selecting the course of treatment. When either procedure would be appropriate, take into account the potential survival advantage of CABG over PCI for people with multivessel disease whose symptoms are not satisfactorily controlled with optimal medical treatment and who: have diabetes or are over 65 years or have anatomically complex three-vessel disease, with or without involvement of the left main stem. Consider the relative risks and benefits of CABG and PCI for people with stable angina using a systematic approach to assess the severity and complexity of the person's coronary disease, in addition to other relevant clinical factors and comorbidities. Ensure that there is a regular multidisciplinary team meeting to discuss the risks and benefits of continuing drug treatment or revascularisation strategy (CABG or PCI) for people with stable angina. The team should include cardiac surgeons and interventional cardiologists. Treatment strategy should be discussed for the following people, including but not limited to: people with left main stem or anatomically complex three-vessel disease people in whom there is doubt about the best method of revascularisation because of the complexity of the coronary anatomy, the extent of stenting required or other relevant clinical factors and comorbidities. Ensure people with stable angina receive balanced information and have the opportunity to discuss the benefits, limitations and risks of continuing drug treatment, CABG and PCI to help them make an informed decision about their treatment. When either revascularisation procedure is appropriate, explain to the person: The main purpose of revascularisation is to improve the symptoms of stable angina. CABG and PCI are effective in relieving symptoms. Repeat revascularisation may be necessary after either CABG or PCI and the rate is lower after CABG. Stroke is uncommon after either CABG or PCI, and the incidence is similar between the two procedures. There is a potential survival advantage with CABG for some people with multivessel disease. Inform the person about the practical aspects of CABG and PCI. Include information about: vein and/or artery harvesting likely length of hospital stay recovery time drug treatment after the procedure. ## People with stable angina whose symptoms are satisfactorily controlled with optimal medical treatment Discuss the following with people whose symptoms are satisfactorily controlled with optimal medical treatment: their prognosis without further investigation the likelihood of having left main stem disease or proximal three-vessel disease the availability of CABG to improve the prognosis in a subgroup of people with left main stem or proximal three-vessel disease the process and risks of investigation the benefits and risks of CABG, including the potential survival gain. After discussion (see 1.5.11) with people whose symptoms are satisfactorily controlled with optimal medical treatment, consider a functional or non-invasive anatomical test to identify people who might gain a survival benefit from surgery. Functional or anatomical test results may already be available from diagnostic assessment. After discussion (see 1.5.11) with people whose symptoms are satisfactorily controlled with optimal medical treatment, consider coronary angiography when: functional testing indicates extensive ischaemia or non-invasive anatomical testing indicates the likelihood of left main stem or proximal three-vessel disease and revascularisation is acceptable and appropriate. Consider CABG for people with stable angina and suitable coronary anatomy whose symptoms are satisfactorily controlled with optimal medical treatment, but coronary angiography indicates left main stem disease or proximal three-vessel disease. # Pain interventions Do not offer the following interventions to manage stable angina: transcutaneous electrical nerve stimulation (TENS) enhanced external counterpulsation (EECP) acupuncture. # Stable angina that has not responded to treatment Offer people whose stable angina has not responded to drug treatment and/or revascularisation comprehensive re-evaluation and advice, which may include: exploring the person's understanding of their condition exploring the impact of symptoms on the person's quality of life reviewing the diagnosis and considering non-ischaemic causes of pain reviewing drug treatment and considering future drug treatment and revascularisation options acknowledging the limitations of future treatment explaining how the person can manage the pain themselves specific attention to the role of psychological factors in pain development of skills to modify cognitions and behaviours associated with pain. # Cardiac syndrome X In people with angiographically normal coronary arteries and continuing anginal symptoms, consider a diagnosis of cardiac syndrome X. Continue drug treatment for stable angina only if it improves the symptoms of the person with suspected cardiac syndrome X. Do not routinely offer drugs for the secondary prevention of cardiovascular disease to people with suspected cardiac syndrome X.# Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Adding a newer anti-anginal drug to a calcium channel blocker What is the clinical and cost effectiveness of adding a newer anti-anginal drug (nicorandil, ivabradine or ranolazine) to a calcium channel blocker for treating stable angina? Why this is important We do not know the long-term clinical and cost effectiveness of adding a newer anti-anginal drug to a calcium channel blocker in people with stable angina. We propose a double-blind placebo-controlled randomised trial comparing the addition of a newer anti-anginal drug to a calcium channel blocker with a calcium channel blocker alone in people with stable angina whose symptoms are not being controlled. Endpoints would include symptom severity, quality of life, long-term morbidity and mortality, and cost effectiveness. The results of the trial would influence clinical practice and inform future updates of key recommendations in this guideline. # Management of stable angina in people with evidence of ischaemia on non-invasive functional testing Do people with stable angina and evidence of reversible ischaemia on non-invasive functional testing who are on optimal drug treatment benefit from routine coronary angiography with a view to revascularisation? Why this is important Revascularisation has traditionally been offered to people with stable angina who have evidence of reversible ischaemia on non-invasive functional testing. Recent trials in people with stable angina (COURAGE, BARI-2D, MASS II) have not shown survival benefit from revascularisation compared with drug treatment. In the nuclear substudy of COURAGE (n = 314), PCI was shown to be more effective in treating ischaemia than optimal drug treatment, and in multivariate analyses reduction of ischaemia was associated with greater event-free survival. It is unclear, however, whether people on optimal drug treatment who have evidence of inducible ischaemia on non-invasive functional testing should routinely have coronary angiography and revascularisation. This question is particularly relevant for people who have responded adequately (for example Canadian Cardiovascular Class 1 or 2) to optimal drug treatment and in whom, based on symptoms alone, revascularisation is not indicated. To answer this question we recommend a randomised trial of interventional management versus continued drug treatment in people with stable angina and myocardial ischaemia on non-invasive functional testing, with all-cause mortality and cardiovascular mortality as the primary endpoints. # Early revascularisation strategy for people with angina and multivessel disease In people with stable angina and multivessel disease (including left main stem disease) whose symptoms are controlled with optimal drug treatment, would an initial treatment strategy of revascularisation be clinically and cost effective compared with continued drug treatment? Why this is important Research is needed to determine whether early investigation and revascularisation can improve longer term survival. People with stable angina may be disadvantaged if they do not have tests to identify whether they have a higher risk profile for early cardiac death, which could be reduced by revascularisation. This disadvantage could be magnified when people who are deemed to fall into very high risk groups (for example, left main stem stenosis > 50% in the MASS II trial) are excluded from randomised trials, resulting in the benefits of revascularisation being underestimated. We propose a randomised trial comparing an initial strategy of revascularisation (CABG or PCI) with an initial strategy of continued drug treatment in people with multivessel disease (including left main stem disease) in whom revascularisation is not needed for symptom relief. The trial should use drug-eluting stents and wider inclusion criteria than BARI-2D and COURAGE. # Cardiac rehabilitation Is an 8-week, comprehensive, multidisciplinary, cardiac rehabilitation service more clinically and cost effective for managing stable angina than current clinical practice? Why this is important Cardiac rehabilitation programmes are an established treatment strategy for certain heart conditions, such as for people who have had a heart attack. However, there is no evidence to suggest that cardiac rehabilitation is clinically or cost effective for managing stable angina. Research to date has looked at short-term outcomes, such as a change in diet or exercise levels, but the effect on morbidity and mortality has not been studied. A randomised controlled trial is required to compare comprehensive cardiac rehabilitation with standard care in people with stable angina, with measures of angina severity (exercise capacity, angina frequency, use of a short-acting nitrate), and long-term morbidity and mortality as endpoints. # Patient self-management plans What is the clinical and cost effectiveness of a self-management plan for people with stable angina? Why this is important Stable angina is a chronic condition. Evidence suggests that addressing people's beliefs and behaviours in relation to angina may improve quality of life, and reduce morbidity and use of resources. Self-management plans could include: educating people with stable angina about the role of psychological factors in pain and pain control; and teaching people self-management skills to modify cognitions, behaviours and affective responses in order to control chest pain. These skills may include pacing of physical activities, modifying stress using cognitive reframing and problem-solving techniques, and relaxation training or mindfulness techniques. The proposed study is a randomised controlled trial in primary care that would assess the clinical and cost effectiveness of self-management plans. This research would inform future updates of key recommendations in the guideline. Furthermore the research would be relevant to a national priority area (National service framework for coronary heart disease chapter 4: stable angina and chapter 7: cardiac rehabilitation) as well as the Coalition White Paper 2010 (Equity and excellence: liberating the NHS) that emphasise the importance of increasing people's choice and control in managing their condition.	{'Introduction': "Angina is pain or constricting discomfort that typically occurs in the front of the chest (but may radiate to the neck, shoulders, jaw or arms) and is brought on by physical exertion or emotional stress. Some people can have atypical symptoms, such as gastrointestinal discomfort, breathlessness or nausea. Angina is the main symptom of myocardial ischaemia and is usually caused by atherosclerotic obstructive coronary artery disease restricting blood flow and therefore oxygen delivery to the heart muscle. The Health Survey for England (2006) reported that around 8% of men and 3% of women aged between 55 and 64\xa0years currently have or have had angina. The figures for men and women aged between 65 and 74\xa0years are around 14% and 8% respectively. It is estimated that almost 2\xa0million people in England currently have or have had angina. Being diagnosed with angina can have a significant impact on a person's quality of life, restricting daily work and leisure activities.\n\nStable angina is a chronic medical condition with a low but appreciable incidence of acute coronary events and increased mortality. The aim of management is to stop or minimise symptoms, and to improve quality of life and long-term morbidity and mortality. Management options include lifestyle advice, drug treatment and revascularisation using percutaneous or surgical techniques.\n\nAnalysis of the comparative efficacy of different treatments for people with stable angina is difficult because of the advances in drug treatment and revascularisation strategies over several decades. Trials of drug treatment versus coronary artery bypass surgery were carried out more than 25\xa0years ago and showed a survival advantage with surgery in patients with severe coronary artery disease. Statins and other secondary prevention treatments were not used when the trials were carried out and these treatments have a significant effect on morbidity and mortality. Percutaneous revascularisation techniques have developed, from balloon angioplasty to bare metal stents and drug eluting stents and each is associated with reduced rates of repeat revascularisation compared with the previous technique. All trials, including trials of revascularisation strategies, have been limited to people considered suitable for the intervention rather than being representative of the whole population with angina.\n\nThe recommendations in this guideline relate only to people with a diagnosis of stable angina. Coronary artery disease can also present as acute coronary syndromes, such as unstable angina or myocardial infarction. The NICE guideline on recent-onset chest pain of suspected cardiac arrest origin, covers the diagnosis of stable angina and should be read in conjunction with this guideline.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.", 'Guidance': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nRecommendations 1.5.2 and 1.5.12 partially update recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.\n\nThe following guidance is for people who have a diagnosis of stable angina and is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Diagnosis\n\nDiagnose stable angina according to the NICE guideline on recent-onset chest pain of suspected cardiac origin. Diagnose and manage unstable angina and NSTEMI according to the NICE guidelines on recent-onset chest pain of suspected cardiac origin, unstable angina and NSTEMI and acute coronary syndromes.\n\n# Information and support for people with stable angina\n\nClearly explain stable angina to the person, including factors that can provoke angina (for example, exertion, emotional stress, exposure to cold, eating a heavy meal) and its long-term course and management. When relevant, involve the person's family or carers in the discussion.\n\nEncourage the person with stable angina to ask questions about their angina and its treatment. Provide opportunities for them to voice their concerns and fears.\n\nDiscuss the person's, and if appropriate, their family or carer's ideas, concerns and expectations about their condition, prognosis and treatment. Explore and address any misconceptions about stable angina and its implications for daily activities, heart attack risk and life expectancy.\n\nAdvise the person with stable angina to seek professional help if there is a sudden worsening in the frequency or severity of their angina.\n\nDiscuss with the person the purpose and any risks and benefits of their treatment.\n\nAssess the person's need for lifestyle advice (for example about exercise, stopping smoking, diet and weight control) and psychological support, and offer interventions as necessary.\n\nExplore and address issues according to the person's needs, which may include:\n\nself-management skills such as pacing their activities and goal setting\n\nconcerns about the impact of stress, anxiety or depression on angina\n\nadvice about physical exertion including sexual activity.\n\n# General principles for treating people with stable angina\n\nDo not exclude people with stable angina from treatment based on their age alone.\n\nDo not investigate or treat symptoms of stable angina differently in men and women or in different ethnic groups.\n\n## Preventing and treating episodes of angina\n\nOffer a short-acting nitrate for preventing and treating episodes of angina. Advise people with stable angina:\n\nhow to administer the short-acting nitrate\n\nto use it immediately before any planned exercise or exertion\n\nthat side effects such as flushing, headache and light-headedness may occur\n\nto sit down or find something to hold on to if feeling light-headed.\n\nWhen a short-acting nitrate is being used to treat episodes of angina, advise people:\n\nto repeat the dose after 5\xa0minutes if the pain has not gone\n\nto call an emergency ambulance if the pain has not gone 5\xa0minutes after taking a second dose.\n\n## Drugs for secondary prevention of cardiovascular disease\n\nConsider aspirin 75\xa0mg daily for people with stable angina, taking into account the risk of bleeding and comorbidities.\n\nConsider angiotensin-converting enzyme (ACE) inhibitors for people with stable angina and diabetes. Offer or continue ACE inhibitors for other conditions, in line with relevant NICE guidance.\n\nOffer statin treatment in line with the NICE guideline on lipid modification.\n\nOffer treatment for high blood pressure in line with the NICE guideline on hypertension.\n\n## Dietary supplements\n\nDo not offer vitamin or fish oil supplements to treat stable angina. Inform people that there is no evidence that they help stable angina.\n\n# Anti-anginal drug treatment\n\n## General recommendations\n\nOffer people optimal drug treatment for the initial management of stable angina. Optimal drug treatment consists of one or two anti-anginal drugs as necessary plus drugs for secondary prevention of cardiovascular disease.\n\nAdvise people that the aim of anti-anginal drug treatment is to prevent episodes of angina and the aim of secondary prevention treatment is to prevent cardiovascular events such as heart attack and stroke.\n\nDiscuss how side effects of drug treatment might affect the person's daily activities and explain why it is important to take drug treatment regularly.\n\nPatients differ in the type and amount of information they need and want. Therefore the provision of information should be individualised and is likely to include, but not be limited to:\n\nwhat the medicine is\n\nhow the medicine is likely to affect their condition (that is, its benefits)\n\nlikely or significant adverse effects and what to do if they think they are experiencing them\n\nhow to use the medicine\n\nwhat to do if they miss a dose\n\nwhether further courses of the medicine will be needed after the first prescription\n\nhow to get further supplies of medicines. [This recommendation is from the NICE guideline on medicines adherence.]\n\nReview the person's response to treatment, including any side effects, 2 to 4 weeks after starting or changing drug treatment.\n\nTitrate the drug dosage against the person's symptoms up to the maximum tolerable dosage.\n\n## Drugs for treating stable angina\n\nOffer either a beta blocker or a calcium channel blocker as first-line treatment for stable angina. Decide which drug to use based on comorbidities, contraindications and the person's preference.\n\nIf the person cannot tolerate the beta blocker or calcium channel blocker, consider switching to the other option (calcium channel blocker or beta blocker).\n\nIf the person's symptoms are not satisfactorily controlled on a beta blocker or a calcium channel blocker, consider either switching to the other option or using a combination of the two. When combining a calcium channel blocker with a beta blocker, use a dihydropyridine calcium channel blocker, for example, slow release nifedipine, amlodipine or felodipine.\n\nDo not routinely offer anti-anginal drugs other than beta blockers or calcium channel blockers as first-line treatment for stable angina.\n\nIf the person cannot tolerate beta blockers and calcium channel blockers or both are contraindicated, consider monotherapy with one of the following drugs:\n\na long-acting nitrate or\n\nivabradine or\n\nnicorandil or\n\nranolazine.Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs.Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016).\n\nFor people on beta blocker or calcium channel blocker monotherapy whose symptoms are not controlled and the other option (calcium channel blocker or beta blocker) is contraindicated or not tolerated, consider one of the following as an additional drug:\n\na long-acting nitrate or\n\nivabradine or\n\nnicorandil or\n\nranolazine.Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs. Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016).When combining ivabradine with a calcium channel blocker, use a dihydropyridine calcium channel blocker, for example, slow release nifedipine, amlodipine, or felodipine.\n\nDo not offer a third anti-anginal drug to people whose stable angina is controlled with two anti-anginal drugs.\n\nConsider adding a third anti-anginal drug only when:\n\nthe person's symptoms are not satisfactorily controlled with two anti-anginal drugs and\n\nthe person is waiting for revascularisation or revascularisation is not considered appropriate or acceptable.Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs.\n\n# Investigation and revascularisation\n\n## People with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment\n\nConsider revascularisation (coronary artery bypass graft [CABG] or percutaneous coronary intervention [PCI]) for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment.\n\nOffer coronary angiography to guide treatment strategy for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment. Additional non-invasive or invasive functional testing may be required to evaluate angiographic findings and guide treatment decisions. [This recommendation partially updates recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.]\n\nOffer CABG to people with stable angina and suitable coronary anatomy when:\n\ntheir symptoms are not satisfactorily controlled with optimal medical treatment and\n\nrevascularisation is considered appropriate and\n\nPCI is not appropriate.\n\nOffer PCI to people with stable angina and suitable coronary anatomy when:\n\ntheir symptoms are not satisfactorily controlled with optimal medical treatment and\n\nrevascularisation is considered appropriate and\n\nCABG is not appropriate.\n\nWhen either procedure would be appropriate, explain to the person the risks and benefits of PCI and CABG for people with anatomically less complex disease whose symptoms are not satisfactorily controlled with optimal medical treatment. If the person does not express a preference, take account of the evidence that suggests that PCI may be the more cost-effective procedure in selecting the course of treatment.\n\nWhen either procedure would be appropriate, take into account the potential survival advantage of CABG over PCI for people with multivessel disease whose symptoms are not satisfactorily controlled with optimal medical treatment and who:\n\nhave diabetes or\n\nare over 65 years or\n\nhave anatomically complex three-vessel disease, with or without involvement of the left main stem.\n\nConsider the relative risks and benefits of CABG and PCI for people with stable angina using a systematic approach to assess the severity and complexity of the person's coronary disease, in addition to other relevant clinical factors and comorbidities.\n\nEnsure that there is a regular multidisciplinary team meeting to discuss the risks and benefits of continuing drug treatment or revascularisation strategy (CABG or PCI) for people with stable angina. The team should include cardiac surgeons and interventional cardiologists. Treatment strategy should be discussed for the following people, including but not limited to:\n\npeople with left main stem or anatomically complex three-vessel disease\n\npeople in whom there is doubt about the best method of revascularisation because of the complexity of the coronary anatomy, the extent of stenting required or other relevant clinical factors and comorbidities.\n\nEnsure people with stable angina receive balanced information and have the opportunity to discuss the benefits, limitations and risks of continuing drug treatment, CABG and PCI to help them make an informed decision about their treatment. When either revascularisation procedure is appropriate, explain to the person:\n\nThe main purpose of revascularisation is to improve the symptoms of stable angina.\n\nCABG and PCI are effective in relieving symptoms.\n\nRepeat revascularisation may be necessary after either CABG or PCI and the rate is lower after CABG.\n\nStroke is uncommon after either CABG or PCI, and the incidence is similar between the two procedures.\n\nThere is a potential survival advantage with CABG for some people with multivessel disease.\n\nInform the person about the practical aspects of CABG and PCI. Include information about:\n\nvein and/or artery harvesting\n\nlikely length of hospital stay\n\nrecovery time\n\ndrug treatment after the procedure.\n\n## People with stable angina whose symptoms are satisfactorily controlled with optimal medical treatment\n\nDiscuss the following with people whose symptoms are satisfactorily controlled with optimal medical treatment:\n\ntheir prognosis without further investigation\n\nthe likelihood of having left main stem disease or proximal three-vessel disease\n\nthe availability of CABG to improve the prognosis in a subgroup of people with left main stem or proximal three-vessel disease\n\nthe process and risks of investigation\n\nthe benefits and risks of CABG, including the potential survival gain.\n\nAfter discussion (see 1.5.11) with people whose symptoms are satisfactorily controlled with optimal medical treatment, consider a functional or non-invasive anatomical test to identify people who might gain a survival benefit from surgery. Functional or anatomical test results may already be available from diagnostic assessment. [This recommendation partially updates recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.]\n\nAfter discussion (see 1.5.11) with people whose symptoms are satisfactorily controlled with optimal medical treatment, consider coronary angiography when:\n\nfunctional testing indicates extensive ischaemia or non-invasive anatomical testing indicates the likelihood of left main stem or proximal three-vessel disease and\n\nrevascularisation is acceptable and appropriate.\n\nConsider CABG for people with stable angina and suitable coronary anatomy whose symptoms are satisfactorily controlled with optimal medical treatment, but coronary angiography indicates left main stem disease or proximal three-vessel disease.\n\n# Pain interventions\n\nDo not offer the following interventions to manage stable angina:\n\ntranscutaneous electrical nerve stimulation (TENS)\n\nenhanced external counterpulsation (EECP)\n\nacupuncture.\n\n# Stable angina that has not responded to treatment\n\nOffer people whose stable angina has not responded to drug treatment and/or revascularisation comprehensive re-evaluation and advice, which may include:\n\nexploring the person's understanding of their condition\n\nexploring the impact of symptoms on the person's quality of life\n\nreviewing the diagnosis and considering non-ischaemic causes of pain\n\nreviewing drug treatment and considering future drug treatment and revascularisation options\n\nacknowledging the limitations of future treatment\n\nexplaining how the person can manage the pain themselves\n\nspecific attention to the role of psychological factors in pain\n\ndevelopment of skills to modify cognitions and behaviours associated with pain.\n\n# Cardiac syndrome X\n\nIn people with angiographically normal coronary arteries and continuing anginal symptoms, consider a diagnosis of cardiac syndrome X.\n\nContinue drug treatment for stable angina only if it improves the symptoms of the person with suspected cardiac syndrome X.\n\nDo not routinely offer drugs for the secondary prevention of cardiovascular disease to people with suspected cardiac syndrome X.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Adding a newer anti-anginal drug to a calcium channel blocker\n\nWhat is the clinical and cost effectiveness of adding a newer anti-anginal drug (nicorandil, ivabradine or ranolazine) to a calcium channel blocker for treating stable angina?\n\nWhy this is important\n\nWe do not know the long-term clinical and cost effectiveness of adding a newer anti-anginal drug to a calcium channel blocker in people with stable angina. We propose a double-blind placebo-controlled randomised trial comparing the addition of a newer anti-anginal drug to a calcium channel blocker with a calcium channel blocker alone in people with stable angina whose symptoms are not being controlled. Endpoints would include symptom severity, quality of life, long-term morbidity and mortality, and cost effectiveness. The results of the trial would influence clinical practice and inform future updates of key recommendations in this guideline.\n\n# Management of stable angina in people with evidence of ischaemia on non-invasive functional testing\n\nDo people with stable angina and evidence of reversible ischaemia on non-invasive functional testing who are on optimal drug treatment benefit from routine coronary angiography with a view to revascularisation?\n\nWhy this is important\n\nRevascularisation has traditionally been offered to people with stable angina who have evidence of reversible ischaemia on non-invasive functional testing. Recent trials in people with stable angina (COURAGE, BARI-2D, MASS II) have not shown survival benefit from revascularisation compared with drug treatment. In the nuclear substudy of COURAGE (n\xa0=\xa0314), PCI was shown to be more effective in treating ischaemia than optimal drug treatment, and in multivariate analyses reduction of ischaemia was associated with greater event-free survival. It is unclear, however, whether people on optimal drug treatment who have evidence of inducible ischaemia on non-invasive functional testing should routinely have coronary angiography and revascularisation. This question is particularly relevant for people who have responded adequately (for example Canadian Cardiovascular Class 1 or 2) to optimal drug treatment and in whom, based on symptoms alone, revascularisation is not indicated. To answer this question we recommend a randomised trial of interventional management versus continued drug treatment in people with stable angina and myocardial ischaemia on non-invasive functional testing, with all-cause mortality and cardiovascular mortality as the primary endpoints.\n\n# Early revascularisation strategy for people with angina and multivessel disease\n\nIn people with stable angina and multivessel disease (including left main stem disease) whose symptoms are controlled with optimal drug treatment, would an initial treatment strategy of revascularisation be clinically and cost effective compared with continued drug treatment?\n\nWhy this is important\n\nResearch is needed to determine whether early investigation and revascularisation can improve longer term survival. People with stable angina may be disadvantaged if they do not have tests to identify whether they have a higher risk profile for early cardiac death, which could be reduced by revascularisation. This disadvantage could be magnified when people who are deemed to fall into very high risk groups (for example, left main stem stenosis\xa0>\xa050% in the MASS II trial) are excluded from randomised trials, resulting in the benefits of revascularisation being underestimated. We propose a randomised trial comparing an initial strategy of revascularisation (CABG or PCI) with an initial strategy of continued drug treatment in people with multivessel disease (including left main stem disease) in whom revascularisation is not needed for symptom relief. The trial should use drug-eluting stents and wider inclusion criteria than BARI-2D and COURAGE.\n\n# Cardiac rehabilitation\n\nIs an 8-week, comprehensive, multidisciplinary, cardiac rehabilitation service more clinically and cost effective for managing stable angina than current clinical practice?\n\nWhy this is important\n\nCardiac rehabilitation programmes are an established treatment strategy for certain heart conditions, such as for people who have had a heart attack. However, there is no evidence to suggest that cardiac rehabilitation is clinically or cost effective for managing stable angina. Research to date has looked at short-term outcomes, such as a change in diet or exercise levels, but the effect on morbidity and mortality has not been studied. A randomised controlled trial is required to compare comprehensive cardiac rehabilitation with standard care in people with stable angina, with measures of angina severity (exercise capacity, angina frequency, use of a short-acting nitrate), and long-term morbidity and mortality as endpoints.\n\n# Patient self-management plans\n\nWhat is the clinical and cost effectiveness of a self-management plan for people with stable angina?\n\nWhy this is important\n\nStable angina is a chronic condition. Evidence suggests that addressing people's beliefs and behaviours in relation to angina may improve quality of life, and reduce morbidity and use of resources. Self-management plans could include: educating people with stable angina about the role of psychological factors in pain and pain control; and teaching people self-management skills to modify cognitions, behaviours and affective responses in order to control chest pain. These skills may include pacing of physical activities, modifying stress using cognitive reframing and problem-solving techniques, and relaxation training or mindfulness techniques. The proposed study is a randomised controlled trial in primary care that would assess the clinical and cost effectiveness of self-management plans. This research would inform future updates of key recommendations in the guideline. Furthermore the research would be relevant to a national priority area (National service framework for coronary heart disease [NSF CHD] chapter 4: stable angina and chapter 7: cardiac rehabilitation) as well as the Coalition White Paper 2010 (Equity and excellence: liberating the NHS) that emphasise the importance of increasing people's choice and control in managing their condition."}	https://www.nice.org.uk/guidance/cg126	This guideline covers managing stable angina in people aged 18 and over. It outlines the importance of addressing the person’s concerns about stable angina and the roles of medical therapy and revascularisation.

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